4.1 Introduction

Advances in cancer therapy have changed the way cancer patients are treated. In many instances, depending on the staging a malignancy is detected, oncologists aim to cure. Clinically, this means the use of aggressive and multiple chemotherapeutic agents and/or radiation therapy. To achieve cure, cytotoxic regimens are being used at the price of severe adverse events for the cancer patient. These adverse side effects can develop in clusters making quality of life miserable. The burden to the patient can be so severe that oncologists must alter therapy protocols to levels that can be tolerated by the patient. The negative result can be a change in the prognosis. One of the most severe adverse event of cancer therapies is oral mucositis (OM).

Photobiomodulation (PBM) is defined as the use of various forms of light delivery to help accelerate tissue healing. This can be achieved by using low-level lasers, light-emitting diodes, and broadband light. Shining light in tissues that need repair leads to changes in the absorption of light by tissue chromophores, a process that is nonthermal and nonionizing and that elicits photochemical and photophysical effects that stimulate tissue repair [1, 2].

In this chapter, we briefly discuss how researchers and clinicians combine the use of PBM to prevent, manage, and treat oral mucositis. We explain what OM is, the current pathobiological modeling that explains the molecular basis of this process, and then how PBM can alter the mechanisms that lead to OM formation. Furthermore, we discuss the current science that supports the use of PBM to prevent and treat this important complication of cancer therapies. In addition, we address a recent concern that the use of PBM in cancer patients could stimulate cancer cells and promote cancer resistance.

4.2 Oral Mucositis

Alimentary mucositis is a general term that describes this complication affecting the entire gastrointestinal system. Oral mucositis (OM) refers to this adverse event occurring solely in the oral mucosa. It is one of the most important and damaging oral complications of cancer therapies [3, 4]. Risk factors are associated with patient characteristics such as genetic polymorphisms, age, oral health, and smoking [5]. The severity of OM varies depending on the type of therapy being used, including radiation of the head and neck and high-dose chemotherapy, associated or not with radiation. The complication can start insidiously presenting clinically as erythema but progressing to become ulcerated. OM affects more often nonkeratinized areas of the oral mucosa and can develop in several anatomic sites depending on the severity. The ulcerative form can bleed easily and can be covered by a layer of necrotic cells and fibrin characterized clinically as a white pseudomembrane [6]. Common signs and symptoms include pain and discomfort at rest, when eating, and when swallowing; burning sensation; difficulty swallowing or talking; and bleeding from the ulcerated areas. These signs and symptoms can significantly alter patient quality of life [7].

There are several scoring criteria for oral mucositis. The scale proposed by the World Health Organization (WHO) is one of the most used. It goes from grades 0 to 4 and is based on both clinical and functional features (Table 4.1, Fig. 4.1).

Table 4.1

WHO oral mucositis scoring criteria

0 = Normal

1 = Soreness with or without erythema; no ulceration

2 = Ulceration and erythema; patient can swallow a solid diet

3 = Ulceration and erythema; patient cannot swallow a solid diet

4 = Severe ulceration and erythema; alimentation not possible

The prevention and management of OM is an unresolved issue. With the development of cytotoxic cancer treatment protocols that usually combine different agents such as high-dose chemotherapy and radiation of the head and neck, the risk of OM grades 3 and 4 has increased, altering the patient’s quality of life and the tumor prognosis. Several remedies have been suggested over the years without observed efficacy and scientific support. So far, the only approved intervention for OM is palifermin (Kepivance^®) [8]. This therapy is expensive, and its use is aimed at only a small number of patients in the cancer populations at risk.

Clinicians have relied on clinical experience and observations about the development of OM depending on the type of therapy. One hundred percent of patients treated with ionizing radiation of the head and neck will develop some degree of OM. The ulcers may prevent eating and affect swallowing and speech [9].

The current pathobiology modeling of OM and the discovery of various molecular pathways involved on the formation of this adverse reaction have opened the opportunity for the exploration of new ways to prevent and treat this important complication of cancer therapy [3, 10, 11]. The pathobiology of mucositis has been described to occur in five distinct stages. The initial stage starts with a direct injury to DNA by radiation and chemotherapy resulting in clonogenic basal epithelial cell death. Of importance is the formation of reactive oxygen species (ROS). This process in combination with the toxicity of chemotherapy and radiation trigger biological events such as the activation of NF-ƙB, Wnt, p53, and their associated pathways. The next stage of the process is the signaling and amplification in which the activation of NF-ƙB and sphingomyelinases by ROS and radiation leads to the production of pro-inflammatory cytokines such as TNF-α that will activate more NF-ƙB and sphingomyelinases leading to tissue injury and cell death. NF-ƙB can stimulate the upregulation of genes that can cause a second phase of tissue damage. Pro-inflammatory cytokines TBF-α and interleukins can lead to the amplification of the tissue injury and cell apoptosis. At this stage, tissue damage overcomes epithelial healing resulting in tissue ulceration. Ulcers become colonized by oral cavity bacteria. The breakdown of bacterial cell wall allows for cytotoxic products to penetrate into the submucosa. This process will stimulate macrophages to produce even more pro-inflammatory cytokines and further augment tissue damage [6, 12–15].

In patients being treated with chemotherapy, the OM process is acute. It develops in the first few days of therapy and will start healing in about 2–3 weeks when the toxic effects of chemotherapy start to ware off. In patients treated with radiation therapy, the damage is cumulative. The treatment is delivered daily, 5 days a week, and can last for up to 7 weeks. This causes the oral mucosal damage to prolong up to the end of therapy and longer. These variations in the type of therapy have to be considered by clinicians when talking about prevention and treatment of OM. There are several suggestions in the literature on how to manage OM. However, they are not supported by solid evidence. In 1994, the mucositis study group of the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology developed the first evidence-based guidelines [4]. These guidelines reported measures that were recommended and those that were only suggestions, due to the lack of solid scientific evidence. One of the recommendations for the prevention and management of OM included patient education, basic oral care, and palliative care [4, 16, 17]. Whereas initially the use of lasers only received a suggestion level of evidence, a large body of publications became available in the literature, suggesting that lasers and LED could have a positive impact on both the prevention and management of the complication. A systematic review confirmed that the use of lasers and other forms of light in oral mucositis confirmed that there was sufficient evidence to support the use of the technology in the prevention and treatment of oral mucositis [18]. The MASCC/ISOO mucositis guidelines were recently updated and included the use of lasers as one recommendation at a level II evidence [19, 20].

There are still a number of unanswered questions regarding the science behind the effect of light over tissues. In spite of the large number of studies in the literature, the variety of devices, parameters of light delivery, and protocols used in the treatment of patients, additional evidence is needed in order to determine ideal protocols [2]. One must also consider that available studies are from individual centers and that multicenter controlled studies are not yet available.

4.2.1 Photobiomodulation (PBM) and Oral Mucositis