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Received: 26 July 2021    Accepted: 10 March 2022

DOI: 10.1111/iej.13726

REVIEW ARTICLE

Head and neck radiotherapy effects on the dental pulp

vitality and response to sensitivity tests: A systematic
review with meta-­analysis

Theodoro Weissheimer   | Bruna Barcelos Só   | Marieli Chitolina Pradebon   |

José Antonio Poli de Figueiredo   | Manoela Domingues Martins   |
Marcus Vinicius Reis Só

Department of Conservative Dentistry, Abstract

School of Dentistry, Federal University
of Rio Grande do Sul (UFRGS), Porto
Alegre, Brazil
Correspondence
Theodoro Weissheimer, Department
of Conservative Dentistry, School of
Dentistry, Rio Grande do Sul Federal
University (UFRGS), Augusto Pestana
Street, 176/6, Porto Alegre, Rio Grande
do Sul, Brazil.
Email: theodoro.theo@hotmail.com
Background: Experimental studies are controversial regarding the effects of radio-
therapy for head and neck cancer (HNC) on the dental pulp. Therefore, a systematic
review of clinical studies is necessary to investigate whether alterations in pulp sta-
tus occur.
Objectives: To evaluate the evidence on radiotherapy for HNC and pulp status.
Methods: A systematic search of articles published until November 2021 was per-
formed in the MEDLINE/PubMed, Cochrane Library, Web of Science (All Databases),
Scopus, EMBASE, and Open Grey databases. The eligibility criteria were based on
the PICOS strategy, as follows: (P) vital teeth of adult patients with intraoral and/or
oropharyngeal cancer; (I) radiotherapy; (C) control group or values of the same tooth
before radiotherapy (basal values); (O) pulpal status after radiotherapy; and (S) clini-
cal studies. The Cochrane Risk of Bias in Nonrandomized Studies of Interventions
tool was used to assess the quality of the included studies. Meta-­analyses were
performed using fixed and random effects. The overall quality of evidence was as-
sessed through the Grading of Recommendations Assessment, Development, and
Evaluation (GRADE) tool.
Results: Six studies were included for qualitative analysis. Five were classified as
serious risk of bias and one as moderate risk of bias. Four studies reported altered
pulp responses to cold thermal tests after radiotherapy initiation. Meta-­analyses
were performed using three included studies. From these, all were included in the
meta-­analysis for pulp response values to cold sensitivity test immediately after ra-
diotherapy initiation (risk ratio: 0.00 [CI: 0.00, 0.02], p < .00001; I2 = 0%); and two in
the meta-­analysis for pulp response values to cold sensitivity test after 4–­5 months of
radiotherapy (risk ratio: 0.01 [CI: 0.00. 0.06], p < .00001; I2 = 0%). Two reported pro-
gressively higher readings to pulp response in the electrical test after radiotherapy in-
itiation (mean difference: −11.46 [−13.09, −9.84], p < .00001; I2 = 68%). Two studies
demonstrated a pulp oxygen saturation (SpO2) decrease at the end of radiotherapy;

Registration: This systematic review was registered on the PROSPERO database (CRD42021244001).

© 2022 International Endodontic Journal. Published by John Wiley & Sons Ltd

Int Endod J. 2022;55:563–578.  wileyonlinelibrary.com/journal/iej   |  563

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564       RADIOTHERAPY EFFECTS ON THE DENTAL PULP RESPONSES

and an increase after 4–­6  months of radiotherapy beginning. And other demon-
strated normal dental pulp SpO2 4–­6  years after treatment. GRADE analysis pre-
sented a moderate certainty of evidence.
Discussion: This review verified that radiotherapy for HNC causes significant al-
terations on the dental pulp responses, but does not seem to induce pulp necrosis.
Significant limitations regarding controlling for confounding factors, classification of
interventions, and measurement of outcomes were verified, evidencing the need for
well-­designed studies.
Conclusions: This systematic review demonstrated that radiotherapy for HNC in-
duced significant changes in the pulp response with moderate quality of evidence.
Such altered responses cannot determine pulp status accurately.

KEYWORDS
dental pulp, head and neck cancer, radiotherapy, systematic review

I N T RO DU CT ION The current scenario of HNC epidemiology and the

Cancer is a critical health issue worldwide, with about
19.3 million new cases in 2020 and 10 million deaths
in the same year (Sung et al., 2021). In 2017, there were
about 890 000 new cases of head and neck cancers (HNC)
worldwide according to the Global Burden of Disease
Study (Global Burden of Disease Cancer Collaboration,
2019). HNC occur in any of the following sites: oral cav-
ity, pharynx, larynx, lips, throat, salivary glands, and nose
(Aupérin, 2020; Cohen et al., 2018).
Surgery, the treatment of choice for HNC, may be as-
sociated or not with radiotherapy and/or chemotherapy
(Badr et al., 2017). Head and neck radiotherapy may lead
to several deleterious side effects to the oral mucosa, alve-
olar bone, masticatory muscles, salivary glands, and den-
tition (Sroussi et al., 2017). The main complications are
oral mucositis, xerostomia, dysgeusia, dysphagia, trismus,
radiation caries, and osteoradionecrosis (Carneiro-­Neto
et al., 2017; Lalla et al., 2017; Sroussi et al., 2017).
There is no consensus about the effects of radiotherapy
on dental pulp in the literature. Some evidence indicates
that head and neck radiotherapy may promote nervous
and vascular alterations in the dental pulp, leading to
pulp necrosis (Meyer et al., 1962). Other studies demon-
strated that the direct effects of radiotherapy do not in-
duce morphologic alterations of the dental pulp (Faria
et al., 2014; Hutton et al., 1974). A study in rats (Madani
et al., 2017) demonstrate that there were no significant
differences in pulp necrosis between the irradiated ani-
mals and the control group. However, vascular conges-
tion outcomes were significantly different. Another study
in rats demonstrated that radiotherapy might cause nu-
clear alterations in dental pulp fibroblasts (Vier-­Pelisser
et al., 2007).
lack of a consensus between these studies warrant the as-
sessment of available clinical evidence. A better compre-
hension of dental pulp status after radiotherapy may guide
a clinician's decision-­making process. Therefore, this sys-
tematic review addressed the following question: Can
head and neck radiotherapy induce dental pulp necrosis?
MATERIAL AND METHODS
This systematic review followed the recommendations
of the Preferred Reporting Items for Systematic Review
and Meta-­Analysis (PRISMA; Table S1—­PRISMA 2020
Checklist; Page et al., 2020), and a protocol was registered
in the PROSPERO database (CRD42021244001).
Search strategy
Two examiners (T.W. and B.B.S.) performed electronic
searches independently using the following databases:
MEDLINE/PubMed, Cochrane Library, Web of Science
(all databases), Scopus, EMBASE, and Open Grey (grey
literature search). Database searches were conducted up
to November 2021, without year or language restriction.
The electronic search strategy used the most cited de-
scriptors in this field according to previous publications,
combining Medical Subject Heading (MeSH) terms and
text words (tw.). The Boolean operators “AND” and “OR”
were applied to combine the terms and create a search
strategy. The search strategies for each database and the
studies retrieved are summarized in Table S2. Additional
manual searches of the reference lists of the selected stud-
ies were performed. All articles selected were imported
WEISSHEIMER et al.
into the Mendeley© (Mendeley Ltd) reference manager
to catalogue the references and facilitate the exclusion of
duplicates.
Eligibility criteria
The eligibility criteria were selected according to the
PICOS strategy (Maia & Antonio, 2012; Moher et al., 2015;
Page et al., 2020).
• Population (P): vital teeth of adult patients with intra-
oral and/or oropharyngeal cancer.
• Intervention (I): radiotherapy.
• Comparison (C): control group or values for the same
tooth before radiotherapy (baseline values).
• Outcome (O): pulp status after radiotherapy.
• Study design (S): clinical studies.
Only clinical studies that evaluated pulp responses of
teeth of adult patients with HNC treated with radiother-
apy were included.
Studies performed in animals, histological studies, sys-
tematic reviews with and without meta-­analysis, reviews,
letters, opinion articles, conference abstracts, case reports,
and case series were excluded.
Selection of the studies
All procedures were performed by two independent au-
thors (T.W. and B.B.S.), who initially conducted the da-
tabase searches, removed duplicates, and screened titles
and abstracts. If the title and abstract were not sufficient
to determine inclusion, the full text was read for a final
decision. After that, potentially eligible studies were then
read for the full-­text assessment using the PICOS criteria.
Discrepancies between reviewers were resolved by discus-
sion with a third author (M.C.P.).
Data extraction
Two authors (T.W. and B.B.S.) extracted data indepen-
dently. Discrepancies were resolved by discussion with
a third author (M.C.P.). Data extracted from the stud-
ies included were: author(s) name(s), year of publica-
tion, country, number of participants, patients’ age, type
of treatment, total radiation dose, radiation technique,
methods of measuring pulp status, teeth evaluated, time-­
points of pulp status measurements, outcomes, and main
findings. In case of missing information, the authors were
contacted three times by e-mail at an interval of 1 week.
     |  565
Qualitative assessment
Study quality was assessed by two independent authors
(T.W. and B.B.S.) to determine the risk of bias of each
study using the Risk of Bias in nonrandomized Studies
of Interventions (ROBINS-­I) tool (Sterne et al., 2016),
which is recommended for non-­randomized clinical tri-
als and observational studies. A third author (M.C.P.) was
consulted in case of discrepancies between reviewers. As
blinding operators and participants cannot be performed
in this type of intervention, these factors were not included
in the assessment. Therefore, the following domains were
assessed and classified:
1. Confounding factors: low risk of bias when all possi-
ble confounding factors were controlled in the study
design or statistical analysis; moderate risk of bias
when confounding factors were partially controlled;
serious risk of bias when no possible confounding
factors were controlled; and critical risk of bias when
possible confounding factors were not even discussed.
2. Participant inclusion in the study: low risk of bias when
all eligible participants were included in the study;
moderate risk of bias when participant selection might
have been associated with the outcome; serious risk of
bias when participant selection was associated with the
outcome; and critical risk of bias when the selection
process was not described.
3. Classification of interventions: low risk of bias when
radiotherapeutic intervention was well described in-
cluding total radiation doses, radiotherapy treatment
method, and description of the irradiated field; moder-
ate risk of bias when only one intervention parameter
was missing; serious risk of bias when two intervention
parameters were missing; and critical risk of bias when
the radiotherapy intervention was not described at all.
4. Deviations from intended interventions: low risk of bias
when no differences occurred after the beginning of the
study, or, if they did, the participant continued in the
study for analysis; moderate risk of bias when differ-
ences occurred after the beginning of the study but did
not seem to affect study outcome (e.g., nonadherence
of participants to the intervention); serious risk of bias
when a few differences occurred after the beginning of
the study and changes in sample or intervention were
required; and critical risk of bias when several differ-
ences occurred after the beginning of the study.
5. Missing data: low risk of bias when the number of par-
ticipants, tooth group, radiotherapy parameters, and
pulp status were accurately reported; moderate risk of
bias when there were some missing data, but the miss-
ing data were not relevant to the purpose of the study;
serious risk of bias when there were some relevant
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566       RADIOTHERAPY EFFECTS ON THE DENTAL PULP RESPONSES
missing data; and critical risk of bias when there were
several relevant data missing.
6. Measurement of outcomes: low risk of bias when a valid
method was used to assess pulp status; moderate risk of
bias when a valid method was not used, although the
method was well described; serious risk of bias when
a valid method was not used and not well described;
and critical risk of bias when the method used was not
described.
7. Selection of reported results: low risk of bias when
pulp alterations during interventions were accurately
reported; moderate risk of bias when pulp alterations
during interventions were accurately reported, but
not described; serious risk of bias when there was any
substantial difference in the description of data during
interventions; and critical risk of bias when informa-
tion about pulp alterations during interventions was
missing.
The risk of bias of each domain was classified as low,
moderate, serious, critical, or no information available.
The overall risk of bias was determined by combining the
levels of bias in each domain. The overall risk of bias was
low when all domains had a low risk of bias, moderate
when at least one domain had a moderate bias, serious
when at least one domain had a serious bias, and critical
when at least one domain had a critical risk of bias.
Meta-­analysis
Qualitative data were tabulated and processed using
Microsoft Excel®. Clinical studies with relatively similar
methods were included in the meta-­analysis. These stud-
ies should contain the following information: (1) same
type of dental pulp tests; (2) similar periods of assessment;
(3) outcome measurements before and after radiotherapy
for comparisons; and (4) quantitative outcomes of dental
pulp tests.
The Review Manager software (RevMan—­Version 5.3.
Copenhagen: The Nordic Cochrane Centre, The Cochrane
Collaboration, 2014) was used for the meta-­analysis.
Heterogeneity was calculated using the T2 and Cochran Q
tests, and I2 statistics. Heterogeneity with an I2 below 30%
was classified as irrelevant, from 30% to 60%, moderate,
from 50% to 90%, substantial, and more than 75%, consid-
erable (Deeks et al., 2021; Higgins et al., 2003). A random-­
effect model was used if I2 was ≥50%. A fixed-­effect model
was used when the studies had an I2 < 50%. The level of
significance was set at p  <  5%. Publication bias may be
assessed visually by the generation of funnel plots only
when 10 or more studies are included in a meta-­analysis
(Page et al., 2021). Apart from that, all the outcomes of
the studies included were qualitatively described and crit-
ically discussed in the sections described below, even if no
meta-­analysis was possible.
Certainty of evidence
The certainty of the evidence of the studies included
was assessed using the Grading of Recommendations
Assessment, Development, and Evaluation (GRADE) tool
(GRADEpro GDT: GRADEpro Guideline Development
Tool, McMaster University, 2015; developed by Evidence
Prime, Inc.), available from gradepro.org: https://gdt.
grade​p ro.org/app/handb​o ok/handb​o ok.html#h.rkkjp​
mwb6m6z (Guyatt et al., 2011a). The GRADE tool has five
domains that can be downgraded and reduce the quality
of the evidence (GRADE Working Group, 2004). The fol-
lowing domains were included in this assessment:
1. Risk of bias.
2. Inconsistency.
3. Indirectness.
4. Imprecision.
5. Other considerations.
RESULTS
Study selection
Figure 1 shows the flow diagram for the search strategy.
Database searches yielded 184 potentially relevant re-
cords. After that, 72 duplicates were removed, leaving
112 studies to be screened based on title and abstract.
In this step, 106 studies were removed, and six studies
(Daveshwar et al., 2021; Garg et al., 2015; Gupta et al.,
2018; Kataoka et al., 2011, 2012, 2016a) were fully read to
assess eligibility. All six studies (Daveshwar et al., 2021;
Garg et al., 2015; Gupta et al., 2018; Kataoka et al., 2011,
2012, 2016a) met eligibility criteria and were included in
this review. No additional studies were included after the
manual search of the references of the studies included.
Data extraction
General descriptions of the studies are summarized in
Table 1. All studies included in this review had a nonran-
domized observational study design. Authors from studies
with missing information were contacted three times by
e-mail, but no additional information was obtained.
Five studies (Garg et al., 2015; Gupta et al., 2018;
Kataoka et al., 2011, 2012, 2016a) used cold thermal pulp
WEISSHEIMER et al.
F I G U R E 1   Flow diagram of the systematic literature search according to PRISMA 2020 guidelines
sensitivity tests for the assessment of pulp status. Three
studies used pulse oximetry to evaluate the pulp status
(Daveshwar et al., 2021; Kataoka et al., 2011, 2016a), and
two others, electrical tests (Garg et al., 2015; Gupta et al.,
2018).
Radiotherapy was used in all studies. In one of them,
the treatment was radiotherapy and chemotherapy for
all patients (Garg et al., 2015). The total radiation dose
ranged from 60 to 70 Gy. Intensity-­modulated radiother-
apy (IMRT) was the primary radiation technique in four
studies (Garg et al., 2015; Gupta et al., 2018; Kataoka
et al., 2012, 2016a). Two studies did not report radiation
techniques (Daveshwar et al., 2021; Kataoka et al., 2011),
and another study (Kataoka et al., 2012) also used three-­
dimensional (3D) conformal radiation therapy.
Three studies evaluated anterior teeth, selecting ei-
ther all anterior teeth (Kataoka et al., 2016a) or only two
mandibular or maxillary incisors in each patient (Kataoka
et al., 2011, 2012). Two studies (Garg et al., 2015; Gupta
et al., 2018) selected four posterior teeth, one from each
quadrant. One study (Daveshwar et al., 2021) selected one
premolar in each participant. Overall, tooth selection was
standardized regardless of the quadrant and the irradiated
area.
Most of the studies evaluated teeth before and after ra-
diotherapy for comparisons (Daveshwar et al., 2021; Garg
et al., 2015; Gupta et al., 2018; Kataoka et al., 2011, 2012).
Only one study (Kataoka et al., 2016a) did not evaluate
     |  567
the patient before radiotherapy and used nonirradiated
patients for comparisons. Additionally, this was the only
study that conducted long-­term assessments, for 4–­6 years
after radiotherapy. Except for this one, studies had a
similar pattern of time-­point assessments: before radio-
therapy (Daveshwar et al., 2021; Garg et al., 2015; Gupta
et al., 2018; Kataoka et al., 2011, 2012), during radiother-
apy (Garg et al., 2015; Kataoka et al., 2011, 2012), at the
completion of radiotherapy (Daveshwar et al., 2021; Garg
et al., 2015; Gupta et al., 2018; Kataoka et al., 2011, 2012),
4–­6 months after initiation of the treatment (Daveshwar
et al., 2021; Garg et al., 2015; Kataoka et al., 2011, 2012), at
treatment completion (Gupta et al., 2018), and 12 months
after treatment (Gupta et al., 2018).
One of the main findings was that all studies that
evaluated pulp status using cold thermal pulp sensitivity
tests reported only negative responses at therapy comple-
tion (Garg et al., 2015; Gupta et al., 2018; Kataoka et al.,
2011, 2012) and 12 months after that (Gupta et al., 2018).
One study reported positive responses to cold thermal
tests 4–­6 years after radiotherapy (Kataoka et al., 2016a).
Studies that evaluated the pulp status using electrical pulp
tests (Garg et al., 2015; Gupta et al., 2018) also revealed
abnormal (increased) measures at the time points after
treatment. In contrast, two studies that used pulse oxim-
etry (Daveshwar et al., 2021; Kataoka et al., 2011) had a
significant decrease in pulp oxygen saturation (SpO2) at
the completion of radiotherapy but were similar to values
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568       RADIOTHERAPY EFFECTS ON THE DENTAL PULP RESPONSES

T A B L E 1   Characteristics of the studies included

Authors (year of Number of Methods of

publication)—­ participants Participants’ Total radiation Radiation measuring pulp
country (per group) age (mean) Type of treatment doses technique status
Kataoka et al. n = 20 35–­55 years Radiotherapy 60–­70 Gy NR Pulse oximetry
(2011)—­Brazil (47.2 years) Cold thermal pulp
sensitivity test

Kataoka et al. n = 20 35–­55 years Radiotherapy 60–­70 Gy 3D-­RT and Cold thermal pulp
(2012)—­Brazil (Group 3D-­RT: 8 (47.2 years) IMRT sensitivity test
Group IMRT: 12)

Garg et al. n = 21 40–­65 years Chemo-­radiotherapy 66–­70 Gy IMRT Cold thermal pulp
(2015)—­India (52.5 years) sensitivity test
Electric pulp test

Kataoka, Setzer, n = 180 35–­65 years Radiotherapy Mean: 61.8 Gy IMRT Pulse oximetry
et al. (2016a) (RT—­group) = 90. (49.4 years Cold thermal pulp
—­Brazil Control—­CO—­ for RT group; sensitivity test
group =90) 49.6 years for
control group)

Gupta et al. n = 79 40–­75 years Radiotherapy 66–­70 Gy IMRT Cold thermal pulp
(2018)—­India (58.8 years) sensitivity test
Electric pulp test
WEISSHEIMER et al.      |  569

Teeth
evaluated Time-­points (TP) of pulp
(total) status measurement Outcomes Main findings
2 teeth per TP1—­Before radiotherapy Oxygen saturation (SpO2) Mean pulp SpO2 values 4–­5 months
patient—­ TP2—­At initial radiotherapy TP1: Mean 93% after the beginning of RT were
regardless after 30–­35 Gy TP2: Mean 83% close to those found at RT
of quadrant TP3—­At the completion of TP3: Mean 77% initiation
and radiotherapy at 60–­70 Gy TP4: Mean 84% Pulp tissue might be able to regain
irradiated TP4—­4–­5 months after Significant differences were observed when normal PBF after RT, even when
area (40 initiation of radiotherapy comparing TP1 and other experimental times pulp sensitivity responses were
teeth) TP3 showed significant differences compared negative
with TP2, without differences between TP2
and TP4
Cold thermal test
Responses to the cold thermal pulp sensitivity
test were significantly different
TP1: All teeth responded positively
TP2: nine teeth responded positively
TP3–­TP4: No positive responses were recorded
2 mandibular TP1—­Before radiotherapy TP1: All teeth responded positively to the cold Radiotherapy decreased the number
or maxillary TP2—­At the initiation thermal test of teeth responding to cold
incisors of of radiotherapy after TP2: nine teeth responded positively (three in thermal tests
each patient 30–­35 Gy the 3D-­RT group and six in the IMRT group) The type of radiotherapy (3D-­RT
(40 teeth) TP3—­At the completion of TP3–­TP4: No tooth in either group responded to or IMRT) had no effect on
radiotherapy at 60–­70 Gy the cold thermal test pulp responses after the end of
TP4—­4–­5 months after No significant differences in positive sensitivity treatment
initiation of radiotherapy responses were found between 3D-­RT and
IMRT at any time point
4 posterior TP1—­Before radiotherapy PT1: All teeth responded positively Radiotherapy decreased the number
teeth—­1 TP2—­After 30–­35 Gy PT2: Only 25 teeth responded positively of teeth responding to pulp
from each TP3—­At the completion of PT3–­PT4: No tooth responded positively sensitivity test after doses greater
quadrant (84 radiotherapy at 66–­70 Gy Significant differences between time points than 30–­35 Gy
teeth) TP4—­4 months after Significant correlation between the maximum
initiation of radiotherapy dose per tooth in each quadrant and
decreased sensitivity
No significant correlation between tumour site
and tooth affected during radiotherapy
All anterior 4–­6 years after radiotherapy All teeth had positive responses to the cold Pulp oxygen saturation within
teeth of both thermal test normal values; positive responses
groups (RT Mean (SD) %SpO2 recorded in group RT was to cold thermal test 4–­6 years
group: 693 92.7% (±1.83%); and 92.6% (±1.80%) in after radiotherapy
teeth. control group
Control group: No significant differences between groups
693 teeth)
4 posterior TP1—­Before radiotherapy TP1: All teeth responded positively to the cold Radiotherapy progressively
teeth—­1 TP2—­At the completion of thermal pulp sensitivity test; mean EPT decreased pulp sensitivity to cold
from each radiotherapy at 66–­70 Gy values were between 9.14 and 9.70 thermal test and increased EPT
quadrant TP3—­4 months after TP4 -­ TP5: All teeth responded negatively to values to pulp response from TP1
(288 teeth) completion of the cold thermal test; E`T had progressively to TP5
radiotherapy higher readings
TP4—­6 months after TP5: Mean EPT values between 48.75 and 49.88
completion of
radiotherapy
TP5—­12 months after
completion of
radiotherapy
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570       RADIOTHERAPY EFFECTS ON THE DENTAL PULP RESPONSES
T A B L E 1   (Continued)
Authors (year of Number of
publication)—­ participants Participants’
country (per group) age (mean)
Daveshwar et al. n = 25 30–­65 years
(2021)—­India (46.04 years)
Abbreviations: 3D-­RT, 3-­dimensional conformal radiotherapy; IMRT, intensity-­modulated radiotherapy; NR, not reported; RT, radiotherapy.
before the treatment after 4–­6 months. In the other study
(Kataoka et al., 2016a), SpO2 of the dental pulp was within
the normal range at 4–­6  years after radiotherapy when
compared with a control group of patients who had never
received the same treatment.
Additionally, there were no significant differences in
pulp responses between radiation techniques—­3D or
IMRT (Kataoka et al., 2012). Apart from that, there was
a significant correlation between the maximum radiation
dose received in each quadrant and the decrease in pos-
itive responses to the cold thermal pulp sensitivity test
(Garg et al., 2015). No correlation was found between the
primary tumour site or affected teeth (Garg et al., 2015).
Qualitative assessment
Figure 2 shows the results of the risk of bias analysis using
the ROBINS-­I tool (McGuinness & Higgins, 2020). All the
studies had a moderate risk of bias in the analysis of con-
founding factors. Similarly, every study had a low risk of
bias in participant selection. The risk of bias in the classifica-
tion of intervention was serious in two studies (Daveshwar
et al., 2021; Kataoka et al., 2011), but it was moderate for the
others. The bias for deviation from intended interventions,
missing data, and selection of reported results was low in all
the studies. The risk of bias for measurement of outcomes
was serious in three studies (Garg et al., 2015; Gupta et al.,
2018; Kataoka et al., 2012) and low in the others. Overall,
the risk of bias was serious in five studies (Daveshwar et al.,
2021; Garg et al., 2015; Gupta et al., 2018; Kataoka et al., 2011,
2012) and moderate in one study (Kataoka et al., 2016a).
Meta-­analysis
A meta-­analysis could not be conducted for all outcomes
because of significant study heterogeneity; it was also not
Methods of
Total radiation Radiation measuring pulp
Type of treatment doses technique status
Radiotherapy 60–­70 Gy NR Pulse oximetry
possible for dental pulp SpO2 using the studies that evalu-
ated it.
As fewer than 10 studies were included in the meta-­
analysis, no funnel plot was generated to detect publica-
tion bias.
An overlapping sample was found in two studies
(Kataoka et al., 2011, 2012). The authors of these studies
were contacted by e-mail and confirmed that their sample
was overlapping. Therefore, only the latter was included
in the quantitative analysis of cold pulp sensitivity testing.
The studies that used cold pulp sensitivity tests (Garg
et al., 2015; Gupta et al., 2018; Kataoka et al., 2012) had a
number of teeth that responded positively or negatively
before and after radiotherapy. As this is a dichotomous
variable, the effect measure used was risk ratio, and the
statistical method was the Mantel–­Haenszel test. There
were significantly more teeth that responded negatively
than positively to the tests immediately after radiotherapy
[p < .00001; RR = 0.00; CI (0.00, 0.02); I2 = 0%], as shown
in Figure 3.
A meta-­analysis of two studies (Garg et al., 2015;
Kataoka et al., 2012) that compared cold thermal pulp sen-
sitivity testing before and 4–­5 months after radiotherapy
was also performed. There was a significant increase in
teeth that responded negatively to the tests immediately
after radiotherapy [p < .00001; RR = 0.01; CI (0.00, 0.06);
I2 = 0%], as shown in Figure 4.
Two studies (Garg et al., 2015; Gupta et al., 2018) pre-
sented the values of electrical tests separately for each
quadrant using mean and standard deviations (SD). As
electrical tests provide continuous variables, the effect
measure was the mean difference, and the inverse vari-
ance method of DerSimonian–­Laird was used for the
meta-­analysis. Figure 5 shows the results of electrical tests
before and immediately after radiotherapy by quadrant.
Separately, every quadrant had significant differences be-
fore and after radiotherapy [Quadrant 1: p < .0001; mean
difference (MD) = −10.20; CI: (−15.16, −5.25); I2 = 77%];
WEISSHEIMER et al.
Teeth
evaluated Time-­points (TP) of pulp
(total) status measurement Outcomes
1 mandibular TP1—­Before radiotherapy Oxygen saturation (SpO2)
premolar of TP2—­At completion of TP1—­Mean 93.6%
each patient radiotherapy at 60–­70 Gy TP2—­Mean 75.12%
(25 teeth) TP3—­6 months after TP3—­Mean 81.04%
radiotherapy There was a significant decrease in mean SpO2 at
the completion of radiotherapy; mean SpO2
6 months after radiotherapy increased.
[Quadrant 2: p < .0001; mean difference (MD) = −11.16;
CI: (−16.22, −6.11); I2 = 54%]; [Quadrant 3: p = .03; mean
difference (MD) = −9.51; CI: (−17.93, −1.10); I2 = 89%];
[Quadrant 4: p = .03; mean difference (MD) = −10.72; CI:
(−17.92, −3.53); I2  =  79%]. The overall effect for all the
subgroups was also significant, which revealed that the
electrical pulp response after radiotherapy is significantly
changed [p < .00001; mean difference (MD) = −11.46; CI:
(−13.09, −9.84); I2 = 68%].
Certainty of the evidence
The results of the GRADE assessment are summarized in
Table 2.
As the ROBINS-­I tool was used to assess the risk of bias
of the studies included, the initial certainty of the evidence
was high (Schünemann et al., 2019). As the studies had a
serious risk of bias, inconsistencies, and imprecision, their
initial quality of evidence was downgraded. Indirectness
was not serious. The studies were upgraded in the other
domains because they had a strong association and a dose-­
response gradient. For these reasons, the overall certainty
of the evidence for the studies included was moderate.
DI S C US S I O N
Head and neck cancer is one of the most common malig-
nancies worldwide (Siegel et al., 2021). Its development is
strongly associated with tobacco and alcohol consumption,
human papillomavirus infection, and socio-­economic fac-
tors (Aupérin, 2020; Cohen et al., 2018; Gupta et al., 2016).
Moreover, HNC carries high mortality rates and may de-
crease a patient's life expectancy (Sung et al., 2021). In
addition to the deleterious effects of radiotherapy on the
oral cavity and adjacent structures (Sroussi et al., 2017),
patients who undergo this type of treatment may also have
     |  571
Main findings
Mean pulp SpO2 values decreased
from initiation to completion of
radiotherapy (60–­70 Gy). After
6 months of treatment end, mean
pulp SpO2 values increased
a higher rate of decayed, missing, and filled teeth (Hong
et al., 2010). However, results in the literature about the
effects of radiotherapy on the dental pulp are controver-
sial (Faria et al., 2014; Hutton et al., 1974; Madani et al.,
2017; Meyer et al., 1962; Vier-­Pelisser et al., 2007).
Therefore, this review examined whether head and
neck radiotherapy-­induced dental pulp necrosis. Six elec-
tronic databases were searched for clinical trials that eval-
uated the pulp status of patients irradiated to treat HNC.
Findings demonstrated that, although the responses to
tests were significantly different, they could not be used
to determine necrotic pulp status because the tests are not
highly accurate.
The evidence associated with pulp response to cold
sensitivity tests and electrical tests indicated that, after
the initiation of radiotherapy, the rate of negative pulp re-
sponses to both tests were higher (Garg et al., 2015; Gupta
et al., 2018; Kataoka et al., 2011, 2012). Likewise, 4 months
after the completion of radiotherapy and up to 1 year after
treatment, teeth responded negatively to cold tests (Garg
et al., 2015; Gupta et al., 2018; Kataoka et al., 2011, 2012).
In addition, electrical test readings were progressively
higher (Garg et al., 2015; Gupta et al., 2018). However,
pulp responses to cold sensitivity tests after 4–­6 years were
positive (Kataoka et al., 2016a). In this systematic review,
the meta-­analysis that examined pulp responses to cold
sensitivity tests immediately after the completion of ra-
diotherapy and 4–­6 months after that revealed highly sig-
nificant differences (p < .00001). In addition, the results of
pulp response to electrical tests immediately after radio-
therapy were also highly significant (p < .00001), with no
differences between quadrant evaluated (p = .99).
The interpretation of electrical test readings is criti-
cal and demands detailed explanations. Recent studies
have shown that electrical and thermal pulp sensitivity
tests are more accurate when used together (Alghaithy &
Qualtrough, 2017). In this review, the meta-­analysis that
examined studies that used electrical tests revealed that
 |
572       RADIOTHERAPY EFFECTS ON THE DENTAL PULP RESPONSES
readings were higher after radiotherapy. Electrical tests
are performed by placing an electrode on each tooth and
increasing the electrical current gradually until the patient
reports pain or pulsation during the stimulus (Šimović
et al., 2018). Therefore, these significantly higher values
after radiotherapy mean that the dental pulp required a
stronger electric current to respond to the stimulus after
the patient underwent radiotherapy. These results may
suggest that tooth sensitivity after radiotherapy is lower
than at baseline (vital teeth), which confirms the results
of cold sensitivity tests. Additionally, as the results of the
studies using electrical tests were divided by quadrants,
the meta-­analysis was also separated into quadrants, but
each subdivision should be interpreted as described above.
Various hypotheses have already been raised for the
loss of pulp sensitivity after radiotherapy. Teeth within and
adjacent to an irradiated field seem to have a decreased
F I G U R E 2   Quality assessment of the studies included in the review, according to the Cochrane Collaboration standard scheme for bias
and ROBINS-­I tool
sensitivity (Knowles et al., 1986). This might be explained
by vascular alterations, as teeth that underwent radiation
might present significant vascular congestion (Madani
et al., 2017), and 2 Gy seems to be enough to destroy even
small capillaries (Dimitrievich et al., 1984). This could lead
to ischemia, a consequent reduction in pulpal blood flow
(PBF), and a considerable decrease in the elimination of
metabolites, or no elimination at all (Madani et al., 2017).
All these events should lead to a state similar to anoxia,
which inhibits myelinated fibres (Ahlquist & Franzén,
1999; Kim, 1990; Madani et al., 2017) and affects pulp re-
sponses to cold and electrical tests.
Another theory has also been associated with radiation-­
induced changes in blood vessels (Gupta et al., 2018).
Currently, available evidence indicates that pulpal inflam-
mation leads to increased tissue pressure, which has been
associated with increased sensory nerve activity (Kim,
WEISSHEIMER et al.
1990; Närhi, 1978). Increased blood flow and the resulting
tissue pressure excite A-­delta and C fibres, whereas flow
reduction may inhibit A-­delta fibres (Närhi, 1978). There
seems to be a 50% blood flow decrease 4 months after ra-
diotherapy, and only 75% is restored after 1 year (Knowles
et al., 1986). This has raised speculations about whether
A-­delta fibres might lose their conduction capacity as a
reaction to ischemia (Dionne et al., 2015), which might
explain the changes in responses found in the studies in-
cluded in this review (Garg et al., 2015; Gupta et al., 2018;
Kataoka et al., 2011, 2012).
The results of the studies that assessed pulp SpO2
(Daveshwar et al., 2021; Kataoka et al., 2011) corrobo-
rate this vascular hypothesis. Although a meta-­analysis
was not possible for these tests, pulp SpO2 was signifi-
cantly lower at the completion of radiotherapy (75.12%
-­ Daveshwar et al., 2021; 77% -­ Kataoka et al., 2011) than
before treatment initiation (93.6% -­ Daveshwar et al., 2021;
93% -­ Kataoka et al., 2011). Although values of pulp SpO2
were close to those found in pulp necrosis (Setzer et al.,
2012), the dental pulp also had a reactive potential. Four to
six months after radiotherapy started, the dental pulp had
similar SpO2 values (81.04% -­ Daveshwar et al., 2021; 85%
-­ Kataoka et al., 2011) to those seen right after treatment
initiation (83%; Kataoka et al., 2011). Additionally, when
dental pulp SpO2 was evaluated 4–­6 years after treatment,
the values (92.7%  ±  1.83) were similar to those of pa-
tients without any history of radiotherapy (92.6% ± 1.80;
Kataoka et al., 2016a), which might suggest that PBF
changes are temporary. These results are in agreement
with those reported in a previous study, which found that
PBF is restored to 75% 1 year after radiotherapy (Knowles
et al., 1986).
As the objective of the studies reviewed here was to
evaluate the effects of head and neck radiotherapy on the
dental pulp, the radiation field was a critical factor in the
analysis of responses. Gupta et al. (2018) found a signifi-
cant correlation between the maximum dose received by
each tooth and the change in response at all time points
after radiotherapy. The study conducted by Gupta et al.
(2018) was the only one that examined the radiation field
in this review, but its method assessed the response of
one tooth per quadrant regardless of the radiation tar-
get area (Gupta et al., 2018). In radiotherapy, the closer
to the target area, the higher the radiation dose the tis-
sue will receive. Other studies about oral side effects of
radiotherapy, which included oral mucositis, changes in
the salivary glands that lead to hyposalivation, and os-
teoradionecrosis, have also revealed that the effects of
higher radiation doses are significantly worse (Al-­Ansari
et al., 2015; Harada et al., 2016; Jensen & Peterson, 2014;
Kataoka et al., 2016b; Nabil & Samman, 2011; Tao et al.,
2017). Therefore, further studies should evaluate teeth
     |  573
within the radiation field and those that are out of the
field or more distant separately. Apart from that, stud-
ies should consistently mention the radiation technique
used, whether it was IMRT, 3D, or any other, because that
also has an effect on oral complications (Sharma & Bahl,
2020). In this review, four studies described which radia-
tion technique was used (Garg et al., 2015; Gupta et al.,
2018; Kataoka et al., 2012, 2016a). Currently, IMRT is the
preferred technique, with significantly better outcomes
for salivary gland dysfunction, dysphagia, and quality of
life domains such as swallowing, mouth opening, and so-
cial eating (Sharma & Bahl, 2020).
In this systematic review, six studies (Daveshwar et al.
2021; Garg et al., 2015; Gupta et al., 2018; Kataoka et al.,
2011, 2012, 2016a) were included and assessed for their
risk of bias, which was found to be moderate (Kataoka
et al., 2016a) to serious (Daveshwar et al., 2021; Kataoka
et al., 2011, 2012; Garg et al., 2015; Gupta et al., 2018)
overall. All studies (Daveshwar et al., 2021; Garg et al.,
2015; Gupta et al., 2018; Kataoka et al., 2011, 2012, 2016a)
partially controlled for confounding factors. Although
controlling for all possible confounding factors is meth-
odologically challenging, none of the studies reported on
important confounding factors, such as radiation caries
(Gupta et al., 2015), which might affect the dental pulp
(Hommez et al., 2012). For this reason, studies were classi-
fied as having a moderate risk in the domain of controlling
for confounding factors. In the domain classification of
interventions, the description of three parameters—­total
radiation doses, radiotherapy treatment method, and de-
scription of the irradiated field—­were included in the
assessment of the risk of bias. These radiotherapy param-
eters were chosen based on systematic reviews of studies
about osteoradionecrosis that have described total dose,
radiotherapy technique, and irradiation field as essential
parameters for the study of side effects of head and neck
radiotherapy on the jaws (Beaumont et al., 2021; Beech
et al., 2017). In this domain, four studies (Garg et al.,
2015; Gupta et al., 2018; Kataoka et al., 2012, 2016a) had
a moderate risk, and two studies (Daveshwar et al., 2021;
Kataoka et al., 2011), a serious risk of bias. In the domain
measurement of outcomes, three studies had a low risk of
bias (Daveshwar et al., 2021; Kataoka et al., 2011, 2016a),
and three studies had a serious risk of bias (Kataoka et al.,
2012; Garg et al., 2015; Gupta et al. 2018), because they
only used sensitivity tests to evaluate the pulp status. All
studies had a low risk of bias in the other domains.
As bias for confounding factors and for classification of
interventions was found in all studies (Daveshwar et al.,
2021; Garg et al., 2015; Gupta et al., 2018; Kataoka et al.,
2011, 2012, 2016a), the domain risk of bias was classified
as serious (Guyatt et al., 2011b). As the meta-­analysis
found that some studies had a high heterogeneity (Garg
 |
574       RADIOTHERAPY EFFECTS ON THE DENTAL PULP RESPONSES

F I G U R E 3   Forest plot of negative dental pulp responses to cold thermal test before and immediately after radiotherapy

F I G U R E 4   Forest plot of negative dental pulp responses to cold thermal test before and 4–­5 months after radiotherapy

F I G U R E 5   Forest plot of dental pulp responses to electrical test per quadrant before and immediately after radiotherapy

et al., 2015; Gupta et al., 2018), the domain inconsistency
was downgraded and classified as serious (Guyatt et al.,
2011c). The domain for indirectness was classified as not
serious because all studies directly compared the inter-
vention with the population of interest (Guyatt et al.,
2011d). In the domain for imprecision, optimal infor-
mation size were met, with the total number of events
higher than 300. However, confidence interval variation
was under 0.75, and this domain was, thus, classified as
serious (Guyatt et al., 2011e). The initial GRADE cer-
tainty of evidence should be classified as high for studies
in which the ROBINS-­I tool is applied, and downgraded
afterwards, if necessary, because selection bias and
confounding are already part of this tool (Schünemann
et al., 2019).
The domain for other considerations had a strong asso-
ciation between effect and dose–­response gradient, which
upgraded the certainty of the evidence. Although upgrad-
ing due to a strong association of effect is usually a result
of the methodological quality of the studies, rating up
the certainty of the evidence has also been recommended
when there is a large magnitude of intervention effect and
considerable confidence about the impact of interventions
on the outcomes (Guyatt et al., 2011f). Four studies (Garg
et al., 2015; Gupta et al., 2018; Kataoka et al., 2011, 2012)
have found changes in dental pulp response immediately
WEISSHEIMER et al.
T A B L E 2   Certainty of the evidence from included studies
Certainty assessment
Number of
studies Risk of bias Inconsistency
6 Observational Seriousa Seriousb
studies
a
All studies had a bias for confounding factors and in the classification of intervention.
b
High heterogeneity (I2 = 68%) for some studies.
c
Although optimal information size criteria were met (total number of events higher than 300), confidence interval variation was under 0.75.
after the initiation of a treatment, which suggests that
there may be a strong association of effect. Some studies in
the literature have discussed whether the dose–­response
gradient-­domain may increase the confidence in the find-
ings and, therefore, upgrade the assigned certainty of the
evidence (Guyatt et al., 2011f). This possible association
between radiation doses and oral complications has been
raised in previous studies (Hommez et al., 2012; Kielbassa
et al., 2006). Moreover, according to the results of four of
the studies included (Garg et al., 2015; Gupta et al., 2018;
Kataoka et al., 2011, 2012), the higher the radiation doses,
the more changes in pulp responses. This suggests that
there may be a dose-­response association, which should
upgrade the certainty of the evidence. Therefore, in the
current systematic review, an overall moderate certainty
of the evidence was demonstrated.
The strength of this systematic review is its systematic
approach to data collection, based on a protocol registered
a priori. All studies included were cautiously analysed to
provide solid evidence about the topic under analysis. In
contrast, the main limitation of this study was the impos-
sibility to determine the time at which the normal pulp
response to cold and electrical tests is back to normal.
Only one study reported that 4–­6 years after the comple-
tion of radiotherapy the pulp responded positively to cold
thermal tests (Kataoka et al., 2016a). In addition, no study
provided information about the return of electrical test
readings to normal. Therefore, it is impossible to deter-
mine whether responses to this test are ever normal again.
Another limitation is that one study (Garg et al., 2015) re-
ported simultaneous chemo-­ and radiotherapy, including
patients that underwent both to treat HNC concurrently.
To the best of our knowledge, there is no scientific evi-
dence of the effects of chemotherapy alone on the den-
tal pulp. For this reason, determining to which extent the
results obtained by Garg et al. (2015) were influenced or
not by chemotherapy is challenging. In addition, none of
the studies reported on the occurrence of radiation caries.
Therefore, it is impossible to determine whether this con-
dition affected pulp response to radiotherapy.
Overall, this review demonstrated that a sensitivity
loss occurs, but radiotherapy does not seem to cause
     |  575
Overall certainty
Indirectness Imprecision Other considerations of evidence
Not serious Seriousc Strong association ⨁⨁⨁◯
Dose–­response gradient MODERATE
irreversible changes to the dental pulp. Importantly,
cold sensitivity and electrical tests only evaluate the
neural response of the pulp, and their accuracy is low
to moderate when assessing pulp necrosis (Mainkar &
Kim, 2018). Therefore, these tests should be used with
caution when assessing the pulp status of patients un-
dergoing radiotherapy. Clinicians must be aware of pulp
necrosis signs and/or symptoms to determine irrevers-
ible changes that may establish a diagnosis. If more
accurate diagnostic tests, such as laser Doppler flowm-
etry and pulse oximetry (Mainkar & Kim, 2018), are not
available, patients should be followed up closely until
pulp response is back to normal.
This systematic review clearly points to a demand for
studies with a stricter control for confounders and a better
description of interventions. Meanwhile, it is not possible
to define whether radiotherapy induces pulp necrosis.
Further studies using reliable methods to assess pulp sta-
tus, such as pulse oximetry and laser Doppler flowmetry,
should be conducted to answer the question that guided
this review. In addition, cold and electrical tests should be
used with caution when assessing pulp necrosis, a diagno-
sis that can only be made using more accurate diagnostic
tests, such as pulse oximetry and laser Doppler flowmetry,
as well as the observation of other clinical signs and symp-
toms of pulp necrosis.
CONCLUSION
Although there are consistently negative responses to cold
and electrical tests, these tests are not accurate enough to
determine necrotic pulp status. In addition, studies that
use pulse oximetry to determine pulp status have not
found significant changes. Therefore, these findings, as
well as the moderate certainty of the evidence, should
not lead to the conclusion that radiotherapy to treat HNC
causes pulp necrosis.
CONFLICT OF INTEREST
The authors deny any conflicts of interest related to this
study.
 |
576       RADIOTHERAPY EFFECTS ON THE DENTAL PULP RESPONSES
ETHICAL APPROVAL
The study did not require ethical approval.
AUTHOR CONTRIBUTION
Study conception and design –­ TW, BBS, MCP, JAPF,
MDM, MVRS; Material Preparation, data collection and
analysis –­ TW, BBS, MCP; First draft of manuscript –­ TW,
BBS; Revision drafting and final approval of manuscript
–­ MCP, JAPF, MDM, MVRS.
ORCID
Theodoro Weissheimer  https://orcid.
org/0000-0001-6810-1877
Bruna Barcelos Só  https://orcid.
org/0000-0002-8144-9760
Marieli Chitolina Pradebon  https://orcid.
org/0000-0002-2910-3498
José Antonio Poli de Figueiredo  https://orcid.
org/0000-0002-8113-9260
Manoela Domingues Martins  https://orcid.
org/0000-0001-8662-5965
Marcus Vinicius Reis Só  https://orcid.
org/0000-0002-1393-5900
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SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of the article at the publisher’s website.
How to cite this article: Weissheimer, T., Só, B.B.,
Pradebon, M.C., de Figueiredo, J.A.P., Martins, M.D.
& Só, M.V.R. (2022) Head and neck radiotherapy
effects on the dental pulp vitality and response to
sensitivity tests: A systematic review with meta-­
analysis. International Endodontic Journal, 55,
563–­578. Available from: https://doi.org/10.1111/
iej.13726