Critical Reviews in Oncology / Hematology 162 (2021) 103335

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Critical Reviews in Oncology / Hematology

journal homepage: www.elsevier.com/locate/critrevonc

Late radiation effects in survivors of head and neck cancer: State of

the science
Gabriela Barbieri Ortigara a, Laura Izabel Lampert Bonzanini b, Riéli Elis Schulz c,
Kívia Linhares Ferrazzo d, *
a
Department of Stomatology, Postgraduate Program in Dentistry; Emphasis on Periodontics, Universidade Federal de Santa Maria (UFSM), Santa Maria, Rio Grande do
Sul, Brazil
b
Postgraduate Program in Dental Clinic, Federal University of Rio Grande Do Sul, Porto Alegre, Rio Grande do Sul, Brazil
c
Multiprofessional Residency Program in Stomatology With Emphasis on Oncology, AC Camargo Center, São Paulo, Brazil
d
Department of Pathology, Universidade Federal de Santa Maria (UFSM), Santa Maria, Rio Grande do Sul, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Head and neck squamous cell carcinoma is one of the most common neoplasms. Radiotherapy (RT) plays an
Head and neck cancer essential role in the management of such cases. Despite advances in the technique, hyposalivation, xerostomia,
Radiotherapy dysphagia, trismus, radiation caries, and osteoradionecrosis remain significant late complications of RT. The aim
Trismus
of this narrative review was to summarize and update the main findings related to late side effects of radio­
Xerostomia
Dysphagia
therapy in survivors of head and neck cancer (HNC). Such effects limit the ability to speak, ingest food and
Osteoradionecrosis medications, and breathe and also exert a negative impact on social well-being and quality of life. This review
Radiation caries highlights research in the field for both researchers and clinicians, assisting in the prevention and management of
these adverse conditions. The findings can contribute to improving preventive management and multidisci­
plinary interventions for HNC patients.

1. Introduction
Radiotherapy (RT) is one of the most widely used therapeutic mo­
dalities for patients with head and neck cancer (HNC) and consists of
ionizing radiation administered to prevent the multiplication of malig­
nant cells as well as eradicate the tumor or diminish its volume (Deloch
et al., 2016). RT can be used for curative or palliative purposes, as an
adjuvant to surgery, or concomitant with chemotherapy (Galbiatti et al.,
2013). High doses of RT can have severe consequences for soft and hard
tissues of the oral cavity, which are strongly associated with the volume
of irradiated tissue, fractionation scheme, and radiotherapy modality
(Bentzen et al., 2010).
The tissue injury mechanism in RT is explained by sclerosis in soft
tissues caused by radiation, which affects lymphatic structures, causing
lymphedema. Lymphedema consists of fluid leaking into tissues near
damaged structures. Consequently, the tissue is replaced with fibrosis,
resulting in the loss of tissue function and causing consequences such as
hyposalivation, trismus, radiation caries, and xerostomia (De Felice
et al., 2018). When occurring during or immediately after RT, these
effects are characterized as acute, whereas late effects are complications
that arise or persist after the completion of treatment. Both short- and
long-term sequelae are capable of significantly affecting the quality of
life of irradiated patients (Bonzanini et al., 2020a, b; Ortigara et al.,
2019; Soldera et al., 2020).
Recent studies have evaluated the impact of cancer treatment on
quality of life and survival comparing different RT modalities, such as
intensity modulated radiotherapy (IMRT), conformed radiotherapy
(3DCRT), or conventional radiotherapy (2DRT), reporting that IMRT
provides better quality of life, whereas a worse survival rate is found
with 2DRT (Santos et al., 2021; Haefner et al., 2017). Other studies
concluded that IMRT generates less toxicity (Kamal et al., 2020) and is
related to a lower incidence of side effects, such as radiation caries and a
reduced salivary flow rate (Gupta et al., 2018).
Despite recent therapeutic advances that seek to minimize the side
effects of RT, a large number of patients receive conventional therapies,
especially at reference centers in developing countries that are main­
tained through public funding Mohamad et al. (2017). Therefore, the
aim of the present narrative review was to analyze the available

* Corresponding author at: Universidade Federal de Santa Maria, Roraima Avenue, 1000. Building 20. CEP: 97105-900, Santa Maria, RS. Brazil.
E-mail addresses: gabriela.ortigara@acad.ufsm.br (G.B. Ortigara), laurabonzanini@hotmail.com (L.I.L. Bonzanini), rielielisschulz@gmail.com (R.E. Schulz),
kivialinhares@uol.com.br (K.L. Ferrazzo).

https://doi.org/10.1016/j.critrevonc.2021.103335
Received 1 February 2021; Received in revised form 3 April 2021; Accepted 6 April 2021
Available online 13 May 2021
1040-8428/© 2021 Elsevier B.V. All rights reserved.
G.B. Ortigara et al.
literature and describe the main late side effects that affect the oral
cavity of patients having been undergone radiotherapy for head and
neck cancer.
2. Materials and methods
The present review offers evidence regarding late oral complications
related to RT in survivors of HNC. Due to the lack of studies on this
subject, the aim of this study was to provide a focused examination of
scientific literature on the definition, prevalence, pathogenesis, diag­
nosis, and management of these effects. Searches were performed in the
PubMed, Scopus, and Web of Science databases for articles published up
to October 2020. Combinations of the following search terms were used:
"head and neck cancer", "radiotherapy", "radiation", "side effects",
"hyposalivation", "xerostomia", "dry mouth", "dysphagia", "swallowing",
"late radiation associated dysphagia", "dysgeusia", "trismus", "osteor­
adionecrosis", "radiation caries", and "oral health". Systematic reviews,
literature reviews, observational, retrospective, or prospective studies,
and clinical trials that addressed at least one of the late side effects of
interest were considered eligible. Studies without any specific results or
conclusions were excluded. This paper corresponds to a literature review
not necessarily focused on a single question, grouping the results of
research on the late side effects of RT in survivors of HNC.
3. Results
3.1. Hyposalivation/Xerostomia
Hyposalivation is characterized by a pathological reduction in sali­
vary flow triggering the sensation of dry mouth or xerostomia. Hypo­
salivation resulting from RT occurs due to the degeneration and
dysfunction of the salivary glands, which results in a reduction in sali­
vary flow (Saleh et al., 2015). This is one of the most prevalent late
effects of RT in the head and neck region (Soldera et al., 2020). The
reduction in salivary flow can affect chewing, swallowing, taste, speech,
and communication, generating a negative impact on quality of life
(Bonzanini et al., 2020a; Soldera et al., 2020).
The mechanism of harm to glandular tissue caused by RT is not fully
understood. Studies suggest that radiation initially causes direct damage
to the plasma membrane of acinar cells, causing the extravasation of
acinar granules, edema, degeneration, and subsequent lysis, resulting in
the massive death of acinar cells. Radiation-induced acinar cell
apoptosis has also been suggested to cause acute glandular tissue
dysfunction (Jensen et al., 2019). Studies have shown an association
between the reduction in glandular function and the increase in radia­
tion dose. Deasy and colleagues suggest that even a dose of 30 Gy is
capable of significantly decreasing the production of saliva as well as the
size of the parotid and submandibular glands, causing xerostomia in the
long term (Deasy et al., 2010). Other studies show that IMRT has a less
harmful effect on the glands, reducing the occurrence of
patient-reported xerostomia (Gupta et al., 2018).
Regarding the clinical diagnosis of hyposalivation, some authors
consider < 0.1 mL/min for resting salivation and < 0.5 mL/min for
stimulated salivation. Other authors consider hyposalivation to be a
stimulated salivary flow of less than 0.7 mL/min (Sreebny, 2000). In
contrast, the best way to assess xerostomia is through self-reports from
patients (Meirovitz et al., 2006). The Xerostomia Questionnaire is a
widely used tool for the assessment of xerostomia and consists of eight
items that the patient classifies on a scale of 0–10, with higher scores
indicating worse xerostomia (Eisbruch et al., 2001).
Several strategies have been investigated with the aim of preventing
or reducing damage to glandular tissue induced by RT. The main tech­
niques are the use of radioprotective drugs, systemic pharmacological
sialogogues, the surgical transfer of the submandibular glands, lubri­
cating or stimulating agents, and the use of intraoral devices (mouth
opener/jaw stabilizer). Although incipient, gene therapy and stem cell
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Critical Reviews in Oncology / Hematology 162 (2021) 103335
transfer appear to be promising approaches to recovering the function of
glandular tissue after RT (Jensen et al., 2019).
Some studies suggest that amifostine can serve as a radioprotective
drug. However, the results should be interpreted with caution, as such
studies have serious methodological limitations and the benefits need to
be weighed against the side effects (Jensen et al., 2019). A recent sys­
tematic review suggests that pilocarpine and cevimeline have promising
results (Mercadante et al., 2017). The use of systemic pilocarpine during
RT seems to prevent dysfunction of the salivary glands due to its ability
to promote functional stimulation, increasing unstimulated salivary
flow and reducing the degree of xerostomia. The long-term use of
cevimeline may induce an increase in unstimulated salivation. Although
the size of the relevant effect appears to be small, patients have reported
a sensation of improvement, which can be considered clinically signif­
icant. Once again, the findings should be interpreted with caution, as the
evidence is limited (Jensen et al., 2019; Mercadante et al., 2017).
Another prevention method that has been investigated is the use of
an oral stent, which is an individual intraoral device that protects
structures adjacent to the tumor. The use of the device seems to decrease
the risk of xerostomia (Chen et al., 2020). Although there is no robust
proven efficacy yet, the authors recommend its use as a preventive
method.
3.2. Radiation-induced dental caries
Radiation caries is an important late effect of RT that can appear as
early as three months after the end of antineoplastic treatment and, in
more severe cases, can lead to complete tooth destruction within a year
(Vissink et al., 2003). This is a specific form of tooth decay with an
estimated incidence of 29 % in the first year and 37 % in two years after
the end of RT (Moore et al., 2020). Radiation caries has a multifactor
etiology. It is currently believed that it originates from the sum of the
direct effect of RT on the hard tissues of the tooth, damaging enamel,
dentin, and the structure of the dentinoenamel junction (Lieshout and
Bots, 2014), as well as the indirect effect of radiation on soft tissues,
resulting in hyposalivation, trismus, dysphagia, and dysgeusia (Moore
et al., 2020).
Studies on the direct effect of radiation on teeth are scarce and offer
conflicting results (Fonseca et al., 2020). Dental deterioration likely
occurs due to micromorphological and biochemical changes in the
organic and inorganic components of the dentinoenamel junction
(Fonseca et al., 2020) and root dentin (de A.C. Velo et al., 2018).
Damage to the dental structure is proportional to the radiation dose.
Doses above 60 Gy seem to greatly increase the likelihood of radiation
caries, causing moderate to severe damage (Walker et al., 2011). In
addition, changes in the volume and composition of saliva alter its
antibacterial properties and ionic concentrations, leading to a reduction
in pH from 7.0–5.0 within the first year (Kielbassa et al., 2006). Tooth
decay is also suggested to occur due to the acidogenic change in the oral
microbiota (Meng et al., 2005), although other evidence suggests that
susceptibility to caries after radiation cannot be explained by microbi­
ological parameters (Zhang et al., 2015). This discussion lends strength
to the theory of a multifactor etiology and demonstrates that further
studies are needed to clarify the etiopathogenesis of radiation caries.
Radiation caries is most commonly found on tooth surfaces that are
relatively immune to tooth decay, i.e., buccal, palatal, incisal, and
occlusal surfaces. The lower anterior teeth, which are normally the most
resistant to caries, are frequently affected (Palmier et al., 2020). Most
often, the lesion extends superficially around the cervical area (Fig. 1)
and then progresses internally, resulting in complete destruction of the
crown. In the molar region, complete destruction is less frequent, but the
caries tends to spread to all molar surfaces, causing changes in trans­
lucency and color as well as increased friability and tooth breakage. Less
frequently, radiation caries is clinically manifested as a dark brown
discoloration of the entire crown accompanied by wear on the incisal
and occlusal surfaces (Vissink et al., 2003) (Fig. 2).
G.B. Ortigara et al.
Fig. 1. Radiation caries characterized by dark brown color and incisal wear.
Fig. 2. Radiation caries involving cervical region of mandibular incisors
and canine.
The prevention of radiation caries should be directed at the treat­
ment of xerostomia, adequate oral hygiene, a change in diet, the control
of cariogenic flora, and frequent fluoride applications (Vissink et al.,
2003). For the management of this condition, composite resin and
resin-modified glass ionomer cement are preferable. Conventional glass
ionomer cement can be used to help reduce recurrent cavities, but
frequent replacements are necessary to ensure the integrity of the
restorative material (Hong et al., 2018). Moreover, the prescription of
chlorhexidine at concentrations ranging from 0.12 to 0.2 % for one
minute twice a day is fundamental to reducing oral microorganisms to
below a pathological level. Patients should be evaluated and counseled
before and after RT (with frequent monitoring) in order to avoid radi­
ation caries and prevent the occurrence of serious damage (Gupta et al.,
2015).
3.3. Trismus
Trismus is defined as limited mouth opening. For patients with head
and neck cancer, trismus is considered mouth opening equal to or less
than 35 mm, measured by the distance between the maxillary and
mandibular incisors (Dijkstra et al., 2006). In partially edentulous or
edentulous patients, the measurement must be made with the prosthesis.
In the absence of a prosthesis, the distance between the upper and lower
alveolar edges is determined, from which the average height of the
missing teeth is subtracted (Fig. 3). However, this can alter the results of
the measurement and is pointed out as a limitation of some studies
(Kamstra et al., 2015).
The prevalence of trismus ranges from 17.3–44.1 % (Kamal et al.,
2020; Cardoso et al., 2020; Watters et al., 2019). A study evaluating the
prevalence in patients treated with surgery, RT, and chemotherapy –
either alone or in combination – found that the prevalence tends to
decrease 12 months after the completion of treatment (Watters et al.,
2019). RT is the main reason for the development of trismus and a
higher incidence is found among patients undergoing RT compared to
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Critical Reviews in Oncology / Hematology 162 (2021) 103335
Fig. 3. Maximum mouth opening of approximately 19 mm in patient having
undergone radiotherapy of head and neck region. As the patient was partially
edentulous, the measurement was performed from maxillary alveolar ridge to
the mandibular incisal edge.
those undergoing other forms of treatment (Shao et al., 2020). Some
authors suggest that IMRT reduces the occurrence of trismus and causes
less swallowing difficulty than conventional RT (Kraaijenga et al.,
2015).
Trismus occurs due to inflammatory changes caused by RT, which
can cause muscle fibrosis. Studies report that trismus is more likely to
occur in patients who have a large tumor close to the masticatory
muscles that requires extensive treatment (van der Geer et al., 2020).
Moreover, RT doses above 70 Gy are associated with a greater likelihood
of causing limited mouth opening (Scott et al., 2008). Trismus can also
lead to other complications, such as difficulty swallowing, chewing, and
speaking as well as psychosocial problems, which can affect quality of
life (Bonzanini et al., 2020b; Ortigara et al., 2019).
A systematic review with meta-analysis of randomized controlled
trials investigated possible therapies for trismus in patients with HNC
(Shao et al., 2020). Most studies use exercises supervised by a physio­
therapist or jaw stretching devices, the most cited of which is Therabite.
The authors reported that the exercise group exhibited greater im­
provements in mouth opening in the short (5–10 weeks) and long term
(three months) compared to the control group. The findings demonstrate
that exercise therapy can lead to an improvement in trismus but cannot
prevent this side effect and some treatment is necessary. Another review
with a similar research question highlights the importance of the timing
of treatment, suggesting the onset of therapy before or during RT
(Scherpenhuizen et al., 2015).
3.4. Dysphagia
Dysphagia is one of the most common, debilitating, and under-
reported acute and late complications faced by HNC patients undergo­
ing RT with or without concomitant chemotherapy (Crowder et al.,
2018). This effect – characterized by difficulty eating – may be related to
an increased risk of aspiration and aspiration-induced pneumonia and
G.B. Ortigara et al.
limits the oral intake of food and medications (Levendag et al., 2007).
Consequently, it exerts a significant influence on the health of these
patients, negatively impacting their nutritional status, social well-being,
and quality of life (Ortigara et al., 2019; Van den Steen et al., 2019).
Evidence suggests that 54–59 % of HNC patients have some degree of
swallowing difficulty (Crowder et al., 2018; Szczesniak et al., 2014).
Severe late dysphagia can occur in 19.2 % of patients (Huh et al., 2019)
and 14–22% can become dependent on a feeding tube (Kraaijenga et al.,
2015).
Impaired swallowing in HNC patients is most often associated with
the location of the primary tumor, which can directly affect the muscles
involved in the eating process and influence any phase of swallowing:
anticipatory, preparatory, oral, pharyngeal, and esophageal (Dodds
et al., 1990). Moreover, RT can cause damage to structures related to
chewing and swallowing and is consistently associated with the
dose-volume received by the masticatory muscles (Dale et al., 2016).
Radiation can cause an acute inflammatory and edema reaction, char­
acterizing acute dysphagia (Denham and Hauer-Jensen, 2002). The late
effect can emerge during the healing phase, as permanent fibrosis may
occur in muscle fibers that have a high glycolytic capacity (e.g., swal­
lowing musculature) (King et al., 2016; Murphy and Gilbert, 2009).
Besides the effects of radiation, it is plausible that atrophy due to the
decreased use of swallowing muscles (Murphy and Gilbert, 2009) and
other generic effects (Denham and Hauer-Jensen, 2002) are involved in
late swallowing difficulty (De Felice et al., 2018).
Late radiation-associated dysphagia can be evaluated with objective
(clinical examinations) and subjective (questionnaires) methods. The
"gold standard" exam for the assessment of swallowing is video-assisted
fluoroscopy, which enables the visualization of the oral, pharyngeal, and
esophageal phases using the modified barium test with esophagography
(Palmer JB and Drennan, 2001) to determine the amount of residual
food after swallowing, the occurrence of aspiration, and swallowing
compensation maneuvers (Martin-Harris and Jones, 2008). Another
objective exam is the Fibreoptic Endoscopic Evaluation of Swallowing
(FEES), which is performed by a speech-language pathologist using a
fiberoptic laryngoscope to assess the pharyngeal phase of swallowing.
For the subjective evaluation, questionnaires have been developed to
assess dysphagia-related quality of life. However, there is still no "gold
standard" for this assessment in HNC patients. The European Organi­
zation for Research and Treatment of Cancer core quality of life ques­
tionnaire has a diagnosis-specific criterion for patients with head and
neck cancer (H&N35) (Bjordal and Kaasa, 1992). The most widely used
questionnaire is the M. D. Anderson Dysphagia Inventory (MDADI),
which was developed specifically for HNC and assesses global,
emotional, functional, and physical domains (Chen et al., 2001). A
comparison of both forms of evaluation (objective and subjective)
showed significantly similar results (Florie et al., 2016).
By definition, a satisfactory result of dysphagia management is the
absence of aspiration and minimal food waste. Several techniques are
proposed for the treatment of this condition (De Felice et al., 2018;
Eerenstein et al., 2019), such as postural changes, changes in diet
(consumption of foods of less consistency), resistance exercises, and
range of motion exercises. These conservative therapies can be com­
bined and enable an improvement in swallowing without necessarily
changing the structures or physiology involved in this process. When
such methods are insufficient, surgical intervention can be considered
(De Felice et al., 2014). The choice of the appropriate treatment is
determined based on the situation of each patient, aiming at favorable
results and the satisfactory function of swallowing structures. Dose/­
volume limits of 50− 60 Gy to the pharynx and larynx (Rancati et al.,
2010), techniques such as IMRT (Ursino et al., 2017), and prophylactic
swallowing exercises are recommended to prevent or reduce the
occurrence of radiation-associated dysphagia (Carmignani et al., 2018).
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Critical Reviews in Oncology / Hematology 162 (2021) 103335
3.5. Dysgeusia
Radiation can also affect the taste buds, causing a change in the sense
of taste, which is denominated dysgeusia (Vissink et al., 2003). Dys­
geusia starts from the second or third week of treatment and can persist
for weeks or months. Taste is usually restored to nearly normal levels in
a period of 60–120 days after treatment (Correia Jham and Regina da
Silva Freire, 2006). It is estimated that approximately 33 % (Carmignani
et al., 2018) and 23 % (Dragan et al., 2019) of patients develop this
complication in the short and long term, respectively. However, the
prevalence of dysgeusia differs across studies due to the different case
definitions employed (Irune et al., 2014).
The reduction in taste sensation occurs due to the reduction in
physical contact between the tongue and food caused by a mechanical
block resulting from the increase in salivary viscosity and the change in
the biochemical components of saliva (Correia Jham and Regina da Silva
Freire, 2006). The loss of flavor is also related to the reduction in the
salivary flow rate (Vissink et al., 2003). The perception of savory and
sweet flavors is less affected by the consequences of radiation compared
to the perception of bitter and acidic flavors (Mossman et al., 1982). A
systematic review by Bressan et al. (2016) showed that this change in
taste triggers a loss of appetite and weight, directly affecting the pa­
tient’s nutritional status (Bressan et al., 2016) and quality of life
(Crowder et al., 2018).
Objective and subjective methods can be used for the diagnosis of
this condition. The objective approach involves measuring taste through
chemical gustometry, which is an analysis of the necessary concentra­
tion of a given substance (with the quality of standard flavors, for
example, bitter or sweet) required so that the individual can identify its
flavor (Conger, 1973). Questionnaires are used for the subjective
assessment and are usually combined with the assessment of general and
specific quality of life. For example, the University of Washington
(UWQOL) questionnaire has a domain for assessing the impact of
treatment on the taste of patients with HNC (Hassan and Weymuller,
1993). Another tool to detect changes in taste was created by the Na­
tional Cancer Institute in 2003 with the aim of investigating acute and
late side events resulting from cancer treatment. The Common Termi­
nology Criteria for Adverse Events (CTCAE version 3.0) also has a spe­
cific section addressing changes in taste (Trotti et al., 2003).
There is still no "gold standard" for the management and prevention
of dysgeusia (Thorne et al., 2015). However, some of the interventions
include dietary guidance (counseling in relation to food choices and
preparation) (Sroussi et al., 2017), dietary supplementation (such as the
use of zinc sulfate) (Chi et al., 2020), and use of marinol, megestrol
acetate, and Synsepalum dulcificum (Thorne et al., 2015). Recently,
techniques such as acupuncture have also been studied for the man­
agement and reduction of dysgeusia. However, the results vary among
post-radiation survivors of head and neck cancer (Kay Garcia et al.,
2013).
3.6. Osteoradionecrosis
Osteoradionecrosis is a serious late adverse reaction to RT defined as
an area of bone exposed for a minimum period of three (Morrish et al.,
1981) to six months (Marx, 1983) in a previously irradiated field, with
no relation to tumor persistence or recurrence (Chronopoulos et al.,
2018). The prevalence of osteoradionecrosis in patients irradiated in the
head and neck region varies widely in the literature. This considerable
difference in the prevalence and incidence of the disease is multifacto­
rial. Most studies determine the crude rate, which may underestimate
long-term risk. A recent study evaluated 252 patients who had oral and
oropharyngeal cancer and found a rate of 5.55 % (Moon et al., 2017).
The factors that increased the prevalence of osteoradionecrosis were
smoking, tooth extraction prior to RT, and the type of RT. The preva­
lence was lower among patients treated with IMRT. Indeed, the authors
concluded that the incidence of mandibular osteoradionecrosis is lower
G.B. Ortigara et al.
in contemporary times due to the preferred use of IMRT (Moon et al.,
2017). With the introduction of modern three-dimensional methods as
well as hyper-fractionated techniques, studies report a reduction of
around 5% in the risk of developing osteoradionecrosis since the 1990s
(Studer et al., 2004).
Tooth extraction after RT is considered an important risk factor for
the development of osteoradionecrosis (Thorn et al., 2000). When ex­
tractions are performed in previously irradiated fields, there is a 3%
increase in the incidence of osteoradionecrosis and the risk is threefold
greater in the mandible than the maxilla (Nabil and Samman, 2011).
Dental extractions performed prior to RT also increase the risk of
developing osteoradionecrosis (Moon et al., 2017; Reuther et al., 2003;
Lajolo et al., 2020), although the risk is lower in this situation (Wang
et al., 2017). The evidence supports the recommendation of the removal
of infectious foci prior to RT, including the extraction of non-viable
teeth, to avoid tooth extractions after RT (Moon et al., 2017; Wang
et al., 2017).
Other factors that increase the risk for the development of osteor­
adionecrosis are primary tumor surgery in the mandibular region prior
to RT, higher doses of RT (Sathasivam et al., 2018), generally above 60
Gy (Owosho et al., 2017), poor periodontal status, and alcohol con­
sumption (Owosho et al., 2017). Osteoradionecrosis has a notable pre­
dilection for the body of the mandible, followed by the mandibular
ramus (Dai et al., 2015). Occasionally, more serious conditions can
occur, such as cutaneous fistulas and fractures, which are more frequent
in the mandible than the maxilla (Bagan et al., 2009) (Fig. 4).
The pathogenesis is not completely understood. According to the
oldest theory (Marx, 1983), osteoradionecrosis is ischemic necrosis of
Fig. 4. A) Bone exposed in anterior region of body of mandible at site where extractions were performed three years after conclusion of radiotherapy; B) Osteor­
adionecrosis in anterior region of mandible and region of mandibular ramus – left side (spontaneous), with pathological fracture. In this case, biopsy was performed
to discard possibility of recurrence of tumor in region of left mandibular ramus.
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Critical Reviews in Oncology / Hematology 162 (2021) 103335
the irradiated bone resulting from a drop in the vascularization potential
of the tissues due to radiation, leading to hypoxic, hypovascularized,
hypocellular tissue, followed by tissue degradation, in which cell death
and collagen lysis exceed cell synthesis and replication. This leads to a
persistent wound that does not heal. A more recent hypothesis proposes
that osteoradionecrosis occurs through a fibro-atrophic mechanism
induced by radiation associated with defects in osteoclastic and osteo­
blastic cells, which culminates in tissue necrosis and healing failure
(Delanian and Lefaix, 2004). Although osteoradionecrosis is not an in­
fectious process (Marx, 1983), secondary bacterial infection can occur in
the region of necrotic tissue, which plays an important role in the
pathogenesis of this condition (Støre et al., 2005).
In view of the morbidity related to osteoradionecrosis and the
treatment difficulties, efforts to prevent this condition are necessary.
Several preventive measures are described in the literature. In addition
to recommending the prior extraction of untreatable teeth in the radi­
ation area as a way to prevent osteoradionecrosis (Wang et al., 2017),
the authors suggest limiting the number of tooth extractions per session,
waiting a minimum of two to three weeks before beginning RT, and
performing the procedure with the least traumatic technique possible
(Marx, 1983). Other preventive measures are regular oral prophylaxis
and daily fluoride applications during and after RT (Reuther et al., 2003)
as well as the systemic use of prophylactic antibiotics, non-steroidal
anti-inflammatory drugs, corticosteroids, pentoxifylline, tocopherol,
and platelet-rich plasma. However, there is insufficient evidence to state
which intervention performs better in preventing osteoradionecrosis of
the jaw in irradiated patients (El-Rabbany et al., 2019).
Some authors defend hyperbaric oxygen therapy as a way of
G.B. Ortigara et al.
preventing and treating osteoradionecrosis, as it increases the potential
for tissue healing (Epstein et al., 1987) and thus promotes a reduction in
osteoradionecrosis when applied after surgical procedures (Nabil and
Samman, 2011). However, the effectiveness of this therapy has been
questioned (Chronopoulos et al., 2018). Just as there is no one preven­
tive intervention that is superior to another (El-Rabbany et al., 2019),
there is no universal treatment for osteoradionecrosis. Treatment de­
pends on the severity of the disease (Epstein et al., 1987). In the early
stages, less severe cases can be managed conservatively, which includes
local wound care, hygiene with mouthwashes, antibiotics, and the
conservative removal of necrotic tissue (Camolesi et al., 2020).
For cases that do not respond to conservative treatment and
advanced cases, more radical treatment is indicated, such as surgical
resection with or without reconstructive microvascular techniques (Dai
et al., 2015; Camolesi et al., 2020). More recently, drug therapy has been
proposed, such as the use of pentoxifylline and tocopherol combined or
not with clodronate and antimicrobials (Delanian et al., 2011), which
seems to play a role in resolving the disease and inhibiting the pro­
gression of osteoradionecrosis in all stages (Heifetz-Li et al., 2019).
However, further studies are needed to establish this protocol. The most
effective method for treating osteoradionecrosis appears to be early
intervention, with the conservative removal of necrotic bone combined
with pharmacological therapy (Camolesi et al., 2020).
4. Discussion
Oral complications induced by RT are complex, dynamic, patho­
biological processes that exert a negative impact on quality of life and
cause serious side effects (Ortigara et al., 2019). Direct cell damage
combined with loss of vascular perfusion and fibroblast production
places irradiated patients at a high risk for the loss of salivary function,
swallowing difficulty, radiation caries, trismus, and bone necrosis,
which can affect patients after completion of RT (Strojan et al., 2017).
To the best of our knowledge, this is the first critical review of the
literature on the late side effects of RT. Regarding hyposalivation, we
found differences regarding the form of diagnosis. In a systematic re­
view, Jensen et al. (2010) found discrepancies in the literature in rela­
tion to the terms hypofunction of the salivary gland (hyposalivation) and
xerostomia. According to the authors, the term xerostomia is often used
as a synonym for hyposalivation, when it should be used only to indicate
the perception of dry mouth reported by the patient (Jensen et al.,
2010). Moreover, most studies measure hyposalivation subjectively,
which may lead to an overestimation of the prevalence.
Likewise, the prevalence of trismus, dysphagia, and dysgeusia re­
ported in the literature differs among studies. This difference may be
explained by the absence of defined criteria as well as the heterogeneity
of the samples evaluated in most studies, which include patients with
different types of tumors and having received different types of therapy.
Despite the inconsistency of these data, most studies that assessed
patient-reported outcomes similarly concluded that limited mouth
opening affects quality of life in a number of ways (Bonzanini et al.,
2020a, b). Difficulty swallowing and changes in taste are also common
and exert a negative impact on nutrition and, consequently, the quality
of life of irradiated patients (Van den Steen et al., 2019). Thus, there is a
need for a multidisciplinary team prepared to act with therapeutic
strategies to reduce the occurrence of these side effects of RT.
Factors associated with the development of swallowing disorders,
such as dysphagia, include a) the treatment of cancer itself, affecting
muscles related to swallowing and mouth opening (King et al., 2016) b)
difficulty eating and dietary modifications, which can lead to a decrease
in use and possible decrease in function (Murphy and Gilbert, 2009), and
c) other side effects described above. Hyposalivation can contribute to
difficulty forming and transporting the bolus (Mercadante et al., 2017)
and trismus can make it difficult to eat (Ortigara et al., 2019), both of
which affect the oral phase of swallowing. Thus, a combination of effects
occurs, leading to a possible vicious cycle, which underscores the
6
Critical Reviews in Oncology / Hematology 162 (2021) 103335
importance of the early, continual monitoring of survivors of HNC.
Unlike other late side effects, osteoradionecrosis has serious com­
plications. Although there is evidence that tooth extraction both before
and after RT is a risk factor for the development of osteoradionecrosis
and the risk is greater when extractions are performed after RT. Thus, it
is important for the dentist to assess the patient before RT and remove
possible infectious foci in order to avoid invasive procedures in the
irradiated area after the end of RT. Educational measures are necessary
to ensure the recognition of symptoms, especially after RT, when pa­
tients are not followed up as often. These aspects demonstrate the
importance of a multidisciplinary team in charge of the treatment and
supervision of such survivors of HNC.
Although recent research has shown that IMRT is associated with a
lower frequency of adverse effects (Kamal et al., 2020) and the use of
this modality is widespread in developed countries, many treatment
centers funded by the public sector in emerging countries use conven­
tional RT. Therefore, it is extremely important for healthcare providers
to be aware of the side effects caused by RT as well as the main forms of
treatment and be prepared to act in a multidisciplinary way in order to
reduce harm after treatment and preserve the patient’s quality of life.
IMRT is a more recent RT technique, an evolution of 3DRT, in which
the modulation of the treatment beam allows better dose distribution in
tissues and greater safety compared to other techniques. This technique
allows the irradiation of high doses in the target tissue and, at the same
time, protects the healthy adjacent tissues from radiation, offering less
toxicity (mainly, to the salivary glands) and better quality of life for the
patient (Santos et al., 2021; Haefner et al., 2017; Kamal et al., 2020;
Gupta et al., 2018). A recent systematic review with meta-analysis
(Alterio et al., 2020) assessed whether treatment with IMRT could
provide similar clinical results to 2DRT/3DRT, but with less toxicity, in
patients who had clinically advanced squamous carcinoma of the
oropharynx. The study results suggest that there were no differences
between conventional techniques and IMRT for clinical results related to
disease, considering the overall survival and disease-free survival pa­
rameters. The lack of homogeneity of the analyzed data did not allow a
quantitative analysis to be made regarding the impact of IMRT on late
toxicities. The most debilitating late toxicities related to alone RT or RT
concomitant with chemotherapy were hyposalivation / xerostomia and
dysphagia. The study suggests, through a qualitative analysis, less acute
and delayed toxicity in patients treated with IMRT. Similarly, other
authors have demonstrated there is good evidence that IMRT signifi­
cantly reduces the risk of moderate to severe acute and late xerostomia
compared to 2DRT/3DRT in radiotherapy treatment with curative intent
of squamous cell carcinoma of the head and neck (Gupta et al., 2018).
Still in relation to the effect of therapeutic modalities for the treat­
ment of squamous cell carcinoma of the head and neck on oral toxicities,
therapeutic schemes that include chemotherapy have been associated
with more acute symptoms when compared to treatment with radio­
therapy alone. However, the additive effect of chemotherapy associated
with radiotherapy on late toxicities has not been demonstrated (van Dijk
et al., 2021).
To date, there are no well-defined prevention routines for most late
side effects of RT, but some studies suggest therapeutic approaches that
can minimize the symptoms. Stretching devices have been recom­
mended for patients with trismus (Shao et al., 2020). Another way to
help reduce the rate of oral complications from radiation therapy is to
use a positioning stent, which is an individualized intraoral device worn
by patients during RT to protect organs adjacent to the tumor, such as
the parotid glands, submandibular glands, tongue, swallowing struc­
tures, and oral mucosa. Moreover, the risk of xerostomia is reported to
be lower based on objective and subjective measures when a positioning
stent is used (Chen et al., 2020).
The present study is a narrative review. This type of design consti­
tutes a limitation in comparison to systematic reviews, which present a
global analysis of the main outcome measures and provide robust evi­
dence when the primary studies analyzed have adequate methodological
G.B. Ortigara et al.
quality. Therefore, we based this study on systematic reviews to compile
the best evidence to date regarding the late oral effects of radiotherapy
in survivors of head and neck cancer, offering an overview of the late
side effects that most affect patients in order to elucidate the etiology,
prevalence, and main forms of treatment.
5. Conclusion
Evidence regarding the prevention and management the late side
effects of RT in the head and neck region remains limited. Well-designed
future research with standardized methods will help clarify the mech­
anisms as well as the main ways of preventing and treating these late
conditions. The authors recommend the following to researchers and
healthcare providers who work with HNC patients: (1) Have knowledge
on the main oral side effects of RT as well as the main forms of pre­
vention and treatment; (2) employ validated instruments to assess these
conditions both objectively and subjectively; (3) evaluate patient-
reported outcomes and quality of life using specific questionnaires;
and (5) act in a multidisciplinary way, addressing cancer survivors ho­
listically in order to reduce the harm caused by treatment.
Contribution of each author
G.B.O: Conceived the ideas, conceptualization of methodology and
wrote the manuscript.
L.I.L.B: Conceived the ideas, conceptualization of methodology and
wrote the manuscript.
R.E.S: Contributed substantially to discussion and wrote the
manuscript.
K.L.F: Contributed substantially to discussion, proofread manuscript
and supervision.
Funding
This study was partially supported by the research incentive fund
(FIPE) of the University of Santa Maria. We thank the Federal University
of Santa Maria for the partial funding of this study through the Research
Incentive Fund.
Declaration of Competing Interest
The authors certify that they have no commercial or associative in­
terest that represents a conflict of interest in connection with the
manuscript.
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Gabriela Barbieri Ortigara Dental Surgeon; Master Degree in Dentistry; PhD Student,
Postgraduate Program in Dentistry with Emphasis on Periodontics, Federal University of
Santa Maria, Santa Maria, Rio Grande do Sul, Brazil.