Laser Phototherapy as a Treatment for Radiotherapy-Induced Oral Mucositis Maíra

Ionizing radiation causes damage to normal tissues located in the field of radiation. Oral mucositis may result from irradiation that induces the death of the basal cells of the mucosal epithelium, usually two weeks after the beginning of radiotherapy (RT) (1,2). Oral mucositis is an inflammatory response of the oral mucosa to the use of antineoplastic drugs or ionizing radiation that are used in treating head and neck cancer. Discomfort or severe oral pain may be caused by oral mucositis, as well as difficulties on drinking, eating, swallowing and speaking, which impair patient’s quality of life (1,3). It starts asymptomatic, later on, an erythema appears and it may be followed by erosion or ulceration of the oral mucosa. The ulcerations may be typically covered by a white fibrinous pseudomembrane (4,5). Histopathological evaluation of mucositis reveals Laser Phototherapy as a Treatment for Radiotherapy-Induced Oral Mucositis


INTRODUCTION
Ionizing radiation causes damage to normal tissues located in the field of radiation.Oral mucositis may result from irradiation that induces the death of the basal cells of the mucosal epithelium, usually two weeks after the beginning of radiotherapy (RT) (1,2).
Oral mucositis is an inflammatory response of the oral mucosa to the use of antineoplastic drugs or ionizing radiation that are used in treating head and neck cancer.Discomfort or severe oral pain may be caused by oral mucositis, as well as difficulties on drinking, eating, swallowing and speaking, which impair patient's quality of life (1,3).It starts asymptomatic, later on, an erythema appears and it may be followed by erosion or ulceration of the oral mucosa.The ulcerations may be typically covered by a white fibrinous pseudomembrane (4,5).
Histopathological evaluation of mucositis reveals

Laser Phototherapy as a Treatment for Radiotherapy-Induced Oral Mucositis
mucosal thinning leading to the formation of a shallow ulcer thought to be caused by inflammation and depletion of the epithelial basal layer with subsequent denudation and bacterial infection (6).The World Health Organization (WHO) Oral Toxicity Scale (OTS) is widely used for assessing the severity of scoring oral mucositis.This scale includes criteria such as the presence of erythema and ulceration, oral pain, and patient's ability to eat, in order to determine an overall score.The WHO OTS score 0 is defined as no abnormality found; score 1 is characterized by the presence of erythema requiring no treatment; score 2 is characterized by presence of pain requiring no analgesics, and difficulty in feeding; score 3 is characterized by ulceration, pain requiring analgesics, and feeding is impossible; and score 4 is characterized by necrosis, requiring total parenteral nutrition (5).
Several therapeutic approaches to treat oral mucositis have been used, including basic oral care, oral rinses, analgesics, antibiotics, cryotherapy, local anesthetics, growth factors and cytokines, biologic mucosal protectants, and anti-inflammatory agents and others.To date, there is no single treatment capable of preventing or treating mucositis in an efficient way (7).
Recently, laser phototherapy (LPT) has been used both to prevent and to treat oral mucositis because of its ability to induce biological effects such as analgesia and modulation of the inflammatory process.The effect of LPT is due to its capacity to modulate diverse metabolic processes by biochemical and photophysical processes induced by the light that are beneficial for the cells (8,9).
Several studies (3,4,6,7,10,11) have suggested that the use of LPT seems to reduce the severity of mucositis, providing comfort and better quality of life.Zanin et al. ( 1) evaluated the effects of a 660-nm diode laser on the prevention and treatment of chemo-and radiotherapy-induced oral mucositis in patients with head and neck cancer.Their results showed that oral mucositis, pain, dysphonia and dysphagia were minimized with the use of LPT.This paper reports the efficacy of LPT in a patient suffering from oral mucositis induced by RT.

CASE REPORT
A 32-year-old Caucasian male patient was prescribed to carry on RT after undergoing surgery to remove an osseous-invasive squamous cell carcinoma of the maxilla (Fig. 1A).The RT protocol included a total dose of 6,000 cGy, within 30 fractions, over 6 weeks.In the second week of RT, he developed oral mucositis and severe oral pain.The patient was referred to the Laser Center of the Dental School of the Federal University of Bahia, Brazil.Clinical examination revealed widespread severely painful ulcerations both intraorally and extraorally (Fig. 2 A-E).The mucositis was scored as 3, according to the WHO OTS criteria.In addition, the patient reported difficulty eating viscous/solid foods and breathing, as the nasal mucosa presented an extensive ulcerative lesion.He presented good oral health, as no periodontal problems or caries lesions were observed.
Oral hygiene guidance was provided and the sharp borders of teeth and restorations were removed with a fine bur and polished.LPT was performed using a GaAlAs diode laser (Twin-Flex ® ; MMOptics, São Carlos, SP, Brazil) without interruption of RT.LPT (l660 nm, ∅=4 mm 2 , 40 mW, contact mode, 5 x 2.4 J/ cm 2 per point, 14.4 J/cm 2 per session) was applied on the palatal and commissural lesions (Fig. 2A-C).The lesion on the nasal mucosa was too deep and impossible to reach with the laser handpiece (Fig. 2D-E).On this area, LPT (∅ = 4 mm 2 , l780 nm, 70 mW, 3 x 2.1 J/cm 2 per point, 6.3 J/cm 2 per session) was used on contact mode on the external area of the nose corresponding to the inner lesion (Fig. 1B).In addition, a single dose (l660 nm, ∅=4 mm 2 , 40 mW, contact mode, 5 x 2.4 J/ cm 2 per point, 14.4 J/cm 2 per session) was applied on the entrance of each nostril (Fig. 1B).The LPT protocol comprise applications 3 times/week during 4 weeks.
At the beginning of treatment, the patient showed improvement of all symptoms.Following the first LPT session, a decrease in pain was reported.Further improvement was seen after the 4th irradiation session.At this time, the oral mucositis score was 2, and the patient was capable of eating solids normally.Ten LPT sessions were necessary to heal all lesions (Fig. 3A-E), allowing the patient to carry on his routine daily activities.

DISCUSSION
To date, oral mucositis treatments are only palliative and include administration of topical antimicrobial agents, vitamins, growth factors, mouthwashes, cryotherapy and LPT (12).LPT is based on nonthermal effects of light on biological tissues, and its use in the prevention and treatment of mucositis induced by antineoplastic treatment has presented promising results, especially in clinical studies (1,3,4,13).The effect of LPT is based on its ability to modulate several metabolic processes.Visible laser energy is absorbed by chromophores in the respiratory chain of the mitochondria, with an increase in ATP production resulting in increased cellular proliferation and protein synthesis, accelerating tissue repair (14).
Campos et al. ( 3), reported improvement in the quality of life of an oncological patient by LPT after 5 irradiation sessions when the mucositis score was 2. In the present case, the patient showed a decrease in pain after the 1st LPT session and after 4 sessions the mucositis score was lowered from 3 to 2. LPT caused an analgesic and anti-inflammatory effect, improving quality of life, reducing the need for analgesics and the medical costs for the patient (15).Prophylactic use of LPT seems to be more effective than when it is used following the establishment of the disease, although the reason is not entirely clear (16).The patient of this case was referred to the Laser Center by the oncologist only after the oral mucositis lesions had been established.Therefore, LPT was used to minimize mucositis progression.LPT was proven beneficial, permitting that more patients can complete RT treatment with no major intercurrences.In the present case, the patient completed all RT sessions without interruption.It is important to highlight that, in addition to avoiding the antineoplasic treatment interruption, the pain relief also resulted in essential  improvements of basic oral functions, such as drinking, eating, swallowing and speech.The use of LPT avoids the need of parenteral feeding, as observed in cases of advanced mucositis (WHO OTS score 4), which demand hospital care.Accordingly, Zanin et al. (1) and Lopes et al. (17) reported that in their studies all patients under RT who received LPT completed the planned RT treatment, whereas patients not treated with LPT had to interrupt the RT because of decreased immunity caused by secondary asthenia and deglutition difficulties, which impacted their survival.Several protocols have been used for treating oral mucositis and the observed results sometimes differ (1,3,4,13,16,17).It is necessary to standardize the protocols for prevention and treatment of this condition in order to make different studies comparable.
In the case described in this paper, LPT was proven a safe and effective method for treating oral mucositis as it resulted in pain relief, promoted healing of the lesions and reduced their severity, allowing the patient to eat normally and carry on his routine activities.The improvement in the patient's quality of life and the maintenance of the RT must be considered as important factors for the treatment outcome.Long-term and randomized controlled clinical trials are necessary to establish preventive and curative protocols using LPT.

Figure 1 .
Figure 1.Radiotherapy Delimitation.A = Radiographic view of the area of the head treated with radiotherapy; B = Clinical photoerythema (arrows) and points of irradiation of the nasal mucosal lesion with l780 nm and l660 nm lasers.

Figure 3 .
Figure 3. Clinical aspect before 10 laser phototherapy sessions.A-B = Right and left comissura; C = Palate; D-E = Right and left nasal mucosa.