OM is the most common complication of chemo and radiotherapy patients with head and neck cancer and has been successfully managed by LLLT [17, 7]. Moreover, considering that OM can favor the development of OC, it is important to know whether the control of OM lesions can influence the manifestation of this fungal infection [18, 19]. In our study, patients with head and neck and oral cancer presented similar frequency in the manifestation of OM and OC, regardless of using LLLT to prevent OM. Additionally, a few cases of OM in patients with head and neck cancer under RT progressed to more severe OM degrees (3 and 4), probably due to the constant clinical follow-up when the patients were submitted to RT.
It is necessary to emphasize that the diagnosis of OM and OC is clinical-based and requires that health professionals are aware of the signs and symptoms of these conditions. In our study, only the pseudomembranous form of OC was included in the analyses, as it is the most frequently observed clinical form in patients undergoing cancer treatment [20]. In addition, the erythematous and hyperplastic forms, rhomboid glossitis, and actinic cheilitis present signs and symptoms that overlap with other characteristics of OM, which can be a confounding factor during diagnosis [21]. These features may contribute to underestimating the prevalence of OC and its association with OM during cancer treatment, which may impact preventive and therapeutic practices for these conditions [16].
Approximately 100% of patients with head and neck cancer under RT have OM, and approximately 56% of these cases progress to higher grades, which consequently weakens patients and increases the need for hospitalization [7]. The risk and severity of radiation-induced mucositis depend on RT dosage and fractionation [22]. This difference in RT parameters directly interferes with the frequency of toxicities associated with the treatment, potentiated by CT [23]. A higher incidence of OM high grades was observed in our study (Fig. 1A and Fig. 1C) for patients with oral cavity cancer compared to those with tumors in other sites of the head and neck (Fig. 2), which may be associated with differences in RT parameters, as well as with differences in tumor behavior. We assume that it is fundamental to analyze the frequency of OM regarding the anatomical region of RT irradiation, which might indicate differences in the prevalence of OM and OC according to primary tumor location. In addition, patients with oral cavity cancer who had lymph node metastasis manifested more OM, regardless of laser treatment, which reinforces the possible interference of different radiotherapy parameters in the manifestation of this condition (Fig. 2). The presence of tumor lesions at oral cavity sites also limits the control of OM with LLLT since this therapy cannot be performed directly on top of the tumor owing to a lack of evidence regarding cancer cell proliferation after exposition to LLLT [24].
Currently, no therapy can avoid OM; therefore, the prevention with photobiomodulation and pain management have been largely driven [15]. The Clinical Practice Guidelines, published by MASCC/ISOO, recommended a preventive dose of 2 J/cm2 to be applied at a wavelength of 650 nm and a power of 40 mW to control OM development. Many studies have been published evaluating the efficacy of OM management through LLLT; however, there are still limitations owing to the use of various LLLT and other light devices with different protocols and wavelengths, which affect data interpretation [25]. Photobiomodulation laser acts on OM management owing to its interaction with biological tissues. Specific wavelengths are absorbed by the chromophores in the mitochondria, which promotes an increase in ATP production and a consequent increase in protein biosynthesis, thereby facilitating tissue repair. Laser light also has an analgesic effect through the modulation of pain perception by altering nervous conduction via the release of endorphins [26].
In this way, the beneficial effects of LLLT make it a promising therapy for the resolution of this illness. Several studies have proven its effectiveness, including that for the prevention of RT or CT-induced OM [27–30]. Other studies showed no efficacy for OM prevention [15], as shown in our study, in which a similar OM frequency was noted in both patient groups followed or not by LLLT. In a similar trial conducted by Oton-Leite et al. [28], photobiomodulation was performed three times a week in patients with head and neck cancer. The protocol involved an InGAIP diode laser with a continuous wavelength of 660 nm, a maximum output power of 25 mW, and an energy per point of 0.24 J (10 s in each point) [28]. LLLT can be conducted on consecutive days or alternate days. According to MASCC/ISOO, the two protocols recommended for laser use have the following parameters in common: wavelength (660 nm), time per spot (10 seconds), and application in contact with the tissue; in contrast, the number of sites in the oral cavity (69 vs. 72 points), fluence (4.2 vs. 6.2), and frequency (5 days a week vs 3 days a week) differed between the protocols.
Although we had observed similar manifestations of OM in patients followed by LLLT compared with the control group (Fig. 1), a few cases of OM presented higher OM grades (grades 3 and 4). This was also reported by other researchers. In a study of 39 patients treated for head and neck cancer performing LLLT with different protocols, the results showed that using a low-power laser alone or in association with a high-power laser when applied three times a week not only maintained OM at grades 1 or 2 but also prevented an increase in the nociceptive reaction [31]. A recent retrospective study showed that the location of the tumor (oropharynx vs. oral cavity), leukopenia, chemotherapy and monoclonal antibody blockage, and feeding orally or by tube are factors associated with the severity of OM in patients under head and neck oncologic treatment [16], but LLLT was not performed in the patients. The clinical management of OM, including LLLT, is an important issue since higher degrees of OM affect patient nutrition and may cause the interruption of cancer treatment and/or increased costs [32].
Concurrently, the prevalence of OC associated with OM ranges from 27–50%, two times more common in patients with OM [18]. OC lesions often overlap with those of radiation-induced OM, and the differential diagnosis between the two is quite difficult [20]. The use of corticoids to treat OM is an acceptable hypothesis for this simultaneous manifestation of OM and candidiasis [33] since this drug might induce local immune modulation [34]. Nonetheless, a retrospective study showed that decreased leukocytosis and grade 2 or higher OM are significantly associated with the risk of developing OC but not using a steroid ointment [16]. Thus, it is expected that the management of OM might consequently decrease the incidence and level of candidiasis manifestation. In our study, a high incidence of OC was noted among patients with OM, and only in patients with tumors at the head and neck, the local metastasis a factor significantly associated with the infection (Fig. 2C). Furthermore, LLLT did not reduce the incidence of OM nor the incidence of OC in radiotherapy-treated patients with head and neck cancer, which reinforces the potential OM-OC association and/or the low-efficiency of LLLT therapy in treating OC in these patients. During the clinical follow-up of our patients, it was prescribed antifungal (nystatin suspension) and/or corticoid mouth rinse when patients presented pseudomembranous OC and/or grade 2 of OM, regardless of the enrollment on photobiomodulation therapy. Additionally, the prophylactic use of antifungal drugs has been recommended, considering that Candida spp. proliferate at the mouth of patients with head and neck under RT [35]. The use of miconazole mucoadhesive tablets attached to the oral mucosa reduced the development of OC and grade 1 OM in patients undergoing head and neck RT, but there was no difference in the progression to grade 2–3 of OM between the controls and the groups treated with the antifungal [33].
Our study has limitations regarding the homogeneity of CT therapeutic schemes, considering some patients were treated with different types, doses, and CT cycles of antineoplastic drugs. In addition, there is no data on the isolation and microbiological characterization of Candida spp. before or during radiotherapy treatment. The ideal protocol in prospective studies should analyze the fungus proliferation after the LLLT at oral mucosa since it was reported that LLLT did not interfere with Candida albicans viability [36]. It is also necessary to consider oral hygiene habits and oral conditions at the beginning of RT treatment, and herein, all patients were submitted to a clinical and radiological evaluation before radiotherapy to avoid osteoradionecrosis and other infections.
Altogether, these data suggest that protocols to prevent candidiasis and severe oral mucositis are an urgent issue in managing oncologic treatment. More studies should be performed to understand the role of LLLT associated with antifungal and anti-inflammatory agents in controlling candidiasis and oral mucositis.