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Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

Dysphagia in head and neck cancer patients treated with radiotherapy and
systemic therapies: Literature review and consensus
Antonio Schindler a, Nerina Denaro b, Elvio G. Russi c,∗ , Nicole Pizzorni a, Paolo Bossi
d, Anna Merlotti e, Massimo Spadola Bissetti f, Gianmauro Numico g, Alessandro Gava h,
Ester Orlandi i, Orietta Caspiani j, Michela Buglione k, Daniela Alterio l, Almalina Bacigalupo m,
Vitaliana De Sanctis n, Giovanni Pavanato o, Carla Ripamonti p, Marco C. Merlano b,
Lisa Licitra e, Giuseppe Sanguineti q, Johannes A. Langendijk r, Barbara Murphy s
a Department
of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy
Oncology Department AO. S. Croce e Carle – Cuneo, Italy
b Medical
c Department of Radiation Oncology, A.O. S. Croce e Carle Cuneo, Italy
d Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
e Radiation Oncology Department, Ospedale di Circolo di Busto Arsizio, Italy
f Department of Audiology–Phoniatrics, Università degli Studi di Torino, Italy
g Medical Oncology Unit, Ospedale U. Parini, Viale Ginevra 3, 11100 Aosta, Italy
h Department of Radiation Oncology, Treviso Regional Hospital, Treviso, Italy
i Radio-Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
j Radiation Oncology Department, Isola Tiberina Fatebenefratelli Hospital, Rome, Italy
k Radiation Oncology Department, Spedali Civili Hospital, Brescia University, Italy
l Advanced Radiotherapy Center, European Institute of Oncology, Milan, Italy
m Radio-Oncology Department, IRCCS San Martino-IST, Largo R Benzi 10, 16132 Genoa, Italy
n Department of Radiotherapy University “La Sapienza”, Rome, Italy
o Department of Radiotherapy, Ospedale Santa Maria della Misericordia, Rovigo, Italy
p Supportive Care in Cancer Unit, IRCCS Foundation National Cancer Institute, Milan, Italy
q Department of Radiotherapy, National Cancer Institute Regina Elena, Rome, Italy
r Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
s Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville, TN, USA

Received 27 January 2015; received in revised form 13 May 2015; accepted 10 June 2015

Contents

1. Background ............................................................................................................................................................................................ 00
2. Materials and methods ............................................................................................................................................................................ 00
3. Results .................................................................................................................................................................................................... 00
4. Comment ................................................................................................................................................................................................ 00
4.1. Assessment scales ....................................................................................................................................................................... 00

∗ Corresponding author. Tel.: +39 3280971299.

E-mail addresses: antonio.schindler@unimi.it (A. Schindler), nerinadenaro@gmail.com (N. Denaro), elviorussi@gmail.com (E.G. Russi),
nicole.pizzorni@virgilio.it (N. Pizzorni), paolo.bossi@istitutotumori.mi.it (P. Bossi), anna.merlotti@virgilio.it (A. Merlotti), spadola.massimo@alice.it
(M. Spadola Bissetti), gnumico@ausl.vda.it (G. Numico), agava@ulss.tv.it (A. Gava), Ester.Orlandi@istitutotumori.mi.it (E. Orlandi), Fabriori@libero.it
(O. Caspiani), michela.buglione@med.unibs.it (M. Buglione), daniela.alterio@ieo.it (D. Alterio), almalina.bacigalupo@hsanmartino.it (A. Bacigalupo),
vitaliana.desanctis@uniroma1.it (V. De Sanctis), pavanato.giovanni@azisanrovigo.it (G. Pavanato), Carla.Ripamonti@istitutotumori.mi.it (C. Ripamonti),
mcmerlano@gmail.com (M.C. Merlano), Lisa.Licitra@istitutotumori.mi.it (L. Licitra), gsangui1@gmail.com (G. Sanguineti), j.a.langendijk@umcg.nl
(J.A. Langendijk), barbara.murphy@vanderbilt.edu (B. Murphy).

http://dx.doi.org/10.1016/j.critrevonc.2015.06.005
1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.
 ARTICLE IN PRESS
2 A. Schindler et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

4.2. Risk factors .................................................................................................................................................................................. 00

4.3. Preventive swallowing dysfunction evaluation ............................................................................................................................ 00
4.4. Deglutologist’s evaluation ........................................................................................................................................................... 00
4.5. Radiotherapic precautions ........................................................................................................................................................... 00
4.6. Preventative and therapeutic swallowing exercises ...................................................................................................................... 00
5. Conclusions ............................................................................................................................................................................................ 00
Conflict of interest statement .................................................................................................................................................................. 00
Funding .................................................................................................................................................................................................. 00
Acknowledgments .................................................................................................................................................................................. 00
References .............................................................................................................................................................................................. 00
Biography ............................................................................................................................................................................................... 00

Abstract
Background: Head and neck cancer (HNC) and its therapy are associated with acute and late swallowing dysfunction. Consensus guidelines
regarding evaluation and management are lacking. To address this gap, a multidisciplinary team of experts (oncologists, practitioners, deg-
lutologists, etc.) met in Milan 17–18 February 2013 with the aim of reaching a consensus on the management of swallowing difficulties in
HNC patients treated with radiotherapy with or without systemic therapies (such as chemotherapy and targeted agents). The consensus was
focused particularly on those statements with limited evidence.
The results of the literature review and the statements that obtained a consensus are reported and discussed in this paper.
Materials and methods: The Delphi Appropriateness Method was used for this consensus. External expert reviewers then evaluated the
conclusions carefully according to their area of expertise.
Results: This paper contains 6 clusters of statements about the management of swallowing problems in radio-treated HNC patients and a
review of the recent literature on these topics.
Conclusions: Dysphagia assessment and its management are difficult and require a multi-team cooperation (ENT specialists, radiation and
medical oncologists, deglutologists, etc.).
© 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Dysphagia; Swallowing dysfunction; Head and neck cancer; Deglutition; Radiotherapy; Chemotherapy; Radiation oncology

1. Background

Dysphagia is defined as the difficulty in swallowing liquids, food, or medication and can occur during the oropharyngeal
or the oesophageal phase of swallowing ([1]). Swallowing dysfunction has been reported in 30–50% of head and neck cancer
patients (HNCPs) treated with intensive non-surgical regimens [1–3]. HNCPs with swallowing dys- function are at risk of
pneumonia and sepsis [4]. Although dysphagia improves over time in 32% of HNCPs, 48% of patients fail to report
improvement in dysphagia-associated symptoms and in 20% of patients symptoms worsen over time [5]. Of note, dysphagia
may develop or worsen years after therapy is completed [5,6].
There are several underlying causes for swallowing dys- function in HNCPs. First and foremost, dysphagia may pre-exist
therapy (14% [7] to 18% [8] of HNCPs) due to the obstruction by the tumour volume or infiltration of struc- tures involved
with swallowing. In the operative population, surgical extirpation of structures necessary for normal deglu- tition results in
swallowing abnormalities. In the population treated with radiotherapy (RT), dysphagia is secondary to damage of neural and
soft tissues [9]. RT-induced swallow- ing dysfunction may occur both acutely during treatment and as a late effect of therapy.
Acute dysphagia is generally asso- ciated with soft tissue inflammation, oedema, pain, mucous production, and xerostomia.
After radiation has completed, soft tissues are able to heal. For some patients, the healing process results in soft tissue
fibrosis, lymphedema, scar tis- sue formation, and neurological impairment. This may result in a decreased swallowing
function.
Predicting which HNCPs will develop swallowing dys- function following non-surgical treatment is challenging [10].
There are, however, a number of factors that have been identified that may correlate with the develop- ment of acute or late
dysphagia. Radiation dose delivery to dysphagia–aspiration-related structures (DARSs), those “anatomical” structures that
are critical to the swallowing function [3], has been shown to predict swallow outcome in a number of studies [3,11–13].
Other important fac- tors include the concomitant [14] use of chemotherapy (CT) and/or targeted therapy (TT) [3,13].
Patients receiv- ing combined modality therapy experience higher-grade mucositis and pain with associated increase of
percutaneous- endoscopic-gastrostomy (PEG) use. Patients who receive radiation following surgery-involving DARSs may
experi- ence worse outcomes. Other factors that may worsen the swallowing function include: xerostomia [15–17], genetic
factors [18,19], malnutrition [20], and tobacco smoking [21,22].
Efforts have been directed at developing predictive mod- els that can be used in the clinical setting to identify patients
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A. Schindler et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx 3

at high risk for radio-induced dysphagia. Langendijk et al.

[23] identified five independent prognostic factors predict- ing G2–G4 swallowing dysfunction (RTOG/EORTC) at 6 months
after treatment (SWALL6 months): i.e. advanced T stage (T3–T4), oropharyngeal and nasopharyngeal tumour site, primary and
bilateral neck irradiation, weight loss at baseline, and treatment modality (accelerated RT or concomi- tant CT–RT).
Based on adverse swallowing outcomes, efforts have been made to ameliorate swallowing dysfunction in HNCPs. The use of
intensity-modulated RT (IMRT) has been introduced in clinical practice in order to reduce the radiation doses to DARSs [15],
masticatory structures [24,25], and sali- vary glands [26], and consequently reduce the incidence and severity of severe
dysphagia [16,27,28]. In addition, more attention has been given to preventive and therapeutic physi- cal exercises associated
with treatments in order to maintain speech and swallowing functions [29–34]. A growing body of literature seems to indicate
that swallowing therapy dur- ing and after treatment may improve long term swallowing outcomes. Data from randomized trials
have been accumu- lated, but many of these are flawed. Of particular concern is the lack of consensus regarding critical issues
such as optimal frequency, intensity, and content of swallowing ther- apy. Nonetheless, it is evident that the prolonged disuse of
structures critical to normal swallowing results in increased rates of late dysphagia. It may be hypothesized that this is due to
increased lymphedema and fibrosis as well as disuse atrophy.
Considering the above, it is necessary to review care- fully the available data and make recommendations for supportive
measures as well as to establish directions for future research. Furthermore, radiation oncologists (ROs), medical oncologists
(MOs), ENTs, nutritionists, deglu- tologists [35,36] (such as swallowing-expert physicians (SEPs) or speech language
pathologists (SLPs)), infec- tious disease specialists, dentists, and nurses from Italy met with the aim of reaching a consensus
on the manage- ment of HNCPs’ swallowing in order to provide standard recommendations for the centres that participate in
com- mon trials. It was felt that standards and consensus were most needed where there was limited evidence to guide
clinicians.
The results of the literature review and the statements that obtained consensus are reported and discussed in this paper.

2. Materials and methods

Due to the lack of evidence from randomized controlled trials on most aspects of best practice in the supportive care of HNCPs
during RT, an alternative approach to provide guid- ance was adopted. A formal consensus methodology was employed
according to the model proposed by the Ameri- can Society of Clinical Oncology (ASCO) [37], through a modified Delphi
strategy. Briefly, a consensus group of 40 experts including ROs, MOs, ENTs, nutritionists, DEs, infec- tious disease specialists,
dentists and nurses was set up in Milan 17–18 February 2013. A facilitator board of 8 expert members, from different clinical
settings (3 ROs, 1 SEP, 1 SLP, 2 MOs, 1 ENT) was appointed. The facilitator board performed a systematic review of the
literature on swallow- ing dysfunction in HNCPs treated with RT with or without systemic therapies.
The MEDLINE database was searched for studies pub- lished from 1990 to March 2013 containing the terms dysphagia,
aspiration, swallowing dysfunction, head and neck cancer, chemotherapy, Cetuximab, and RT. The liter- ature search was
limited to articles in Italian, English, and French regarding human cancers treated with RT.
Potentially relevant abstracts presented at annual meetings of the ASCO, the American Society for Radiation Oncology
(ASTRO) and the European Society of Medical Oncology (ESMO) were also examined.
The study selection included the following:
(a) Observational and prospective studies concerning assessment and treatment; (b) randomized, double blind, placebo-
controlled, or uncontrolled studies; (c) retrospec- tive and uncontrolled studies; (d) systematic reviews and meta-analyses;
and (e) consensus guidelines. Furthermore, the electronic search results were supplemented by a man- ual examination of
reference lists from selected articles and were periodically updated to April 2014 (before the second meeting).
On the basis of this literature review, the facilitators identified a series of statements, which were differentiated according
to the timing of intervention (pre-, during-, and post-treatment) and included an indication of the person in charge of the
management of each behavioural physi- cal social aspect (e.g. physician, nurse, patient, caregiver,
etc.).
Then, all experts rated these statements through a two- round process. A scale of 4 steps was used, where (1) was defined as
“high consensus”, (2) “low consensus”, (3) “no consensus”, and (4) “unable to express an opinion”.
A web meeting was held before the second rating where statements were discussed. The statements that received a weak
or no approval (less than 75% of votes) were redefined according to the observations of panellists. The second rat- ings were
analyzed to identify the statements that reached a consensus.
Each expert (including facilitators) was equally weighted in scoring the statements.
Then, two external ROs (JAL, GS), one MO (BM), and one SEP (SA) reviewed the statements.
The statements were then finalized according to the sug- gestions of external reviewers. The process lasted from March 2013
to April 2014.
The panellists had a second meeting in Milan on 5 May 2014 in order to approve the final version of the statements.
Furthermore, the literature review had been updated to March 2014 before the second meeting.
 Table 1

ONCH-2000; No. of Pages 13

therapies: Literature review and consensus. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.06.005
Please cite this article in press as: Schindler A, et al. Dysphagia in head and neck cancer patients treated with radiotherapy and systemic

Consensus-reached statements.
Item Phase Description Whom is it in charge The degree of
of? consensus
1. Pre-therapy/therapy/follow- Assessment scales Oncology Physician – Nurse 83%
up 1.1 Patient-reported outcome (PRO)-scales: It is suggested that a PRO scale evaluating subjective
dysphagia and its impact on Health-related quality of life (HRQoL) be administered to all patients, before
treatment starts, again at the time treatment ends and regularly during follow up. Among the multiple
self-administered questionnaire available at the present time, the M.D. Anderson Dysphagia inventory
(MDADI) was considered a practical option for a dysphagia screening tool because it is disease-specific,
short, and specifically designed to evaluate dysphagia in patients with HNC
1.2 Operator-reported outcome (ORO)-scales: An ORO scale, such as NCI-CTCAE grading scale, can be 76%

A. Schindler et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

associated
2. Pre-treatment Risk factors Oncology Physician – 77%
2.1 All patients need to be clinically evaluated in order to search for signs and symptoms that herald Nurse
dysphagia and/or inhalation and/or aspiration (e.g. “Murphy’s trigger symptoms”, 3-ounce water swallow

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test, recent history of recurrent pneumonia, etc.) at baseline, during and after treatment
3. Pre-treatment Preventive swallowing dysfunction evaluation Oncologist – Nurse – 85%
3.1 It is recommended that nutritionists and deglutologist evaluate patients before starting treatment and Nutritionists and
at any time there is a clinical indication of swallowing impairment Deglutologists
4. Pre-treatment Deglutologist’s evaluation Oncology Physician – Nurse 90%
4.1. The detailed swallowing evaluation by a deglutologist aims to: (1) identify swallowing – Deglutologist
abnormalities, (2) prescribe additional testing (clinical/radiological tests) in order to assess
inhalation/aspiration risks, and (3) develop an appropriate treatment plan (correction of swallowing
mechanisms through patient education and exercises)
4.2. Instrumental evaluation: In order to identify swallowing abnormalities, instrumental testing such as 88%
FEES (Fibreoptic Endoscopic Evaluation of Swallowing) and/or SVF (Swallowing Video-fluoroscopy)
can be recommended on the basis of the deglutologist’s prescription and of test availability/accessibility
5. Pre-treatment Radio-therapeutic precautions Radiation 78%
5.1. Simulation Computerized Tomography (S-CT)-based delineation of DARS and the collection of Oncol-
dosimetric parameters are suggested and encouraged, although available data from literature are not yet o-
consolidated for routine use in clinical practice gist
5.2. A multimetric model (more than one parameter: e.g. Dmean, different DVHs) should be considered 85%
in order to evaluate DARS dose constraints. Christianen’s predictive model for swallowing dysfunction
can help ROs to predict the risk in non-operated patients without pre-treatment dysphagia
5.3. It is recommended that the dose to the main DARS (i.e. swallowing muscles, Parotid glands, and oral 95%
mucosa outside PTV) be minimized as far as possible
5.4. Acute mucositis can worsen dysphagia; therefore dose distribution through oral mucosa (outside 85%
PTV) needs to be kept as low as possible (≤30 Gy in 6/7 weeks)
6. Pre-treatment/during therapy Preventative and therapeutic swallowing exercises Oncology Physician – Nurse 95%
6.1. Patients may benefit from strategies aimed at the prevention of swallowing dysfunction after curative – Deglutologist
RT ±CT/TT such as preventative swallowing exercises during treatment. Swallowing exercises should
be prescribed and supervised by a SLP
6.2. Two types of exercises can be suggested for patients with dysphagia, both of which are to be 88%
performed at the beginning, during and after treatment: indirect (exercises to strengthen swallowing
muscles) and direct (postural exercises to be performed while swallowing)
6.3. If enteral nutrition is adopted, patients should be encouraged to continue to swallow and to wean 95%
from artificial nutrition as quickly and safely as is feasible, regardless of the method (e.g. nasogastric
tube, PEG, and parenteral nutrition)
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A. Schindler et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx 5

Before RT During RT Follow up period

Timeline Baseline 1stw 2ndw Other w Lastweek
PRO-SCALE Yes Yes Yes Yes Yes Yes at each visit
ORO-SCALE Yes Yes Yes Yes Yes Yes at each visit
Searching for Sign and Symptoms Yes Yes Yes Yes Yes Yes at each visit
Nutritionist evaluation Yes On demand On demand On demand On demand Yes at 1st visit, then on demand
Deglutologist evaluation Yes On demand On demand On demand On demand Yes at 1st visit, then on demand
Instrumental evaluation On demand No No No No On demand
Radiotherapeutic precautions Yes -- -- -- -- --
Swallowing exercises Yes Yes Yes Yes Yes
Pain assessment and control Yes Yes Yes Yes Yes Yes

Fig. 1. The recommendations along the timeline.

3. Results

Consensus-reached statements are listed in Table 1 and summarized along a timeline in Fig. 1.
Seventeen statements were presented at the first round of rating, after which 8 statements reached a high level of consensus.
Nine were deleted, changed, revised, or modified according to the experts’ comments.
After the second round of rating, 15 statements were pro- posed, of which 13 received a high consensus. These were
proposed to external experts’ revision following which state- ments 11 and 12 were merged. Then, they were clustered together
into 6 groups (clusters).

4. Comment

4.1. Assessment scales

4.1.1 Patient-reported outcome (PRO)-scales: It is sug- gested that a PRO scale evaluating subjective dysphagia and its impact
on health-related quality of life (HRQoL) be administered to all patients, before treatment starts, again at the time
treatment ends and regularly during follow up. Among the multi- ple self-administered questionnaires available at the
present time, the M.D. Anderson Dysphagia Inven- tory (MDADI) was considered a practical option as a dysphagia-
screening tool because it is disease-specific, short, and specifically designed to evaluate dysphagia in patients with HNC.
4.1.2 Operator-reported outcome (ORO)-scales: An ORO scale, such as NCI-CTCAE grading scale, can be asso- ciated.

Accurate and detailed information about acute and late swallowing dysfunction assessment is limited. Objective measures of
the swallowing function, such as the MBS and FEES, provide detailed and rich information, but are costly, time-consuming,
and operator-dependent. Clinical tri- als often report blunt surrogated endpoints such as feeding tube dependence (e.g. NCI-
CTCAE grading system [38]) to report swallowing abnormalities [3]. However, this grossly underrepresents swallowing
dysfunction. As an alternative, investigators are interested in using patient-reported out- comes (PROs) to assess the swallowing
function. PROs are subjective reports garnered directly from the patient. PROs have the benefit of being brief, inexpensive, and
amenable to repeated measures. Yet, inadequate sensitivity, specificity, and predictive values of these PRO scales have been
identified in comparisons to the objective findings of aspiration or pene- tration in patients undergoing FEES evaluation of
swallowing [39]. Available PRO tools include: swallowing-related ques- tions in cancer specific HRQOL tools, such as the
EORTC QLQ 30 H&N 35 [40], FACT-HN [41], EAT-10 [42], SWAL-
QOL [43,44] and the M.D. Anderson Dysphagia Inventory (MDADI) [45]. The MDADI has the advantage of brevity [46–
49]. Unfortunately, these measures were developed as research tools, not as screening tools. A screening tool must be: brief,
clinically directed, able to identify actionable items and proven to enhance clinical outcomes. In order for screen- ing to impact
on outcomes, there should be a clearly defined and effective treatment for the condition for which screen- ing is attempted. In
addition, screening tools must be easily incorporated into the provider’s routine clinical flow and pro- cedures. Unfortunately,
none of the existing tools has been tested to determine whether they screen effectively for dys- phagia. Further perspective
longitudinal studies are needed to develop and test screening tools. While awaiting such results it is reasonable to choose a
brief questionnaire with items directed at identifying swallowing dysfunction in order to refer for swallowing evaluation.
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4.2. Risk factors

4.2.1 All patients need to be clinically evaluated in order to search for signs and symptoms that herald dyspha- gia and/or
inhalation and/or aspiration (e.g. “Murphy’s trigger symptoms” or a recent history of recurrent pneumonia, etc.) at
baseline, during and after treat- ment. Patients should be educated about the signs and symptoms of aspiration and told
to report them immediately to their health care providers. Unfortunately, HNCPs often underes- timate trigger
symptoms, thus, clinicians should inquire about swallowing issues and investigate any signs and symptoms that herald
dysphagia or aspiration at each visit pre, during and after treatment [3,50–53] (Table 2).
 ARTICLE IN PRESS
Table 2
Murphy’s trigger symptoms.
Inability to control food, liquids, or saliva in the oral cavity Pocketing of food in cheek
Excessive chewing Drooling
Coughing, choking, or throat clearing before, during, or after swallowing Abnormal vocal quality after swallowing; “wet” or “gurgle” voice
Build-up or congestion after a meal Complaint of difficulty swallowing Complaint of food “sticking” in throat Nasal
regurgitation
Weight loss

4.3. Preventive swallowing dysfunction evaluation

4.3.1 It is recommended that nutritionists and deglutologists evaluate patients before starting treatment and at any time there is
a clinical indication of swallowing impair- ment.

HNCPs benefit from an early evaluation by both deglutolo- gists [32,53–60] and nutritionists [20] at the time of diagnosis in
order to identify any issues that need to be addressed prior to initiation of therapy. In addition, such an evaluation should be
undertaken at any point along the treatment and recovery trajectory if patients are found to have any signs or symptoms of
swallowing difficulty or nutritional deficits.

4.4. Deglutologist’s evaluation

4.4.1 The detailed swallowing evaluation by a deglutolo- gist aims to (1) identify swallowing abnormalities, (2) prescribe
additional testing (clinical/radiological tests) in order to assess inhalation/aspiration risks, and (3) develop an
appropriate treatment plan (correction of swallowing mechanisms through patient education and exercises).

The primary role of the deglutologist is to identify swal- lowing abnormalities [32,53–60]. Data from the swallowing
assessment will allow for: (1) the identification of aspira- tion risk [61,62], (2) recommendations for compensatory
manoeuvres and dietary modifications [59], and (3) treat- ment planning (e.g. swallowing preservation exercises during RT
CT/TT) [63]. The risk of aspiration may be eliminated by the use of postures, manoeuvres, and modifications to bolus size and
consistency. The choice between FEES or SVF can be guided on the basis of the opinion of the deglutologist and of test
availability/accessibility.
±
 ARTICLE IN PRESS
4.4.2 Instrumental evaluation: In order to identify swal- lowing abnormalities, instrumental testing, such as fibreoptic
endoscopic examination of swallowing (FEES) and/or swallowing video-fluorography (SVF), can be recommended on
the basis of the deglutologist’s prescription.
Based on the clinical swallowing evaluation, the deg- lutologist may recommend instrumental assessment of the
swallowing function using the Modified Barium Swallowing Study (MBSS) procedure with video-fluorography (SVF) and
fibreoptic endoscopic examination of swallowing (FEES). Both procedures have been shown to identify patients at risk for
aspiration pneumonia outcomes in patients with neurological-disease-related dysphagia [61]. During SVF the patient is
required to swallow barium-labelled elements of different volumes and densities. SVF is entirely recorded and each phase of
swallowing (oral, pharyngeal and oesophageal) is analyzed and timed. Thus, SVF allows transit abnormalities of different
viscosity bolus, intra- and extra-luminal struc- tural abnormalities, hyoid–laryngeal activity and reduced upper oesophageal
sphincter (UOES) opening to be assessed [64,65]. During FEES, the evaluation of swallowing by trans- nasal endoscopy allows
for the evaluation of various viscosity substances during phonation, spontaneous deglutition and voluntary swallowing. Hence,
FEES cannot provide informa- tion on the oral stages of swallowing, but it has the advantage over SVF of allowing for the
direct observation of anatom- ical structures (especially the vocal cord dysfunction), and for sensory tests (touching the
pharynx with the tip of the endoscope, and if necessary using air-pulse stimuli) [66–68]. Furthermore, it is less expensive and
is repeatable as needed, in considering the fact that there is no radiation exposure [61,68]. Determination of whether to use
FEES or MBSS is based on the clinical scenario.

4.5. Radiotherapic precautions

4.5.1 Simulation Computerized Tomography (S-CT)-based delineation of DARS and the collection of dosimet- ric
parameters are suggested and encouraged, although available data from literature are not yet consolidated for routine
use in clinical practice.
4.5.2 A multimetric model (more than one parameter: e.g. Dmean, different DVHs) should be considered in order to evaluate
DARS dose constraints. Christianen’s pre- dictive model for swallowing dysfunction can help ROs to predict the risk in
non-operated patients without pre-treatment dysphagia.
4.5.3 It is recommended that the dose to the main DARS (i.e. swallowing muscles, Parotid glands, and oral mucosa outside
Planning Target Volume or PTV) be minimized as far as possible.
4.5.4 Acute mucositis can worsen dysphagia; therefore dose distribution through oral mucosa (outside PTV) needs to be kept
as low as possible (≤30 Gy in 6/7 weeks).
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A. Schindler et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx 7

Table 3
Dose–volume Data for different DARS and different dysphagia dysfunctions.
Dmean V30Gy V40Gy V50Gy V55Gy V60Gy V65Gy V70Gy DARS
Dysphagia 52–55 Gy [81] PC
80% [77] 30% [77] SPC
36 Gy [81] SGL
Liquids 55 Gy [80] 33% [1] SPC
51 Gy [80] MPC
37 Gy [80] IPC
Pureed food 62 Gy [80] SPC
61 Gy [80] MPC
47 Gy [80] IPC
Solid food 52 Gy [80] MPC
47 Gy [80] IPC
33 Gy [80] PC
Aspiration 80% [15,78] PC
69 Gy [80] SPC
50 Gy [80] IPC
53 (47–60) Gy UES
[74]
36 Gy SGL
[81]–59 Gy
[74]
41 Gy [1] 50% [15,78] 70% [15,78] SGL + GL
Stricture 85% [15,78] PC
33% [80] SPC
75% [1] 53% [1] MPC
GT <51 Gy [1] <65% [1] <48% [1] <21% [1] <15% [1] 42% [89] IPC
<6% [1]
8% [88] UES
<51 Gy [1] <65% [1] <41% [1] <37% [1] <33% [1] <29% [1] <10% [1] SGL + GL
Decreased OPSE >80% [77] SC
65% [77] Ant. OC
DARS, dysphagia/aspiration related structures; Dmean, mean dose (Gy); GL, glottic larynx; GT, gastric tube, PC, pharyngeal constrictor muscle; SPC, superior
pharyngeal constrictor muscle; MPC, middle pharyngeal constrictor muscle; IPC, inferior pharyngeal constrictor muscle; OPSE, oropharyngeal swallowing
efficiency; SGL, supraglottic larynx; UES, upper esophageal sphincter; Vx, volume of an organ at risk of receiving ≥x Gy (%).

The functional changes after RT [3,7] are due to a poor syn- chronization between pharyngeal contractions, the opening of the
UOES and larynx closure. Indeed, a decreased pha- ryngeal peristalsis and a defective posterior movement of the tongue base
towards the posterior pharyngeal wall, an altered closure of the laryngeal sphincters, a decreased inversion of the epiglottis and
decreased elevation of the hyoid bone and larynx, and a delayed opening of the crico-pharyngeal- UOESs [7,12,15,69,70] have
all been demonstrated.
All these alterations are due to radio-induced inflam- matory oedema or fibrosis of structures involved in the swallowing
process (such as mucosa, laryngeal and pha- ryngeal constrictors, masticator muscles, connective tissue of intra-visceral spaces,
terminal afferent and efferent nerve fibres present in mucosa, etc.). All these abnormalities can be responsible for an altered
swallowing process and for a post-swallowing residue in the oropharynx, valleculae and hypo-pharynx, which may
subsequently be aspirated. Radio-induced dysphagia can often be associated to altered sensitivity, which may cause a silent
aspiration and deficient cough reflex [15,70–74].
The results of various studies, which have investigated the correlation between the dose delivered to organs involved in
swallowing and the reduction of the swallowing function after RT [10,25,75–87], are concordant in showing a strong cor-
relation between swallowing disorders and the dose received by the pharyngeal constrictors, larynx, and crico-pharyngeal
and/or UOESs.
Thus, irradiated patients could have a significantly reduced oral and pharyngeal swallowing performance, with longer oral
transit times, lower oropharyngeal swallowing efficiency, increased pharyngeal residue, and reduced crico- pharyngeal
opening duration [3,88].
Recent reports and the “Quantitative Analysis of Nor- mal Tissue Effects in the Clinic” (QUANTEC) guidelines suggested
minimizing the volume of DARS. DARS were first described by Eisbruch et al. [7], and, successively, various authors tried to
outline them in planning CT data sets. Yet, they were not defined in the same way. For instance, the pharyngeal/oesophageal
sphincter region has been described by some authors as the whole cervical oesoph- agus “outlined from the level of the inferior
edge of the cricoid cartilage through the most distal axial CT image containing targets in the low neck” without mentioning
 ARTICLE IN PRESS
any difference between the crico-pharyngeal muscle and the oesophagus inlet muscle [15,81,85], whereas others only
considered the crico-pharyngeal muscle [80,83,89] or the UOES (defined as the first centimetre of the oesopha- gus below
the crico-pharyngeal muscle [74,80,83]) or both without distinction between them [87]. Furthermore, the pha- ryngeal superior
constrictor has been contoured differently by different authors [74,86,87]. Finally, Alterio et al. reported that MRI-derived
contouring can ameliorate operator-related variability [90].
All this variability in contouring the various DARS under- mines the reliability of the relationship between DARS
dosimetric parameters and the predictive models of swallow- ing dysfunction.
Thus, a single dose parameter such as the mean dose to a specified DARS or the dose given to a percentage of an irradiated
DARS volume (defined as VxGy) gives neither a reliable constraint [91] nor an ideal representation of the 3D dose distribution
through the DARS [90,92]. Consequently, the panel prudently advised adopting a multimetric model (more than one index:
e.g. Dmean and more than one VxGy value) in clinical practice (Table 3).
At any rate, a recent systematic review of dose–volume constraints for DARS [91] suggested that dose–volume con-
straints for the pharyngeal constrictors are in the same range as those proposed by the QUANTEC group [93] and Eins- bruch
[81] (i.e. reducing the mean doses to the non-involved pharyngeal constrictors from 61–64 Gy to 52–55 Gy, as well as lowering
the mean doses to the supraglottic larynx from 48–54 to 36–38 Gy).
Furthermore, the panel suggested that Christianen’s pre- dictive model for swallowing dysfunction (see Christianen’s
appendix [83]) could help ROs to predict the risk in non-operated patients without pre-treatment dysphagia. The guideline for
delineations of DARS based on CT image are also provided [90,92].
 ARTICLE IN PRESS
Regarding the relationship between xerostomia and dys- phagia, there is some evidence for dose–volume relationships
linking the major salivary gland dose to mouth dryness [16] and consequently the reduced salivary flow to an impaired
swallowing function [74,94–96].
Clear dose limits exist for the parotid glands [16,97–99], but there are also limits for the submandibular and minor
salivary glands, which influence the moistening of oral tis- sues [79,100–103]. To prevent or reduce salivary gland hypo-
function and xerostomia, parotid-sparing intensity- modulated radiation therapy [16] (IMRT) is recommended as a standard
approach in HNCPs. In addition, treatment should focus on approaches to further reduce the radiation dose to the
submandibular and minor salivary glands [79,100–103]. Furthermore, the mucosa-sparing IMRT can impact on swal- lowing
dysfunction due to reduced mucosa fibrosis and the reduced negative effect on minor salivary glands [79,104]. Finally,
Sanguineti reported that PEG use was drastically reduced when the weekly dose–volume histogram (DVH) (V9.5Gy) of oral
mucosa was <64 cm3. These results need to be validated [79].
In conclusion, the DARS-sparing IMRT should prioritize in the following order: salivary glands, swallowing muscles, and
oral mucosa (outside PTV). This order takes into account the varying strengths of evidence. In any case, DARS-sparing IMRT
has to be optimized without compromising target doses [15].

Table 4
Swallowing exercises.
Exercise Target Procedure
Tongue resistance To improve range and strength of the tongue Patient is to move side to side up and down in/out the
tongue also against resistance (spatula)
Tongue base Improve tongue base to posterior pharyngeal wall Pull the back of your tongue as far back as you can.
retraction contact and therefore improve pharyngeal propulsion of Pretend you are trying to scratch the back wall of your
the bolus throat with the back of your tongue. Hold for a few
seconds
Masako o tongue hold Glossopharyngeal muscle responsible for tongue base Gently hold your tongue in between your front teeth and
retraction and medialization of pharyngeal constrictors swallow your saliva
Mendelson To increase the extent and duration of laryngeal Patients swallow when the larynx reaches the highest
elevation and prolong crico-pharyngeal opening times level then hold few seconds and then relax
Supraglottic swallow Provide volitional airway protection Patient is to take deep breath, hold the breath while they
or breath hold swallow then exhale forcefully
Super-supraglottic Technique facilitates closure of the airway entrance Inhale and hold your breath very tightly, bearing down
swallow before and during the swallow and also increases tongue Keep holding your breath and bearing down as you
base motion and speed and extent of laryngeal elevation. swallow
Cough when you are finished
Shaker To strengthened the supra-hyoid muscle complex The patient is instructed to lie on their back, lift their
head up so that they can see their toes, but do not lift up
their shoulders. Hold for a minute and then rest for 1 min
Jaw exercises To improve and retain movement of mandible

4.6. Preventative and therapeutic swallowing exercises

4.6.1 Patients may benefit from strategies aimed at the prevention of swallowing dysfunction after cura- tive RT ± CT/TT
such as preventative swallowing exercises during treatment. Swallowing exercises should be prescribed and supervised
by an SLP; Two types of exercises can be suggested for patients with dysphagia, both of which are to be performed at the
beginning, during and after treatment: indi- rect (exercises to strengthen swallowing muscles) and direct (postural
exercises to be performed while swal- lowing); Swallowing exercises are designed to increase the range of movement of
the tongue, lips, and jaw. Exercising swallowing muscles seems to improve and/or maintain the ability to swallow [29,30]
(Table 4).
 ARTICLE IN PRESS
A. Schindler et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx 9

exercises are designed to increase the range of movement of the tongue, lips, and jaw. Exercising swallowing muscles
seems to improve and/or maintain the ability to swallow [29,30] (Table 4).
For each group of swallowing muscles, patients will be guided to perform a range of motion and resistance exercises.
Physicians or deglutologists will select tai- lored exercises for each patient: i.e. the number of repetitions, the duration of
each exercise, and the inter- val between them should be customized.
4.6.2 If enteral nutrition is adopted, patients should be encouraged to continue to swallow and to wean from artificial nutrition
as quickly and safely as is feasible, regardless of the method (e.g. nasogastric tube, PEG, and parenteral nutrition);

Initial malnutrition affects the response to treatment and the prognosis of HNCPs treated with RT( CT/TT) [105]. This cohort
± tional support and/or prophylactic gastrostomy before the beginning of treatment.
of patients might therefore benefit from nutri-
Once a feeding tube is placed, either prophylactically or in response to treatment-related toxicity, patients should be encouraged
to continue swal- lowing exercises as prescribed by the SLP in order to retain the swallowing function and prevent long term
swallowing impairment. Sometimes, the pain control is crucial in order to keep the patient swallowing and to maintain the
functional- ity of swallowing muscles. Every effort should be adopted to support the patient with an adequate and personalized
antalgic therapy. Patients should move to oral intake when safe.

5. Conclusions

Dysphagia in HNCPs has often been misunderstood, under-diagnosed, and improperly treated. Adequate treat- ment of
dysphagia is fundamental to plan a correct oncological programme, by reducing the side effects that neg- atively impact on
HRQoL and might affect overall survival. Recommendations for dysphagia assessment and manage- ment during RT( CT/TT)
for HNCPs have been defined with a recognized methodology, in an area where high quality evidence is lacking. The consensus
highlighted the need for interdisciplinary collaboration, accurate and early diagnostic workup and effective and therapeutic
strategies to manage dysphagia successfully.
±
Conflict of interest statement

The authors have no financial and personal relationships with other people or organisations that could inappropriately
influence (bias) this work.

Funding

This study was partly supported by Lega Tumori sezione di Cuneo.

Acknowledgments

Airoldi Mario (Turin), Azzarello Giuseppe (Padova), Bol- ner Andrea (Trento), Cavagnini Roberta (Brescia),Corvò Renzo
(Genova), Fiscella Michela (Milan), Gavazzi Cecilia (Milan), Carmine Pinto (Parma), Grisanti Salvatore (Bres- cia), Magrini
Stefano (Brescia), Maurizi Enrici Riccardo (Rome), Orlandi Ester (Milano), Paiar Fabiola (Firenze), Sal- garello Stefano
(Brescia).
 ARTICLE IN PRESS

8 A. Schindler et al. / Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx

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Biographies
Elvio G. Russi, M.D. (corresponding author) earned his
M.D. degree at the University of Messina. He completed
residency programmes in Radiation Oncology, in Medical
Oncology, and in Radiodiagnosis. He is currently Head of the
Radiation Oncology department at Teaching Hospital “A.O.
S. Croce e Carle” in Cuneo (Italy). Dr. Russi headed the
“Head and neck study group” of Italian Association of Radi-
ation Oncologist (AIRO) between 2012 and 2013. He was
a board member for AIRO (Italian Association of Radia-
tion Oncologist) between 2010 and 2012. He has authored
or co-authored over 80 original articles, book chapters with
a predominant emphasis on Head and neck cancer treatment.
“Author H index”: 13 (Scopus 2014).
Marco C. Merlano, M.D. earned his M.D. degree at the
University of Genoa. He is currently Chair of Oncological
Department at Teaching Hospital “A.O. S. Croce e Carle”
in Cuneo (Italy). Dr. Merlano has authored or co-authored
over 135 original articles, book chapters with a predominant
13
emphasis on Head and neck cancer treatment. “Author H
index”: 20 (Scopus 2014).
Lisa Licitra, M.D. is Chief of Head and neck cancer unit –
Istituto Nazionale dei Tumori Milano (Italy). She specialized
in Medical Oncology at the University of Parma. Dr. Licitra
was Chair of Head and neck cancer group of EORTC (Euro-
pean Organisation For Research And Treatment Of Cancer)
– member of PDQ (Physician’s Data Query) of the National
Cancer Institute USA. She is honorary member of European
Society For Therapeutic Radiology And Oncology (ESTRO).
Member of the editorial board – Cancer Treatment Reviews
(2007–2009). She has authored or co-authored over 135 orig-
inal articles, book chapters with a predominant emphasis
on Head and neck cancer treatment. “Author H index”: 27
(Scopus 2014).
Giuseppe Sanguineti, M.D. is currently Head of Depart-
ment of Radiation Oncology at Istituto Nazionale Tumori
Regina Elena, Rome, Italy. He completed his residency pro-
grammes at University of Genoa (Italy) in both Radiation
Oncology and Clinical Oncology and his fellowship in Radi-
ation Oncology at MD Anderson Cancer Center in Houston,
USA between 1994 and 1995. He has been Associate Pro-
fessor in Radiation Oncology at the University of Texas
Medical Branch (2002–2007) and Johns Hopkins Univer-
sity (2007–2011). He has authored or co-authored over 135
original articles, book chapters with a predominant emphasis
on Head and neck cancer treatment. “Author H index”: 26
(Scopus 2014).
Johannes Albertus Langendijk is Director of Department
of Radiation Oncology, University Medical Center Gronin-
gen, University of Groningen, Groningen, The Netherlands.
He has authored or co-authored over 120 original articles,
book chapters with a predominant emphasis on Head and
neck cancer treatment. “Author H index”: 33 (Scopus 2014).
Barbara A. Murphy, M.D. graduated from the Wake
Forest University School of Medicine. Fellowship in med-
ical oncology at Memorial Sloan-Kettering Cancer Center;
internal medicine Residency at Greenwich Hospital (Yale
University affiliated). She is Professor of Medicine (Hema-
tology/Oncology), Director of Head & Neck Oncology,
Program Director of Pain & Symptom Management Pro-
gram in Vanderbilt University, Nashville, USA. Dr. Murphy
has authored or co-authored over 110 original articles, book
chapters, with a predominant emphasis on supportive care
and on improving survival and quality of life in patients with
head and neck treated with chemo-radiation therapy. “Author
h-index”: 36 (Scopus 2014).