We evaluated the effects of a prophylactic extraoral PBM in the outcomes of RT-induced OM and oncological outcomes. The demographic characteristics of the included patients in this interim analysis were similar to those presented in the literature, patients with advanced OOPSCC, mostly males, with history of tobacco and alcohol use [10, 22–24]. Additionally, the oncological treatment reflected the standard of care from international cancer centers, based on a multimodal approach, associated with a better prognosis, but also with an increase of acute side effects, particularly OM .
In our study, a delay in the development of OM for the PBM group, along with a difference on severity duration due to later OM onset, reinforces the prophylactic effect of PBM. However, there was a high incidence of grade 3 OM for both groups during the last week of treatment. While there is robust evidence of the effectiveness of PBM in OM , different PBM effectiveness results can be attributed to many factors including PBM parameters, oncological treatment regimen, and patient’s characteristics [6, 22, 25, 26]. One of the challenges when comparing PBM results between studies is the heterogeneity of PBM protocols and parameters used [9, 10, 26–28]. Few studies have evaluated the effectiveness of extraoral PBM for OM [21, 36, 37], due to the lack of evidence and the lack of validated protocols for extraoral PBM for OM .
During the last week of RT, we observed severe OM primarily in the oropharynx, and posterolateral border of the tongue. The oropharynx was the most frequent primary tumor site for both groups, with the primary radiation dose the area and greater difficulty in OM management. Also, these areas with greater OM grade 3 were distant from the extraoral light surface, and the literature shows that light delivery to target tissue is affected by its distance from the light source [26, 27–30]. For extraoral PBM, tissues with greater energy delivered include the buccal mucosa, the vestibule, and the oral surfaces of the lips [26–29].
PBM effectiveness on severe OM control, may also be due to insufficient PBM parameters, and adjustments in the extraoral PBM protocol need to be optimized with the goal of achieving greater efficacy. The use of extraoral application plus intraoral delivery on selected high-risk oral regions per radiation treatment plan, may enhance compliance and reduce time for light application in the clinical setting. Additional studies are warranted. Furthermore, the evaluation of site-specific patterns of OM may improve the development of PBM protocols [19, 31]. It is important to highlight that extraoral PBM is considered to be a simple, well-tolerated and easily applied intervention.
In our study, patients from the PBM group experienced less severe pain associated with OM, lower mean pain score during RT with reduced opioid use. Important differences in pain assessment and analgesics between PBM and placebo were observed to be greatest during the last week of RT. PBM is known to be associated with pain reduction and thus may lead to reduced use of opioid analgesics [29, 30, 32–34]. Similar studies, Antunes et al., 2013  and Gautam et al., 2015  reported significantly less severe oral pain scores for PBM treated patients compared to placebo, in addition to reduced opioid use during RT.
Higher prescriptions of anti-inflammatory agents were observed in the placebo group, which may also have influenced the OM severity incidence. Although no guideline supports the use of systemic anti-inflammatory agents to manage OM, inflammation is considered to be an important major effect of RT-induced OM and anti-inflammatory inhibition is a potential treatment strategy in this context [36, 37].
Oral and oropharyngeal cancer is associated with reduced QoL due to the effects of primary tumor and treatment side effects impairing patient’s daily functional and self-image [10, 38]. Worsening levels of general QoL were observed at the end of the treatment, as reported in previously published studies [33, 34, 38, 39]. The variability of QoL is directly associated with cancer treatment toxicities alterations in swallowing, chewing, saliva changes, taste and especially OM-related pain . Our study shows better social-emotional QoL in those treated with PBM, which could be explained by the positive impact in OM symptoms attenuation specifically decreased pain levels [34, 39].
It is imperative that an intervention used to support cancer patients during therapy does not adversely affect tumor behavior, or tumor response to treatment [11, 12, 22, 27, 40]. Data about PBM impact on tumor activity and oncological treatment response based on in vitro studies are conflicting. Contradictory results may be correlated to the variation of PBM parameters, tumor cell lines, and tumor genomic heterogeneity between studies [8, 12, 41]. Current literature indicates that any in vitro experiment assessing the effect of PBM should not be considered representative of what happens in the clinical care. Based on the existing data, confirmation of the safety of PBM in the management of OM is important to be examined in prospective randomized controlled clinical trials in oral and oropharynx tumors [9, 42]. Our evaluation of tumor outcomes was not adversely affected by PBM.
No significant adverse side effects were noted in the present study in the setting of oral and oropharynx cancer patients submitted to PBM during RT. This is in agreement with the current literature [9, 10, 22, 26, 34, 35, 41, 43]. Furthermore, no relevant negative effect of PBM on tumor biology was demonstrated, also in agreement with other similar studies [9, 22, 34, 41, 44]. No differences in OS were seen in the current study in PBM versus placebo groups. Additional data will be available upon the final analysis of 18 months of follow-up. As PBM mechanisms continue to be studied, the effects of different parameters on tumor heterogeneity will add information based on solid science [9, 42].
Limitations of the study
The present study is a planned interim analysis of an ongoing clinical trial and results could change at completion of the trial and enlargement of the study sample.