TABLE 2.

Study characteristics of the in vivo studies investigating the effect of PBMT on cancer animal models

Author (Ref.)	Year	Animal type	Tumor type	PBM device	Wavelength	Fluence	Exposition time (sec)	Application protocol	Tumor growth rate/Tumorigenicity
Mikhailov 82	1993	Rat	Walker's carcinosarcoma Cancer of the mammary gland (RMK−1)	LD	890 nm	0.46, 1.53 J/cm2	15 s	Five applications on consecutive days directly on the tumor	PBM at 0.46 J/cm2 led to retardation in tumor growth and life span was prolonged versus control animals. PBM increased dystrophic and necrotic changes in the tumor. Tumor weight increased at 1.53 J/cm2.
Abe 81	1993	Mouse	Glioma	GaAlAs LD	830 nm	N.S.	15 s	Two applications/day, one day post implantation and Two applications/day, 14 days post implantation directly on the skin over the tumor site or indirect on the abdominal skin	PBM applied on the first day after glioma implantation, both in a direct and indirect manner, inhibited the tumor growth. At 14 days postimplantation indirect PBM enhanced tumor growth.
Ulrich 71	1996	Rat	Rhabdomyosarcomas (R1H)	LD	830 nm	1 and 100 J/cm2	N.S.	15 fractions over 3 weeks	Single doses PBM do not inhibit nor stimulate tumor growth. Fractionated PBM does not alter growth kinetics of the tumors. Increase in tumor necrosis after 15 fractions of 100 J/cm2
Frigo 62	2009	Mouse	Melanoma cell line (B16F10)	LD	660 nm	150 J/cm2 1050 J/cm2	60 s 420 s	Once a day for three consecutive days	PBM at 150 J/cm2 was safe with only negligible effects on cell proliferation in vitro and no significant effect on tumor growth in vivo. PBM at a high irradiance (2.5 W/cm2) combined with high dose of 1050 J/cm2, could stimulate melanoma tumor growth.
Zhang 79	2009	Mouse	Human cervical carcinoma cell line (HeLa)	LED	650 nm	N.S	N.S.	Single application	PBM diminished the tumor growth of tumors on day 50 and weakened the elevation of vascular endothelial growth factor (VEGF). PBM could induce HeLa cell apoptosis and have antitumor properties.
Monteiro 76	2011	Hamster	Squamous cell carcinoma (SCC)	LD	660 nm	56.4 J/cm2	133 s	Every other day for 4 weeks	PBM led to a significant progression of the severity of SCC
Myakishev‐Rempel 77	2012	Mouse	UV‐induced skin cancer	GaAlAs LED	760 nm	2.5 J/cm2	312 s	Twice daily for 37 days	PBM did not have an effect on the growth of the UV‐induced skin cancer.
Monteiro 78	2013	Hamster	Squamous cell carcinoma (SCC)	LD	660 nm	95 J/cm2	133 s	Every other day for 4 weeks	PBM did not influence tumor behavior, four weeks after tumor induction.
Wikramanayake 83	2013	Rat	Chemotherapy induced alopecia	LD	655 nm	N.S.	60 s	Daily for 10 days	PBM did not affect the efficacy of chemotherapy
Ottaviani 63	2016	Mouse	Melanoma cell line (B16F10)	InGaAlAsP LD	660 nm 800 nm 970 nm	3 or 6 J/cm2	30–60 s	Once a day for 4 consecutive days	PBM hindered tumor progression, provoked tumor vessel normalization and stimulated the immune system to produce type I interferons.
Rhee 75	2016	Mouse	Human anaplastic thyroid cell line (FRO)	LD	650 nm	15, 30 J/cm2	150 and 300 s	Single application	PBM decreased TGF‐β1 and increased p‐Akt/HIF−1α which resulted in proliferation and angiogenesis of anaplastic thyroid carcinoma (ATC)
Khori 74	2016	Mouse	Mouse mammary carcinoma (4T1, ATCC CRL−2539)	LD	405, 532, and 632 nm	N.S	N.S	10 treatments three times a week with a weekend break	PBM (405–532 nm) significantly reduced the tumor size.
Petrellis 73	2017	Rat	Walker's carcinosarcoma	LD	660 nm	35.7, 107.14, 214.28 J/cm2	10 s 30 s 60 s	Three times on alternate days	PBM increased inflammatory markers IL−1β, COX−2, iNOS. PBM decreased inflammatory markers IL−6, IL−10, and TNF‐α. PBM at 1 J−35,7 J/cm2 produced cytotoxic effects by ROS generation.
Frigo 62	2018	Mouse	Melanoma cell line (B16F10)	InGaAlP LD	660 nm	150, 450, 1050 J/cm2	60 s 180 s 420 s	Each 24 h for three consecutive days	High PBM doses (≥ 9 J) showed a dose‐dependent tumor growth, different collagen fibers characteristics, and eventually blood vessel growth. A PBM dose of 3 J did not affect the melanoma cell activity.
Barasch 72	2019	Mouse	Human squamous cell carcinoma of the oral tongue (Cal−33)	LD	660 nm 850 nm	18.4 J/cm2 3.4 J/cm2	75 s	(1) PBM at 660 nm, 18.4 J/cm2, and 5 RT ×4 Gy doses delivered daily; (2) PBM at 660 nm, 18.4 J/cm2, and 1 × 15 Gy RT; (3) PBM at 660 nm +850 nm, 45 mW/cm2, 3.4 J/cm2, and 1 × 15 Gy RT	RT‐treated animals survived significantly longer and had significantly smaller tumor volume when matched with the control and PBM treatment groups. No significant differences were discovered between the RT alone and PBM +RT groups in any of the experiments.

Abbreviations: LD, laser diode; LED, light emitting diode; PBMT, photobiomodulation therapy; ROS, reactive oxygen species; SCC, squamous cancer cell.