Review Could the biological robustness of low level laser therapy (Photobiomodulation) impact its use in the management of mucositis in head and neck cancer patients Stephen T. Sonis a,b,⇑ , Sepehr Hashemi c , Joel B. Epstein d,e , Raj G. Nair f,g , Judith E. Raber-Durlacher h,i a Division of Oral Medicine, Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, Boston, MA, USA b Biomodels, LLC, Watertown, MA, USA c Harvard School of Dental Medicine, Boston, MA, USA d Samuel Oschin Comprehensive Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA e Division of Otolaryngology and Head and Neck Surgery, City of Hope National Medical Center, Duarte, CA, USA f Discipline of Oral Medicine, Oral Pathology and Human Diseases, Griffith University, Menzies Health Institute Queensland, Australia g Hematology and Oncology, Gold Coast University Hospital, Queensland Health, Australia h Department of Oral- and Maxillofacial Surgery, Academic Medical Center, The Netherlands i Department of Medical Dental Interaction, ACTA, University of Amsterdam, Amsterdam, The Netherlands article info Article history: Received 20 October 2015 Received in revised form 4 January 2016 Accepted 6 January 2016 Available online 3 February 2016 Keywords: Photobiomodulation Low level laser therapy Head and neck cancer Oral mucositis Tumor behavior Radioprotection summary Low level laser therapy (LLLT) has been noted to be effective in mitigating the development of oral mucositis among patients being treated with chemoradiation for cancers of the head and neck. To explain the biological basis for this observation we performed a comprehensive literature search. Our investiga- tion identified a substantial number of LLLT-activated pathways that have been strongly associated with negative tumor outcomes including proliferation, invasion, angiogenesis, metastases and cancer- treatment resistance. In light of these findings, we suggest an investigational strategy to assure that LLLT’s anti-mucositis efficacy is independent of its possible potential to enhance threatening tumor behaviors. Included are appropriate pre-clinical modeling, short- and long-term follow-up of LLLT-treated patients, and the requirement for consistency of LLLT parameters. Ó 2016 Elsevier Ltd. All rights reserved. Introduction Low level laser therapy (LLLT) was first introduced for potential clinical applications by Mester in the late 1960s. This form of laser treatment, currently referred to as photobiomodulation (PBM), limits radiation intensity by transferring low energy to tissues and thereby does not generate heat. Among the clinical indications for which LLLT has been reported to be efficacious are pain relief (back and neck, orthodontic, shoulder), wound healing, carpal tun- nel syndrome, colorectal cancer, elbow disorders, fibromyalgia, lymphedema, musculoskeletal dysfunction, myofascial pain syn- drome, neurological dysfunctions, patella-femoral pain syndrome, rheumatoid arthritis, shoulder impingement syndrome, and tinni- tus. It has also been reported to be useful in the treatment of a number of oral or perioral diseases including dentin sensitivity, alveolar osteitis, osteonecrosis, dental extraction wound healing, aphthous stomatitis, lichen planus, herpes labialis, xerostomia, trismus and mucous membrane pemphigoid. Among its other clin- ical applications, the potential of LLLT to effectively mitigate oral mucositis associated with anti-cancer drug or radiation regimens has achieved significant attention. There exists a substantial body of data in which the course, severity or incidence of mucositis has been favorably impacted by LLLT [1]. In fact, the possible use of LLLT as a mucositis intervention is noted in the most recent Multinational Association for Supportive care in Cancer/Interna- tional Society for Oral Oncology (MASCC/ISOO) guidelines [2]. As with any treatment for a cancer supportive care indication, it is critical that the intervention used to mitigate cancer-treatment associated normal tissue injury does so at no cost to tumor treat- ment efficacy or, worse, does not enhance the malignant potential, local growth, or invasion of the primary tumor. Although investiga- tions evaluating these questions with respect to LLLT are limited and have had contradictory results [3–6], it has been largely assumed that LLLT posed no threat to either tumor behavior or responsiveness to treatment. However, as data accumulates on LLLT’s biological pleotropism, this supposition needs to be critically http://dx.doi.org/10.1016/j.oraloncology.2016.01.005 1368-8375/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: Division of Oral Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. E-mail address: ssonis@partners.org (S.T. Sonis). Oral Oncology 54 (2016) 7–14 Contents lists available at ScienceDirect Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology