Safety and Tolerability of the Use of Copaiba in Patients With Oral Cancer Submitted to Radiotherapy

This study aims to propose an alternative and auxiliary methodology for the prevention and treatment of Oral Mucositis (OM) in patients undergoing radiotherapy or radio and chemotherapy for head and neck neoplasms through the use of copaiba-based mouthwash, since the treatment that currently has proven efficacy for the prevention of OM(Low Power Laser Therapy) cannot be applied in tumor regions due to the risk of stimulating the tissue proliferation of malignant cells.

This is a phase I study, carried out in a single institution to assess the safety and tolerability of using the aqueous copaiba solution for mouthwash in 03 to 36 patients diagnosed with cancer in the oral cavity.

In the selection/baseline period, the investigator or professional designated by him will assign a unique number to the patient being evaluated to participate in the study.

The investigator or professional designated by him may register the patient as soon as the eligibility for participation is confirmed and he signs the free and informed consent form. The patients included in the study will receive instructions on oral hygiene and the aqueous copaiba solution for mouthwash.

The recruitment and design of the study will be carried out according to the "3 + 3" design (modified Fibonacci design) with the planned inclusion of 6 successive cohorts (of 3 patients) with different patients. Each cohort of patients will be closely monitored for one week before moving on to a new cohort. There will be no dose escalation in the same patient. The concentration of the aqueous copaiba solution and the frequency of the mouthwash will be considered dose.

Patients will be treated according to the dose levels listed below, from the first day of radiation therapy:

* Cohort 1: 3 to 6 patients will be instructed to rinse with the solution 10% copaiba water, twice a day, for a period of 33 to 37 days\*.
* Cohort 2: 3 to 6 patients will be instructed to rinse with the solution 10% copaiba water, 3 times a day, for a period of 33 to 37 days\*.
* Cohort 3: 3 to 6 patients will be instructed to rinse with the solution 10% copaiba water, 4 times a day, for a period of 33 to 37 days\*.
* Cohort 4: 3 to 6 patients will be instructed to rinse with the solution 15% copaiba water, twice a day, for a period of 33 to 37 days\*.
* Cohort 5: 3 to 6 patients will be instructed to rinse with the solution 15% copaiba water, 3 times a day, for a period of 33 to 37 days\*.
* Cohort 6: 3 to 6 patients will be instructed to rinse with the solution 15% copaiba water, 4 times a day, for a period of 33 to 37 days\*.

  * If radiotherapy is interrupted for any reason and the patient is having benefit with the use of the copaiba mouthwash, the patient will continue the performance of the mouthwash during the period of interruption.
  * It will be admitted that in the D1 of radiotherapy/use of the copaiba mouthwash the patient performs only one of the mouthwashes described by the protocol.

Criteria for defining dose-limiting toxicity (DLT) Safety Safety assessments will be carried out by monitoring and recording all adverse events (AEs), including serious adverse events.

Adverse events For this protocol, an AE was defined as the appearance of undesirable medical signs, symptoms or conditions or worsening of existing ones, occurring from the signing of the informed consent form until the end of the study, even if the event is not considered as related to the interventions of the study.

AEs will be classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, except for the event of interest in this study - oral mucositis - which will be classified according to the Organization's oral mucositis scale World Health Organization (WHO).

The degree of OM according to the classification of the WHO of 1979, is subdivided into Degree 0 - No alteration (Absent); Grade 1 - Presence of erythema, Grade 2 - Presence of erythema and ulcers, but the patient can eat solid and liquid; Grade 3 - Presence of ulcers, but the patient can only eat a liquid and pasty diet and Grade 4 - Presence of ulcers and the ingestion of solids or liquids is impossible.

In this study, the criteria for defining DLT were established, as well as criteria for temporary interruptions of treatment with copaiba as described below.

Oral mucositis If oral mucositis grade 3 occurs in the first week of treatment in the tumor area, which will not be treated with laser therapy, treatment with copaiba will be interrupted for 1 week and symptomatic treatment with dipyrone and mouthwash with dexamethasone should be prescribed. If oral mucositis grade 4 occurs in the first week of treatment in the tumor area, which will not be treated with laser therapy, treatment with copaiba will be interrupted for 2 weeks and symptomatic treatment with dipyrone and mouthwash with dexamethasone should be prescribed. If the problem is resolved (or stabilized to a degree ≤ 2) within a maximum of 2 weeks, treatment may be restarted at the same dose level. If the problem persists for more than 2 consecutive weeks or 3 non-consecutive weeks, the respective patient should be discontinued from treatment (dose-limiting toxicity) and continue treatment with laser therapy, in areas not involved by the tumor, daily until the end of radiotherapy and with radiotherapy and cisplatin at the discretion of the attending physician.

If grade 2, 3, or 4 oral mucositis occurs after the second week of treatment in the tumor area, which will not be treated with laser therapy or in another region of the oral cavity receiving laser therapy, copaiba treatment will be maintained and treatment symptomatic with dipyrone or opioid should be prescribed.

Pain The pain will be classified according to CTCAE v5.0, associated with the Visual Analogue Scale, where a value of 0 corresponds to the absence of pain and 10, the greatest pain he can imagine. According to the standards established by the scale, values from 0 to 3 correspond to mild pain, from 4 to 6 to moderate pain, and from 7 to 10, severe pain.

In the absence of oral mucositis, if the patient reports pain in the grade 3 oral cavity, for the first time, in the first week of treatment in the tumor area, which will not be treated with laser therapy, the copaiba treatment will be interrupted for 1 week and one symptomatic dipyrone treatment should be prescribed. If pain in the grade 4 oral cavity occurs in the first week of treatment in the tumor area, which will not be treated with laser therapy, copaiba treatment will be interrupted for 2 weeks and symptomatic treatment with dipyrone or opioid should be prescribed.

In the absence of oral mucositis if the problem is resolved (or stabilized to a degree ≤ 2) within a maximum period of 2 weeks, treatment may be restarted at the same dose level. If the problem persists for more than 2 consecutive weeks or 3 non-consecutive weeks, the respective patient should be discontinued from treatment (toxicity limiting dose) and continue treatment with laser therapy, in areas not involved by the tumor, daily until the end of radiotherapy and with radiotherapy and cisplatin at the discretion of the attending physician.

In the presence of oral mucositis, the pain will not be considered dose-limiting toxicity (DLT), and if grade 2 or 3 oral pain occurs after the second week of treatment in the tumor area (which will not be treated with laser therapy) or in another region of the oral cavity receiving laser therapy, copaiba treatment will be maintained and symptomatic treatment with dipyrone or opioid should be prescribed.

If DLT is not observed in 3 patients at a given dose level, the dose will be escalated to the next level.

If the incidence of DLT is 33% (1 in 3 patients) 7 consecutive days, then 3 more patients will be treated with the same dose level. If DLT cases are not seen in these other 3 patients, then the dose will be escalated to the next level. Otherwise, the dose escalation will be stopped and recruitment will be terminated.

If the incidence of DLT is greater than 33% at a given level, then the dose escalation will be interrupted, the DLT will be defined as the maximum tolerated dose (MTD).

The patient will continue to be followed every two weeks (+/- 3 days) for eight weeks for safety assessment after the end of treatment with copaiba. Patients prematurely discontinued from the study treatment will only carry out the visit of discontinuation within seven days after the end of treatment. The end of treatment is defined such as the date of the safety assessment visit or discontinuation visit, whichever occurs first.

Radiotherapy and chemotherapy protocol

- Radiotherapy Radiotherapy (RT) will be performed according to the location of the tumor, using megavoltage radiotherapy with intensity-modulated radiotherapy techniques (IMRT). A total dose of 60 to 70 Gy will be applied daily between 30 to 35 fractions, 5 days a week, using IMRT or volumetrically modulated arc radiotherapy (VMAT).

The primary tumor and cervical lymph nodes will be treated with fields determined by imaging studies, with three-dimensional planning with image fusion (computed tomography, PET scan, or Resonance). The areas of macroscopic disease, as well as lymph node enlargement determined by images, will receive 70 Gy. The areas surrounding the injury will receive 59.4 Gy. The elective nodal areas will receive 56 Gy. In the case of postoperative adjuvant radiotherapy, the patient will receive 60 to 65 Gy according to the presence of compromised limits in the histopathological exam.

Radiation therapy will be suspended if patients present grade 4 dermatitis or weight loss greater than 10% and must be restarted after the clinical condition is restored, according to the protocol of the INCA Radiotherapy Service.

If the patient has a weight loss greater than 10%, he will receive nutritional support through a nasoenteral tube or gastrostomy.

- Chemotherapy Patients who have a clinical indication will be treated with cisplatin administered at a dose of 100mg / m², intravenously in 3 cycles of (more or less) 21 in 21 days.

Cisplatin will be suspended for one week if patients have grade 3 hematological toxicity, grade 2 nephrotoxicity, and grade 2 ototoxicity. In cases of grade 3 nephrotoxicity and grade 3 ototoxicity, cisplatin treatment will be discontinued, according to the protocol of the Clinical Oncology Section of INCA.

Oral hygiene protocol Patients will be instructed to perform oral hygiene after all meals, solid or liquid. In cases of exclusive use of a nasoenteral tube, patients will be instructed to brush their teeth three times a day. Oral hygiene will be performed with fluoridated toothpaste. From the tenth day of treatment with radiotherapy, patients will use an oral humidifying gel four times a day (Oral Balance®).

Low Power Laser Therapy The application of the LPLT will be carried out by the researcher responsible for the study in the Dentistry Section of INCA.

The assessment of the patient's oral mucosa will be performed by two dentists appointed by the principal investigator.

The application of the LPLT will start on the same day as the beginning of the RT and chemotherapy (CT), extending until the end of both and or the end of oral mucositis.

The application of LPLT will be performed daily, from Monday to Friday, before the radiotherapy session.

The application will be carried out with the DMC device (São Carlos, São Paulo, Brazil), with a gallium-aluminum indium phosphide diode (InGaAlP) with radiation emission in the red region of the electromagnetic spectrum (660 nm), with 100mW, with a beam area of 0.24cm². An energy of 1 J / point and an energy density of 4 J / cm² / point were determined, which will be applied punctually, with a distance between points of 1 cm, for 10s per point, totaling 9 points per region. A power meter (Handheld Laser Power Meeter (RoHS) will be used weekly to assess the condition of the device.

The treated regions of the oral mucosa will be: right and left cheek mucosa, lower and upper lip, upper and lower lip mucosa, right and left lateral border of the tongue, lingual belly, and buccal floor.

LPLT will not be performed in the tumor area. When patients have grade 2 oral mucositis, they will receive therapeutic LPLT with the energy of 2 J / point and energy density of 8 J / cm² / point.

Prevention of candidosis

Patients will use fluconazole 50 mg/day, orally, from Day 6 of radiotherapy until the end of it.

The aqueous solution of Copaiba

A 10% and 15% aqueous solution of copaiba (Copaifera Officinalis Resin) manufactured by Interativo Farmácia de Manipulação will be used, under the formula: 10% copaiba oil (Copaifera Officinalis Resin) and 15% liquid mint aroma 5% , tween 80 1%, Aqueous solution (Distilled water + 0.1% Nipagin) qsp 100%.

The product will be stored at room temperature and will be stored in the Dentistry Section of INCA.

Data collect

Patient data will be collected from physical and electronic medical records and will be transcribed to the specific clinical record of the study. The data of interest are age, sex (female and male), the education level (illiterate, elementary, middle and higher, complete or incomplete), underlying disease, the treatment used for the disease, with specification on the type of chemotherapy and radiotherapy performed, the dose received and fractionation, presence of associated comorbidities, adverse events, and data related to physical examination during the study. The presence of habits such as smoking and alcohol consumption (duration of the habit, daily amount, if the habit was abandoned or not; if so, for how long) will also be recorded. The data will be included in REDCap®, an electronic data collection system, in forms customized for this research project.

- Dental Evaluation

Patients will undergo daily intraoral physical examination from the beginning to the end of treatment, using the research form. Sialometry will be assessed weekly.

The mucous membranes will be evaluated for their color, hydration, integrity, presence of OM. The characteristics of pseudomembranous and erythematous candidiasis according to Neville will be considered signs of fungal infection. Pseudomembranous candidiasis appears in the form of white, creamy, detachable plaques and halitosis, while the erythematosus appears as red spots. Viral infections will be classified as those that present as multiple small and erythematous papules, which form clusters of liquid-filled vesicles, which break, forming ulcers in the sequence forming crusts within 2 days, thus characterizing herpes simplex.

The degree of OM will be established according to the classification of the World Health Organization (WHO) of 1979, which subdivides it into Degree 0 - No alteration (Absent); Grade 1 - Presence of erythema, Grade 2 - Presence of erythema and ulcers, but the patient can eat solid and liquid; Grade 3 - Presence of ulcers, but the patient can only eat a liquid and pasty diet and Grade 4 - Presence of ulcers and the ingestion of solids or liquids is impossible.

The investigators will also use the criteria established by Sonis et al in 1999, which considers the presence and size of ulcerations/pseudomembranes and erythema. Ulcerations/pseudomembranes will be assessed in the following scores: 0 - in the absence of lesions, 1 - in lesions smaller than 1 cm3, 2 - in lesions measuring between 1 and 3 cm3, and 3 - in lesions larger than 3 cm3. Erythema will be evaluated according to the following scores: 0 - when absent, 1 - when present, but not severe, and 2 - when present and severe.

On the Sonis scale, the daily calculation of the sum of the weighted average of the ulcerated area and the intensity of the erythema (MP = 2.5 x \[(∑ui: 3 x Nu) + (∑ei: 2 x Ne)\] will be performed, where ∑ ui = sum of the ulcerated area, Nu = number of ulcerated areas, ∑ei = sum of the erythema intensity and Ne = number of areas with erythema. A millimeter dental ruler was used to measure the area.

Since xerostomia is the term used to describe a subjective condition of dry mouth sensation due to the absence of saliva, the assessment of this item will be made according to the presence of the complaint about this condition or not by the patient, associated sialometry according to CTCAE v5.0.

Regarding pain, patients will be asked about its presence or absence. The pain will be classified according to CTCAE v5.0, associated with the Visual Analogue Scale, where a value of 0 corresponds to the absence of pain and 10, the greatest pain he can imagine. According to the standards established by the scale, values from 0 to 3 correspond to mild pain, from 4 to 6 to moderate pain, and from 7 to 10, severe pain.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years old.
* Patients enrolled at INCA with a diagnosis of cell carcinoma squamous, adenoid cystic carcinoma, mucoepidermoid carcinoma, carcinoma of acinar cells, low-grade polymorph adenocarcinoma, located in the oral cavity (ICD-10 C00 to C06); located in the oral cavity with the indication of exclusive radiotherapy (by IMRT/VMAT technique) or radiotherapy (by IMRT/ VMAT) associated with chemotherapy.
* Performance status (PS) 0 or 1.
* Patients with intact oral mucosa (except the tumor area) without color change and volume on the first day of treatment.
* Patients able to cooperate with treatment.
* Patients capable of performing the oral hygiene protocol.
* Patients who after the information and instructions signed the term of free and informed consent of the patient in accordance with Resolution 466/12 of the National Health Council.

Exclusion Criteria:

* Patients who are receiving drugs for the treatment and/or prevention of oral mucositis.
* Patients undergoing radiotherapy with planning that excludes the oral cavity of the treatment field.
* Patients undergoing palliative radiotherapy.
* Patients with cervical lymph node metastasis greater than 6cm (N3).
* Patients who report any type of allergy to copaiba-based compounds.
* Patients diagnosed with oral lichen planus.