Clinical trial NCT06217224: Evaluation of Prophylactic Photobiomodulation Therapy in Patients With Osteosarcoma
Official title: Evaluation of Prophylactic Photobiomodulation Therapy in Patients With Osteosarcoma Undergoing High Doses of Methotrexate
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Mucositis Oral
Keywords: osteosarcoma
Mucositis Oral
Methotrexate Toxicity
Low-Level Light Therapy
Lead sponsor: Instituto Nacional de Cancer, Brazil
Sponsor class: OTHER_GOV
First posted: 2024-01-22
Enrollment: 53
Sex: ALL
Maximum age (years): 19
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 3, randomized study with patients diagnosed with OS, enrolled at INCA, candidates for the Glato protocol (chemotherapy -doxorubicin, cisplatin, dexamethasone and MTX + surgery). Patients will be randomized through the computerized system to groups 1 or 2.

Randomization will be performed in permuted blocks.
Primary purpose: PREVENTION

Brief summary: This study aims to evaluate the photobiomodulation therapy (PBMT) for the prevention of oral mucositis in osteosarcoma patients submitted to high doses of methotrexate, through two different protocols. As a hypothesis, photobiomodulation for the prevention of oral mucositis after cycles of Cisplatin, Doxorubicin and Methotrexate is more effective than just the application of preventive low-power laser after Methotrexate alone.

Detailed description: This is a phase 3, randomized study, with patients diagnosed with osteosarcoma, enrolled at national cancer institute in Brazil (INCA), candidates for the Glato protocol (chemotherapy with doxorubicin, cisplatin, methotrexate and surgery). Patients will be randomly randomized in permuted blocks to groups 1 or 2. After confirming the eligibility criteria, patients will be invited to participate in the research before starting treatment and the TCLE/TALE will be applied in accordance with the Good Clinical Practice Guide and national ethical standards.

After signing the TALE/TCLE, patients will be instructed to perform oral hygiene after all meals, solid or liquid, with fluoridated toothpaste. On the first day of chemotherapy, in addition to the oral hygiene protocol, patients will be instructed to rinse their mouth twice a day with 0.12% chlorhexidine for 7 days. Once hyposalivation is diagnosed, patients will use oral humidifying gel four times a day (brand provided by the institution).

Photobiomodulation therapy

* Preventative photobiomodulation therapy will be performed with the MMO device (São Carlos, São Paulo, Brazil), with an indium gallium aluminum phosphide (InGaAlP) diode with radiation emission in the red region of the electromagnetic spectrum (660 nm) with power of 100mW, with a beam area of 0.03cm². An energy of 1J/point and an energy density of 33.3 J/cm²/point were determined, which will be applied punctually, with a distance between points of 1cm, for 10s per point, totaling 9 points per region .
* The technique will be performed on the first day of methotrexate infusion and until the patient reaches a serum concentration equal to or lower than 0.3 mmol/L; on the days of doxorubicin and cisplatin infusion and the day after; and on the days of infusion of doxorubicin alone in weeks 24 and 28 of the Glato protocol. Photobiomodulation will be performed in all cycles of chemotherapy treatment depending on patient randomization.
* Group 1- Preventive photobiomodulation will be carried out on the day of methotrexate infusion and until the patient reaches a serum concentration equal to or lower than 0.3 mmol/L, from weeks 4, 5, 9, 10, 17, 18, 22, 23 , 26, 27, 30 and 31). On the days of infusion of doxorubicin and cisplatin and doxorubicin isoleted, patients will not receive photobiomodulation therapy.
* Group 2- Preventative photobiomodulation will be carried out on the days of doxorubicin infusion (weeks 1, 6, 14, 19, 24 and 28) and cisplatin (weeks 1, 6, 14 and 19) and on the day after doxorubicin infusion and cisplatin (weeks 1, 6, 14, 19), on the days of infusion of doxorubicin isoleted, weeks 24 and 28, photobiomodulation will be performed only on the first and second day. The technique will also be performed on the day of methotrexate infusion and on subsequent days until the patient reaches a serum concentration equal to or less than 0.3 mmol/L, from weeks 4, 5, 9, 10, 17, 18, 22, 23 , 26, 27, 30 and 31).
* If the patient presents oral mucositis Grade 1, 2, 3 or 4, they will receive treatment with the MMO device (São Carlos, São Paulo, Brazil), with an indium gallium aluminum phosphide diode (InGaAlP) with radiation emission in the red region of the electromagnetic spectrum (660 nm) with a power of 100mW, with a beam area of 0.03cm². An energy of 2J/point and an energy density of 66.6 J/cm²/point were determined, which will be applied punctually, for 20s per point in the area with MO and in healthy areas.
* The regions treated with laser of the oral mucosa will be: right and left buccal mucosa, lower and upper lip, upper and lower labial mucosa, right and left lateral border of the tongue, lingual belly, floor of the mouth and soft palate.
* Assessment of the patient's oral mucosa will be carried out by members of the research project team.

Oral assessment

Patients will be evaluated at the beginning of chemotherapy treatment (D1) and in a second moment between the third and seventh subsequent days (D3 to D7). In weeks 24 and 28, the dental evaluation will be carried out on D1 and between the second and seventh day (D2 to D7). In the weeks when the patient does not attend the hospital, a teleconsultation will be carried out to monitor the symptoms and, if a need for face-to-face evaluation is identified, an appointment will be scheduled.The mucous membranes will be evaluated for color, hydration, integrity, presence of oral mucositis and fungal, bacterial and viral infections.

The assessment of oral mucositis will be established according to the 1979 World Health Organization (WHO) classification and the criteria established by Sonis et al in 1999 (OMAS). The WHO assessment scale is made up of: Grade 0 - no change (Absent); Grade 1 - presence of erythema; Grade 2 - presence of erythema and ulcers, but the patient is able to ingest solids and liquids; Grade 3 - presence of ulcers, but the patient can only ingest a liquid and pasty diet and Grade 4 - presence of ulcers and impossibility of ingesting solids or liquids.

The OMAS scale considers the presence and size of ulcerations/pseudomembranes and erythema. Ulcerations/pseudomembranes will be evaluated according to 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 3cm3. Erythema will be evaluated according to the following scores: 0 - when absent, 1 - when present but not severe and 2 - when present and severe. A daily calculation will be made of the sum of the weighted average of the ulcerated area and intensity of the erythema (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 A millimeter dental ruler will be used to measure the area.

Patients will be asked about the presence or absence of oral and oropharyngeal pain. Both will be classified according to CTCAE v5.0 into grades 1, 2 and 3, associated with the Visual Analogue Scale, where the value 0 corresponds to no pain and 10, the greatest pain. According to the standards established by the visual analogue scale, values from 0 to 3 correspond to mild pain, from 4 to 6 to moderate pain and from 7 to 10 to severe pain.

The collection of adverse events will only be directed to events of interest to the study, related to toxicities in the oral cavity. It is not expected that there will be collection and analysis of serious adverse events in this study.

Xerostomia will be assessed according to the presence or absence of complaints about this condition on the part of the patient, associated with sialometry according to CTCAE v5.0 in grades 1, 2 and 3, on the first day of each chemotherapy cycle and between the third and seventh day (D3 and D7) of the same week of chemotherapy. In weeks 24 and 28, salivary flow will be assessed on the first day (D1) and between the second and seventh day (D2 to D7).

Unstimulated saliva collection will be performed according to the method described by Davies et al. (2002) The patient will remain seated vertically in a comfortable place. The first saliva sample will be discarded and the rest will be collected in a decontaminated bottle. The collected saliva will be converted into ml/minute and an unstimulated salivary flow of less than 0.1mL/min will be considered hyposalivation. Clinical criteria will also be used to identify xerostomia, such as sublingual salivary lake, salivary thickening and adherence of the wooden spatula to the oral mucosa, associated with the patient's complaint.

Eligibility criteria: Inclusion Criteria:

* Patients enrolled at INCA diagnosed with OS (ICD10-C41), aged 0 to 19 years;
* Patients with indication for Glato chemotherapy protocol, which will use high doses of MTX (HD-MTX (\>1 g/m2).
* Patients who, after receiving information and instructions, signed the patient's informed consent/assent form, in accordance with Resolution 466/12 of the National Health Council.

Exclusion Criteria:

- Patients who do not agree with the proposed treatment.

Primary outcomes:
measure: Evaluate the best photobiomodulation protocol for preventing oral mucositis
timeFrame: Throughout the entire glato protocol.
Secondary outcomes:
measure: Incidence of Oral Mucositis
timeFrame: From the first day of infusion of each chemotherapy agent to the third and seventh day of the same week of infusion throughout the entire glato protocol.
measure: Oral mucositis development time
timeFrame: From the first day of infusion of each chemotherapy agent to the third and seventh day of the same week of infusion throughout the entire glato protocol.
measure: Assess salivary flow
timeFrame: From the first day of infusion of each chemotherapy agent to the third and seventh day of the same week of infusion throughout the entire glato protocol.
measure: Methotrexate serum levels
timeFrame: From the first day of meotrexate infusion until serum regularization.
measure: Hospital internment
timeFrame: Throughout the entire glato protocol.
Other outcomes:
Locations:
city: Rio De Janeiro
country: Brazil
facility: National Cancer Institute
Study officials:
affiliation: National Cancer Institute (NCI)
name: Heliton S Antunes, Dr.
role: STUDY_DIRECTOR
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