In this retrospective study, we aimed to evaluate the short and long-term safety of the PBMT in prevention and treatment of OM in HCT patients. We evaluated the development of adverse reactions of PBMT in the oral cavity and the occurrence of secondary malignancies. To our knowledge this is the first single-center long-term study with a high number of patients (693) focused on the analysis of the safety of PBMT in HCT.
The analysis of early and late oral complications PBMT-induced did not reveal any harm, suggesting that PBMT is a safe therapy in this patient population. There were also no associated systemic side effects. The frequency of the secondary malignancies in the head and neck region, particularly in the oral cavity, was low not revealing a specific association with PBMT. Another important finding was that moderate and severe OM affected the overall survival of these patients.
The variation of PBMT parameters
This was a long-term study over a period of 15 years. During this period of time, several changes occurred in the type of laser wavelength and parameters used in the delivery of PBMT. Most of the variations in parameters involved the increase of power and energy density delivered to the oral tissues and OM lesions. A significant variation was the implementation of a laser device that could deliver light in the red and infrared wavelengths simultaneously.
The increase of energy and power densities were related to two specific facts: first, the majority of low intensity laser machines in Brazil have the power fixed at 0.1W, not allowing adjustments of this setting; second, the clinicians observed that the clinical outcomes of the PMBT protocol with higher energy and power density produced better effect in the treatment of OM. The laser machine that emits the red and infrared wavelengths simultaneously promotes healing of inflammation and pain control. This is desired when delivering care at bedside. In addition, the PBMT protocol was adjusted over time based on the evidence of increased OM risk.
The prevention and treatment protocols for OM
The HCT patients enrolled in the present study were treated with two different PBMT protocols, one for prevention and other for the treatment of oral mucositis. The two protocols involved energy densities considered high (from 8J/cm2 to 22.2J/cm2) when compared to the literature for oral mucositis control.
The prevention protocol involved shorter irradiation time per point, leading to a lower energy density (up to 11.1J/cm2). The main objective of this protocol was to maintain the epithelial and connective tissue integrity by stimulating keratinocytes and fibroblasts renewal (George et al., 2018). Moreover, a prevention protocol can reduce the risk of oral mucositis in the critical periods of the transplantation. Recent systematic reviews and meta-analyses (He et al., 2018; de Lima et al., 2020; Peng et al., 2020) have demonstrated efficacy of PBMT in the prevention of oral mucositis severity, although more clinical studies focused on HCT patients are necessary for improving the scientific evidence of this therapy.
The treatment protocol was indicated when clinical signs of oral mucosal injury were present. This protocol increased the irradiation time and used a higher energy density (up to 22.2J/cm2). In addition to higher doses, the laser machine delivered 660nm and 808nm wavelengths simultaneously, aiming to improve the photon interaction with different chromophores and promoting the photon resorption at different depth levels (Hamblin, 2017). The main objective of this protocol was to induce analgesia, for the reestablishment of oral intake and the improvement of patient´s quality of life.
Past studies have demonstrated efficacy in reducing pain caused by oral mucositis in HCT patients (Schubert et al., 2007, Ferreira et al., 2016), but their protocols used red lasers and lower energy densities. A previous study demonstrated a significant reduction of oral mucositis severity and analgesics prescription in cancer patients submitted to radiotherapy in the head and neck region when 660nm and 808nm were associated with a higher energy density (300J/cm2) (Soares et al., 2018). Furthermore, the association of red and infrared wavelengths can improve tissue repair by the increasing the collagen matrix and reducing inflammation (Santos et al., 2011); Nevertheless, more comprehensive clinical studies involving the oral mucosa, variations on the dosimetry, and association of the two wavelengths are necessary to confirm this trend.
Scientific evidence has suggested that dosimetry up to 6J/cm2, 150mW, and use of 633-685nm and 780-830nm wavelengths is safe (Zecha et al., 2016b). Systematic reviews of PBMT used to prevent and control oral mucositis recommended higher values, including 12, 35, and 70J/cm2 (Migliorati et al., 2013, Zadik et al., 2019). Others showed that PBMT applied in patients who underwent radiotherapy in the head and neck region was not associated to any adverse effects (Antunes et al., 2017; de Pauli Paglioni et al., 2019). Another study used 10J/cm2 daily, without adverse events and safety issues reported in H & N cancer patients (Brandão et al., 2018). However, the majority of the studies in the current literature had short follow-ups. Therefore, the question about the risk of secondary malignancies or tumor recurrence in the head and neck region needs further investigation (de Pauli Paglioni et al., 2019).
In the current study, the highest doses were 11,1J/cm2 and 22,2J/cm2, which were compatible with the range of dosimetry values reported in other studies with HCT patients (Table 1). Based on the absence of adverse effects, no association with secondary malignancies in the head and neck region, and low frequency of severe of oral mucositis (grades 3 and 4) we can consider the parameters used in the present study to be safe.
Secondary malignancies are the one of the most important late complications in post-HCT period, affecting mainly patients receiving allogeneic transplantation (Heydari et al., 2020). Second primary oral cancers are one of the most frequent neoplasms in the HCT patients (Santarone et al., 2020). A study showed 2.7% incidence of oral squamous cell carcinoma as a second primary malignancy in allogeneic HCT. Risk factors associated with the malignancy development included myeloablative conditioning and presence of chronic GVHD in the oral cavity (Santarone et al., 2020).
In the present study, only 1/693 (0.01%) patient developed a secondary malignancy in the oral cavity. We were not able to find any association of PBMT adverse reactions with the development of this neoplasm.
Overall survival and oral mucositis
The frequency of severe oral mucositis was low (12.0%). A comprehensive systematic review (Chaudhry et al., 2016) showed frequencies of severe oral mucositis varying from 19.4 to 83.0% and from 23.5 to 90.6% in allogeneic HCT performed with myeloablative conditioning and reduced intensity conditioning, respectively. Although oral care protocols and oral cryotherapy were used, none of them implemented the use of PBMT. In the current study, a daily specialized oral care protocol was done for all HCT patients. In addition, oral cryotherapy was used in patients who underwent melphalan conditioning. Therefore, based on the very low frequency of grades 3 and 4 oral mucositis, the implementation of oral care, cryotherapy when indicated and PBMT use can be recommended in the transplant setting (Bezinelli et al., 2014). Further clinical studies with HCT patients are necessary to confirm this hypothesis.
Although the frequency of severe oral mucositis was low, grades 3-4 oral mucositis reduced significantly the overall survival, suggesting that the prevention and control of OM is one of the most important steps in transplantation. New PBMT strategies focused on the patients at high risk for severe oral mucositis, such as those receiving allogeneic transplantation, myeloablative regimens, and with GVHD prophylaxis using methotrexate, must be investigated.
A significant limitation of this study was the absence of a control group, not allowing a complete extrapolation regarding to the PBMT safety. Absence of oral GVHD data is also an important limitation, because the oral mucositis is considered a possible risk factor for this complication, and probably the PBMT may have a positive role on oral acute and chronic GVHD. The use of PBMT for other oral conditions, such as infectious, traumatic, and immune-mediated lesions, was not addressed, limiting also the knowledge about the PBMT effect and safety in these circumstances.
In conclusion, the PBMT protocols for oral mucositis prevention and treatment in the HCT patients were not associated with immediate and late adverse effects and were not related to the development of secondary malignancies in the oral cavity. The low frequency of severe OM detected in this study encourages the implementation of these protocols, with a special emphasis on the need for the correct use of dosimetry in PBMT.