15 Sep An Enlightening Summer Research Experience: Using Light Treatment for Oral Cancer Carez
Written by Jaeyoung Choi and Praveen Arany, BDS, MDS, MMSc, PhD
Upon completing my first year at Dental School, I was looking at getting involved with dental research this summer to learn more about progress in the field of clinical care delivery. Although we had just started learning about the sophisticated biomaterials and biotechnologies revolutionizing clinical dentistry, I was fascinated by the process of how these are developed and adopted into clinical practice. Learning more about the rich history and prestige of our school at the University of Buffalo, I discovered my summer project was able to be chosen from many exciting areas of research in every imaginable field from stem cells, the oral microbiome, biomaterials, oral cancer and saliva. However, one particular area caught my attention – using ‘light’ as a form of therapy. It first sounded like science fiction. My cynicism was further promoted by a quick scan of the internet that showcased several anecdotal stories. Nonetheless, my curiosity got the better of me and I set out to explore this scientific area more carefully.
The myths and magic of lasers
From super hero cartoons to James Bond movies, laser beams conjure up popular images of destruction and burning to selectively remodel or destroy targets. In medicine, this has been extended to cutting and reshaping tissues (think LASIK eye surgery) or to destroy microbes and tumors. These latter effects have been selectively enhanced with either simple exogenous dyes or more sophisticated versions using nanoparticles or liposomes. This technique is called Photodynamic Therapy and is gaining much attention especially with oral cancer. A third, less well-known form of therapy uses low dose light treatments to inhibit pain or inflammation as well as promote tissue healing and regeneration. This treatment is called Photobiomodulation (PBM) therapy. Various terms have been previously used to describe this treatment such as cold lasers, low level light/laser therapy, photostimulation, among many others. Following intensive searching I found that the Arany lab at University at Buffalo School of Dental Medicine (UB SDM) is leading some of this research with specific interest on tissue regeneration and wound healing. Amongst numerous applications being explored in his lab was managing oral mucositis and dysgeusia with PBM therapy.
An unfortunate sequelae in Oral Cancer Care: Oral Mucositis
Oral cancers are one of the most prevalent cancer type with high mortality rates in the United States and worldwide. Current treatments for oral or head and neck cancer patients include surgery, chemotherapy and radiation therapy, either as stand alone or combined approaches. While these treatments are directed at killing rapidly dividing cancer cells, they unfortunately also damage or destroy normal cells such as hair follicles, salivary glands, and lining mucosal cells in the mouth and gut. Consequently, a majority of patients undergoing oncotherapy experience pain and ulcers in the mouth called Oral Mucositis (OM). Depending on the course and type of cancer treatments, its duration and severity can vary over days to weeks or months.
These side-effects can significantly affect quality of life in those patients by causing agonizing oral and throat pain resulting in reduced normal nutritional intake compounded by impaired sense of taste (dysgeusia), loss of appetite, oral dryness and depression. Moreover, severe side effects can be so debilitating so as to interfere with ongoing courses of cancer treatments often necessitating discontinuation or cessation that can affect treatment outcome. Current interventions for treatment-associated mucositis have been largely empirical with palliative mouthwashes, often including opioids. While these treatments provide temporary relief, they do not address the underlying causes of OM. There is clearly an urgent need for new approaches for OM management.
A new paradigm: precise light activated pathways for therapy
The use of PBM therapy has gained much attention in recent years for its ability to relieve pain or inflammation and promote wound healing and tissue regeneration in various clinical scenarios. PBM utilizes specific types of lasers or LEDs and even broad-band light in the visible or near-infrared range spectrum at low doses. These wavelengths are in the non-ionizing range of the electromagnetic spectrum and do not produce tissue damage. PBM therapy generates therapeutic benefits in a non-thermal or heat producing non-surgical manner. Given the non-invasive and safe energy levels of light used for this treatment, there have been several comparisons drawn with sunlight and photosynthesis in plants. Our current understanding of the PBM therapeutic mechanisms can be categorized into three discrete areas of light-biological tissue interactions namely, within the cell (intracellular), at the cell surface (cell membrane), and outside the cell (extracellular). In the intracellular delivery pathway, light is applied and absorbed which results in disruption of the normal energy transport chain resulting in increased levels of destructive products within the cell. This low level laser energy has beneficial effects by producing dissociation of nitric oxide (NO) resulting in increased ATP and NO levels boosting cellular function and performance including blood vessel expansion (vasodilator function) that increases blood-supply to tissues that would have beneficial effects on inflammation and wound healing.
A second PBM mechanism involves absorption of light by photosensitive cell membrane receptors and transporters. This has been shown to have a central role in pain relief (analgesia) which are transient and reversible with no permanent damage to the tissues being reported.
A third PBM mechanism that was recently reported involves generation of very low amounts of extremely reactive chemical intermediates termed Reactive Oxygen Species (ROS), which have several biological targets including a latent protein called TGFβ-1. This growth factor has several potent biological roles on a wide variety of cell types such as epithelial cells, fibroblasts, endothelial cells and macrophages. One of many key functions of this factor is to effect wound healing by promoting cell migration and matrix synthesis such as collagen and fibronectin. Another fascinating role of TGF-β1 is its ability to harness the regenerative potential of naturally present adult stem cells located in tooth pulp, mucosa and bone marrow, which promote tissue regeneration. A better understanding of these mechanisms in these clinical scenarios will enable more robust, reproducible clinical protocols to speed recovery.
The less-trodden path from the lab to the clinic
The well documented track record of the clinical safety and effectiveness of photobiomodulation therapy is of note. The oft cited ‘pyramid of evidences’ for clinical practice identify the most credible findings as those performed by systematic reviews and meta-analyses, where the validation of this approach will be confirmed. In addition to the advances made in the laboratory, an important update to the clinical practice guidelines was recently announced by the Multinational Association of Supportive Care in Cancer (MASCC). It recommends PBM therapy as a routine treatment for cancer therapy-induced OM. A group of global experts rigorously analyzed data from 35 randomized, blinded human studies and concluded that there was clear data supporting the use of PBM therapy to prevent and treat oncotherapy-induced OM.
The clinical benefits of this non-invasive, non-pharmacological treatment appears to be a sustainable, cost-effective and safe approach with no reported side effects.
Several regulatory agencies and policy institutes including insurance companies, now recognize PBM therapy as a useful clinical intervention, with commercially available devices that can be used both intra-orally or extra-orally.
Studies concerning the role of PBM in supportive cancer care have garnered much attention, with a broad range of treatment applications from fibrosis (trismus) to taste dysregulation (dysgeusia). Like every therapeutic intervention, there appears to be a range of PBM device parameters and delivery techniques requiring attention.Another important aspect of this treatment is that is can be used to reduce the incidence of pain associated with OM lesions when performed before and during actual treatment. This has significant implications for the use of this treatment with routine oncotherapy as it appears to pre-condition the tissues and improves both physiological and psychological resiliency in undergoing cancer treatments.
A Br-(L)-ight Future!
There is increasing realization of the oral-systemic connection that emphasizes good oral care as a key constituent of overall general health. The key role of clinicians involved in cancer care is perhaps best exemplified by the management of oral mucositis. This appears to showcase the central role for the oral care specialist in the 2030 UNESCO oral health paradigm. The specific area of research around PBM therapy appears to have tremendous implications for cancer care as well as overall human health. The use of opioids in cancer care has brought renewed attention to the potentially limitations and detrimental side effects of these drug-based treatments. While opioids are extremely effective medications for various cancer-associated and other chronic pain ailments, it appears we may have a viable alternative for managing pain due to oral mucositis. The use of biophysical pain management approaches, such as neurostimulation and PBM therapy, offer an attractive alternative to reduce both exposure and prescription of opioids. Hopefully these novel and safe to use technologies will become more routinely employed in the near future.
Editors Note: Jaeyoung Choi is a second year dental student at University at Buffalo School of Dental Medicine (UB SDM) in Buffalo, NY. He had also served as a Non-Commissioned Officer in U.S. Army Reserve and recently was commissioned via Army Health Professions Scholarship Program. He has been pursuing research since his undergraduate at UB as a Biomedical Science major and has continued his research interests as a dental student in the Arany lab, Oral Biology department since Feb 2018. The main topic of his interest is Photobiomodulation therapy for oral cancer care treatments in management of oral mucositis and altered taste sensation. Up on his expected graduation in 2022, he will serve as a dental officer in the Army. He looks forward to serving our country with his clinical and research skills and knowledge.
Praveen R. Arany received his dental degree and completed a joint PhD-Residency program in dental medicine at Harvard University as a Harvard Presidential Scholar. He has two certificates in clinical translational research from Harvard Medical School and National Institute of Health. He pursued postdoctoral fellowships at Indian Institute of Sciences, National Cancer Institute and Harvard School of Engineering & Applied Sciences. He served as an Assistant Clinical Investigator at NIDCR, NIH, Bethesda. He is currently an Assistant Professor in Department of Oral Biology and Biomedical Engineering, University at Buffalo. Dr. Arany currently holds various key leadership positions including the current President of the World Association for Photobiomodulation Therapy (WALT). His primary research focuses on the molecular mechanisms and clinical translation of Photobiomodulation Therapy.
Address correspondence to: