Laser therapy and cancer

The effect of photobiomodulation (PBM) therapy on tumour growth

David Lane, DVM, ACVSMR, of Points East West Veterinary Services in Squamish, B.C., uses a therapeutic laser. Photos courtesy David Lane/Points East West Veterinary Services
David Lane, DVM, ACVSMR, of Points East West Veterinary Services in Squamish, B.C., uses a therapeutic laser.
Photos courtesy David Lane/Points East West Veterinary Services

Photobiomodulation (PBM) therapy has been used for more than half a century. It is sometimes referred to as laser phototherapy; low-level laser (or light) therapy (LLLT); cold or soft laser; high-intensity laser therapy (HILT); Class 4 or Class 3 laser therapy; or light-emitting diode (LED)/red light therapy. Within veterinary medicine, its popularity has grown rapidly in the past 15 to 20 years. The U.S. National Library of Medicine (NLM) adopted ‘photobiomodulation’ as a Medical Subject Headings (MeSH) term in November 2015.

Laser has traditionally been the predominant source of non-ionizing radiation used clinically for PBM therapy. However, LEDs and infrared-emitting devices (IREDs) can also be used effectively for some indications.

Regardless of the light source used and its specific clinical application, the fundamental mechanisms affected are largely the same; thus, ‘photobiomodulation’ is best defined as:

[a] form of light therapy that utilizes non-ionizing forms of light sources, including lasers, LEDs, and broadband light, in the visible and infrared spectrum. It is a non-thermal process involving endogenous chromophores eliciting photophysical (i.e. linear and non-linear) and photochemical events at various biological scales. This process results in beneficial therapeutic outcomes, including, but not limited to, the alleviation of pain or inflammation, immunomodulation, and promotion of wound healing and tissue regeneration.1

As with any other therapeutic modality, there are concerns about precautions and contraindications, as well as questions of risk versus benefit. Many contraindications to PBM are often listed, including pregnancy, pacemakers, active epiphyses and open fontanels, irradiation of the thyroid, and active malignancy. Much has been written about the accuracy and relevance of listed contraindications,2 and there are numerous seemingly contradictory data in the literature. This article looks specifically at the evidence for and against PBM with respect to cancer and neoplasia.

In vitro

There have been several studies showing laser irradiation can cause tumour cell proliferation,3,4 while other researchers have found laser therapy does not exhibit a tumour-promoting effect.5-9

Generally, however, in vitro studies have limited applicability when compared to in vivo studies, where various physiologically active cells and systems interact in the targeted tissue. There is a concomitant effect of light on endothelial, epithelial, mesenchymal, and immune cells, which must be studied together to identify real-time effects.13

In vivo

Four studies have demonstrated tumour mass can increase after laser irradiation in vivo;10-12,14 however, in two of these,10,12 anti-cancer effects were also shown, and in one, the effects were dose-dependent.

Within veterinary medicine, the popularity of photobiomodulation (PBM) therapy has grown rapidly in the past 15 to 20 years.
Within veterinary medicine, the popularity of photobiomodulation (PBM) therapy has grown rapidly in the past 15 to 20 years.

1) Frigo et al10 studied an in vivo mouse model of melanoma. A control group (n=7) received no irradiation. The active groups received daily transdermal irradiation for three days with a 50-mW continuous wave 660-nm laser, beam spot 0.02 cm2 (2.5 W/cm2), at two doses:

a) Low-dose group (n=7) was irradiated for 60 sec., and received 3 J (150 J/cm2) per treatment session. Tumours in the low-dose group reduced (insignificantly) in size compared to the control group.

b) High-dose group (n=7) was irradiated for 420 sec., and received 21 J (1050 J/cm2) per treatment session. The total tumour mass volume in this group increased significantly versus control.

2) Rhee et al11 studied an in vivo mouse model of human anaplastic thyroid carcinoma. A control group (n=10) received no irradiation. The two active groups each received a single direct irradiation to the surgically exposed thyroid with a 2-mW continuous wave 650-nm laser, beam spot 0.02 cm2 (100 mW/cm2), at two doses:

a) Low-dose group (n=10) was irradiated for 150 sec., and received 0.3 J (15 J/cm2). Tumours increased significantly in size compared to the control group.

b) High-dose group (n=10) was irradiated for 300 sec., and received 0.6 J (30 J/cm2). The total tumour mass volume in this group increased significantly versus both control and the low-dose group.

3) Ottaviani et al12 studied both melanoma and oral carcinoma in mice, with three different sets of laser parameters:

a) L1: Wavelength 660 nm, laser power 100 mW, irradiance 50 mW/cm2, fluence 3 J/cm2, time 60 sec., continuous wave.

b) L2: Wavelength 800 nm, laser power 1 W, irradiance 200 mW/cm2, fluence 6 J/cm2, time 30 sec., continuous wave.

c) L3: Wavelength 970 nm, laser power 2.5 W, irradiance 200 mW/cm2, fluence 6 J/cm2, time 30 sec., continuous wave.

Irradiation was performed daily for four days. A control group for each of the cancer types received no irradiation. Tumour growth continued in all active groups, but the growth rates of the tumours were significantly decreased in all groups versus control. This result was attributed to a ‘normalization’ of tumour vasculature and an increase in immune cell activation.

4) A 2018 study by Frigo et al14 investigated the effect of various doses of laser energy—3 J (150 J/cm2), simulating LLLT; 21 J (1050 J/cm2), simulating HILT; and an in-between dose of 9 J (450 J/cm2)—upon tumour growth, finding: “high doses (>9 J) … showed a dose-dependent tumour growth, different collagen fibres characteristics, and, eventually, blood vessel growth, while a typical LLLT dose (3 J) appeared harmless on melanoma cell activity.”

In a fifth study, Myakishev-Rempel et al15 employed a standard SKH mouse non-melanoma UV-induced skin cancer model to study the effects of LLLT/PBMT on tumour growth. After visible squamous cell carcinomas were present, the active study group received automated full-body 670-nm irradiation twice a day at 5 J/cm2. Measurements on 330 tumours were taken over 37 consecutive days, while the animals received daily LLLT/PBMT and demonstrated no measurable effect of LLLT on tumour growth. This suggests the outcome of LLLT/PBMT depends upon competition between possible activation of tumour growth, on the one hand, and improvement of systemic anti-tumour immune response on the other.

The authors concluded: “[t]he present study failed to demonstrate a harmful effect of whole-body red LLLT on tumour growth in an experimental model of UV-induced SCC. There was a transient and small reduction in relative tumour area in the treatment group compared with controls. This study suggests LLLT/PBMT should not be withheld from cancer patients on an empiric basis.”

An in vivo study by Mikhailov et al16 saw similar results in rats, demonstrating PBM therapy was able to “reduce and let even completely disappear small tumours.”

According to Bensadoun et al:13

[T]his led to the hypothesis that the upregulation of ATP signaling by PBM stimulated differentiation of tumour cells and apoptosis, leading to an inhibition of tumour proliferation. A normal cell produces ATP via the process
of oxidative phosphorylation. This gives a yield of around 32–38 ATPs per glucose molecule. Cancer cells naturally change from ‘cellular respiration’ to the very ineffective glycolysis for their ATP needs (i.e. Warburg effect). Cancer cells perform anaerobic glycolysis, which implies they produce most of their energy from glycolysis. This produces only two ATPs per glucose molecule. The potential of PBM to promote anti-inflammatory and repair of normal tissue while not enhancing tumour cell proliferation may be related to this differential effect.

Duncan the cat receives acupuncture and laser therapy.
Duncan the cat receives acupuncture and laser therapy.

It is recommended to take every case individually, of course, and to be especially cautious when utilizing high intensities and high doses; however, using PBM therapy on patients with known or suspected neoplasia or tumours is not specifically contraindicated. There are also numerous studies on the benefits of PBM therapy in the treatment and prevention of oral mucositis in patients undergoing radiation and chemotherapy for leukemia and lymphoma,17,18 head and neck cancer,19 and acute lymphoblastic leukemia,20 all of which demonstrate safety and efficacy. Further, the immune-supportive effects of low-dose PBM following tumour removal may be more beneficial than not, even if the margins are not clean.

Summary

To summarize the current position on laser therapy/PBM with respect to cancer and neoplasia, this author refers to the conclusions drawn from the systematic review undertaken by Bensadoun et al (2020),13 in which the authors state: “[i]n vivo studies and clinical trials with a follow-up period demonstrated that PBMT is safe with regards to tumour growth and patient advantage in the prevention and treatment of specific cancer therapy-related complications” and “[a] significant and growing literature indicates PBMT is safe and effective, and may even offer a benefit in patient overall survival.”

Peter Jenkins [ORCID ID: 0000-0002-8456-5919] is founder and director of education and technology for SpectraVET Inc., a U.S.-based developer and manufacturer of veterinary laser/LED/IRED photobiomodulation (PBM) therapy devices.  He also co-founded the Australian Medical Laser Association (now Australian Medical Photobiomodulation Association– AMPA) and Immunophotonics Inc., a biotech company focused on cancer immunotherapy.

References

1 Goldberg, ME. Laser therapy—Indications and contraindications. Taking a look at what laser therapy is used for and how it works. https://www.veterinarypracticenews.com/indications-and-contraindications-2019 (Accessed 1 July 2021)

2 Anders JJ, Lanzafame RJ, Arany PR. Low-level light/laser therapy versus photobiomodulation therapy. Photomed. Laser Surg. 2015;33:183–184.

3 Sperandio FF, Giudice FS, Correa L, Pinto DS Jr, Hamblin MR, de Sousa SC. Low-level laser therapy can produce increased aggressiveness of dysplastic and oral cancer cell lines by modulation of Akt/mTOR signaling pathway. J Biophotonics 2013;6:839–847.

4 Gomes Henriques ÁC, Ginani F, Oliveira RM, Keesen TS, Galvão Barboza CA, Oliveira Rocha HA, de Castro JF, Della Coletta R, de Almeida Freitas R. Low-level laser therapy promotes proliferation and invasion of oral squamous cell carcinoma cells. Lasers Med Sci. 2014 Jul;29(4):1385-95.

5 Schartinger VH, Galvan O, Riechelmann H, Dudás J. Differential responses of fibroblasts, non-neoplastic epithelial cells, and oral carcinoma cells to low-level laser therapy. Support Care Cancer. 2012 Mar;20(3):523-9.

6 Berns MW, Nelson , JS. Laser applications in biomedicine. Part I: biophysics, cell biology, and biostimulation J Laser Appl 1988;1:34–39.

7 McGuff PE, Deterling RA Jr, Gottlieb LS. Tumoricidal effect of laser energy on experimental and human malignant tumors. New Engl J Med 1965;273:490–492.

8 McGuff PE, Deterling RA Jr, Gottlieb LS. Laser radiation for metastatic malignant melanoma. JAMA 1966;195:393–394.

9 McGuff PE, Gottlieb LS, Katayama I, Levy CK. Comparative study of effects of laser and/or ionizing radiation therapy on experimental or human malignant tumors. Am J Roentgenol Radium Ther Nucl Med 1966;96:744–748.

10 Frigo L, Luppi JS, Favero GM, Maria DA, Penna SC, Bjordal JM, Bensadoun RJ, Lopes-Martins RA. The effect of low-level laser irradiation (In-Ga-Al-AsP – 660 nm) on melanoma in vitro and in vivo. BMC Cancer. 2009 Nov 20;9:404.

11 Rhee YH, Moon JH, Choi SH, Ahn JC. Low-Level Laser Therapy Promoted Aggressive Proliferation and Angiogenesis Through Decreasing of Transforming Growth Factor-β1 and Increasing of Akt/Hypoxia Inducible Factor-1α in Anaplastic Thyroid Cancer. Photomed Laser Surg. 2016 Jun;34(6):229-35.

12 Ottaviani G, Martinelli V, Rupel K, Caronni N, Naseem A, Zandonà L, Perinetti G, Gobbo M, Di Lenarda R, Bussani R, Benvenuti F, Giacca M, Biasotto M, Zacchigna S. Laser Therapy Inhibits Tumor Growth in Mice by Promoting Immune Surveillance and Vessel Normalization. EBioMedicine. 2016 Sep;11:165-172.

13 Bensadoun RJ, Epstein JB, Nair RG, Barasch A, Raber-Durlacher JE, Migliorati C, Genot-Klastersky MT, Treister N, Arany P, Lodewijckx J, Robijns J; World Association for Laser Therapy (WALT). Safety and efficacy of photobiomodulation therapy in oncology: A systematic review. Cancer Med. 2020 Nov;9(22):8279-8300.

14 Frigo L, Cordeiro JM, Favero GM, Maria DA, Leal-Junior ECP, Joensen J, Bjordal JM, Roxo DC, Marcos RL, Lopes-Martins RAB. High doses of laser phototherapy can increase proliferation in melanoma stromal connective tissue. Lasers Med Sci. 2018 Aug;33(6):1215-1223.

15 Myakishev-Rempel M, Stadler I, Brondon P, Axe DR, Friedman M, Nardia FB, Lanzafame R. A Preliminary Study of the Safety of Red Light Phototherapy of Tissues Harboring Cancer. Photomedicine and Laser Surgery, 2012;30(9), 551–558.

16 Mikhailov VA, Skobelkin OK, Denisov IN, Frank GA, Voltchenko NN. Investigations on the influence of low level diode laser irradiation on the growth of experimental tumours. Laser Therapy. 1993;5(1):33–38

17 Cruz LB, Ribeiro AS, Rech A, Rosa LG, Castro CG Jr, Brunetto AL. Influence of low-energy laser in the prevention of oral mucositis in children with cancer receiving chemotherapy. Pediatr Blood Cancer. 2007 Apr;48(4):435-40.

18 Kuhn A, Porto FA, Miraglia P, Brunetto AL. Low-level infrared laser therapy in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in children. J Pediatr Hematol Oncol. 2009 Jan;31(1):33-7.

19 Bjordal JM, Bensadoun RJ, Tunèr J, Frigo L, Gjerde K, Lopes-Martins RA A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in cancer therapy-induced oral mucositis. Support Care Cancer. 2011 Aug;19(8):1069-77.

20 Rimulo AL, Ferreira MC, Abreu MH, Aguirre‐Neto JC, Paiva SM. Chemotherapy‐induced oral mucositis in a patient with acute lymphoblastic leukaemia. European Archives of Paediatric Dentistry, 2011;12(2), 124–127.

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