Extraoral and intraoral light therapy comparable in child cancer trial

A randomized trial in children and adolescents receiving high-dose methotrexate found that extraoral photobiomodulation produced clinical outcomes comparable to intraoral treatment for preventing oral mucositis, while requiring far less time at each session. Among 155 analyzed patients, oral mucositis developed in 35.5% of the study population. The occurrence was 30.5% with extraoral photobiomodulation and 41.1% with the intraoral approach, a difference that was not statistically significant. The findings support extraoral red-light therapy as a practical alternative for pediatric oncology patients, although the study did not include an untreated control group and was conducted at one hospital.

The prospective, single-blind randomized study was conducted at a reference pediatric oncology hospital between July 2022 and July 2025. It enrolled patients aged 1 to 18 years who were receiving high-dose methotrexate for leukemia, lymphoma, or osteosarcoma. Of 174 patients assessed for eligibility, 172 were randomly assigned, and 155 remained in the analysis after 17 participants missed both the day-5 and day-10 follow-up assessments. The analyzed cohort comprised 73 patients assigned to intraoral photobiomodulation and 82 assigned to extraoral photobiomodulation. Patients and treating operators could not be blinded because the interventions differed physically, but oral assessments were conducted by a trained examiner who did not know the participants’ group assignments.

Both treatment protocols used 660-nanometer red light from diode laser devices, with equivalent stated dosimetry of 100 milliwatts and 1 joule per application point. In the intraoral group, the laser contacted the mucosa directly and was applied to sites including the buccal and labial mucosa, floor of the mouth, tongue, soft palate, and corners of the mouth. Each point received 1 joule over 10 seconds, corresponding to an energy density of 10 joules per square centimeter. This approach required about six minutes of effective irradiation per session. The extraoral device contained eight emitters and was placed in contact with the skin at the bilateral cheek regions and the orbicularis oris muscle. Its effective irradiation time was 30 seconds per session.

Preventive treatment began one day before chemotherapy and continued daily throughout the hospital stay, generally for three to five days. All participants and their caregivers received standardized oral-hygiene instructions, including gentle brushing with a soft-bristed toothbrush and fluoride toothpaste three times daily and flossing at least once daily. No mouthwash was prescribed. Patients who developed mucositis could receive additional intraoral photobiomodulation as rescue treatment regardless of their original assignment, but all analyses followed the groups to which participants had initially been randomized. Oral mucositis was assessed on the day before chemotherapy and on days 3, 5, and 10 after treatment began, using the World Health Organization Oral Toxicity Scale, which ranges from no alteration to ulceration with an inability to tolerate oral feeding.

Most patients remained free of clinically important mucositis, and the study detected no statistically significant difference between treatment modalities in either occurrence or severity. Occurrence was 41.1% in the intraoral group and 30.5% in the extraoral group, with a p-value of 0.168. Severity comparisons also failed to reach statistical significance on day 3, day 5, or day 10, with p-values of 0.826, 0.056, and 0.057, respectively. Only 7.4% of patients evaluated on day 10 had severe mucositis, defined as World Health Organization grades 3 or 4. Although exploratory comparisons showed fewer advanced lesions and a larger mucositis-free proportion in the extraoral group at later follow-up, those descriptive differences were not statistically significant and should not be interpreted as evidence that one method was superior.

Patient-reported or caregiver-reported pain remained minimal overall. Median pain scores were zero in both groups at every assessment, and the groups did not differ significantly on days 3, 5, or 10. Among the 55 patients who developed mucositis, pain was generally mild to moderate and peaked on day 5: the median score was 3 in the intraoral group and 1 in the extraoral group, with no statistically significant difference at any follow-up point. Salivary pH also remained near neutral and stable in both groups, with no significant between-group differences. Baseline visible plaque measurements were comparable, as were the median treatment durations of four days in each group. These secondary findings indicate that the two protocols produced broadly similar oral and patient-experience outcomes under the study conditions.

Multivariable ordinal logistic regression further indicated that treatment modality was not independently associated with mucositis severity on day 10. Instead, greater age and higher methotrexate dose were associated with more severe disease. For each additional year of age, the odds ratio for greater severity was 1.14, with a 95% confidence interval of 1.04 to 1.25 and a p-value of 0.004. For each increase in methotrexate dose, the corresponding odds ratio was 1.24, with a 95% confidence interval of 1.03 to 1.49 and a p-value of 0.021. Age and dose were entered into separate models because dose information was available for only 80 patients, 61 of whom completed the day-10 assessment. Among those with dose data, patients who developed mucositis had received higher doses than those who did not.

The study’s authors suggest that comparable performance may reflect effects that are not limited to direct illumination of damaged oral tissue. Possible mechanisms include modulation of inflammatory activity, changes in microcirculation, and effects on cellular redox state, all of which could potentially be influenced by transcutaneous light delivery. They also note that tissue attenuation and scattering make the dose reaching the oral mucosa difficult to estimate during extraoral irradiation. Although the reported protocols used 660-nanometer red light, near-infrared wavelengths may penetrate more deeply and could offer advantages in future extraoral trials. Such proposals remain hypotheses because the present study did not compare wavelengths or directly measure light dose at the oral mucosa.

Extraoral delivery nevertheless offers a marked practical advantage: the effective treatment time was 30 seconds rather than approximately six minutes, excluding the time needed to position and handle patients. The approach also avoids placing a laser directly against sensitive or injured oral tissues. That could make it more feasible for children who have difficulty opening their mouths, cooperating with treatment, or tolerating an intraoral procedure. The study used strict infection-control measures for both methods, but the authors argue that a non-invasive skin-based protocol may reduce opportunities for cross-contamination while permitting broader coverage. These features do not establish superior efficacy; rather, they make extraoral photobiomodulation a potentially more convenient option when comparable prevention is the main aim.

Several limitations constrain how broadly the results can be applied. The trial was not prospectively registered, was conducted at a single center, and could not blind participants or operators. Randomization produced a baseline age imbalance: the intraoral group had a median age of eight years, compared with six years in the extraoral group, and the authors state that this difference likely arose by chance. Adjusting for age reduces but cannot eliminate possible residual confounding. Methotrexate dose was missing for roughly half the cohort, caregiver reports may be less precise than children’s self-reports for very young patients, and the absence of a no-photobiomodulation group means the trial established similarity between the two protocols rather than quantifying either protocol’s absolute preventive effect against natural mucositis rates. Even with those caveats, the randomized comparison, blinded outcome assessment, low pain scores, and similar oral outcomes show that extraoral red-light photobiomodulation is a credible alternative to intraoral treatment in children receiving high-dose methotrexate. Multicenter trials using standardized wavelengths, application sites, and dosimetry are needed to confirm the finding and optimize pediatric protocols.

Subject of Research: Comparison of extraoral and intraoral photobiomodulation for preventing oral mucositis during high-dose methotrexate treatment in pediatric oncology

Article Title: Comparable efficacy of extraoral and intraoral photobiomodulation in preventing oral mucositis during high-dose methotrexate therapy in pediatric oncology: A single-blind randomized controlled trial

Article References: Freitas, I. D. O. P., Schuartz, I., Renz, G. L. K., Mobile, R. Z., França, M. L. S., Pianovski, M. A. D., Sassi, L. M., & de Araujo, M. R. (2026). Comparable efficacy of extraoral and intraoral photobiomodulation in preventing oral mucositis during high-dose methotrexate therapy in pediatric oncology: A single-blind randomized controlled trial. Supportive Care in Cancer, 34(11), Article 1125. https://doi.org/10.1007/s00520-026-11372-9

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11372-9

Keywords: pediatric oncology, oral mucositis, photobiomodulation, high-dose methotrexate, red-light therapy, childhood cancer, randomized clinical trial, supportive care, Comparable, efficacy, extraoral, intraoral