Quality Assessment of PBM Protocols for Oral Complications in Head and Neck Cancer Patients: Part 1

Background: Radiotherapy and chemotherapy are frequently employed in head and neck cancer (HNC) patients causing significant side effects that impair life quality and prognosis. Photobiomodulation (PBM) has become a growing approach to managing such oral complications. Despite its proven efficacy and absence of contraindications, there is still a lack of universally accepted disease-specific PBM protocols.

Objective: A narrative review was conducted to identify the current proposals relating to the use of PBM to treat complications of oncological treatments in HNC patients.

Methods: An electronic search in PubMed and Scopus databases was performed with the following keywords: (“photobiomodulation” OR “PBM” OR “laser therapy” OR “LLLT” OR “laser”) AND (“head and neck cancer” OR “oral cancer”) AND (“mucositis” OR “oral mucositis” OR “dysgeusia” OR “oedema” OR “xerostomia” OR “dermatitis” OR “trismus”) until October 2021.

Results: A total of 35 papers were included in the narrative review. Oral mucositis was the most studied complication, and advisable protocols are conceivable. Although there is a growing interest in PBM to manage of xerostomia, radiodermatitis, pain, and trismus, literature is still scarce to propose a universally feasible protocol.

Conclusions: PBM therapy could significantly prevent or reduce the severity of many side effects related to cancer therapies. More research is needed to obtain recommendations over the preferable parameters.

Introduction

Head and neck cancer (HNC) is primarily treated with surgery in combination with radiotherapy (RT) and/or chemotherapy (CT). RT and/or CT in the head and neck region (HNR) have several side effects that can be debilitating and heavily affect patients' quality of life (QoL) and prognosis. The most common side effects include oral mucositis (OM), xerostomia, dysgeusia, oedema, radiation caries, radiodermatitis, and trismus [1]. These spectra of ailments share a common etiopathology of these complications involving sensitization and tissue damage by the oncotherapy agent. Photobiomodulation (PBM) is a non-invasive light therapy increasingly being applied in supportive care for cancer patients. Its main properties cover the field of wound healing and inflammation. However, there is still no clear consensus over the standard protocols and devices to employ. Recent insights have been made about molecular mechanisms, biological responses, and biomarkers for safe and effective PBM treatments [2, 3]. Concurrently, there have been significant advancements with device technologies, increasing availability of wavelengths, and precise control of the beam and output parameters [4]. Therefore, the objective of the present paper was to produce a narrative review of the available scientific evidence to identify the current proposals and related protocols of PBM to manage the most prevalent complications of oncological treatments in the HNR.

Methods

An electronic search in the PubMed and Scopus databases was conducted with the following keywords: (“photobiomodulation” OR “PBM” OR “laser therapy” OR “LLLT” OR “laser”) AND (“head and neck cancer” OR “oral cancer”) AND (“mucositis” OR “oral mucositis” OR “dysgeusia” OR “oedema” OR “xerostomia” OR “dermatitis” OR trismus) until October 2021. Papers in languages different from English, Italian, Spanish, Portuguese, and French were excluded. Only original articles and reviews were initially included, excluding short reports and case reports. Further, articles not specifying laser protocol were also excluded. A global group of experts in oral medicine, oncology, radiation biology, and PBM examined and discussed this literature to further develop consensus.

Results

A total of 148 studies were obtained after the electronic search. Two different reviewers read all abstracts. After the abstract screening, 58 were excluded, and 90 were subdivided among reviewers' full-text analyses performed independently by two reviewers. After the full-text screening, 35 papers were included in the narrative review. The majority of papers were about preventing or treating more than one side-effect. Twenty-seven studies dealt with OM, 10 with xerostomia, 4 with radiodermatitis, and 2 with pain and trismus. Other interesting topics included the evaluation of QoL outcomes, systemic analgesia, functional impairment, nutritional status, survival, interruption of RT, adherence, cost-effectiveness, safety, feasibility, and tolerability of PBM. In general, no adverse effects were reported, and all authors supported safety and tolerability. Although clinical time constraints and patient compliance were often considered limitations to PBM therapy, feasibility was high. Further detailed analysis of these results will be conducted in another review by our group. In the phase of full-text screening, reviews and systematic reviews were excluded as they did not mention detailed laser parameters.

Study Characteristics

Overall, 7 papers were published between 1999 and 2010, 19 papers between 2011 and 2019, and 9 papers in the last 2 years, witnessing the increasing interest in the field of PBM applied to supportive care in cancer patients (Table 1). A total of 14 studies investigated the role of PBM in preventing the onset of the side effect, 13 in treating the complications, and 8 studies mentioned both protocols. Twenty-two studies included HNC patients subjected to RT sessions alone or combined with surgery, whereas 13 studies included HNC patients subdued to combined CT and RT, with exclusive regimens or as adjuvants to surgical treatments.

TABLE 1

Table 1. Characteristics of studies included in the narrative review.

Light Parameters

Detailed characteristics of PBM protocols in included studies are outlined in Table 2. We noted considerable variations in the types of used lasers, mode of application, frequency of treatment, and treatment parameters. Our analysis precludes robust clinical guidelines. Nonetheless, an overview of the most relevant protocols for each category is outlined to assist clinical implementation.

TABLE 2

Table 2. Laser parameters of the studies included in the narrative review.

PBM for Oral Mucositis

The results for OM management were consistent, and guidelines for both prevention and treatment could be outlined in the current narrative review (Supplementary Table 1). All Authors choose diode lasers, more often indium gallium aluminum phosphide (InGaAlP) diode laser, and Helium-Neon (He/Ne) laser. The most preferred wavelength was red (632–660 nm) for both prevention and treatment protocols in continuous wave (CW) mode using fiber in contact or reduced (<1 cm) distance. Power output reported varied (5–5,000 mW), but most papers did not discriminate between nominal and effective, resulting in overestimated values, especially in non-contact protocols. A suggestion could be between 10 and 100 mW effective power. While some Authors mention irradiance per treatment point, others suggest a defocused beam ranging between 0.024 and 150 mW/cm². As per the new PBM dosing, the most effective preventive protocol would use a total dose of 1.2 Einstein (photon fluence at 650 nm = 5.7 p.J/cm²). The data suggests successive intraoral applications on single spots on the oral cavity, rather than a scanning motion over the entire mucosal surface, may offer the most predictable outcomes. Also, the time of application was very variable, ranging from sessions of 270 s to 25 min. A minimum of 30 s per point with three (up to 5) sessions a week is recommended in preventive and treatment protocols. Overall, preventive protocols need more repetitions per week than treatment protocols.

PBM for Xerostomia

All authors employed diode lasers, specifically indium gallium aluminum phosphide (InGaAlP) or Gallium Aluminum Arsenide (GaAlAs), preferring low power protocols (Supplementary Table 2). Both visible red (650–660 nm) and infrared (780–808 nm) wavelengths were used in CW mode. In two cases, the application was both intraoral and extraoral. Output power varied consistently, ranging from 10 to 100 mW for intraoral to 15–30 mW for extraoral applications. Also, time per site reported significantly gone from 3 to 400 s. Fluence went between 2 and 60 J/cm², equating to 3.8–114 p.J/cm² (photon fluence at 650 nm) or 0.8–25 Einstein. Sessions should be repeated at least twice a week but would be best effective if performed each day of RT (5-day per week), both in preventive and therapeutic protocols.

PBM for Radiodermatitis

Among the four papers dealing with PBM for dermatitis management, two proposed a red wavelength, while the other used infrared (Supplementary Table 3). All Authors employed very heterogeneous diode devices (e.g., He/Ne, InGaAlP). Only Robjins et al. studied dermatitis specifically, while other authors did not distinguish between prevention or treatment of specific side effects [38]. Outputs varied between 100 and 2,500 mW and irradiance between 100 and 168 mW/cm² when mentioned. The fluence varied between 2 and 60 J/cm², equating to 3.8 to 114 p.J/cm² (photon fluence at 650 nm) or 0.8 to 25 Einstein. Treatment time per session varied from 270 to 720 s while repetitions varied between 2 and 5 times a week for the whole course of RT. Although the publications on this topic are scarce and heterogeneous, there is a feeling toward the appropriateness of 2 or 3-weekly applications instead of daily sessions, preferring a preventive or combined strategy rather than just using PBM in a curative way. DeLand et al. reported that LED treatments immediately after RT reduces dermatitis incidence in breast cancer patients. These findings may inspire a protocol for HNC subjects. Despite the variability of the parameters, a general recommendation can be hypothesized [40].

PBM for Pain and Trismus

PBM treatments for the management of pain and trismus induced by RT were assessed by two papers (Supplementary Table 4) [26]. While both protocols were focused on treatment, and the parameters were too heterogeneous for comparison, such as wavelength (660 red vs. 950 infrared), output powers (100 vs. 15 mW), and fluences (60 vs. 7.6 J/cm² per session). Further, Elgohary et al. compared various techniques, including PBM, that were not the study's primary objective [25]. Based on our clinical experience, we recommend using a combination of 660 and 810 nm PBM devices, both intraoral and extraoral, at 50 mW/cm² for 30 s per site, treating multiple areas in a scanning motion for a total fluence of 6 J/cm² which equates to 9 p.J/cm² at 810 nm or 2 Einstein. Treatments should be repeated up to 3 times per week for at least 3–4 weeks.

Discussion

The present review offers an overview of the literature on PBM therapy in HNC patients with RT-related side effects, specifically OM, xerostomia, dermatitis, pain, and trismus. The most studied side effect of cancer treatments remains OM [41]. Literature has increased substantially, outlining preventive, therapeutic, or combined protocols [42]. The results section of our literature review has provided reliable suggestions for creating an effective protocol. PBM biological responses depend on the treatment parameters, delivery protocols, and redox state of the cells. It is well-established that PBM dosing is biphasic and relies on the underlying pathology and patient-associated factors that may affect individual outcomes. Further, inappropriate dosing may result in poor or adverse therapeutic effects. The PBM dose window is defined by correct treatment timing, the number of repetitions, and specific adaptation of protocols for each indication [43].

In general, PBM was noted to be effective in both the prevention and treatment of OM [27, 32]. It is almost universally accepted that the primary goal of treatment is reducing pain and improving QoL; most studies confirmed this regardless of the protocol. Even the low PBM efficacy papers noted reduced severity of OM grades (scores 3 and 4 according to the World Health Organization scale) and fewer treatment interruptions during RT. Most of the papers included in our systematic review used CW protocols. This contrasts with prior reports that pulsed, low-frequency (<100 Hz) may be superior for wound healing or the damage prevention. Moreover, while most studies used intraoral PBM treatments, there is evidence for extra-orally administered PBM that appears to be more effective for managing of OM of the buccal mucosa, vestibule, and inner lips when combined with an intraoral approach [44, 45].

The PBM studies on salivary glands after RT employed combined external and intraoral applications with both infrared and visible red wavelengths [17, 23]. There appears to be a dose-effect relationship for PBM on reduction of hyposalivation after RT, especially after 15 sessions with red or combined red and infra-red wavelengths [46]. For example, Ribeiro et al. conducted a cross-sectional study with a quantitative approach applying extraoral infrared PBM during the whole course of RT. They demonstrated unchanged unstimulated salivary flow during RT but decreased saliva quantity 1 month after the end of cancer treatment. Despite not corroborating the role of PBM in modulating hyposalivation and salivary gland damage, a concomitant intraoral, lower dose protocol was used for OM that was not the main objective of the study confounding the interpretations of their results [35]. Interestingly, the control of hyposalivation induced by RT seems to be positively affected by PBM treatment strategies [47]. On the contrary, the effect was not marked in preventive protocols. Three studies did not evidence a beneficial impact of PBM in reducing salivary flow connected to RT or combined CT/RT [15, 32, 35]. Note that only one of them is a randomized clinical trial and they all include a limited number of subjects. Moreover, there was no specific protocol for salivary complications that can be distinguished from other side effects, such as OM.

All the publications included in this narrative review suggest that PBM is a safe and valuable strategy for cutaneous complications in the HNR. Encouraging results were noted for PBM management or prevention of radiodermatitis. Many papers have been published regarding radiodermatitis in other body districts, breast in primis. However, little has been investigated in the cervical and facial sites, although it is associated with significant pain, disfigurement, risk of RT interruption, and poor cancer prognosis [38]. For cutaneous areas other than the HNR, the literature suggests that preventive PBM application, starting concomitantly or even before RT or combined CT/RT, may not only mitigate the severity of dermatitis but also positively impact the onset and severity of late complications, via the mechanisms of tissue repair and regeneration. For example, a study on pigs suggested that combined wavelengths positively influence the development of late radiation damage to the skin. This indicates that this approach may also be applied in the HNR [48]. The fact that all the included publications were very recent (2018–2022) indicates increased interest and recognition of the efficacy of this treatment, together with its proven safety, suggesting that a universal protocol may be feasible shortly.

Specific interest has emerged in this review in trismus management, which is not corroborated by previous literature work. HNC patients are often subdued to destructive surgery, which provokes muscle spasms and reduced mouth opening. The evidence that PBM reduces fibrosis and promotes muscle regeneration could be the primary rationale for the clinical benefit looked for by the Authors, even if it is evident that this topic needs further clinical research [45].

In summary, the available evidence shows that PBM was satisfactory in managing complications related to cancer therapies, both in the prevention of onset and in the reduction of severity and duration, especially for OM. Objective and subjective parameters were studied with comparable rates of success, and the favorable implications on QoL outcomes and wellbeing accounted for most of the positive results expressed by the authors [37]. PBM generates beneficial effects, including reducing of inflammation and pain [49], promoting tissue repair, reducing fibrosis, and favoring nerve regeneration. Therefore, it is clear why studies on PBM application cover a vast range of acute and chronic cancer-related complications in HNC patients.

Moreover, there is growing evidence that PBM is cost-effective both in preventing and treating cancer treatment-related toxicities, such as OM and breast cancer-related lymphedema. This scenario may provide a wider acceptance of PBM at cancer treatment centers, especially if fomented by additional clinical studies to validate cost-effectiveness for preventing and managing cancer treatment-related toxicities other than OM [50].

PBM dosimetry has raised significant interest in recent years, primarily due to its efficacy in a broad range of clinical applications, regardless of the underlying pathology and varying protocols. But since Mester's first description of its benefits, PBM has been used rather empirically as a magic wand, without actual knowledge of photobiological, molecular, and intercellular mechanisms of laser-tissue interaction that cannot be ignored [51]. The absence of clear guides for standardizing protocols description and data presentation remains an issue that can limit comparison among studies and the creation of coherent clinical practice guidelines. Inconsistencies in clinical outcomes are mainly due to problems in reporting PBM dosing and delivery. For the latter, using “treatment surface irradiance” rather than laser irradiance alone is expected to reduce confusion about power output, spot size, and distance, especially when using contact and defocused (distant) PBM treatments [24]. This should assist in significantly improving dose reproducibility. The availability of large arrays has encouraged defocused, large treatment areas that reduce treatment time and thermal damage in tissues. Eventually, disease-focused protocols could be created as specific wavelengths target biological chromophores at varying penetration depths and evoke discrete biological responses. Universal protocols may seem convenient and somewhat effective, they are likely to generate inconsistent or irreproducible results [52].

Even in the case of different protocols applied to the same condition, the evoked PBM responses may vary. The absorption of light by a chromophore depends on the affinity with the used wavelength. Even if the wavelength falls within the correct absorption spectrum, low doses of energy are insufficient to start the biological effect, and excessive dosages can result in inhibitory. Moreover, therapeutic responses are restricted to a limited therapeutic dose window termed the Arndt Schultz curve [53]. Recent papers emerged in the literature regarding the possibility of enabling comparisons between protocols, creating a system of “dosing consistency,” which is effective with multiple combined wavelengths. Young et al. suggested using the terms photonic fluence (p.J/cm²) and “Einstein” (photonic fluence at 810 nm as a reference wavelength) [51]. This enables easy, universal interoperability between dose recommendations with different wavelengths. This novel dose system has been recently applied to the dosing recommendations by the World Association for Photobiomodulation Therapy (WALT) to increase practical implementation irrespective of individual wavelengths or devices that are available globally while preventing overdosing and enabling dose combination with various wavelengths [51].

The similarities of the pathophysiology in different complications and the fact that the same patients may suffer from more than one side effect represent a clear clinical challenge. Moreover, based on the logical extension of acute complications as precursors for chronic ones, preventive (“pre-conditioning”) PBM protocols could effectively reduce early and late complications [54]. PBM should be applied using the optimal parameters based on the biological target, device parameters, and delivery technique. Therefore, it is rational to posit that optimal protocols could maximize clinical efficacy, creating a reproducible, and consistent treatment irrespective of the device being used. This work attempts to outlining some of these parameters to pave the way for universal PBM protocols.

Conclusion

PBM seems to be an efficacious intervention for several complications of cancer therapy. Robust evidence of the clinical benefit elicited by the correct biological and molecular patterns of light stimulation exists. There is a strong perception that multiple protocols may be applied to similar conditions but to maximize the effect on specific tissue targets, there is an urgent need for standardization and reproducibility of dosages. The increasing number of papers regarding the management of HNC complications via PBM witnesses a strong interest in the field. The very recent publications proposing dosage standardization indicate we are moving in the right direction.

Author Contributions

GO and MG contributed to conception and design of the study. MG, EM, PA, R-JB, AS-S, LG, and GO performed the articles screening and data collection. MG wrote the first draft of the manuscript. EM, PA, R-JB, AS-S, LG, and GO wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Funding

The authors gratefully acknowledge the support of Eltech K-Laser Company for the publication financial support. Eltech K-Laser Company was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/froh.2022.945718/full#supplementary-material

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