Photobiomodulation Therapy

Photobiomodulation therapy (PBMT) is a light therapy that promotes tissue repair (skin wounds, muscles, tendons, bones, nerves), reduces inflammation or reduces pain. In healthy people it increases strength, reduces fatigue and speeds up recovery. PBMT has been the subject of systematic reviews for a range of musculoskeletal pathologies with favorable conclusions reported by The Lancet, BMJ, and International Association for the Study of Pain and the World Health Organization. PBMT was previously known as “Low Level Laser Therapy” or “Low Level Light Therapy” because the light is applied using a low power laser or LED. It is a non-invasive therapy and, unlike drugs, it has no side effects. PBMT is not an ablating or heating based therapy, it is more akin to photosynthesis with light being absorbed by the cells and catalyzing chemical changes.

When our cells are stressed they produce a molecule called Nitric Oxide. This molecule blocks the receptor site that Oxygen belongs in during the respiratory process — the process of turning sugar in our blood into cellular energy. Usually, through rest and the consumption of anti-oxidants, the body is able to dispose of excess Nitric Oxide. However, when stressed the body does not have the capacity to remove enough Nitric Oxide. This leads to molecules known as “reactive oxygen species” being leaked into the cell. This is known as “Oxidative Stress.” Reactive oxygen species are toxic and trigger mechanisms for inflammation, cell death and the expression of genes responsible for cancer, Alzheimer’s, osteoarthritis and more.

Photobiomodulation has been used for many years on sports injuries, arthritic joints, neuropathic pain syndromes, back and neck pain. Over 700 randomized clinical trials have been published on Photobiomodulation, half of which are on pain.

Photobiomodulation and Cancer

PBMT has been shown to be highly effective in the mitigation of numerous distressing side-effects that occur as a result of a range of different kinds of cancer therapy [1, 2]. These side-effects can be so severe that they often lead to the suspension or discontinuation of the cancer therapy with consequent risk to the patient. Perhaps the single most effective indication for PBMT (amongst all known diseases and conditions) is that of oral mucositis [3]. Oral mucositis is a common side-effect of many kinds of chemotherapy and of radiotherapy for head and neck cancer [4]. Other side-effects that are under investigation by PBMT treatment are chemotherapy-induced peripheral neuropathy [5], radiation dermatitis associated with breast cancer therapy [6], and lymphoedema as a result of breast cancer surgery [7].

Photobiomodulation - Directly/Indirectly may Attack Cancer

When we consider the possibility that PBMT can have a beneficial effect on cancer, it is important to realize that there are three possible ways by which this may happen. The first involves the direct effect of the light on the tumor cells themselves, and may be thought of as a deliberate use of the biphasic dose response curve to “overdose” the cancer cells [8]. This possible methodology has been championed by Da Xing’s laboratory in China [9]. They call this approach “high fluence low-power laser irradiation, HF-LPLI”, and this group often uses a 632 nm HeNe laser delivering 1200 J/cm2 at 500mW/cm2, over 40 min [10]. After publishing several in vitro papers they carried out an in vivo study in BALB/c mice bearing EMT6 breast tumors [11]. A single dose of 1200 J/cm2 caused complete regression of tumors, which did not occur in rho-zero EMT6 tumors (lacking functional mitochondria). Moreover, since EMT6 tumors are known to be immunogenic, the mice that were cured of cancer showed some long-term immunological memory.

The second method relies on taking advantage of a differential effect of PBMT between malignant cancer cells compared to the effects seen on healthy normal cells. This involves combining PBMT with an additional cytotoxic anti-cancer therapy, so that it increases the killing of cancer cells, while at the same time protecting normal healthy cells. While this may appear “too good to be true”, there are some scientific reasons why it may, in fact, be the case. These considerations are related to the Warburg effect, by which the mitochondria of cancer cells change their metabolism to carry out aerobic glycolysis instead of oxidative phosphorylation [12]. This phenomenon occurs due to the rapid growth of tumor cells outpacing the development of a sufficient blood supply, forcing the cancer cells to become tolerant to chronic hypoxia. Glycolysis consumes much less oxygen than oxidative phosphorylation. The consequences of the Warburg effect are that malignant cells and normal cells may behave very differently in response to PBMT. In cancer cells, where ATP supply is quite limited, the ATP boost given by PBMT may allow the cancer cells to respond to pro-apoptotic cytotoxic stimuli with more efficiently executed cell death (apoptosis) programs which are heavily energy-dependent (i.e. require a lot of ATP [13]). On the other hand, in normal healthy cells that have an adequate supply of ATP, the effect of PBMT produces a burst of ROS that could induce protective mechanisms and reduce the damaging effects of cancer therapy on healthy tissue. Although this favorable scenario remains a hypothesis at present, there are some published papers that suggest it could indeed be the case in some anti-cancer strategies, such as reports that PBMT can potentiate the killing of cancer cells by photodynamic therapy [14] and also by radiation therapy [15]. These researchers have reported that, in theory, PBMT increases cell death in cancer cells in response to cytotoxic stimuli. Alternatively, while in normal cells, PBMT will exert its protective effect as is well known in the case of neurotoxins, for example [16].

The third mechanism, by which PBMT could be beneficial to cancer patients, is its possible role in stimulation of the immune system to fight against the cancer. Ottaviani et al [17] showed in a mouse model of melanoma that PBM using three different protocols (660 nm, 50mW/cm2, 3J/cm2; 800 nm or 970 nm, 200mW/cm2, 6 J/cm2, once a day for 4 days) could all reduce tumor growth, increase the recruitment of immune cells (in particular T lymphocytes and dendritic cells secreting type I interferons). PBM also reduced the number of highly angiogenic macrophages within the tumor mass and promoted vessel normalization, which is another strategy to control tumor progression.

A recent paper from Brazil [18] used PBM (660 nm, 100 mW, delivering 35, 107, or 214 J/cm2) to the tumor site 3 times every two days starting 14 days after rat Walker sarcoma tumor implantation. They measured the expression of IL-1β, IL-6, IL-10, TNF-α by ELISA and COX-1, COX-2, iNOS, eNOS by RT-PCR in the subcutaneous tumor tissue. Although tumor response was not directly measured, they claimed that the lowest dose (35 J/cm2) produced significant increases in IL - 1β , COX - 2, iNOS, and significant decreases in IL-6, IL-10, TNF-α and concluded the 35 J/cm2  “produced cytotoxic effects by the generation of ROS causing acute inflammation”.

Clinical Evidence

A very interesting recent paper [19] reported that PBMT could actually increase treatment outcome and progression-free survival in cancer patients. 94 patients diagnosed with oropharynx, nasopharynx, and hypopharynx cancer, were subjected to conventional radiotherapy plus cisplatin every 3 weeks. Preventive PBMT was applied to nine points on the oral mucosa daily, from Monday to Friday, and lasted on average 45.7 days. Over a follow-up period of 41 months, patients receiving PBMT had a statistically significant better complete response to treatment than those in the placebo group (p=0.013). Patients subjected to PBMT had better progression-free survival than those in the placebo group (p=0.030) and had a tendency for better overall survival.

Santana-blank et al [20] carried out a Phase 1 trial of PBMT on 17 patients suffering from a variety of “advanced malignancies”. They used a 904nm infrared laser, pulsed at 3 MHz, applied using a 2 mm-high top hat with a 10-mm beam diameter and placed at right angles to the surface of the patient’s skin in previously determined areas of closest proximity to the biologically closed electric circuits and the vascular interstitial closed circuit that would most efficiently carry the laser energy to the target tissues [23].  This approach was first described by Nordestrom [21] who inserted wires through the thoracic wall to reach pulmonary tumors and circulated electric current. Patients were given a laser device to use at home each day and were allowed to remain in the trial as long as possible. In addition to evaluation by the attending physicians, the patients were asked to keep a journal over the length of their time in the trial, and to record the time and duration of each PBMt application as well as any sign, symptom, or problem/side effect experienced. No dose-limiting toxicity was observed. Five patients reported occasional headaches (grade 2), and four referred local pain (grade 2). Statistically significant increases in Karnovsky performance status (KPS) and quality-of-life (QLI) were observed in all of the follow-up intervals compared with pretreatment values. In the six surviving patients, one patient had a complete response, 1 partial response, 4 stable disease >12 months, and 1 progressive disease. In the patients that died during the trial, significant increases in QLI were observed during the first two intervals. Eight patients had stable disease >6 months and 2 had progressive disease. The overall response rate was 88.23% in these terminally-ill (late stage) patients.

References:

1. Zecha, J.A., et al., Low-level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 2: proposed applications and treatment protocols. Support Care Cancer, 2016.

2. Zecha, J.A., et al., Low level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 1: mechanisms of action, dosimetric, and safety considerations. Support Care Cancer, 2016.

3. Weissheimer, C., et al., New photobiomodulation protocol prevents oral mucositis in hematopoietic stem cell transplantation recipients-a retrospective study. Lasers Med Sci, 2017.

4. Maria, O.M., N. Eliopoulos, and T. Muanza, Radiation-Induced Oral Mucositis. Front Oncol, 2017. 7: p. 89.

5. Argenta, P.A., et al., The effect of photobiomodulation on chemotherapy-induced peripheral neuropathy: A randomized, sham-controlled clinical trial. Gynecol Oncol, 2017. 144(1): p. 159-166.

6. Strouthos, I., et al., Photobiomodulation therapy for the management of radiation-induced dermatitis : A single-institution experience of adjuvant radiotherapy in breast cancer patients after breast conserving surgery. Strahlenther Onkol, 2017. 193(6): p. 491-498.

7. Lima, M.T., et al., Low-level laser therapy in secondary lymphedema after breast cancer: systematic review. Lasers Med Sci, 2014. 29(3): p. 1289-95.

8. Kiro, N.E., M.R. Hamblin, and H. Abrahamse, Photobiomodulation of breast and cervical cancer stem cells using low-intensity laser irradiation. Tumour Biol, 2017. 39(6): p. 1010428317706913.

9. Wu, S., et al., High fluence low-power laser irradiation induces mitochondrial permeability transition mediated by reactive oxygen species. J Cell Physiol, 2009. 218(3): p. 603-11.

10. Wu, S., et al., Cancer phototherapy via selective photoinactivation of respiratory chain oxidase to trigger a fatal superoxide anion burst. Antioxid Redox Signal, 2014. 20(5): p. 733-46.

11. Lu, C., et al., Phototherapy-Induced Antitumor Immunity: Long-Term Tumor Suppression Effects via Photoinactivation of Respiratory Chain Oxidase-Triggered Superoxide Anion Burst. Antioxid Redox Signal, 2016. 24(5): p. 249-62.

12. Kalyanaraman, B., Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism. Redox Biol, 2017. 12: p. 833-842.

13. Eguchi, Y., S. Shimizu, and Y. Tsujimoto, Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res, 1997. 57(10): p. 1835-40.

14. Tsai, S.R., et al., Low-Level Light Therapy Potentiates NPe6-mediated Photodynamic Therapy in a Human Osteosarcoma Cell Line via Increased ATP. Photodiagnosis Photodyn Ther, 2014.

15. Djavid, G.E., et al., Photobiomodulation leads to enhanced radiosensitivity through induction of apoptosis and autophagy in human cervical cancer cells. J Biophotonics, 2017.

16. Wong-Riley, M.T., et al., Photobiomodulation directly benefits primary neurons functionally inactivated by toxins: role of cytochrome c oxidase. J Biol Chem, 2005. 280(6): p. 4761-71.

17. Ottaviani, G., et al., Laser Therapy Inhibits Tumor Growth in Mice by Promoting Immune Surveillance and Vessel Normalization. EBioMedicine, 2016. 11: p. 165-172.

18. Petrellis, M.C., et al., Laser photobiomodulation of pro-inflammatory mediators on Walker Tumor 256 induced rats. J Photochem Photobiol B, 2017: p. DOI: doi: 10.1016/j.jphotobiol.2017.09.011.

19. Antunes, H.S., et al., Long-term survival of a randomized phase III trial of head and neck cancer patients receiving concurrent chemoradiation therapy with or without low-level laser therapy (LLLT) to prevent oral mucositis. Oral Oncol, 2017. 71: p. 11-15.

20. Santana-Blank, L.A., et al., Phase I trial of an infrared pulsed laser device in patients with advanced neoplasias. Clin Cancer Res, 2002. 8(10): p. 3082-91.

21. Nordenstrom, B.E., Fleischner lecture. Biokinetic impacts on structure and imaging of the lung: the concept of biologically closed electric circuits. AJR Am J Roentgenol, 1985. 145(3): p. 447-67.

22. Santana-Blank, L.A., et al., Evaluation of serum levels of tumour necrosis factor-alpha (TNF-alpha) and soluble IL-2 receptor (sIL-2R) and CD4, CD8 and natural killer (NK) populations during infrared pulsed laser device (IPLD) treatment. Clin Exp Immunol, 1992. 90(1): p. 43-8.

23. zhevago, N.A., et al., [The efficacy of polychromatic visible and infrared radiation used for the postoperative immunological rehabilitation of patients with breast cancer]. Vopr Kurortol Fizioter Lech Fiz Kult, 2012(4): p. 23-32.