TOOTH EXTRACTION BEFORE RADIOTHERAPY IS A RISK

FACTOR FOR DEVELOPING OSTEORADIONECROSIS OF THE

JAWS: A SYSTEMATIC REVIEW
carlo lajolo, gioele gioco, cosimo rupe, giuseppe troiano, massimo cordaro, alberta lucchese, gaetano paludetti,
michele giuliani

Head and Neck Department, Fondazione Policlinico Universitario A. Gemelli IRCCS,

Roma, Università Cattolica del Sacro Cuore, Rome, Italy

PRESENTED BY: Dr. SANJITIMADAN

MODERATOR: Dr. ABHISHEK MOTIMATH
 ABSTRACT
Objectives: The aim of this Systematic Review is to estimate the osteoradionecrosis rate in patients with head
and neck cancer due to teeth extraction performed before radiotherapy and to identify possible risk factors.

Material and Methods: PRISMA protocol was used to evaluate and present the results. PubMed, Scopus, and
Web of Science were used as search engines: English full-length papers of clinical studies, in peer-reviewed
journals, were investigated. Cumulative meta-analysis was performed with a random effects model. PROSPERO
registration code: CRD42018079986.

Results: Among 2,020 records screened, 8 were included in this review. Sixteen of 494 patients who underwent
tooth extraction before radiotherapy developed osteoradionecrosis, with an osteoradionecrosis incidence of
2.2% (95% Confidence of Interval = 0.6-3.9, p.<0.185, I^2=3044%). All cases were reported in the mandible. No
other clinical risk factor for osteoradionecrosis was detected.

Conclusions: Even if it is generally recommended to remove oral foci before radiotherapy, this systematic review
confirmed that teeth extractions before radiotherapy represent a risk factor for osteoradionecrosis; the
considerable amount of missing data prevented us from identifying other possible risk factors for
osteoradionecrosis onset. Major efforts should be done to perform sounder methodological clinical
investigations.
 INTRODUCTION
• Radiotherapy (RT) has gained a fundamental role in the treatment of head and neck
cancers, and nearly 75% of all these patients undergo this therapy, either with curative,
adjuvant, or palliative indication (Ratko, Douglas, de Souza, Belinson, & Aronson, 2014).
• Unfortunately, RT may cause acute and/or late onset side effects on oral and
maxillofacial tissues, especially when combined with chemotherapy, which significantly
affects quality of life and could be life-threatening (Kielbassa, Hinkelbein, Hellwig, &
Meyer-Lückel, 2006) (Dong, et al., 2017)
• Osteoradionecrosis (ORN) of the jaws was first described by Regaud in 1922 (Regaud,
1922), and it represents the most severe late onset side effect of RT. Many
classifications have been proposed since it was identified as a disease, but today, there
is no agreement among clinicians on which should be systematically adopted
(Chronopoulos, Zarra, Ehrenfeld, & Otto, 2018).
• In any case, according to the most recent literature, it consists of exposed irradiated bone
that fails to heal over a period of 3 months without evidence of persisting or recurrent
tumour (Chronopoulos, et al., 2018).
• Nevertheless, the current definition does not clarify all aspects, for example, the
possibility of developing ORN without bone exposure and the time-lapse of bone
exposure necessary to make a diagnosis, which can vary from 1 to 6 months, according to
the literature (Marx, 1983) (Epstein, Rea, Wong, Spinelli, & Stevenson-Moore, 1987).
• Furthermore, the reported incidence of ORN is between 2% to 22% of patients exposed
to irradiation, according to different studied populations and to different diagnostic
parameters (Ben-David, et al., 2007) (Beumer, Harrison, Sanders, & Kurrasch, 1983).
• Although ORN pathogenesis remains unclear, both hypovascularity (an impaired blood
supply, thrombosis, hypoxia) and hypocellularity (decreased osteoblasts and osteoclasts)
resulting in a fibroatrophic process (Marx, 1983) (Delanian & Lefaix, 2004) seem to play a
key role in its development, especially in the case of traumatic events, among which
tooth extractions are the most common.
• Considering oral risk factors, a thorough dental examination and the removal of oral
foci are generally recommended before starting RT, to minimise the risk of ORN: the
removal of oral foci before RT, taking advantage of the normal bone healing capability,
seems to reduce ORN onset (Epstein, et al., 1987)
• Furthermore, the possible progression of untreated dental diseases, whenever not
treated before RT, together with RT oral effects (e.g. hyposalivation, radiation caries,
trismus), can increase post-RT dental extractions and enhance the risk of ORN
development, due to the impaired bone response to trauma (Koga, Salvajoli, & Alves,
2008).
• However, some authors have claimed that pre-RT extractions may also increase the
risk of developing ORN (Wahl, 2006) and the results of a recent Cochrane review were
not satisfactory on this topic because no randomised controlled trials have evaluated
the impact of dental extraction before RT on ORN development (Eliyas, Al-Khayatt,
Porter, & Briggs, 2013).
Pre-RT dental management is mainly based on expert opinions and subjective
clinical experience, more than on sound evidence-based data; particularly, some
main issues are still debated:
1) the lack of decision-making algorithms on questionable teeth,
2) what adjuvant clinical protocols (i.e. antibiotic, chlorhexidine) could help
prevent ORN onset, and
3) which is the most favourable time-lapse before the beginning of RT
AIM
(i) To estimate the ORN rate in patients with head and neck cancer undergoing
tooth extraction before RT
(ii) Which clinical protocol would result in a lower osteoradionecrosis incidence
(iii) What is the suggested time-lapse before radiotherapy to prevent
osteoradionecrosis due to teeth extraction
(iv) What variable, except for tooth extraction, could mainly contribute to ORN
onset
 METHODS
INCLUSION CRITERIA
1. Inclusion criteria were full papers;
2. English literature published after 1978;
3. Observational clinical studies, namely, prospective and retrospective (cohort and case-
control) and randomised clinical trials (RCTs);
4. Patients who received RT in H&N district for H&N cancer, according to the eighth edition of
the American Joint Committee on Cancer (AJCC) Staging Manual: tumors which arise in the
mucosal surfaces of the upper aerodigestive tract, tumors of the major and minor salivary
glands and nonmelanoma skin cancer (Lydiatt, et al., 2017);
5. Minimum sample size of 10 patients who underwent tooth extractions prior to radiotherapy;
6. Mean 6 months follow-up after RT;
7. Bone exposure at the extraction site for at least 3 months
EXCLUSION CRITERIA

1. Exclusion criteria were case reports, reviews, cross-sectional studies, studies in

which no clear definition of ORN was reported, and studies not specifying
whether ORN developed at the extraction site.
2. Studies on therapies of ORN patients were included only if the ORN was
effectively due to dental extractions and the total number of patients receiving
tooth extractions was clearly stated.
3. Studies without a clear definition of ORN were excluded to avoid the risk of false
positives or negatives, namely, at least 3 months of exposed bone was the
minimum follow-up period for the diagnosis of ORN.
SEARCH STRATEGY
The PubMed, Scopus, and ISI Web of Science databases were searched to identify
the available clinical studies on ORN development in patients who underwent tooth
extraction prior to RT for head and neck cancer, from January 1978 to September
2018
DATA EXTRACTION
• Data regarding the characteristics of the included studies (i.e. general information
of the studies, number of participants, diagnostic criteria of ORN, demographic
characteristics, ORN data, other population-related factors)
• and specific information regarding patients who underwent tooth extractions (i.e.
patient data, tooth extraction data, extraction-related ORN) were extrapolated
and entered in an ad hoc extraction sheet.
• Missing data were not estimated and thus not included in the analysis
ASSESSMENT OF RISK OF BIAS IN THE INCLUDED STUDIES
The quality of the included studies was assessed by 2 reviewers (C.R. and C.L.) who
used the Cochrane’s tool for the same.
RESULTS
• This review retrieved 1,249 patients affected by head and neck cancer, among
whom 494 underwent tooth extractions prior to RT; among these, 16 cases of
ORN were observed in 16 patients (mean follow-up: 30.6 months), with an overall
ORN risk of 2.2%
• Considering the specific clinical characteristics of patients who developed ORN,
only scattered information could be gathered from the selected articles: all
reported cases of ORN were in the mandible
• In Morrish et al. (1981), 19 patients received tooth extractions before radiotherapy. After 6
months of follow-up, no ORN was diagnosed.
•  In Epstein et al. (1987), 92 patients received a total of 454 tooth extractions before
radiotherapy. The mean time between tooth extractions and the beginning of radiotherapy
was 26 days. After a mean 60 months follow-up, 5 ORN cases were diagnosed. The onset
time of ORN varied between 3 and 100 days after tooth extraction, with a mean time of 43
days.
• In Oh et al. (2004), 55 patients underwent a total of 99 tooth extractions before
radiotherapy. All teeth extracted were third molars. The mean time between tooth
extractions and the beginning of radiotherapy was 32.4 days. After a median of 33.5 months
follow-up, 2 ORN cases were diagnosed. Both ORN developed after the extraction of a
mandibular third molar. The mean onset time of ORN was 3 months after tooth extraction.
• In Ben-David et al. (2007), 30 patients received tooth extractions before radiotherapy. The
mean time between tooth extractions and the beginning of radiotherapy was 14 days. After a
mean 35 months follow-up, no ORN was diagnosed
• In Schuurhuis et al. (2011), 56 patients received a total of 431 tooth extractions
before radiotherapy. After a 26 months median follow-up, 4 ORN cases were
diagnosed. The mean onset time of ORN was 13.5 months after tooth extraction
• In Batstone et al. (2012), 22 patients received tooth extractions before
radiotherapy. All patients received 2 extractions in the posterior mandible, in a
split-mouth design. One site was treated using platelet-rich plasma (PRP) to fill
the socket after tooth extraction, and the other side received no additional
treatment after tooth extraction. The mean time between tooth extractions and
the beginning of radiotherapy was 34 days. After a 12 months follow- up, 4 ORN
cases were diagnosed.
• In Kojima et al. (2017), 132 patients received tooth extractions before
radiotherapy. After a follow-up of at least 12 months, 1 ORN case was diagnosed.
• In Moon et al. (2017), 88 patients received tooth extractions before
radiotherapy. After a mean 25 months follow-up, 1 ORN case was diagnosed.
 RISK FACTOR ANALYSIS
• Site: Mandibular teeth extractions seem to be linked to an increased risk of ORN.
Notably, in this systematic review, all ORN cases due to tooth extractions developed in
the mandible.
• Surgical technique: The surgical technique used to perform a tooth extraction before
RT may be at risk of development of ORN. The included studies did not provide
sufficient information on the surgical technique. However, in the studies by Oh et al.,
(2004) and Batstone et al., (2012), all teeth extractions (i.e. wisdom teeth and
mandibular molars) were performed with the elevation of a mucosal flap. The ORN
rate obtained by these authors (3.6% and 13.6% respectively) was higher than the
mean of this systematic review.
• LIMITATION- The sample size was small (55 and 22 patients), and often, wisdom tooth
extractions can be more traumatic (osteotomy is sometimes performed)
• Peri-operative supportive medical care: Although the role of bacteria in the ORN
pathogenesis remains unclear, many studies have demonstrated that the bacterial
contamination of an ORN site can hinder the healing process.
• Epstein et al., (1987) and Oh et al., (2004) have prescribed antibiotic prophylaxis to
prevent the infection of the surgical site; on the contrary of what could be expected, the
ORN rate found in these articles was higher than the mean of this systematic review,
notwithstanding the sample size was too small to draw definitive conclusions. No data
were available regarding chlorhexidine.
• Reasons for tooth extraction: These reasons are crucial because it is unclear if the
extraction of teeth affected by an inflammatory-infectious process results in an increased
risk of ORN compared with the extraction of teeth with a healthy periodontium.
• Therefore, an important clarification is if the pre-RT extractions of the teeth affected by
different diseases could result in different risks of developing ORN.
• In this systematic review, the only clear data available have been extrapolated from the
studies by Oh et al., (2004), Batstone et al. (2012) and Kojima et al. (2017). According to
their results, the prophylactic extraction of healthy teeth slightly increases the risk of
ORN onset and does not reduce it.
• Kojima et al. (2017) found out a Hazard Ratio (HR) of 5.13% for teeth affected by
periapical periodontitis at pre-RT.
• The authors found out that periapical periodontitis is an independent risk factor for ORN
development.
• Time interval between tooth extraction and start of RT: This systematic review
highlights the absence of controlled studies for this variable, making the analysis
of the effective role played by this factor on ORN onset impossible. To reduce the
healing time, Batstone et al., (2012), in their split-mouth randomised control
study, added PRP to half of the sockets. This measure did not reduce the risk of
ORN; by contrast, the ORN rate was higher among the PRP group.
DISCUSSION
• The treatment of ORN is somehow difficult, frustrating, and time-consuming;
thus, for years, a prevention strategy has been considered crucial for the quality
of life of patients who undergo radiotherapy.
• Many risk factors have been demonstrated in ORN onset, although their role has
not been completely clarified.
• In general, the clinical recommendation is to remove dental foci before the
radiotherapy starts (Merlotti, et al., 2014): notably, the flare-up of a dental
disease, especially an odontogenic abscess, could heavily interfere with radiation
therapy schedule, potentially reducing the survival rate of these patients
(Thomas, et al., 2017).
• For this reason, tooth extractions are often recommended before RT, but only
limited information is available on surgical protocols and on the time-lapse before
the beginning of RT (Wahl, 2006).
• Considering the above-mentioned risk factors, clear conclusions cannot be drawn
for the majority of them.
• Nevertheless, the site of tooth extraction and reason for tooth extraction seem to
be the most relevant. Even if few studies state the exact location of the extractions,
mandible is by far more affected by ORN than maxilla: the higher bone density
(Misch, 1990) and the lower vascular support of the mandible (Bras, de Jonge, &
van Merkesteyn, 1990) could explain the difference in ORN rate between maxilla
and mandible.
• Although the reason for tooth extraction seems to be a relevant risk factor for
ORN development, as highlighted by Kojima et al. (2017), the role of a careful
management of the post-extractive socket should not be underestimated.
• In this light, non-surgical tooth extraction is usually less invasive, but the elevation
of a mucoperiosteal flap allows the clinician to easily achieve a primary intention
closure and to perform a bone remodelling, when necessary.
• The time-lapse between extraction and the beginning of RT is another debated
risk factor: in order to reduce the risk of ORN, the post-extractive site should heal
completely.
• Nevertheless, the healing of alveolar bone is a complex remodelling process,
continuing even longer than 3 months (Cardaropoli, Araujo, & Lindhe, 2003) and,
although it seems reasonable to believe that widening the time-lapse between
tooth extraction and the beginning of RT may lead to a risk reduction, this time-
lapse is far too long for oncologic patients.
• Furthermore, only a few studies specified the time of occurrence of the ORN. In
the study by Oh et al., (2004) the ORN was diagnosed after a mean time of 3
months after RT. In studies by Kojima et al., (2017) and Moon et al., (2017) they
reported ORN cases diagnosed after 30 and 40 months after radiotherapy at the
extraction site. Hence, studies with a longer follow-up would be necessary to
clearly define the ORN rate following teeth extractions
• Another clinical consideration should be made on data concerning oral hygiene
status of patients undergoing tooth extractions before RT. None of the studies
included in this systematic review take into proper consideration this variable:
Schuurhuis et al.(2011) suggest periodontal disease as a possible risk factor for
ORN development, but Full Mouth Plaque Score and Bleeding Score were not
always recorded for these patients.
• Future studies should record the oral hygiene level of patients undergoing tooth
extractions in order to clarify this topic.
CONCLUSION AND LIMITATIONS
• Systematic review confirmed that teeth extractions represent a risk
factor for ORN development.
• The analysed literature was unable to provide information on the
other possible risk factors for the ORN onset (i.e. tumour site,
comorbidities or other oncologic therapies).
• No decision-making algorithm can be drawn based on the studied
literature to determine which specific dental disease is more suitable
to cause ORN, which is the suitable time-lapse before starting the RT
and which surgical extraction protocol or Peri-operative supportive
medical care could help to reduce ORN.
SUPPORTING ARTICLE
CRITICAL APPRAISAL
• TITLE: Appropriate
• ABSTRACT: Well structured
• TEXT: Well written
• DATA ANALYSIS: done using appropriate tools
• DISCUSSION: Well written
• REFERENCING: authors followed Vancouver style, number of
references were judicious and appropriate
THANK YOU