Use of Pentoxypline and Tocopherol in the treatment of Osteorradionecrosis: a literature review

The main complications of using RT are mucositis, xerostomia, candidiasis, dysgeusia, caries, soft tissue necrosis and osteoradionecrosis (ORN). Despite better control of risk factors seen today, such as greater attention to Osteoradionecrosis (ORN) is a complication of radiotherapy (RT), which affects patients with head and neck cancer. Once established, an ORN does not disappear spontaneously and a standard treatment has not yet been defined. Treatment is often complex and multimodal. With a better understanding of the pathophysiology of ORN, new treatments and possibilities for the most predictable results of this difficult prognosis pathology arise. Under these circumstances, good results have been observed with an association of peripheral vasodilator drugs and antioxidants, such as pentoxifylline and tocopherol. The objective of this work was, through a review of the literature, to describe a pathophysiology of the ORN of the jaws and discuss as new perspectives of a conservative treatment with pentoxifylline and tocopherol. It was observed as an alternative to the drug association as a therapeutic alternative of the ORN, mainly in the early stages, it showed good results; However, it requires more controlled clinical studies to measure and consolidate the benefits that this treatment can provide patients.


Introduction
Head and neck cancer worldwide represents 10% of malignant tumors. It is estimated, for Brazil, in 2016, 11,140 new cases of cancer of the oral cavity in men and 4,350 in women. These values correspond to an estimated risk of 11 new cases per 100,000 men and 4 per 100,000 women [1].
The recommended treatment for these neoplasms is through surgery, Radiotherapy (RT) and Chemotherapy (QT), with only one method or the association of two or more methods, depending on the characteristics of the disease. However, despite the good results obtained with RT, complications arose from its use, resulting in reduced quality of life, interference in therapy and increased morbidity [2-3].
The main complications of using RT are mucositis, xerostomia, candidiasis, dysgeusia, caries, soft tissue necrosis and osteoradionecrosis (ORN). Despite better control of risk factors seen today, such as greater attention to Osteoradionecrosis (ORN) is a complication of radiotherapy (RT), which affects patients with head and neck cancer. Once established, an ORN does not disappear spontaneously and a standard treatment has not yet been defined. Treatment is often complex and multimodal. With a better understanding of the pathophysiology of ORN, new treatments and possibilities for the most predictable results of this difficult prognosis pathology arise. Under these circumstances, good results have been observed with an association of peripheral vasodilator drugs and antioxidants, such as pentoxifylline and tocopherol. The objective of this work was, through a review of the literature, to describe a pathophysiology of the ORN of the jaws and discuss as new perspectives of a conservative treatment with pentoxifylline and tocopherol. It was observed as an alternative to the drug association as a therapeutic alternative of the ORN, mainly in the early stages, it showed good results; However, it requires more controlled clinical studies to measure and consolidate the benefits that this treatment can provide patients. oral hygiene and dental health care, and modern advances in RT methods, ORN remains a reality today [5].
RT has been used in the treatment of malignant tumors of the head and neck region, exclusively, or associated with surgery and chemotherapy. It is known that radiosensitization of cells adjacent to the tumor can limit the treatment and, depending on the irradiated field, result in important morbid sequelae [3].
Due to medical advances, patients undergoing radiotherapy or chemotherapy, even those with acute or chronic side effects, have achieved a longer survival. This has resulted in an increase in the demand of such patients seeking dental treatment, making it essential that the Dental Surgeon is aware of such effects, as well as their relationship with dental treatments [5].
The need to maintain the oral health of cancer patients undergoing RT aims to provide a better quality of life. The periodontium must be maintained in healthy condition through procedures performed routinely, before and during irradiation. Guidance on oral hygiene techniques, motivation and the patient's ability to cooperate are essential to achieve the best prognosis [2].
ORN is characterized as one of the late adverse effects of RT [5]. For Marx [6], ORN can be considered as an ischemic necrosis, with superficial infection of the exposed bone characterized by hypocellularity, hypoxia, hypovascularization, with the mandible being the structure that presents a greater predisposition to the development of osteonecrosis, not only because of its dense bone configuration as well as the type of blood supply [5,7].
The treatment of ORN is still a challenge for the clinician. Currently, it seems to be a consensus that the ORN should be handled, initially in a conservative way, through debridement and cleaning of surgical wounds with antimicrobial solutions, antibiotic therapy and surgical debridement [8].
Conservative treatment includes local irrigation (with saline solutions, chlorhexidine, hydrogen peroxide or povidone iodine), curettage of the lesion, elimination of small sequestrations, with or without the use of hyperbaric oxygenation. The elimination of habits, such as tobacco and alcohol, elimination of traumatic prostheses, use of hygiene measures and antiseptic mouthwashes several times a day, use of analgesics, are part of conservative therapy. Other therapeutic approaches include Hyperbaric Oxygen Therapy (HBO), use of peripheral vasodilator drugs and antioxidants, laser therapy, platelet aggregates, ozone therapy and ultrasound [9][10].
The use of peripheral vasodilator drugs and antioxidants, such as pentoxifylline and tocopherol, in the treatment of patients with maxillary ORN, has shown promising results, which may or may not be associated with Clodronate, in cases of progressive ORN to obtain maximum benefit [11].
In this context, the present study aimed, through a literature review, to describe the pathophysiology of maxillary ORN and to discuss the new perspectives of a conservative treatment with pentoxifylline and tocopherol.
The inclusion criteria used in this bibliographic search were: full text, written in Portuguese and English. The articles used are casecontrol studies, retrospective studies, bibliographic reviews and systematic reviews with up to 15 years of publication. From the totality of articles found, all those whose theme and objectives were not related were excluded. articles on osteoradionecrosis that were not related to the oral cavity, maxilla and mandible were also excluded.

Results (Review) Head and Neck Cancer
Cancer is the name given to a set of more than 100 diseases that have in common the disordered growth of cells that invade tissues and organs and can spread to other regions of the body. This uncontrollable reproduction of cells tends to be very aggressive, determining the formation of tumors or malignant neoplasms [1].
Based on the document World Cancer Report, 2014, by the International Agency for Research on Cancer (IARC), of the World Health Organization (WHO), it is unquestionable that cancer is a public health problem, especially among developing countries, where it is expected that, in the coming decades, the impact of cancer on the population will correspond to 80% of the more than 20 million new cases estimated for 2025 [1].
The National Cancer Institute (INCA) revealed that cancer of the oral cavity has an incidence in the population around 40% of all malignant tumors that affect the head and neck region. Approximately 300 thousand new cases were estimated in the world in 2012, and of these, approximately two thirds are in males. For mortality, 145 thousand deaths from cancer were estimated in the world in 2012 [1].

Without
considering nonmelanoma skin tumors, cancer of the oral cavity in men is the fourth most frequent in the Southeast (14.58/100 thousand). In the Northeast (6.86/100 thousand) and Midwest regions, it occupies the fifth position (9.15/100 thousand). In the South Region (15.91/100 thousand), it occupies the sixth position, and in the North Region (3.46/100 thousand) it is the seventh most frequent. For women, it is the ninth most frequent in the Northeast Region (4.11/100 thousand). In the Southeast Region (5.29/100 thousand), it occupies the tenth position. In the North (1.76/100 thousand) and Midwest (2.79/100 thousand), it is the 12th most frequent, and in the South (3.32/100 thousand), it occupies the 15th position [1].
With the gradual evolution in the treatment of carcinomas in the head and neck region, the cure rate has grown substantially. The patient can be treated with surgery, RT and chemotherapy concomitantly or not [3]. Combined surgery with RT has been used in the treatment of advanced malignant tumors of the head and neck, providing higher cure and survival rates than the isolated treatment [12].
Complications resulting from radiotherapy treatment depend, in addition to the total dose, on other factors, such as: type and radiosensitivity of healthy irradiated tissue, dose fractionation, age, systemic conditions, some addictions such as alcoholism and smoking, and inadequate oral hygiene [7].
High doses of radiation can cause hypoxia, reduced blood supply, necrosis and, consequently, infection. Likewise, the skin and mucosa found in the irradiated field can undergo changes such as desquamation, blistering, erythema, necrosis, as well as pain and burning in the most severe cases, favoring the development of structural and functional tissue changes [13].
Vissink et al. [14], in their studies, evaluated the forms of treatment and the prognosis of patients with squamous cell carcinoma of the oral cavity. They stated that a cure for this carcinoma can be achieved with surgery, RT and a combination of both. They also considered the problem that oral cavity tumors are still not adequately treated, emphasizing the need for diagnosis in the early stages.
A protocol that minimizes the sequelae of RT must be previously instituted and monitored before, during and after the end of the treatment. A comprehensive multidisciplinary clinical approach allows preventing, diagnosing and controlling the side effects of RT. Psychological aspects are relevant and the patient's self-esteem can favor adherence to the proposed treatment, personal care and with their teeth [2].

Radiotherapy and its consequences
RT is a treatment modality for malignant tumors, such as squamous cell carcinoma, whose therapeutic agent is ionizing radiation. This radiation is capable of creating unstable atoms that damage the cell's DNA and prevent the neoplastic cell from replicating. The radiation dose is measured in gray units (Gy), and generally, patients with head and neck carcinomas receive, as a curative dose, between 50 and 70 Gy (1 Gy = 1 J/kg = 100 rads). This dose is usually applied in fractions, for a period of five to seven weeks, once a day, five days a week and with a daily dose in the tumor around 2 Gy. In doses low of 10 Gy there is already the appearance of side effects (radiation skin syndrome, mucositis and glandular alterations) [14].
Ionizing radiation is divided into corpuscular and electromagnetic radiation. The corpuscular ones are represented by electrons, protons and neutrons; the electromagnetic ones are called photons, being represented by Xrays and gamma rays. They act on nuclear DNA leading to death or loss of their reproductive capacity. However, the ability to multiply varies according to cell type. Thus, there is a radiosensitivity scale for both tumor cells and normal cells. Embryonic neoplasms and lymphomas are radiosensitive tumors, while carcinomas are moderately radiosensitive [15].
However, RT has been associated with many deleterious effects such as mucositis, xerostomia, radiation caries, dysgeusia, radiodermatitis, fibrosis and ORN. The occurrence of these reactions depends on the radiation dose, the location of the irradiated area, age and systemic conditions and other concomitant treatments [16].
As for the treatment of head and neck CA, ORN is a sequelae arising from RT, characterized by the loss of skin tissue and/or mouth lining mucosa that progresses to the consequent exposure of necrotic bone tissue after a minimal period, in general from three to six months, but which can appear after treatment indefinitely [14].
RN is one of the most severe complications of RT, occurring seven times more in the mandible than in the maxilla, due to its high bone density and less vascularization. About 74% of cases occur within the first three years after RT. Ionizing radiation makes the vascular channels narrow, which reduces blood flow, producing an area that is poorly resistant to trauma and poorly regenerated. Therefore, traumatic procedures that can promote bone necrosis are not indicated. Extractions, for example, must be performed at least two weeks before radiotherapy treatment [17].
Predisposing factors commonly related to ORN of the mandible include poor oral hygiene, periodontal disease, dentoalveolar abscess, extensive caries, anatomical site of the tumor, increasing doses of RT, and dentoalveolar surgery during RT or in the postoperative period [2].
In 1983, Marx [6] described the first pathophysiological theory about ORN, which has been the most accepted since then. According to the author, radiation would cause tissue changes resulting in hypoxia, hypocellularity and hypovascularization, which promotes a disturbance in tissue healing.
Nabil and Samman [4] critically reviewed 19 selected articles to analyze the incidence and factors influencing ORN development after tooth extraction in irradiated patients. They found a total incidence of 7% of ORN after tooth extraction in irradiated patients. When extractions were performed in conjunction with prophylactic HBOT, the incidence of ORN was 4%, whereas when extraction was preceded by prophylactic antibiotics, the incidence was 6% [4].
The authors concluded that, although the incidence of ORN after post-irradiation tooth extractions was low, the extraction of mandibular teeth within the radiation field, in patients who received doses greater than 60 Gy, represents a greater risk for the development of ORN [4].
ORN is a complex and multifactorial process with vascular alterations (endothelial, perivascular, and microvascular tissue) and cellular components (both intracellular and extracellular), induced by ionizing radiation. It also causes dysregulation of fibroblastic activity, alters the expression of inflammatory cytokines and growth factors, leading to fibrosis, disturbance of normal bone remodeling and cell death. Therefore, local trauma can act as a reinforcing factor for its onset; scheme described in (Figure 1) [18]. Several classifications have already been proposed for the ORN. Tables 1 to 3 show the classifications proposed by Notani et al. [19], Støre et al. [20] and Epstein et al. [21], respectively. There is still no consensus on the most appropriate classification for the disease [13].

New treatment options for osteoradionecrosis
The management of ORN is difficult and not always successful because of the lack of and effective prevention methods, accompanied by several risk factors. Maxillary ORN is usually treated conservatively or surgically.
Conservative therapies include frequent irrigation with saline, 0.12% chlorhexidine solutions, povidone-iodine solutions, and antibiotic therapy during periods of active infection. Another conservative approach is the use of HBOT [22].
HBOT would increase oxygen supply to tissues in hypoxia, which would stimulate fibroblast proliferation, collagen formation and angiogenesis.
Its use has been advocated in the pre-and postoperative period of patients at high risk of tooth extraction or surgical intervention. In addition, it can also be used in small lesions, together with other conservative measures, in order to avoid extensive surgical resections of the mandible, obtaining an 81% response rate of osteoradionecrosis to treatment with HBOT, associated   [17] suggested that treatment options for ORN of the mandible could combine the three main approaches already cited for ORN control (Figure 2). reported when associated with radiation [24].

Discussion and Conclusion
Despite technological advances in radiotherapy devices and the improvement of surgical techniques, the incidence of osteoradionecrosis (ORN) has not decreased in recent decades.
Depending on the institution analyzed, the incidence of ORN has varied from 1% to 40% of cases [12].