Comparative effectiveness of intraoral vs. combined intraoral/extraoral photobiomodulation for oral chemotoxicity prophylaxis: a pilot study

Introduction

Patients undergoing chemotherapy for various mali­gnancies are frequently exposed to a range of complications due to compromised immune function, organ dysfunction, and the administration of aggressive the­rapeutic protocols. Among these complications, oral side effects are particularly prevalent, affecting approxi­mately 40% of patients receiving chemotherapy. These oral complications arise from a combination of factors, such as direct damage to the oral mucosa, neutropenia, changes in saliva quantity and quality, alterations in immunoglobulin levels, and disruption of the oral microbiota [1]. Oral mucositis (OM) ranks among the most clinically significant treatment-induced complications, characterized by intense mucosal inflammation and ulcerative lesions. According to National Cancer Institute standards, this condition consistently produces a triad of detrimental effects, including severe pain requiring analgesic intervention, functional impairment, and disruption of mucosal integrity that elevates infection susceptibility [2]. Apart from OM, chemotherapy can cause a host of other oral complications, such as dysphagia, xerostomia, speech difficulties, and chronic pain. As defined by the World Gastroenterology Organization, dysphagia is characterized by either challenges in early stages of swallowing or the feeling that food or liquids are somehow blocked as they travel from the mouth to the stomach [3]. Additionally, chemotherapy disturbs normal function of salivary glands, impairing production of saliva, which compromises its protective functions, such as lubrication and antimicrobial activity, thereby increasing mucosal susceptibility to both mechanical injury and pathogenic infiltration [4]. These oral side effects reduce quality of life, and may interrupt cancer treatment and affect its success. Effective prevention and management are crucial, yet current options remain limited [5].
Contemporary clinical research has increasingly recognized photobiomodulation (PBM) as an emerging moda­lity with considerable therapeutic potential. PBM uses low-intensity light to promote cellular repair, reduce inflammation, and alleviate pain without causing thermal damage. It supports tissue regeneration, mucosal healing, and immune modulation, making it effective for managing oral toxicities. PBM is non-invasive, painless, and suitable for cancer patients. Numerous studies have shown positive results in treating OM with PBM [6]. Despite its therapeutic potential, limited clinical investigations have explored PBM applications for managing additional treatment-induced oral toxicities apart from mucositis [7].

Objectives

Therefore, this clinical investigation aimed to determine the differential efficacy of two PBM delivery me­thods: conventional intraoral red laser application versus an innovative combined intraoral/extraoral irradiation strategy.

Material and methods

This study received ethical approval from the Scientific Research Council at Damascus University (Ref No: 2027; 18/01/2023). Signed informed consent was obtained from all participants prior to enrollment.
The study cohort included patients with histologically confirmed digestive tract malignancies, and starting their first-line chemotherapy with either: FOLFOX regimen: leucovorin calcium (200 mg/m²), fluorouracil (400 mg/m² bolus + 2400 mg/m² infusion), and oxali­pla­tin (85 mg/m²); XELOX regimen: oxaliplatin (130 mg/m²) plus oral capecitabine (1000 mg/m² twice daily).
Key inclusion criteria: adequate hematologic function (neutrophils ≥ 1500/µl, platelets ≥ 100,000/µl), cli­ni­cally healthy oral mucosa (no active lesions at baseline), preserved functional status (Karnofsky performance status ≥ 60%) [8].
Exclusion criteria: history of head-neck radiotherapy, existing oral mucosal pathologies (dysplastic or malignant lesions), acute oral infections/hemorrhage, diagnosed diabetes, concurrent mucositis prophylaxis use, or general ineligibility for study participation.
Eligible participants were randomly allocated using an online randomization tool, GraphPad QuickCalcs.

Blinding

A researcher, who was unaware of outcome assessments, administered the interventions. Patients were blinded to their assigned treatment, as all procedures, including sham laser (device powered off), were performed identically in duration and technique. Independent evaluators conducted all outcome assessments to maintain blinding integrity.

Sample size calculation

An a priori sample size calculation was done using OpenEpi (version 3.01), based on effect size data from Arbabi-Kalati et al.’s 2013 randomized trial [9]. Main parameters included: control event rate – 91.6% (unexposed group); intervention effect – 8.33% incidence with PBM (OR = 0.008); statistical thresholds – α = 0.05 (two-tailed), β = 0.20 (80% power); allocation ratio – 1 : 1, balanced design.
This calculation yielded a minimum requirement of 7 participants per arm.
The study included 45 participants evenly allocated to three intervention arms (15 per group), with balanced distributions of age, sex, chemotherapy protocol, and pretreatment oral mucosal status (Table 1, Figure 1).
Group 1: Received informed consent and basic oral care instructions. All participants followed a standardized oral hygiene protocol, involving twice-daily 90-second brushing with soft-bristled manual toothbrushes, daily flossing, and regular rinsing with sterile 0.9% saline solution. They were instructed to maintain adequate hydration and avoid potential irritants, including tobacco, alcohol, extreme temperature food, and spicy, acidic, or hard-textured items. Denture wearers additionally performed twice-daily prosthesis cleaning with overnight soaking and pre-insertion saline rinses [6].
Group 2: Underwent the standard oral care regimen, with adjunctive 635 nm intraoral PBM (MEDENCY® TRIPLO diode laser) targeting the buccal mucosa, labial mucosa, tongue surfaces, floor of the mouth, and soft palate (Table 2).
Group 3: Received identical as group 2 intraoral PBM (635 nm), supplemented with extraoral 980 nm diode laser therapy (MEDENCY® TRIPLO diode laser) applied bilaterally to six cervical points: two below the jawline, two mid-neck near the larynx, and two near the base of the neck [10] (Table 2).
Oral health status was evaluated as the primary endpoint using the validated Oral Assessment Guide (OAG) developed by Eilers et al. (1988), which systema­tically assesses eight clinical domains: 1) voice quality; 2) swallowing function; 3) lip integrity; 4) tongue condition; 5) salivary flow; 6) mucosal status; 7) gingival health; and 8) teeth/denture status, with each category scored on a 3-point scale (1 = normal, 2 = mild/ moderate impairment, 3 = severe dysfunction), with a cumulative score range of 8 (optimal oral health) to 24 (significant pathological involvement) [11].
Assessments were conducted before chemotherapy, and at one and two weeks after the first session. Normality of parametric variable was evaluated using Kolmogorov- Smirnov test, one-way ANOVA compared group means at each time point, while paired sample t-tests assessed pairwise differences between time points. Null hypo­thesis (H0) was that mean OAG scores remain constant across all assessment periods, whereas alternative hypo­thesis (H1) was that mean OAG scores vary significantly across time points.

Results

The mean OAG scores were 8.64 ± 1 (standard error [SE] = 0.117) at baseline. At one week follow-up, scores increased significantly to 9.84 ± 1.5 (SE = 0.231), declining slightly to 9.60 ± 1.4 (SE = 0.209) at two weeks follow-up. Significant between-group differences in OAG scores were observed at both follow-up intervals (week 1: p < 0.001; week 2: p < 0.001), as detailed in Figures 2 and 3, particularly in swallowing, lips, tongue, mucosa, saliva, and gums. However, no significant differences were found in terms of voice and teeth at both one- and two-week follow-up (Table 3).
Pairwise comparisons showed significant OAG improvements in laser groups versus controls at weeks 1-2 (both p < 0.05), and non-significant differences were observed between intraoral-only and combined intraoral/extraoral PBM groups (p > 0.05). Both the laser groups demonstrated protective effects in lips, tongue, mucosa, saliva, and gums compared with controls, while swallowing was the only parameter differing between the two laser groups. Finally, significant differences were observed in the mean OAG scores when comparing the two study intervals independently (Figure 4).

Discussion

In our study, we compared two PBM protocols to optimize outcomes. The first used intraoral irradiation at 635 nm according to World Association for Photobiomodulation Therapy guidelines [12], while the second combined intraoral red laser with extraoral infrared laser to reach deeper tissues, such as the oropharynx [10]. Both protocols adhered to power settings recommended by Bensadoun et al. [13] and energy density constraints suggested by Cronshaw et al. [14]. Also, both approaches presented equally positive results in preventing chemotherapy-induced changes in the oral mucosa, tongue, and lips, with significant protective effects compared with basic oral care. These results corroborate the exi­sting literature on PBM’s prophylactic efficacy against chemotherapy-induced OM. Previous randomized trials by Arbabi-Kalati et al. [9] (630 nm diode laser) and de Menezes et al. [15] (660 nm wavelength) similarly demonstrated significant reductions in OM incidence among chemotherapy patients. De Castro et al. [16] observed better outcomes with 660 nm and 830 nm lasers in children treated with methotrexate. Our findings align with Malta et al.’s [17], who reported a reduced OM incidence in breast cancer patients receiving combined 660/808 nm PBM during chemotherapy. However, our results contrast with those reported by Cruz et al. [18], where no significant therapeutic benefit from PBM treatment was observed. This discrepancy may be attributed to fundamental differences in study populations; their cohort included patients with pre-existing chemotherapy-induced mucositis, where persistent microvascular compromise (angiogenesis impairment and endothelial damage) likely diminish PBM’s biostimulatory effects. These findings collectively highlight the critical importance of administering PBM during the pretreatment phase, when mucosal tissue retains optimal physiologi­cal responsiveness to PBM therapy.
Regarding salivary function, both PBM protocols successfully mitigated chemotherapy-induced salivary dysfunction, consistent with the findings of Golež et al. [19] and Arbabi-Kalati et al. [9]. These studies emphasized PBM’s capacity to alleviate xerostomia by targeting the submandibular gland, which accounts for approximately 70% of unstimulated saliva production. Notably, the submandibular gland is particularly vulnerable to 5-fluorouracil (5-FU)-induced toxicity, as 5-FU promotes oxidative stress and inflammatory responses, which predominantly affect this gland. Such pathologi­cal changes lead to periductal edema and cellular necrosis, ultimately disrupting both salivary flow rate and composition [20]. In contrast, Saleh et al. [21] found no PBM effect on sali­vary function, likely due to their cohort undergoing radiotherapy, which impacts salivary glands differently.
Research on PBM’s effects on voice is still in its early stages, and no studies have explored its impact on chemotherapy-induced voice changes. In our study, no significant effect was found, possibly due to the short follow-up period. The lack of research regarding PBM’s effect on voice may be attributed to its secondary status compared with issues, such as dry mouth and oral ulcers.
Chemotherapy with 5-FU has been linked to increased gingivitis [1], which can occur even with good oral hygiene, suggesting that immunosuppression, including changes in the IgG/IgA ratio, plays a role [22, 23]. Our study showed that both PBM protocols effectively reduce chemotherapy-induced gingival changes, supporting Rosin et al.’s [24] findings that brief radiation exposure can protect gingival fibroblasts from 5-FU-induced stress.
Regarding swallowing, the current study revealed that the PBM protocol combining intraoral red laser and extraoral infrared laser was more effective than intraoral red laser alone in preventing chemotherapy-induced swallowing changes. No significant effect was observed with intraoral red laser alone. This combined approach enhances PBM efficacy by more effectively targeting affected tissues, helping to reduce inflammation, alleviate mucositis-related pain, and manage fibrosis. These effects are particularly beneficial in critical areas involved in swallowing, such as the tongue, pharynx, and larynx, which play key roles in the development of dysphagia [25]. Our findings are in line with De Lima et al. [26], who found no improvement in severe dysphagia with intraoral red laser PBM (660 nm) in head and neck cancer patients. From another perspective, with regards to the combination of intra- and extraoral lasers, our findings support the outcomes reported by El Mobadder et al. [27]. Their case study demonstrated that dual intra­oral and extraoral application of a 980 nm diode laser effectively mitigated dysphagia, a treatment-induced adverse effect in a patient undergoing hormonal therapy for cancer. However, our findings contrast with those of Cowen et al. [28], who utilized an intraoral helium-neon (He-Ne) laser (632.8 nm) in patients with hematologic malignancies receiving high-dose chemoradiotherapy. Their study demonstrated a significant enhancement in swallowing function among patients treated with PBM compared with controls. These discrepancies may be attributed to variations in patient demographics or diffe­rences in cancer treatment protocols.
Finally, concerning dental health, no statistically significant differences in plaque accumulation were observed among the three study groups. This finding might reflect consistent adherence to standardized oral hygiene protocols across all participants. To our knowledge, no prior studies have explicitly investigated the effects of PBM therapy on dental plaque formation.

Limitations

The interpretability of our findings is constrained by the relatively short-term follow-up period, which precluded comprehensive evaluation of long-term treatment outcomes. Moreover, prolonged observation intervals might introduce confounding variables, as subsequent therapeutic interventions (e.g., analgesic protocols for chemotherapy-induced complications) could potentially mask the definitive therapeutic benefits attri­buted solely to PBM in OM prevention.

Conclusions

PBM treatment, whether administered intraorally or as a combined intraoral and extraoral approach, demonstrates efficacy in mitigating oral complications induced by chemotherapy. The combined laser protocol show enhanced benefits in swallowing-related outcomes, emphasizing its potential as a valuable adjunctive therapy.

Disclosures

1. Institutional review board statement: This study received ethical approval from the Scientific Research Council at Damascus University (Ref No: 2027; 18/01/2023).
2. Assistance with the article: None.
3. Funding: Damascus University, No: 501100020595.
4. Conflicts of interest: None.

References