dentistry journal

Article
Prophylactic Use of Pentoxifylline and Tocopherol for Prevention
of Osteoradionecrosis of the Jaw after Dental Extraction in
Post-Radiated Oral and Oropharyngeal Cancer Patients: An
Initial Case Series
Adepitan A. Owosho 1, * , Katherine A. DeColibus 2 , Osariemen Okhuaihesuyi 3 and Layne C. Levy 4

1 Department of Diagnostic Sciences, College of Dentistry/Department of Otolaryngology—Head & Neck

Surgery, College of Medicine, The University of Tennessee Health Sciences Center, 875 Union Avenue,
Memphis, TN 38163, USA
2 Department of Diagnostic Sciences, College of Dentistry, The University of Tennessee Health Sciences Center,
Memphis, TN 38163, USA
3 Missouri School of Dentistry and Oral Health, A.T. Still University, Kirksville, MO 63501, USA
4 Advanced Education in General Dentistry, College of Dentistry, The University of Tennessee Health Sciences
Center, Memphis, TN 38163, USA
* Correspondence: [email protected]

Abstract: Osteoradionecrosis of the jaw is a morbid complication of radiotherapy in patients with

oral and oropharyngeal cancers that may be precipitated by dental extractions. Pentoxifylline and
tocopherol (PENTO) has been utilized in the management of osteoradionecrosis and as prophylaxis
for post-radiated head and neck oncology patients requiring an invasive dental procedure. This
observational study aims to report the outcome of the prophylactic use of PENTO in the prevention of
osteoradionecrosis of the jaw after dental extractions in post-radiated oral and oropharyngeal cancer
patients and to review the current literature on this topic. Four post-radiated oral and oropharyngeal
oncology patients were referred to the dental oncology clinic of the University Dental Practice, Uni-
Citation: Owosho, A.A.; DeColibus, versity of Tennessee Health Sciences Center for dental extractions. All four patients were prescribed
K.A.; Okhuaihesuyi, O.; Levy, L.C. pentoxifylline 400 mg BID (twice a day) and tocopherol 400 IU BID (oral tablets) for 2 weeks before
Prophylactic Use of Pentoxifylline and extraction(s) and for 6 weeks after extraction(s). All patients were followed up every week after the
Tocopherol for Prevention of second week post-extraction if feasible until the extraction site(s) healed (covered by mucosa). The
Osteoradionecrosis of the Jaw after assessment endpoint was defined as 6 weeks post-extraction with the outcomes assessed as using four
Dental Extraction in Post-Radiated Oral categories determined by the area of exposed bone: complete healing (complete mucosal coverage
and Oropharyngeal Cancer Patients:
of extraction site); partial healing (reduction in size of extraction site); no change; and progression
An Initial Case Series. Dent. J. 2024, 12,
(increase in size of the extraction site). At the assessment endpoint, all patients had complete healing
83. https://doi.org/10.3390/
of all extraction sites. The ORN rate at the patient level (0/4) and individual tooth level (0/8) was 0%.
dj12040083
All patients tolerated the PENTO medications and no adverse effects from the use of these medica-
Academic Editor: Claude Jaquiéry tions were reported. This limited study in addition to the other reviewed studies estimates the rate of
Received: 16 February 2024
ORN at the patient level as 3.2% (14/436) for post-radiated head and neck oncology patients after
Revised: 13 March 2024 dental extractions/invasive oral procedures. In conclusion, this PENTO regimen can reduce/prevent
Accepted: 21 March 2024 the incidence of ORN in post-radiated head and neck oncology patients. This safe and cost-effective
Published: 22 March 2024 protocol (PENTO regimen) should be further evaluated as prophylaxis for post-radiated head and
neck oncology patients requiring an invasive dental procedure. We recommend large prospective
studies to be carried out to further validate these findings.

Copyright: © 2024 by the authors.

Keywords: osteoradionecrosis; radiation therapy; radiotherapy; jaw; oral cancer; oropharyngeal
Licensee MDPI, Basel, Switzerland.
cancer; pentoxifylline; vitamin E
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).

Dent. J. 2024, 12, 83. https://doi.org/10.3390/dj12040083 https://www.mdpi.com/journal/dentistry

Dent. J. 2024, 12, 83 2 of 13

1. Introduction
In the year 2024, an estimated 58,450 individuals will be diagnosed with oral and
pharyngeal cancer in the United States (U.S.) [1], a majority of which will be squamous cell
carcinoma. Over 70% of these new cases occur in males and it is the eighth most common
newly diagnosed malignancy in males [1]. The primary etiologies for these cancers are
tobacco smoking and human papillomavirus (HPV), and the incidence of HPV-related
oropharyngeal cancers is on the rise [2]. Approximately 70% of new oral and pharyngeal
cancer cases are diagnosed at a late stage [3], thereby warranting the use of radiotherapy
either as neoadjuvant or adjuvant therapy in combination with other therapeutic modalities
such as surgery and chemotherapy. Oral and pharyngeal cancer patients typically receive
radiation doses up to 60–70 Gy. Even with advanced radiation delivery techniques such
as intensity-modulated radiation therapy (IMRT) and proton therapy, enabling improved
tumor dose conformality and tissue/organ sparing capability, oral complications such as
xerostomia, caries, trismus, and osteoradionecrosis (ORN) still exist [4–8].
Post-radiation oral and oropharyngeal cancer patients are prone to developing ram-
pant dental caries secondary to xerostomia (Figure 1), inadequate quality/buffering action
of saliva, and trismus which interferes with keeping good oral hygiene. This may result in
non-restorable teeth, thereby requiring dental extractions. Tooth extraction/dentoalveolar
surgery (trauma) are considered major risk factors for the development of ORN [9,10].
Other risk factors are radiation dose > 60 Gy, poor oral hygiene, tobacco smoking, and
alcohol use [11–13]. ORN, a morbid complication of radiotherapy to the head and neck, is
defined as an area of exposed necrotic bone in a previously irradiated area that does not
heal over a period of 3–6 months [14]. Radiation to the jaw bone results in a decrease in
vascularity resulting in hypoxia, hypovascularity, and hypocellularity [14]. These have been
described as etiological factors in the development of ORN. The reported prevalence of
ORN varies widely from 0.4 to 56% [15]. However, in the era of IMRT, 4.3–6.8% of patients
who had radiation therapy using IMRT modality in the treatment of oral and oropharyngeal
cancer developed ORN [11–13]. A recent study found the prevalence of ORN in head and
neck cancer patients treated using proton therapy to be 10.6% (13/122) [7]. Although ORN
is a rare disease, its devastating effect on a patient’s quality of life is profound. To date, there
is no consensus on standard protocol for the management of ORN and emphasis has been
made on its prevention. The management approaches employed have historically been
wound care with chlorhexidine rinse; the use of antibiotic, pharmacologic management of
pain; passive removal of exposed necrotic bone when indicated; hyperbaric oxygen therapy;
and surgical treatment such as alveolectomy, maxillectomy, or segmental jaw resection
and reconstruction with bone graft/flap in severe cases [16–18]. The prevention of ORN
entails pre-radiation dental evaluation, prompt treatment of dental caries and periodontal
disease, and dental extraction of grossly carious and periodontally involved teeth with poor
prognosis. Invasive dental procedures should be completed not less than 2 weeks before
the commencement of radiation therapy [19,20]. However, in real-world experiences, many
post-radiation oral and pharyngeal cancer patients are faced with the need for extractions.
The risk of ORN post-extraction in an irradiated oral/pharynx cavity is lifelong [21,22].
Pentoxifylline and tocopherol (PENTO) are now used in the management of ORN
based on the new theory of radiation-induced fibrosis which states that the dysregulation
of fibroblastic activity is the critical event in the pathogenesis of ORN [23]. A therapeutic
regimen with PENTO (pentoxifylline 400 mg BID [twice daily] and tocopherol 400 IU BID)
for managing ORN has been developed, showing noteworthy results in managing ORN
(Figure 2). The study by Delanian et al. in 2011 reported the complete restoration and mu-
cosal healing in all fifty-four refractory mandibular osteoradionecrosis cases by prolonged
treatment with a pentoxifylline-tocopherol-clodronate combination in a phase II trial [24].
Subsequently, other studies have reported patients with complete mucosal coverage of
exposed bone after PENTO treatment, ranging from 16.6% to 86.6% [25]. Pentoxifylline a
methylxanthine derivative was originally approved by the U.S. Food and Drug Adminis-
tration for the management of peripheral artery disease, such as intermittent claudication.
Dent. J. 2024, 12, 83 3 of 13

Pentoxifylline improves peripheral blood flow by enhancing vasodilation, reduction in

blood viscosity, and increasing erythrocyte flexibility. It also reduces inflammation and
decreases fibrosis by inducing anti-tumor necrosis factor beta effects [26]. Tocopherol,
a potent oxygen radical scavenger, reduces free radical damage during oxidative
Dent. J. 2024, 12, x FOR PEER REVIEW 3 of stress,
15
thereby protecting cell membranes, reducing inflammation, and tissue fibrosis [26].

Figure
Dent. J. 2024, 12, xFigure
FOR PEER1. REVIEW
Post‐radiated oral cancer survivor presenting to the dental oncology clinic with rampant 4 of 1
1. Post-radiated oral cancer survivor presenting to the dental oncology clinic with rampant
dental caries.
dental caries.
Pentoxifylline and tocopherol (PENTO) are now used in the management of ORN
based on the new theory of radiation‐induced fibrosis which states that the dysregulation
of fibroblastic activity is the critical event in the pathogenesis of ORN [23]. A therapeutic
regimen with PENTO (pentoxifylline 400 mg BID [twice daily] and tocopherol 400 IU BID)
for managing ORN has been developed, showing noteworthy results in managing ORN
(Figure 2). The study by Delanian et al. in 2011 reported the complete restoration and
mucosal healing in all fifty‐four refractory mandibular osteoradionecrosis cases by pro‐
longed treatment with a pentoxifylline‐tocopherol‐clodronate combination in a phase II
trial [24]. Subsequently, other studies have reported patients with complete mucosal cov‐
erage of exposed bone after PENTO treatment, ranging from 16.6% to 86.6% [25]. Pentox‐
ifylline a methylxanthine derivative was originally approved by the U.S. Food and Drug
Administration for the management of peripheral artery disease, such as intermittent
claudication. Pentoxifylline improves peripheral blood flow by enhancing vasodilation,
reduction in blood viscosity, and increasing erythrocyte flexibility. It also reduces inflam‐
mation and decreases fibrosis by inducing anti‐tumor necrosis factor beta effects [26]. To‐
copherol, a potent oxygen radical scavenger, reduces free radical damage during oxida‐
tive stress, thereby protecting cell membranes, reducing inflammation, and tissue fibrosis
[26]. Figure 2.male
A 57‐year‐old male oral cancer survivor to
was referred
Figure 2. A 57-year-old oral cancer survivor was referred the dental to the dental
oncology oncology
clinic clinic for th
for the
management of osteoradionecrosis. (A) Osteoradionecrosis of the left alveolar ridge with expose
management of osteoradionecrosis. (A) Osteoradionecrosis of the left alveolar ridge with exposed
bone. (B) Area of exposed bone covered with mucosa after being on pentoxifylline and tocophero
bone. (B) Area offorexposed bone covered with mucosa after being on pentoxifylline and tocopherol
3 months.
for 3 months.
Given these findings, it has been hypothesized that the prophylactic use of PENTO
in irradiated oral and pharyngeal cancer patients needing dental extractions may improv
oral mucosa healing, therefore preventing ORN [27–30]. There are only five retrospectiv
case studies published on the prophylactic use of PENTO to prevent ORN: four studie
conducted in Europe, one study in India and none reported in the U.S. Across four retro
spective case studies that utilized PENTO in a tablet form, the ORN rate in patients wa
Dent. J. 2024, 12, 83 4 of 13

Given these findings, it has been hypothesized that the prophylactic use of PENTO in
irradiated oral and pharyngeal cancer patients needing dental extractions may improve
oral mucosa healing, therefore preventing ORN [27–30]. There are only five retrospective
case studies published on the prophylactic use of PENTO to prevent ORN: four studies
conducted in Europe, one study in India and none reported in the U.S. Across four ret-
rospective case studies that utilized PENTO in a tablet form, the ORN rate in patients
was 3.1% (12/387), and at the individual tooth level, it was 0.9% (11/1269) [31]. The fifth
study used a liquid formulation of pentoxifylline and tocopherol and the majority of the
patients (38/45) had only dental extractions carried out; the ORN rate in patients was 4.4%
(2/45) [32]. The two ORN patients eventually healed after continual use of PENTO for 19
and 44 months [32].
This observational study aims to report the outcome of the prophylactic use of PENTO
in the prevention of ORN of the jaw after dental extraction(s) in post-radiated oral and
oropharyngeal cancer patients.

2. Patients and Methods

This observational retrospective study was exempt from review by The University of
Tennessee Health Sciences Center (UTHSC) Institutional Review Board. Head and neck
oncology patients are routinely referred to the dental oncology clinic of the University
Dental Practice, UTHSC for pre- and post-radiation therapy dental management. In the
past 18 months, four post-radiated oral and oropharyngeal oncology patients who were
referred for dental management required dental extraction(s) (Figures 3 and 4). Patients
were duly informed about the possible risk of developing ORN of the jaw after dental
extractions and informed about the potential success of mitigating this risk with the use of
PENTO (pentoxifylline 400 mg BID and tocopherol 400 IU BID) oral tablets administered
prior to and continually after the extraction(s). The following medical conditions were
ruled out: uncontrolled diabetes mellitus, prior history of ORN or MRONJ, history of
stroke, ocular hemorrhage, kidney disease, liver disease, recent history of major surgery,
peptic ulcer, and anti-thrombotic (anti-coagulant and anti-platelet) medication use. The
following information was collected: Age and gender of the patient, tumor type, primary
tumor site, radiation dose to primary tumor site, number of tooth/teeth extracted, and
extracted tooth/teeth sites. In line with other studies [27,28,30], patients were categorized
as high, moderate, or low risk for ORN after dental extraction, based on the proximity
of the tooth to be extracted to the primary tumor/radiation field. High risk is defined
as extraction(s) on the same side as the primary tumor and within the radiation-planned
treatment volume. Moderate risk is defined as extraction(s) on the contralateral side of
the primary tumor and/or opposite jaw location. Low risk is defined as extraction(s) in
an area distant from the site of the primary tumor, for example, extraction of mandibular
molar(s) in a patient with a laryngeal tumor. All patients were prescribed pentoxifylline
400 mg BID and tocopherol 400 IU BID for 2 weeks before extraction(s) and for 6 weeks after
extraction(s). All patients signed informed consent and treatment waivers understanding
that the risk for ORN remains even with the prophylactic use of PENTO. Only one patient
was prescribed antibiotics for a week prior to dental extraction for the draining abscess,
all other patients were not given antibiotics. All procedures were simple extractions using
2% lidocaine with epinephrine 1:100,000, elevators, and forceps. No mucosal flap was
raised. Extraction site(s) were irrigated with chlorhexidine gluconate 0.12% oral rinse. All
patients were followed up every week after the second week post-extraction if feasible until
the extraction site(s) healed (covered by mucosa). The assessment endpoint was defined as
6 weeks post-extraction with the outcomes assessed using four categories determined by
the area of exposed bone: complete healing (complete mucosal coverage of extraction site);
partial healing (reduction in size of extraction site); no change; and progression (increase in
size of the extraction site).
 No mucosal flap was raised. Extraction site(s) were irrigated with chlorhexidine gluconate
0.12% oral rinse. All patients were followed up every week after the second week post‐
extraction if feasible until the extraction site(s) healed (covered by mucosa). The assess‐
ment endpoint was defined as 6 weeks post‐extraction with the outcomes assessed using
four categories determined by the area of exposed bone: complete healing (complete mu‐
Dent. J. 2024, 12, 83 5 of 13
cosal coverage of extraction site); partial healing (reduction in size of extraction site); no
change; and progression (increase in size of the extraction site).

Figure 3. A 69‐year‐old male patient managed with 70 Gy radiation therapy for his base of tongue
Figure 3. A 69-year-old male patient managed with 70 Gy radiation therapy for his base of tongue
squamous cell carcinoma (Case 1) was referred to the dental oncology clinic on account of a painful
squamous cell
tooth (#19) carcinoma
associated (Case
with 1) wasabscess.
a draining referredPatient
to thewas
dental oncology
prescribed clinic onfor
antibiotics account
a weekof a painful
prior to
tooth (#19)
dental
Dent. J. 2024, 12, x FOR PEER REVIEW associated
extraction with
for the a draining
draining abscess. Patient was prescribed antibiotics for a week
abscess. 6 ofprior
15 to
dental extraction for the draining abscess.

Figure 4. A 70‐year‐old male patient managed with 70 Gy radiation therapy for his right ventral
Figure
tongue A 70-year-old
4.and male
floor of mouth patient managed
squamous with(Case
cell carcinoma 70 Gy2)radiation therapy
was referred to thefor his right
dental ventral
oncology
tongue and floor of mouth squamous cell carcinoma (Case 2) was referred
clinic on account of painful teeth (#24, #25, #26, and #30) and oral rehabilitation.to the dental oncology
clinic on account of painful teeth (#24, #25, #26, and #30) and oral rehabilitation.
3. Results
Table 1 summarizes the clinical characteristics of the patients, tooth/teeth extracted,
and treatment outcomes. There were four patients (male n = 3, female n = 1; ages 59–75
years). Three patients were managed for squamous cell carcinomas (Cases 1–3) and one
patient for adenoid cystic carcinoma (Case 4). In two of the patients, the primary tumor
location was in the oral cavity (ventral tongue/floor of mouth and palate/maxillary sinus)
Dent. J. 2024, 12, 83 6 of 13

3. Results
Table 1 summarizes the clinical characteristics of the patients, tooth/teeth extracted, and
treatment outcomes. There were four patients (male n = 3, female n = 1; ages 59–75 years).
Three patients were managed for squamous cell carcinomas (Cases 1–3) and one patient
for adenoid cystic carcinoma (Case 4). In two of the patients, the primary tumor location
was in the oral cavity (ventral tongue/floor of mouth and palate/maxillary sinus) and
in the other patients, the primary tumor location was in the oropharynx (base of tongue
and tonsil). All patients received ≥ 66 Gy of radiation to the primary tumor site and were
Dent. J. 2024, 12, x FOR PEER REVIEW 7 of 15
all treated with IMRT. Two patients had one tooth extracted, one patient had two teeth
extracted, and one patient had four teeth extracted. Mandibular first molars were extracted
in three patients, mandibular second molars were extracted in one patient, and mandibular
incisors inTonsil (Oro‐ Two patients were classified as having a high risk for ORN after
one patient.
Squamous cell Mandibular First Complete Heal‐
3 F 59 dental extraction
pharynx)(Cases 1 and 2) and two were patients classified
70 Gy/(Yes) Moderateas having a moderate
carcinoma Molar (#19) ing
risk for ORN [Right]
after dental extraction (Cases 3 and 4). At the assessment endpoint at 6 weeks
post-extraction,
Hardall patients had complete healing of all extraction sites (Figures 5–7). The
pal‐
Mandibular Sec‐
ORN
Adenoid rate ate/Maxillary
cystic at the patient level (0/4) and individual tooth level (0/8) was 0%. All
Complete patients
Heal‐
4 M 75 66 Gy/(No) ond Molars (#18 Moderate
tolerated the
carcinoma PENTO
Sinus (Oralmedications and no adverse effects from the use of these medications
ing
and #31)
were reported.
Cavity) [Left]

Figure 5. A 69‐year‐old male patient managed with 70 Gy radiation therapy for his base of tongue
Figure 5. A 69-year-old male patient managed with 70 Gy radiation therapy for his base of tongue
squamous cell carcinoma (Case 1) placed on pentoxifylline and tocopherol before extraction of tooth
squamous
Dent. J. 2024, 12, x FOR PEER REVIEW cell carcinoma
#19. (A) Clinical picture of(Case 1) placed on pentoxifylline
the post‐extraction site at 3 weeks.and tocopherol
(B) Clinical before
picture extraction
of the of tooth
8 of 15
post‐extrac‐
#19.
tion(A)
siteClinical picture
at 5 weeks of thecomplete
showing post-extraction
mucosasite at 3 weeks.
coverage of the(B) Clinicalsite.
extraction picture of the post-extraction
(C) Clinical picture of
theatpost‐extraction
site 5 weeks showing site atcomplete
23 weeks.mucosa coverage of the extraction site. (C) Clinical picture of the
post-extraction site at 23 weeks.

Figure 6. A 70‐year‐old male patient managed with 70 Gy radiation therapy for his right ventral
Figure 6. A 70-year-old male patient managed with 70 Gy radiation therapy for his right ventral
tongue and floor of mouth squamous cell carcinoma (Case 2) placed on pentoxifylline and tocoph‐
tongue and floor
erol before of mouth
extraction squamous
of teeth cell#26,
#24, #25, carcinoma
#30. (A) (Case 2) placed
Clinical picture on pentoxifylline sites
of post‐extraction and tocopherol
at 2
before extraction
weeks. of picture
(B) Clinical teeth #24, #25, #26, #30.sites
of post‐extraction (A)atClinical
5 weekspicture
showingofcomplete
post-extraction sites at of
mucosa coverage 2 weeks.
(B)the extraction
Clinical site. (C)
picture Clinical picture ofsites
of post-extraction the post‐extraction site at 7 complete
at 5 weeks showing weeks. mucosa coverage of the
extraction site. (C) Clinical picture of the post-extraction site at 7 weeks.
Dent. J. 2024, 12, 83 7 of 13

Table 1. Clinical characteristics of the patients, tooth extracted, and outcome.

Radiation Dose to
Tumor Site Primary Extracted Risk for
Case No Gender Age Tumor Type Outcome
[Laterality] Tumor/Chemotherapy Teeth ORN
(Yes/No)
Squamous Mandibular
Base of Tongue Complete
1 M 69 cell 70 Gy/(Yes) First Molar High
(Oropharynx) Healing
carcinoma (#19)
Mandibular
Ventral
Squamous Incisors and
Tongue/Floor of Complete
2 M 70 cell 70 Gy/(Yes) First Molar High
Mouth (Oral Healing
carcinoma (#24, #25, #26,
Cavity) [Right]
and #30)
Squamous Tonsil Mandibular
Complete
3 F 59 cell (Oropharynx) 70 Gy/(Yes) First Molar Moderate
Healing
carcinoma [Right] (#19)
Dent. J. 2024, 12, x FOR PEER REVIEW Hard 9 of 15
Adenoid Mandibular
palate/Maxillary Complete
4 M 75 cystic 66 Gy/(No) Second Molars Moderate
Sinus (Oral Healing
carcinoma (#18 and #31)
Cavity) [Left]

Figure 7.
Figure 7. A
A 59‐year‐old
59-year-oldfemale
femalepatient
patientmanaged
managed with 70 70
with GyGyradiation therapy
radiation for her
therapy forright tonsiltonsil
her right
squamous cell carcinoma (Case 3) placed on pentoxifylline and tocopherol before extraction of tooth
squamous cell carcinoma (Case 3) placed on pentoxifylline and tocopherol before extraction of tooth
#19. A clinical picture of the post‐extraction site at 4 weeks showing complete mucosa coverage of
#19. A clinicalsite.
the extraction picture of the post-extraction site at 4 weeks showing complete mucosa coverage of
the extraction site.
4. Discussion
4. Discussion
ORN is the most morbid oral complication of radiation to the oral and oropharyngeal
ORN
region. is the
Dental most morbid oral complication
extraction/dentoalveolar of radiation
surgery (trauma) to the oral
are considered and risk
major oropharyngeal
factors
region.
for the development of ORN [9,10]. The systematic review by Nabil and Samman risk
Dental extraction/dentoalveolar surgery (trauma) are considered major factors
places
for the development of ORN [9,10]. The systematic review by Nabil and
the incidence of ORN after dental extraction at the patient level as 7% and a more recent Samman places
the incidence of ORN after dental extraction at the patient level as 7%
systematic review and meta‐analysis by Balermpas et al. reported the risk of developing and a more recent
systematic review and meta-analysis by Balermpas et al. reported the risk
dental extraction‐related ORN at the patient level as 7.6% in head and neck cancer patients of developing
dental
treatedextraction-related
with IMRT [33,34]. ORNTheatreported
the patient level as of
prevalence 7.6%
ORN in head and neck
in patients cancerwith
managed patients
treated with IMRT
proton therapy [33,34].
is 10.6% The
(13 out of reported
122) [7]. Inprevalence of patients
these thirteen ORN inthat patients managed
developed ORN,with
proton therapy
the primary tumoris 10.6%
site was(13inout
theof 122)
oral [7]. and
cavity In these thirteen patients
oropharyngeal region, that developed
and there was noORN,
reported precipitating dental extraction, dentoalveolar surgery or trauma [7]. The two
main historic prophylactic strategies used to prevent or decrease the risk of ORN after
invasive dental treatment in a post‐radiated head and neck cancer patient have been the
use of antibiotics prophylaxis (AP) and hyperbaric oxygen therapy (HBOT) [35,36]. A ran‐
domized prospective clinical trial by Marx et al. comparing AP with prophylactic HBOT
in the prevention of ORN reported the rates of ORN after dental extraction as 29.9% and
Dent. J. 2024, 12, 83 8 of 13

the primary tumor site was in the oral cavity and oropharyngeal region, and there was
no reported precipitating dental extraction, dentoalveolar surgery or trauma [7]. The two
main historic prophylactic strategies used to prevent or decrease the risk of ORN after
invasive dental treatment in a post-radiated head and neck cancer patient have been the
use of antibiotics prophylaxis (AP) and hyperbaric oxygen therapy (HBOT) [35,36]. A
randomized prospective clinical trial by Marx et al. comparing AP with prophylactic
HBOT in the prevention of ORN reported the rates of ORN after dental extraction as
29.9% and 5.4%, respectively [36]. The randomized controlled trial by HOPON study
comparing AP with prophylactic HBOT to prevent ORN reported the rates of ORN after
dental extraction as 5.7% and 6.4%, respectively [37]. A systematic review by Nabil and
Samman estimated the ORN rates after dental extraction using AP or prophylactic HBOT as
6% and 4% of patients, respectively, and 1.7% and 2.9% of individual teeth, respectively [33].
The systematic review by Fritz et al. on using prophylactic HBOT to prevent ORN reported
the rate of ORN after dental extraction as 4.1% [38].
Based on the new theory of radiation-induced fibrosis where the dysregulation of
fibroblastic activity is the critical event in the pathogenesis of ORN, PENTO is now utilized
in the management of ORN. It has been proposed that the prophylactic use of PENTO in
irradiated head and neck cancer patients needing dental extractions may improve oral
mucosa healing, therefore preventing ORN [22,27,39–47]. A recent systematic review
of four studies (Patel et al., Aggarwal et al., Samani et al., and Lombardi et al.) that
prophylactically used PENTO prior to dental extractions in order to prevent ORN estimated
the ORN rate at patient level as 3.1% and at individual tooth level as 0.9% [31]. For the
fifth study (liquid formulation of PENTO), where the majority of the patients (38/45) had
only dental extractions carried out (one patient had both extractions and implant placed
and the remaining six patients had implants placed), the ORN rate at patient level was
4.4% (2/45) [32]. Both patients eventually healed after continual use of PENTO for 19
and 44 months. Table 2 summarizes the literature review on studies with prophylactic
pentoxifylline and tocopherol use before dental extractions to prevent ORN. Comparing
the use of PENTO to AP or prophylactic HBOT for the prevention of ORN after dental
extraction clearly shows that PENTO has better results than AP or prophylactic HBOT in
reducing the incidence of ORN after dental extraction in irradiated head and neck cancer
patients. In this limited study of four patients, the ORN rates at the patient level and
individual tooth levels were 0%.

Table 2. Literature review on studies with prophylactic pentoxifylline and tocopherol use before
dental extractions to prevent ORN.

Total Number of
Patients Who Had
Total Number of ORN Rate by
Study PENTO Regimen Extractions (% of Oral ORN Rate by Teeth
Teeth Extracted Patient
and Oropharyngeal
Tumor Sites)
Pentoxifylline 400 mg BID and Vitamin
E 1000 IU daily, 1 month
Patel et al. (2016) [27] 82 (54.9%) 390 1/82 (1.2%) 1/390 (0.3%)
preoperatively and postoperatively
until extraction site healed
Pentoxifylline 400 mg BID and Vitamin
Aggarwal et al. E 1000 IU daily, 1 month
110 (56.3%) 450 2/110 (1.8%) Not reported
(2017) [28] preoperatively and postoperatively
until extraction site healed
Pentoxifylline 400 mg BID and Vitamin
167 (Not reported) 879 6/167 (3.6%) 10/879 (1.1%)
Samani et al. (2022) [29] E 1000 IU daily, 1 week preoperatively
148 * 775 * 5/148 (3.4%) * 8/775 (1.0%) *
and postoperatively for 3 months
Pentoxifylline 400 mg BID and Vitamin
Lombardi et al.
E 800 IU daily, 1 week preoperatively 28 (58.7%) 152 3/28 (10.7%) Not reported
(2022) [30]
and postoperatively for 8 weeks
Dent. J. 2024, 12, 83 9 of 13

Table 2. Cont.

Total Number of
Patients Who Had
Total Number of ORN Rate by
Study PENTO Regimen Extractions (% of Oral ORN Rate by Teeth
Teeth Extracted Patient
and Oropharyngeal
Tumor Sites)
Liquid pentoxifylline 200 mg QID and
liquid vitamin E 1 g (10 mL) daily,
Patel et al. (2023) [32] # 45 (71.1%) Not reported 2/45 (4.4%) Not reported
1 week preoperatively and
postoperatively for 3 months
Pentoxifylline 400 mg BID and Vitamin
E 400 IU BID, oral tablets, 2 weeks
Current 4 (100%) 8 0/4 (0%) 0/8 (0%)
preoperatively and postoperatively for
6 weeks

* Patients with complete medication regimen compliance, # The majority of patients (38/45) had only dental
extractions carried out (one patient had both extractions and implant placed and the remaining six patients had
implants placed).

At this time, the utility of prophylactic HBOT in the prevention of ORN after dental
extraction cannot be justified since studies have now shown that at the least, prophylactic
HBOT does not provide better outcomes when compared to PENTO and for the following
reasons: lack of general and ready availability, logistical challenges, and cost. A total of
30 dives (20 pre-extraction and 10 post-extraction) in a compression chamber at 2.4 atmo-
spheres, each for 90 min, totaling 45 h is recommended for a dental extraction. HBOT cost
per dive ranges between USD 250 and 600, with amounts between USD 7500 and 18,000 for
the 30 dives recommended for a dental extraction. In contrast, the medications used for
the PENTO regimen are readily available in most pharmacies. Pentoxifylline is dispensed
by prescription and tocopherol can be purchased over the counter. These medications can
be used by patients without any special accommodations and are incomparably cheaper
when compared with HBOT. An 8-week regimen of pentoxifylline and tocopherol costs
between USD 44 and 112 and USD 22, respectively, making a total ranging between USD
66 and 134 for both medications. That is more than a 100-fold difference in cost between
both options; this also holds true in the United Kingdom [29]. The major setbacks with
pentoxifylline use are that it is contraindicated in patients with a history of a recent stroke,
ocular hemorrhage, kidney problems, liver problems, recent major surgery, stomach ulcer,
and patients on anti-thrombotic (anti-coagulant and anti-platelet) medication use. Also, the
adverse effects of these medications such as nausea, vomiting, gastric irritation, headaches,
vertigo, hot flushes, and epigastralgia may result in non-compliance with the medication
use. A study carried out by Patel et al. found that 7.3% of patients could not tolerate these
medications [27]. Aggarwal et al. reported in their study that 9.1% of patients developed
adverse effects from the medications [28] and a study by Samani et al. reported that 4.8%
of their patients developed well-recognized adverse effects to the medications [29]. In our
limited study, no patient reported any adverse effects to the medications. This may be
because our patients were on the medications for a shorter duration (8 weeks) than those in
the other studies. However, no logical conclusion can be made due to the small sample size
of our study. The use of the liquid formulation for both pentoxifylline and tocopherol by
Patel et al. was to encourage patients who suffer from dysphagia to have an alternative
option in using these medications [32]. Amongst all five studies, the duration of use of
these medications varies from 1 week to 1 month preoperatively and 6 weeks to 3 months
postoperatively (Table 2). A standardized duration may be required.
The use of photobiomodulation therapy (PBMT) has been encouraged for the preven-
tion of ORN in post-radiated head and neck cancer patients requiring dental extraction [48].
The study by da Silva et al. used PBMT in conjunction with antibiotic therapy and surgical
alveolotomy to ensure primary closure of the extraction sites [48]. Nineteen patients were
enrolled in the test group and the extraction sites were exposed to PBMT using Flash Laser
III (DMC, São Paulo, Brazil) at 40 mW, 100 J/cm2 , 70 s/point, and 2.8 J/point on five points
(total of 70 J/alveolus). The PBMT was applied four times every week [48]. All 19 patients
had complete mucosal healing by 28 days post-extraction [48]. This is the only study on
Dent. J. 2024, 12, 83 10 of 13

the use of PBMT prophylactically in the prevention of ORN in post-radiated head and neck
cancer patients requiring dental extraction. More studies are encouraged to know its true
efficacy. Also, the use of antibiotics can be a confounding factor in the results.
The PENTO protocol should be a game changer in oncology clinical practice. As stated
earlier, the emphasis has been on the prevention of ORN. In some oncology clinical practices,
patients are encouraged to extract all their teeth with the slightest pathoses, before begin-
ning head and neck radiation therapy. A recent study by Buurman et al. estimated that 74%
(1274/1759) of teeth extracted before head and neck radiation therapy have been removed
redundantly based on a dosimetry dose mean of <40 Gy [49]. If the use of prophylactic
PENTO, which is cheap and safe, can prevent/reduce ORN in irradiated patients, clinicians
may be more comfortable preserving patient’s dentition to a reasonable limit. Studies have
shown that loss of dentition in these patients affects their functional units, mastication,
swallowing, and nutritional status, contributing to a decreased quality of life [50–54]. Many
oral care providers are not comfortable carrying out invasive dental procedures such as
root planning and extractions in post-irradiated oncology patients. As such, many head
and neck cancer survivors must endure complications such as dentoalveolar infections,
cellulitis, osteomyelitis, sepsis, and odontogenic cysts. These complications can be easily
prevented by a simple dental extraction of a non-restorable tooth. Instituting PENTO
as a standard protocol in the management of non-fractured ORN and as prophylaxis for
post-radiated head and neck oncology patients requiring an invasive dental procedure may
help alleviate these complications.

5. Conclusions
This limited study, in addition to the other reviewed studies, estimates the rate of
ORN using PENTO protocol at the patient level as 3.2% (14/436) for post-radiated head
and neck oncology patients after dental extractions/invasive oral procedures. The PENTO
regimen can reduce/prevent the incidence of ORN in post-radiated head and neck oncology
patients. This safe and cost-effective protocol (PENTO regimen) should be instituted as
prophylaxis for post-radiated head and neck oncology patients requiring an invasive dental
procedure. We recommend large prospective studies to be carried out to further validate
these findings.

Author Contributions: Conceptualization, A.A.O.; data curation, A.A.O. and L.C.L.; methodology,
A.A.O., K.A.D., O.O. and L.C.L., formal analysis, A.A.O., K.A.D., O.O. and L.C.L.; writing—original
draft preparation, A.A.O.; writing—review and editing, A.A.O., K.A.D., O.O. and L.C.L.; supervision,
A.A.O. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding. The article processing charge was partly
sponsored by A. T. Still Research Institute.
Institutional Review Board Statement: Exempt from review by the Institutional Review Board of
the University of Tennessee Health Science Center.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are contained within the article.
Acknowledgments: The UTHSC dental oncology clinic would like to thank our referring oncologists
(David Schwartz, John Gleysteen, Courtney Shires and Burton Wood) and our patients.
Conflicts of Interest: All authors declare that there are no financial conflicts associated with this
study and that the funding source has no role in conceiving and performing the study.

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