Osteoradionecrosis of the jaws: case series treated with adjuvant low-level laser therapy and antimicrobial photodynamic therapy

Abstract Background: Osteoradionecrosis of the jaw (ORNJ) is the most severe and complex sequel of head and neck radiotherapy (RT) because of the bone involved, it may cause pain, paresthesia, foul odor, fistulae with suppuration, need for extra oral communication and pathological fracture. We treated twenty lesions of ORNJ using low-level laser therapy (LLLT) and antimicrobial photodynamic therapy (aPDT). The objective of this study was to stimulate the affected area to homeostasis and to promote the healing of the oral mucosa. Methods: We performed aPDT on the exposed bone, while LLLT was performed around the bone exposure (red spectrum) and on the affected jaw (infrared spectrum). Monitoring and clinical intervention occurred weekly or biweekly for 2 years. Results: 100% of the sample presented clinical improvement, and 80% presented complete covering of the bone exposure by intact oral mucosa. Conclusion: LLLT and aPDT showed positive results as an adjuvant therapy to treat ORNJ.


Introduction
Cancer is as a major public health problem worldwide. Oral cancer is responsible for 300.000 new cases and 145.000 deaths 9 . Thus, this disease needs attention and research for the best practices in prevention and cure.
Treatments of oral cancer include surgery, radiotherapy (RT), chemotherapy or the combination of these methods, associated or not, all of them cause sequels to the patients. The chronic side effects on the oral cavity occur mainly because of impairments on cells and/or tissues, decreasing the capacity of bone repair, especially in the jaw. Infection or trauma may cause bone necrosis 8 . The condition in which the irradiated bone is exposed to the oral cavity for at least three months is called osteoradionecrosis of the jaw (ORNJ). This condition occurs in the absence of tumor recurrence, tumor necrosis during RT or metastases in the bone 20 . Many risk factors may cause ORNJ 18,21, [23][24][25]28 , as shown in Figure 1.
ORNJ results from imbalance in the homeostasis of all tissues affected by head and neck RT 25 . The pathophysiology is composed by three phases: (1) initial pre-fibrotic (injuries to endothelial cells due to reactive oxygen species caused by RT); (2) constitutive organized (continuous liberation of cytokines and reactive oxygen species causing abnormal fibroblastic activity); and (3) late fibro-atrophic process (start of a fragile tissue healing) 5 . There is no cure for established ORNJ, only clinical control, since the damage caused by head and neck RT is irreversible on the jaw 21 .
Despite the numerous and well-reported therapeutic methods found in literature 7,15,17 , there are no reports of the use of low-level laser therapy (LLLT) associated with antimicrobial photodynamic therapy (aPDT).
LLLT is associated with the increase of cellular metabolism through the activation of the mitochondrial respiratory chain, increasing the levels of ATP synthesis, cell proliferation, protein synthesis and angiogenesis, which are essential for wound healing 12 .
LLLT also causes an analgesic effect, by inhibiting electrophysiological activity on the nerves, altering the release of neurotransmitters that are associated with pain relief, improving lymphatic flow, among others 3 .
The aPDT acts on exogenous photoreceptors, promoting the interaction of the light with a photosensitizer, producing reactive oxygen species, which causes microbial reduction 2 . Moreover, its antimicrobial action does not cause bacterial resistance or microbial selection 27 .
By reducing pain, improving the wound healing process and eliminating the opportunistic microorganisms, the use of both therapies allow the patient to continue the cancer treatment, while preserving his/her basic oral functions, such as eating, drinking, swallowing and talking. Thus, the patient is more likely to maintain a good general health status, better responding to the treatment for ORNJ. Additionally, these therapies are non-invasive, atraumatic and no significant adverse effects associated with them are reported in literature 29 .
Thus, the objective of this study was to assess the clinical effects of LLLT and aPDT to treat ORNJ in patients who underwent head and neck RT, as well as to propose an adjuvant treatment protocol to the pathology.
Osteoradionecrosis of the jaws: case series treated with adjuvant low-level laser therapy and antimicrobial photodynamic therapy

Risk Factors
Greater susceptibility to ORNJ Oral condition Caries, periodontal disease, poorly adapted prosthesis 6,25 Oral surgery Tooth extraction and dental implant after RT7, 25 Smoking and drinking Before, during and after RT 9 Nutritional status Malnourished 3 LLLT and aPDT protocol for ORNJ We used a laser device (Therapy XT ® -Diode laser nm, DMC, São Carlos, SP, Brazil) at λ660 nm (red spectrum) and λ808 nm (infrared spectrum), with fixed power of 100 mW. We used the red LLLT first and the aPDT after, these therapies were performed only in cases of bone exposure and/or infection. Infrared LLLT was performed imperatively, even when there was no infection or exposed bone, this procedure was performed on the interval between red LLLT and aPDT (time pre-irradiation, in which methylene blue 0.01% was used to stain the area related to bone exposure) ( Table 1)   Test to verify the association between ORNJ stages and healing of the injured oral mucosa by treatment with LLLT and aPDT. The level of significance adopted was 5% (p<0.05).

Results
The sample consisted of patients from 40 to 71 years old, the mean age was of 59.1 years. Men presented a much higher prevalence of ORNJ lesions than women, with a ratio of 9:1 cases. Only one patient had melanoderma (5%), the other patients had leukoderma (95%). When asked about drugs, most patients (85%) mentioned smoking and drinking (  distinct protocols, due to being treated at different RT treatment centers. The minimum radiation dose each patient received was 66Gy and the maximum was 92Gy, with mean total radiation dose of 72Gy. However, on five cases (25%) ORNJ was developed by receiving a total radiation dose above the mean, these patients did not reach stage III.
All cases of ORNJ stage III occurred after 24 months.
Half the patients presented the first ORNJ lesions Chi-Square Test. Value with statistical significance is in italics.   According to the results of this study, we found that aPDT applied directly to an exposed bone with suppuration can be beneficial to control infected ORNJ lesions. Furthermore, we observed the remission of ORNJ and partial or total repair of the oral mucosa.

Table 3-LLLT and aPDT clinical outcomes on ORNJ lesions
Therefore, we can claim that LLLT and aPDT were essential to the success of disease control, reinforcing the importance of its applicability and indication.

Conclusion
The results of this study suggest that LLLT and aPDT Based on our results, we recommend the use LLLT, in both red and infrared spectra, and aPDT as an adjuvant treatment of ORNJ. We suggest further research to obtain more relevant data on the action of LLLT and aPDT to treat ORNJ lesions. students who helped the researchers during the assistances.

Ethics in Science
The manuscript has not been submitted to more than Journal of Applied Oral Science for simultaneous consideration. The material has not been published previously (partly or fully). This study is not split up into several parts to increase the quantity of submissions and submitted to various journals or to one journal over time. No data have been fabricated or manipulated (including images) to support our conclusions.
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (n.724.398, from July/2014) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent
All participants of this study provided consent