Low Power Laser Therapy As Prevention Of Oral Mucositis And Oropharyngeal Pain In Patients Undergoing Allogenetic HSCT

This is a phase III, double-blind, randomized study that will use low-power laser to prevent oral mucositis and oropharyngeal pain in two protocols with different dosimetry (divided into Group A and Group B).

The groups will be composed of patients evaluated in the Odontology Section of INCA, based on referrals from the Onco-Hematology team at the institution. After confirming the eligibility criteria, patients will be invited to participate in the research between the period of the pre-HSCT evaluation dental consultation and hospitalization for HSCT conditioning, and the TCLE will be applied according to the Good Clinical Practices Guide and the national ethical regulations. The TCLE must be applied before the D-7 or at the D-7 (beginning of conditioning). Randomization (simple) will be performed in permuted blocks using the REDCap® program, after inclusion in the study, by a member of the non-blinded team.

The pre-HSCT dental evaluation, according to the institutional routine, will consist of: intraoral physical examination performed by a dental surgeon (main researcher or another designated by him), radiographic examination (panoramic radiography) and pre-HSCT dental treatment (For example: resolution oral mucosa infections; removal of sources of trauma; scaling and root planing of teeth with 4-5mm periodontal pocket; restoration of minor carious lesions; adjustment or replacement of defective restorations; endodontic treatment of carious lesions with pulpal involvement, asymptomatic periapical lesion <1mm; extraction of teeth with abscesses, periapical lesion ≥1mm, or periodontal pocket ≥6mm, furcation lesion, mobility ≥2mm, partially erupted teeth, root remnants, intraosseous lesions, abnormalities such as root resorption; poorly fitting or removing prostheses adapted).

Participation in the study will end on the date of the "take" of the bone marrow. After that date, participants who present with oral mucositis will receive standard treatment according to the hospital's routine and will be followed up until the resolution of the event (More details in the section "Treatment of oral mucositis").

Prophylactic low-power laser therapy protocol

• The application of the low-power laser will be performed by a dental surgeon (main researcher or another designated by him), on weekdays, starting on the first day of conditioning (D-7) and ending on the day of "take the tooth". marrow" (patient presents 500 neutrophils for three consecutive days, the third consecutive day being considered the catch), which occurs on average between D+14 and D+21;
• In the extraoral application, the treated region will be the bilateral carotid triangle, limited by the superior belly of the omohyoid, posterior belly of the digastric and by the anterior margin of the sternocleidomastoid muscle.
• In the intraoral application, the treated regions of the oral mucosa will be: right and left buccal mucosa, lower and upper lip, upper and lower labial mucosa, right and left lateral edge of the tongue, lingual belly, buccal floor and soft palate.
• A power meter (Handheld Laser Power Meeter (RoHS) will be used weekly to assess the conditions of the device.
• The laser pointer will be disinfected with a 70% alcoholic solution, coated with a PVC film and disinfected with a 70% alcoholic solution. After the application of the laser, the PVC film will be removed and discarded, and then a new disinfection with 70% alcoholic solution of the device will be carried out;
• Patients and dentists will use protective eyewear, for individual use, with total light blocking during laser application, which will also be disinfected with a 70% alcoholic solution before and after use;
• The dentists responsible for applying the LBP will be previously trained;
• Patients and dentists responsible for evaluating patients will be blinded to the study, that is, they will not know what treatment the patient will receive. The mucositis evaluation step (blinded team) must occur before the laser application step (non-blinded team).

Oral hygiene protocol during HSCT Patients will be instructed to perform oral hygiene after all meals, solid or liquid, upon awakening and before going to sleep. In cases of exclusive use of TPN, patients will be instructed to brush their teeth three times a day. Oral hygiene will be carried out daily, from D-7 to taking the medulla, with a soft or extra soft brush and fluoride toothpaste.

Patients will be instructed to perform mouthwashes with a 0.12% chlorhexidine digluconate solution, a non-alcoholic solution, twice a day, from D-7 until the marrow takes hold.

The oral hygiene kit (toothbrush and toothpaste), 0.12% chlorhexidine digluconate solution will be routinely provided by the hospital to patients.

Signs of fungal infection will be considered, the characteristics of pseudomembranous and erythematous candidiasis described by Neville et al., (2016), where pseudomembranous candidiasis presents itself in the form of white, softened, detachable plaques, while the erythematous one is shown as red spots. From the diagnosis of fungal infection, patients will be treated according to the sector's routine and medical prescription.

Viral infections will be those that present themselves as multiple small and erythematous papules, which form groups of vesicles filled with liquid, which rupture, forming ulcers, which then form crusts within 2 days, thus characterizing a picture of herpes simplex. From the diagnosis of viral infection, patients will be treated according to the sector's routine and medical prescription.

Evaluation of oral mucositis The evaluation of oral mucositis will be carried out daily on weekdays, from D-7 until marrow attachment, by a blind sub-investigator, dental surgeon, previously designated by the main researcher, through intraoral physical examination. Weekly intraoral photographs will be taken from the first day of evaluation.

The WHO and OMAS scales will be used for the evaluation of oral mucositis. The WHO mucositis assessment scale consists of: grade 0, the patient does not have ulcers or erythema in the oral mucosa; grade 1, the patient does not have ulcers, but has erythema; grade 2, the patient has mouth ulcers, but manages to ingest solid foods and liquids; grade 3, the patient has mouth ulcers, but is able to ingest only liquid foods and in grade 4, the patient has mouth ulcers and is unable to ingest solid foods and liquids.

On the OMAS scale, the anatomical structures (upper and lower lips, right and left buccal mucosa, right and left tongue sides, dorsum and belly of the tongue, floor of the mouth, hard and soft palates) are scored according to the area of ulcerations and pseudomembranes, with the aid of a dental millimeter ruler (0: absent; 1: 1cm²; 2: 1 to 3cm² and 3: 3cm²) and erythema (0: absent; 1: Moderate and 2: Severe). Thus, the daily calculation of the sum of the weighted average of the ulcerated area and erythema intensity will be performed (MP=2.5 x [(∑ui : 3 x Nu )+ (∑ei: 2 x Ne)], where ∑ui= sum of ulcerated area, Nu= number of ulcerated areas, ∑ei= sum of erythema intensity and Ne= number of areas with erythema.

Treatment of oral mucositis From the diagnosis of oral mucositis, the patients will receive the therapeutic laser therapy protocol in the lesions, and will continue to receive the prophylactic in the other regions. The blind dentist (the evaluator) is the one who will define the moment of switching from the prophylactic to the therapeutic laser, according to the evaluation of the mucositis. The oral cavity assessment step (blinded team) precedes the laser application step (non-blinded team). The protocol will consist of daily applications (weekly working days), until the lesions are resolved, with an Indium-Gallium-Aluminum Phosphide (InGaAlP) laser diode, DMC, São Carlos, São Paulo, Brazil, with radiation emission in the region red light of the electromagnetic spectrum with 660nm, with power of 100mW, beam area of 0.09842 cm², 2J, 20.32J / cm².

Pain assessment The assessment of pain in the oral cavity will be performed daily, on weekdays, from D-7 until the marrow is taken, by a blind sub-investigator, dental surgeon, previously designated by the main researcher, according to the CTCAE scale v5.0 which classifies it as grade 1 (mild), grade 2 (moderate) with some limitation of daily activities and grade 3 (severe) with limitation of self-care in daily activities.

The assessment of pain in the oropharynx will be performed daily, on weekdays, from D-7 until the spinal cord is taken, by a blind sub-investigator, dental surgeon, previously designated by the main researcher, according to the CTCAE v5 scale .0, which classifies it as Grade 1 (mild pain), Grade 2 (moderate pain; altered oral intake; no use of narcotics; with topical analgesics started) and Grade 3 (severe pain; severely altered eating/swallowing; narcotics started; requires parenteral nutrition).

The CTCAE v5.0 scale will be associated with the pain scores of the Visual Analog Scale, where a value of 0 corresponds to the absence of pain and 10, the worst pain imaginable (Image 2). Will be considered: Absence of pain (zero); from 1 to 2 equivalent to a mild pain; from 3 to 7 moderate pain; and from 8 to 10, severe pain. Patients will be treated according to the sector's routine and medical prescription.

Dysphagia assessment Dysphagia assessment will be performed daily, on weekdays, from D-7 until marrow attachment, by a blind sub-investigator, dental surgeon, previously designated by the main researcher, according to the CTCAE v5.0 scale. They will be classified as: Absence of dysphagia (asymptomatic and able to eat a regular diet); Grade 1 (symptomatic, able to eat regular diet); Grade 2 (symptomatic with change in diet); Grade 3 (severely altered swallowing; TPN feeding); Grade 4 (Life-threatening consequences; urgent intervention indicated); and Grade 5 (death). Patients will be treated according to the sector's routine and medical prescription.

Evaluation of the use of total parenteral nutrition The presence or absence of TPN will be evaluated, and in cases where it is prescribed, the date of its onset until the marrow is taken will be recorded.

Evaluation of opioid use The presence or not of continuous prescription of opioids for the oral cavity/oropharynx will be evaluated, until the medulla takes hold. In cases where there is a prescription, the start date, substance and dosage will be recorded. The prescription will be carried out according to the sector's routine and medical prescription.

Data collect The data of interest will be collected from physical records and electronic systems of the institution, through standardized forms and will be included in REDCap®, an electronic data collection system, in customized forms for this research project.

In the clinical evaluation form 1 (Appendix 1) data will be recorded regarding age (in years), date of birth, sex (female and male), underlying disease, associated comorbidities, date of hospitalization for HSCT, conditioning protocol , conditioning start date, HSCT date, marrow take date, length of stay during HSCT (considering the start of conditioning) and drugs prescribed for GVHD prophylaxis.

In the clinical evaluation form 2 (Appendix 2), data referring to the mucositis evaluations by the WHO and OMAS, visual analogue scale for pain in the oral cavity and oropharynx, CTCAE v5.0 scale for pain in the oral cavity, oropharynx and dysphagia, TPN and use of opioids.