Keywords osteoradionecrosis - bone defect - bone regeneration - platelet-rich fibrin - pentoxifylline
- tocopherol
Introduction
According to the Global Burden of Cancer Study, a quarter million people have suffered
from oral cancers worldwide.[1 ] Radiotherapy is recommended for the definitive or palliative treatment of oral cancer
patients alone or in conjunction with surgery. However, radiotherapy has considerable
drawbacks as it results in acute and late side effects. Acute side effects, such as
moist desquamation, skin erythema, taste loss, and mucositis are often weakening but
resolve with time. However, the late side effects, such as radiation caries, trismus,
xerostomia, myelitis, fibrosis of the skin, and osteoradionecrosis (ORN) are more
significant and be life-long problems for the cancer survivor patients.[2 ]
ORN of the jaws defined as the exposed irradiated bone that fails to heal over a period
of 3 months without any evidence of persisting or recurrent tumor. The prevalence
of ORN has been reported to be 5 to 15% and commonly affects patients over 55 years
of age.[3 ] The most common pathophysiologic models of ORN are described by hypoxic-hypocellular-hypovascular
theory and radiation-induced fibroatrophic (RIF) theory. These debilitating conditions
can arise on their own but they are frequently triggered by soft and hard tissue manipulation,
such as tooth extraction and trauma.
The management of “at-risk” individuals for ORN is still a challenge for the physicians;
prevention and education are essential. The dental treatments can be performed but
precautions need to be taken when performing the oral surgical procedures. There has
been no clear consensus on the prevention of ORN but primary closure of wounds, systemic
antibiotics, and antiseptic mouthwashes are important considerations. Novel medications
to prevent the ORN are promising, as hyperbaric oxygen (HBO) therapy is no longer
recommended.[4 ] In addition, HBO therapy requires special equipment and long course of treatment,
limiting the accessibility.
Combination of pentoxifylline and tocopherol has been introduced as a noninvasive
option for the ORN prevention. Pentoxifylline is an inhibitor of tumor necrosis factor-α
(TNF-α). It improves the erythrocyte flexibility, causes blood vessels dilatation,
inhibits inflammatory reactions, decreases the proliferation of human dermal fibroblasts,
helps extracellular matrix synthesis, and boosts collagenase activity. Tocopherol
(vitamin E) is used to scavenge the reactive oxygen species produced by preserving
the cell membranes against peroxidation of lipids, causes partial suppression of transforming
growth factor (TGF)-1 and helps in developing the genes procollagen that decrease
fibrosis under oxygen stress.[5 ] These two drugs act synergistically as powerful antifibrotic agents, causing a 66%
regression of the surface area of RIF process following 12 months of therapy.[6 ]
In addition, platelet-rich fibrin (PRF), originally developed by Choukroun et al[7 ] in 2001, was introduced as the blood concentrate system that did not require the
use of extra anticoagulants. PRF-based matrices contain a variety of inflammatory
cells, such as leukocytes and platelets, as well as plasma proteins embedded in a
fibrin network.[8 ] The components of PRF-based matrices are recognized to have an essential role in
the wound healing process. Local PRF administration can minimize the postoperative
discomfort and complications. Advanced-PRF+ (A-PRF + ) is a new PRF-based matrix developed
by Ghanaati et al.[9 ] in 2014. The low speed of relative centrifugation force demonstrated enhanced growth
factor release within PRF-based matrices. Literature suggests that PRF is useful in
poor healing potential, such as in ORN and its properties, they are useful as an adjunct
in the prevention and treatment of ORN.[10 ]
[11 ]
In this case report, we aim to present the preventive strategy and outcomes of A-PRF+
as a surgical adjunct for ORN.
Case Report
A 72-year-old man presented to an advanced dentistry department of an academic tertiary
hospital in Thailand, with persistent pain at edentulous area of the upper right first
molar. The patient was previously diagnosed with squamous cell carcinoma in the left
side of the tongue with minimal submucosal invasion (staging T2N0M0) 6 years prior,
treated with wide excision with modified radical neck dissection (mandibular split).
External beam radiation therapy was performed at a total dose of 5,940 cGy in 33 Days.
In the following 6 years after radiotherapy, he has had severe hyposalivation and
multiple dental caries. The tooth no. 16 was surgically extracted due to caries and
persistent pain. A few months following extraction, he presented to our clinic with
trouble chewing meals and expressed a desire for a new denture. An intraoral examination
showed gingival inflammation and tenderness with palpation around the edentulous area
of tooth no. 16. Upper right second premolar tooth (no. 15) had no symptoms. Upper
right second molar tooth (no. 17) was unoccluded tooth with supraeruption and first
degree mobility. The furcation involvement grade I at buccal aspect, with horizontal
bone loss at apical one-third of root length and root caries, was detected.
Radiological examination revealed retained root of no. 16 with radiolucent area and
horizontal bone loss around tooth no. 17. Our prosthodontist recommended that the
tooth (no. 17) had to be removed because of poor prognosis with no space for opposing
denture. Retained roots of teeth no. 16 and 17 were removed and the sockets were debrided,
the A-PRF+ membranes were prepared and placed as described in the following sections
followed by primary wound closure ([Fig. 1 ]).
Fig. 1 (A ) Preoperative periapical radiographic examination showed retained root of 16 with
radiolucent area; (B ) clinical findings showed unhealed edentulous area.
Advanced-Platelet-Rich Fibrin+ Preparation
A-PRF+ application was used to stimulate and accelerate wound healing as described
by Ghanaati et al.[9 ] Briefly, 20-mL peripheral blood was drawn from the patient and collected in two
10-mL sterile glass tubes (A-PRF tubes process for PRF, Nice, France; Mectron, Cologne,
Germany) without additional anticoagulants then placed in a centrifuge machine (Duo
centrifuge, process for PRF, Nice, France; Mectron, Cologne, Germany). The centrifuge
had a fixed angle rotor with a radius of 110 mm with no brake. The preparation stages
were performed at room temperature using the following protocols: 1,300 rpm; 8 minutes;
and 208 g. The centrifugation process completed automatically following the centrifugation
time, and the centrifuge stops in 2 to 5 seconds. Clots were gently removed from the
tubes and separated from the red blood cell fraction using sterile scissors after
incubation for 5 minutes for clot development. The clot A-PRF was then placed on the
PRF Box grid (Process for PRF, Nice, France) and covered with the lid ([Fig. 2 ]).
Fig. 2 (A ) PRF were incubated for 5 minutes at room temperature; (B ) the maturated PRF clot was removed from tube with a sterile tweezer; (C ) the fibrin clot was separated from the red blood cell fragment, using a scissor;
(D ) the A-PRF+ membrane after incubating in PRF Box grid for 5 minute. A-PRF + , advanced
platelet rich fibrin
Surgical Procedure
Surgical removal of remaining root no. 16 and tooth of no. 17 were performed using
aseptic techniques under local anesthesia (using Articaine 4% with Epinephrine 1:100,000
1.7 mL). Access to target site was achieved by raising a full-thickness mucoperiosteal
flap to fully exposed bone area of no. 16. Then the retained root and tooth no. 17
were gently removed.[5 ] The granulation tissues were removed using a curette and the irrigation was performed
using normal saline. Afterward, the periosteum was released to ensure a tension-free
wound closure. The A-PRF+ membranes were then placed into the denuded bone, followed
by primary wound closure using resorbable suture, Vicryl 4–0.
The patient was given the postoperative instructions and a course of antibiotics (Amoxycillin
500 mg, thrice a day) for 7 days. Because the patient has multiple risk factors of
developing postextraction ORN, a pharmacologic approach was devised. To prevent the
development of ORN, pentoxifylline of 800 mg and tocopherol 1,000 IU were given daily
for a week before the surgical operation and were continued until the 8-week course
was finished ([Fig. 3 ]).[5 ]
[6 ]
Fig. 3 (A ) Immediate postoperative periapical radiographic examination showed that the residual
root was completely removed. (B ) A full thickness mucoperiosteal flap was performed and the tooth 17 has extracted;
(C ) A-PRF+ application on denuded bone; (D ) Tension-free wound closure was achieved; (E–J ) At 1, 2, 4, 8, 16, and 24 weeks of postoperative follow-up J caption is repeated.
Please remove.
Follow-up
At regular follow-up visits, no reports of pain or edema were observed. At 2 weeks'
visit, examination revealed early epithelization and progressed to complete mucosal
coverage at 2 months. At 6-month post–follow-up, no symptoms were reported, and clinical
examination demonstrated that the edentulous ridge was completely healed. There was
no sign of dehiscence. On cone-beam computerized tomography (CBCT), no adverse changes
or ORN in radiological finding were seen ([Fig. 4 ]).
Fig. 4 (A and B ) 6 months postoperative periapical radiographic and CBCT examination showed the new
bone formation without pathological findings. CBCT, cone-beam computed tomography.
Discussion
Five-year survival rate for people with oral or oropharyngeal cancer is approximately
55% with many survivors living for decades without decreasing their ORN risk.[12 ] Analysis of epidemiological research on ORN does not offer precise data on the incidence
and prevalence of ORN in the jaw due to a lack of agreement on its definition, differences
in the length of follow-up between studies, and a lack of data from prospective studies.[5 ] The primary risk factors of ORN are the possibilities of “at risk” operations, such
as tooth extraction and bone surgical insulation. Dental extractions have been identified
as one of the most common beginning factors in the development of ORN in irradiated
jaws. The rate of ORN after tooth extraction in irradiated patients is estimated to
be between 2 and 18%. A radiation dose higher than 60 Gy and abuse of alcohol and
tobacco are also known as etiological factors of ORN.[5 ]
[13 ] In addition, an increase in local inflammation and tissue infection are related
to ORN as a consequence of dental caries and periodontal disease.[14 ]
The pathophysiology of ORN is unclear and various hypotheses are used to explain ORN.
Marx's initial suggestion of a nonhealing wound hypoxia, hypovascularity, and hypothesis
of hypocellularity have lately been questioned, as were the findings of numerous other
investigations not completely substantiated.[15 ]
[16 ] According to the RIF process, ORN is a radiation-generated fibroatrophic process,
encompassing free-radical formation, endothelial dysfunction, inflammation, microvascular
thrombosis, fibrosis and remodeling, and bone and tissue necrosis.[17 ]
[18 ] In various studies, the researchers used treatments based on the RIF hypothesis,
and indicated that the condition is responsive to antioxidant treatment using combination
of pentoxifylline and tocopherol.[17 ]
[18 ]
Pentoxifylline, a methylxanthine derivative, has extensive use and vasodilatory benefits
in patients with peripheral, vascular, and stroke conditions. Pentoxifylline has been
proven to decrease inflammatory responses and platelet aggregation while increasing
erythrocyte flexibility, hence lowering blood viscosity and coagulation potential.
Vitamin E (tocopherol), which prevents the free radical production of lipid peroxidation,
is a powerful antioxidant. Moreover, tocopherol is associated with fibrosis reduction.[19 ] As previously stated, novel therapy regimens have been proposed to reverse alterations
in reactive oxygen species that causes RIF and eventually ORN.
Several reports have shown that the PRF can be used as an adjuvant to conventional
nonsurgical periodontal treatment and as a regenerative material in oral implantation
to elicit new bone formation. Tsai et al[20 ] reported that PRF can improve healing process in the patient with osteonecrosis
of jaw, and it also promotes new bone formation. In addition, King et al[10 ] in 2019 reported early epithelization at 2-week postoperation in use of leukocyte-PRF
(L-PRF) prophylaxis of ORN.
Further reports demonstrated its advantage, as it can express a range of activated
signaling molecules, platelet-derived growth factor (PDGF), vascular endothelial growth
factor (VEGF), and TGF-β. These growth factors are crucial for tissue regeneration
and the tissue vascularization.[21 ]
[22 ]
[23 ]
The biological effects of PRF in regenerative bone was investigated and proven, PRF
can promote osteoblast attachment, proliferation through the Akt pathway, and matrix
synthesis through the actions of heat shock protein 47.[24 ] Another concept for PRF (A-PRF+ or A-PRF + ), which is a new PRF-based matrix, which
was described by Ghanaati et al.[9 ] A-PRF+ highly showed VEGF release when comparing with the A-PRF and conventional
PRF after 7 days, and A-PRF+ also showed the highest concentration on day 10.[25 ]
VEGF plays a key role in wound healing and tissue regeneration to encourage vascularization
and the development of new vessels.[26 ] Sustained and improved VEGF release by A-PRF+ could therefore lead to greater regeneration
and vascularization benefits, so providing a nutrition source to promote wound healing,
and improve the pattern of bone and tissue regeneration. In addition, in 2017, Choukroun
and Ghanaati[9 ] reported that using A-PRF+ increases the quantity of inflammatory cells and platelets
and the growth factor in the matrices of the PRF.
Although the current case report resulted in satisfactory treatment outcome, there
are several effective therapeutic strategies for improving healing process with combination
of preoperative oral pentoxifylline/tocopherol and A-PRF+ wound closure. Further studies
are needed to validate its therapeutic efficacy for radiated patients.
Conclusion
Oral examination prior to radiation and regular dental check-ups following radiation
can reduce the risk of ORN development. It is found that tooth extraction following
radiotherapy greatly increases the risk of developing ORN. Tooth extractions following
the radiation should be performed with minimal trauma, primary closure, and adjuvant
therapy. Our case demonstrates that the combination of pentoxifylline/tocopherol and
the A-PRF+ surgical approach is useful for would healing and prevention of ORN. Further
studies are needed to validate its efficacy in preventing ORN in radiated patients.
