Can Photobiomodulation Therapy Reduce Salivary Nitrite in Oral Mucositis? A Systematic Review

Background

Oral mucositis (OM) is a clinically significant inflammatory condition of the oral mucosa, characterized by progressive tissue damage that evolves from initial erythema to mucosal atrophy and ulceration, frequently accompanied by pseudomembranous formation. This cancer treatment-associated complication predominantly develops in cancer patients receiving chemotherapy (CT) and/or head and neck radiotherapy (RT) as part of their treatment regimen. ¹ Epidemiological data indicate that OM occurs in approximately 30–40% of cancer patients treated with CT. This incidence rises to 60–85% in patients undergoing hematopoietic stem cell transplantation (HSCT) and reaches nearly 90% in head and neck cancer (HNC) patients treated with combined RT and CT. ² The clinical manifestations of OM can lead to debilitating sequelae, including severe oral pain, functional impairments (dysphagia, odynophagia, and speech difficulties), and heightened susceptibility to local and systemic infections. These complications not only significantly impair patients’ quality of life but may also necessitate dose modifications or treatment interruptions, potentially compromising the therapeutic efficacy of anticancer regimens. ³ The pathogenesis of OM is closely associated with increased local production of reactive oxygen species (ROS).^4–6 While ROS play critical roles in normal physiological processes, such as bacterial clearance by phagocytes,^7,8 an imbalance or excessive ROS generation can result in significant tissue damage. This overproduction activates key transcription factors, including nuclear factor-kappa B (NF-κB) and Signal Transducer and Activator of Transcription 3 (STAT3), which subsequently induce the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta.^4–6

These cytokines, in turn, stimulate the production of nitric oxide (NO) through the upregulation of inducible NO synthase (iNOS). The resulting NO contributes to lipid peroxidation, protein oxidation, and enzyme inactivation, which collectively amplify inflammation and tissue damage. In addition, iNOS-derived NO enhances the expression of other pro-inflammatory mediators, such as TNF-α, IL-6, and CXC chemokines, further exacerbating the inflammatory response and tissue injury. ⁹

Photobiomodulation (PBM) has emerged as a promising therapeutic approach, utilizing low-level lasers or light sources in the red and infrared spectrum to achieve favorable clinical outcomes. PBM has demonstrated efficacy in both the prevention and treatment of OM by alleviating pain, promoting tissue repair, and modulating inflammatory processes. Moreover, PBM may influence immune system activity, further enhancing its therapeutic potential. ¹⁰ Based on this evidence, the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology (ISOO) have recommended PBM as a treatment modality for OM. ¹¹

Despite its potential, the broader application of PBM is hindered by limited understanding of the mechanisms underlying its interaction with biological tissues and significant variability in protocols and light sources used globally. Although research on PBM’s effects on oxidative stress in humans is still developing, existing studies suggest that PBM effectively reduces oxidative stress induced by physical exercise in muscle cells and in patients with rheumatoid arthritis.^12–14 Elevated nitrite levels, a byproduct of NO metabolism, serve as a reliable biomarker for oxidative stress and are strongly associated with inflammation and tissue damage. ¹⁵ Limited research has specifically explored the impact of PBM on oxidative stress, particularly nitrite levels, in the context of OM. To date, the literature lacks review studies that specifically evaluated the effect of PBM on oxidative stress, especially nitrite levels, in the context of OM. Hence, this review aims to evaluate the effect of PBM therapy on nitrite levels in patients with OM.

Materials and Methods

This systematic review was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ¹⁶ and registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251053529.

Data collection process

A standardized extraction protocol was implemented to collect key study characteristics from eligible publications. The extracted variables comprised first author name, year of publication, tumor type, anticancer treatment regimen, sample size, control group characteristics, PBM device specifications, irradiation parameters (wavelength, power density, energy density), number of treatment points, and PBM administration schedule relative to cancer therapy. These data were systematically organized into a comparative table (Table 1) to facilitate analysis.

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Table 1.

General Characteristics of the Included Studies with Detailed Information About the Subjects and Intervention Methods

Author/date	Tumor\therapy	Sample size	Comparison group	Type of PBM device	Wave length	Energy density	PBM duration	Power	Irradiation points	Timing
Salvador et al., 2017 17	Hematological malignancies undergoing high-dose chemotherapy, with or without radiotherapy	51 patients	Only standard oral hygiene guidelines	InGaAlP	660 nm	4 J/cm2	4.0 s per point	40 mW	The laser was applied to 10 specific intraoral sites, including the upper and lower labial mucosa, right and left buccal mucosa, right and left lateral tongue, ventral tongue, and floor of the mouth	Treatment began on the first day of the conditioning regimen and was administered daily until the seventh day post-transplant (D + 7)
Martins et al., 2021 18	Head and neck cancer undergoing radiotherapy (RT), either alone or in combination with chemotherapy	48 patients	Placebo treatment alongside standard preventative oral care program	InGaAlP	660 nm	6.2 J/cm2	10 s at each point	25 mW	The laser was administered at multiple intraoral sites, including: - Buccal mucosa (10 points per side) - Labial mucosa (4 points per lip) - Hard palate (3 points) - Lateral tongue surfaces (10 points per side) - Soft palate (3 points) - Dorsal tongue (3 points) - Floor of the mouth (2 points) - Labial commissures (1 point per side)	Treatment was initiated on the first day of radiotherapy, with subsequent sessions performed three times per week on non-consecutive days, always prior to each RT session, and continued until the completion of radiotherapy
Khalil et al., 2025 19	Digestive tract cancer\ chemotherapy	45 patients	Preventative oral care program, Intraoral PBM, Intraoral & Extraoral PBM	Diode laser	635 nm\635 nm+ 980 nm	4 J/cm2	20 s at each point	100 mW	Intraoral PBM: - Buccal mucosa (4 points per side, 8 total) - Labial mucosa (2 upper, 2 lower, 4 total) - Tongue (3 right side, 3 left side, 2 ventral surface, 8 total) - Floor of the mouth (2 points) - Soft palate (2 points) Extraoral PBM targeted six points on the neck	Treatment commenced on the same day as the first chemotherapy session, prior to its initiation

Results

PRISMA flowchart

A visual representation of the study selection process was generated using the PRISMA 2020 flowchart template (available at (www.prisma-statement.org/prisma-2020-flow-diagram) ¹⁷ (Fig. 1).

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FIG. 1.

flow chart for the included studies.

Salvador et al. evaluated the effect of PBM on salivary nitrite levels in patients undergoing HSCT using a 660 nm InGaAlP diode laser (40 mW, 4 J/cm², 0.16 J per point) and found that PBM significantly reduced nitrite levels. ¹⁸ Martins et al. examined the effect of PBM on salivary nitrite levels in head and neck cancer patients undergoing RT using a 660 nm InGaAlP diode laser (25 mW, 6.2 J/cm², 0.25 J per point) and noted a trend toward stabilized nitrite levels in the PBM group during the initial phases of treatment, although the results were not statistically significant. ¹⁹ Khalil et al. examined the effect of PBM on salivary nitrite levels in patients with gastrointestinal cancers undergoing CT. They utilized an intraoral laser alone (635 nm, 100 mW, 4 J/cm²) and a combination of an intraoral laser (635 nm, 100 mW, 4 J/cm²) with an extraoral laser (980 nm, 100 mW, 4 J/cm²). The study observed a statistically significant decrease in salivary nitrite levels in both laser-treated groups compared with the control group. ²⁰

Risk of bias assessment

The methodological rigor of the included studies was systematically evaluated using the Revised Cochrane Risk of Bias tool for Randomized Trials (RoB 2.0) (Fig. 2). This comprehensive assessment examined potential sources of bias across multiple domains, including the randomization procedure, adherence to planned interventions, handling of incomplete outcome data, objectivity of outcome measurement, and transparency in results reporting. The evaluation aimed to identify any systematic errors that could affect the validity of the study findings.

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FIG. 2.

Cochrane Risk of Bias for Randomized Trials (RoB 2.0) tool. The table was generated using the website (https://www.riskofbias.info/welcome/robvis-visualization-tool).

Discussion

OM is a severe inflammatory and ulcerative condition of the oral mucosa, commonly arising as a side effect of CT and/or RT. Non-surgical anti-cancer therapies generate ROS to target malignant cells but also inadvertently harm healthy tissues. The resultant oxidative stress, driven by an imbalance between ROS production and the body’s antioxidant defense, leads to DNA damage, protein modifications, and activation of transcription factors that regulate inflammatory pathways and cell death.^21,22 On a biological level, heightened oxidative stress may elevate the risk of cancer and contribute to a predisposition toward inflammatory diseases and conditions.^6,22–26 ROS play a critical role in the initiation phase of OM. ⁶ During this phase, they directly activate transcription factors such as NF-κB, STAT3, and nuclear factor erythroid 2-related factor 2 (Nrf2). ⁶ These transcription factors stimulate the production of pro-inflammatory cytokines,^4–6 which, in turn, induce the expression of inducible NO synthase (iNOS), leading to NO production. NO exerts cytotoxic effects on surrounding tissues, contributing to mucosal ulceration and manifesting clinically as treatment-induced OM. ⁹ Patients with OM often experience profound discomfort due to inflammation and ulceration, which adversely affect their ability to eat, maintain an adequate diet, and practice proper oral hygiene. When ulceration penetrates the submucosal layers, the risk of secondary infections increases, potentially leading to further complications. Effective supportive care is therefore crucial in managing mucositis.^21,27

PBM has gained recognition as a promising approach for both the prevention and treatment of OM. By employing LLLT, or light-emitting diodes, PBM modulates cellular processes and reduces inflammation, thereby mitigating the extent of mucosal damage. This therapy not only helps maintain the structural integrity of the oral mucosa but also accelerates tissue repair and regeneration, ultimately decreasing the incidence and severity of OM in patients undergoing treatment.^28,29

Despite its potential, the limited understanding of light-tissue interactions and the variability in protocols and light sources used globally present significant barriers to its widespread adoption. Studies suggest that PBM achieves its anti-inflammatory effects through mechanisms involving the modulation of cyclooxygenase-2, neutrophils, and NF-κB activity.^30–32 In addition, PBM sessions have been shown to exhibit notable antioxidant properties. ³³ Evidence indicates that PBM reduces oxidative stress induced by exercise in muscle cells and mitigates oxidative damage in patients with rheumatoid arthritis.^12–14 However, research investigating PBM’s specific effects on oxidative stress markers, particularly nitrite levels, in the context of OM remains limited.

In our systematic review, we identified three studies that met the inclusion criteria. Despite differences between the studies in terms of the type of anticancer therapy and irradiation parameters, all studies demonstrated the role of PBM therapy in reducing salivary nitrite levels. This reduction may be an important event that can contribute to decreasing the incidence of OM.

Conclusion

PBM therapy demonstrated effectiveness in reducing OM severity, likely through its ability to lower salivary nitrite levels. Furthermore, research is needed to confirm these findings and refine PBM protocols for broader use.

Authors’ Contributions

All authors contributed conceptualization, data curation, formal analysis, investigation, methodology, writing—original draft, validation and writing—review and editing.