Photobiomodulation therapy in management of cancer therapy-induced side effects: WALT position paper 2022.

Disclaimer: This article is based on recommendations from the 12th WALT Congress, Nice, October 3-6, 2018, and a follow-up review of the existing data and the clinical observations of an international multidisciplinary panel of clinicians and researchers with expertise in the area of supportive care in cancer and/or PBM clinical application and dosimetry. This article is informational in nature. As with all clinical materials, this paper should be used with a clear understanding that continued research and practice could result in new insights and recommendations. The review reflects the collective opinion and, as such, does not necessarily represent the opinion of any individual author. In no event shall the authors be liable for any decision made or action taken in reliance on the proposed protocols. Objective: This position paper reviews the potential prophylactic and therapeutic effects of photobiomodulation (PBM) on side effects of cancer therapy, including chemotherapy (CT), radiation therapy (RT), and hematopoietic stem cell transplantation (HSCT). Background: There is a considerable body of evidence supporting the efficacy of PBM for preventing oral mucositis (OM) in patients undergoing RT for head and neck cancer (HNC), CT, or HSCT. This could enhance patients' quality of life, adherence to the prescribed cancer therapy, and treatment outcomes while reducing the cost of cancer care. Methods: A literature review on PBM effectiveness and dosimetry considerations for managing certain complications of cancer therapy were conducted. A systematic review was conducted when numerous randomized controlled trials were available. Results were presented and discussed at an international consensus meeting at the World Association of photobiomoduLation Therapy (WALT) meeting in 2018 that included world expert oncologists, radiation oncologists, oral oncologists, and oral medicine professionals, physicists, engineers, and oncology researchers. The potential mechanism of action of PBM and evidence of PBM efficacy through reported outcomes for individual indications were assessed. Results: There is a large body of evidence demonstrating the efficacy of PBM for preventing OM in certain cancer patient populations, as recently outlined by the Multinational Association for Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Building on these, the WALT group outlines evidence and prescribed PBM treatment parameters for prophylactic and therapeutic use in supportive care for radiodermatitis, dysphagia, xerostomia, dysgeusia, trismus, mucosal and bone necrosis, lymphedema, hand-foot syndrome, alopecia, oral and dermatologic chronic graft-versus-host disease, voice/speech alterations, peripheral neuropathy, and late fibrosis amongst cancer survivors. Conclusions: There is robust evidence for using PBM to prevent and treat a broad range of complications in cancer care. Specific clinical practice guidelines or evidence-based expert consensus recommendations are provided. These recommendations are aimed at improving the clinical utilization of PBM therapy in supportive cancer care and promoting research in this field. It is anticipated these guidelines will be revised periodically.

Shoulder Rotational Strength Profiles of Danish National Level Badminton Players.

BACKGROUND: Increased age has been shown to be associated with weaker external rotators and stronger internal rotators of the shoulder in pitchers and tennis players. Whether this age-associated change is present in elite badminton players is unknown. PURPOSE: To compare the internal and external rotation strength of the shoulder in adolescent and adult elite badminton players. STUDY DESIGN: Cross-sectional. METHODS: Thirty-one adolescent (12 females aged 16.8 ± 1.6 years and 19 males aged 17.1 ± 1.6 years) and 29 adult (10 females aged 25 ± 2.9 years and 19 males aged 26.2 ± 4.6 years) national level badminton players were tested pre-seasonally for external rotation (ER) and internal rotation (IR) isometric muscle strength bilaterally, using a hand-held dynamometer. Within-group ER to IR strength ratios were calculated (ER/IR×100%). RESULTS: The adolescents had stronger shoulder ER than the adults on both sides (p < 0.05). The adult males tended to have stronger IR of the dominant shoulder than the adolescent males (p = 0.071). In the dominant shoulders, the strength ratios for adult females and males were 77% and 78%, respectively, while the same ratio for adolescent females and males were 85% and 99%, respectively. In the non-dominant shoulders, the ER/IR strength ratios for adult females and males were 90% and 87%, respectively, while the ratios for adolescent females and males were 116% and 102%, respectively. CONCLUSION: This study is the first to demonstrate that in shoulder injury-free national team badminton players, adolescents have stronger shoulder ER than adults on both sides. Therefore, increased age appears to be associated with weaker shoulder ER muscles in elite badminton players. LEVEL OF EVIDENCE: 3b.

Photobiomodulation Therapy is Able to Modulate PGE2 Levels in Patients With Chronic Non-Specific Low Back Pain: A Randomized Placebo-Controlled Trial.

BACKGROUND AND OBJECTIVES: Non-specific low back pain (LBP) is responsible for triggering increased biomarkers levels. In this way, photobiomodulation therapy (PBMT) may be an interesting alternative to treat these patients. One of the possible biological mechanisms of PBMT involved to decrease pain intensity in patients with musculoskeletal disorders is modulation of the inflammatory mediators' levels. The aim of this study was to evaluate the effects of PBMT compared with placebo on inflammatory mediators' levels and pain intensity in patients with chronic non-specific LBP. STUDY DESIGN/MATERIALS AND METHODS: A prospectively registered, randomized triple-blinded (volunteers, therapists, and assessors), placebo-controlled trial was performed. Eighteen patients with chronic non-specific LBP were recruited and treated with a single session of active PBMT or placebo PBMT. The primary outcome of the study was serum prostaglandin E2 levels and the secondary outcomes were tumor necrosis factor-α, interleukin-6 levels, and pain intensity. All outcomes were measured before and after 15 minutes of treatment session. RESULTS: PBMT was able to decrease prostaglandin E2 levels at post-treatment compared with placebo, with a mean difference of -1470 pg/ml, 95% confidence interval -2906 to -33.67 in patients with LBP. There was no difference between groups in the other measured outcomes. Patients did not report any adverse events. CONCLUSION: Our results suggest that PBMT was able to modulate prostaglandin E2 levels, indicating that this may be one of the mechanisms involved in the analgesic effects of PBMT in patients with LBP. Trial registration number (ClinicalTrials.gov): NCT03859505. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Histological Assessment of a Combined Low-Level Laser/Light-Emitting Diode Therapy (685 nm/470 nm) for Sutured Skin Incisions in a Porcine Model: A Short Report.

OBJECTIVE: The aim of our study was to evaluate, from a histological point of view, the effect of photobiomodulation (PBM) with combined low-level laser therapy (LLLT)/light- emitting diode (LED) on porcine skin wound healing. BACKGROUND DATA: Most LLLT/LED wound healing studies have been performed on various types of rat models, with their inherent limitations. Minipigs are evolutionary and physiologically closer to humans than rats. MATERIALS AND METHODS: With the animals under general anesthesia, one full-thickness skin incision was performed on the back of each minipig (n = 10) and immediately closed using simple interrupted percutaneous sutures. The minipigs were randomly allocated into two groups: a PBM-treated group (LLLT λ = 685 nm, LED λ = 470 nm, both light sources producing power densities at 0.008 W/cm2; each light source delivering total daily doses of 3.36 J/cm2) and a sham-irradiated control group. Half of the animals in each group were killed on postoperative day 3, and the other half were killed on the postoperative day 7, and samples were removed for histological examination. RESULTS: Combined red and blue PBM accelerated the process of re-epithelization and formation of cross-linked collagen fibers compared with sham irradiated control wounds. CONCLUSIONS: Our results demonstrate that the current dose of combined red and blue PBM improves the healing of sutured skin incisions in minipigs.

Low-level laser therapy with 810 nm wavelength improves skin wound healing in rats with streptozotocin-induced diabetes.

OBJECTIVE: The aim of present study was to evaluate whether low-level laser therapy (LLLT) can reverse the impaired wound healing process in diabetic rats. BACKGROUND DATA: Impaired wound healing in diabetic patients represents a major health problem. Recent studies have indicated that LLLT may improve wound healing in diabetic rats, but the optimal treatment parameters are still unknown. MATERIALS AND METHODS: Male Sprague-Dawley rats (n=21) were randomly divided into three groups: a healthy control group, a diabetic sham-treated group, and a diabetic LLLT-treated group. Diabetes mellitus was then induced by streptozotocin administration to the two diabetic groups. One 4 cm long full thickness skin incision and one full thickness circular excision (diameter=4 mm) were performed on the back of each rat. An infrared 810 nm laser with an output of 30 mW, a power density of 30 mW/cm(2), and a spot size of 1 cm(2) was used to irradiate each wound for 30 sec (daily dose of 0.9 J/cm(2)/wound/day). RESULTS: In diabetic rats, the histology of LLLT-treated excisions revealed a similar healing response to that in nondiabetic controls, with significantly more mature granulation tissue than in the sham-treated diabetic control group. LLLT reduced the loss of tensile strength, and increased the incision wound stiffness significantly compared with sham-irradiated rats, but this did not achieve the same level as in the nondiabetic controls. CONCLUSIONS: Our study demonstrates that infrared LLLT can improve wound healing in diabetic rats. Nevertheless, further research needs to be performed to evaluate the exact underlying mechanism and to further optimize LLLT parameters for clinical use.

What makes transcutaneous electrical nerve stimulation work? Making sense of the mixed results in the clinical literature.

Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological treatment for control of pain. It has come under much scrutiny lately with the Center for Medicare Services rendering a recent decision stating that "TENS is not reasonable and necessary for the treatment of CLBP [chronic low back pain]." When reading and analyzing the existing literature for which systematic reviews show that TENS is inconclusive or ineffective, it is clear that a number of variables related to TENS application have not been considered. Although many of the trials were designed with the highest of standards, recent evidence suggests that factors related to TENS application need to be considered in an assessment of efficacy. These factors include dosing of TENS, negative interactions with long-term opioid use, the population and outcome assessed, timing of outcome measurement, and comparison groups. The purpose of this perspective is to highlight and interpret recent evidence to help improve the design of clinical trials and the efficacy of TENS in the clinical setting.

Transcutaneous electrical nerve stimulation for the management of painful conditions: focus on neuropathic pain.

The management of neuropathic pain is challenging, with medication being the first-line treatment. Transcutaneous electrical nerve stimulation (TENS) is an inexpensive, noninvasive, self-administered technique that is used as an adjunct to medication. Clinical experience suggests that TENS is beneficial providing it is administered at a sufficiently strong intensity, close to the site of pain. At present, there are too few randomized controlled trials on TENS for neuropathic pain to judge effectiveness. The findings of systematic reviews of TENS for other pain syndromes are inconclusive because trials have a low fidelity associated with inadequate TENS technique and infrequent treatments of insufficient duration. The use of electrode arrays to spatially target stimulation more precisely may improve the efficacy of TENS in the future.

Inhibitory effects of laser irradiation on peripheral mammalian nerves and relevance to analgesic effects: a systematic review.

OBJECTIVE: The objective of this review was to systematically identify experimental studies of non-ablative laser irradiation (LI) on peripheral nerve morphology, physiology, and function. The findings were then evaluated with special reference to the neurophysiology of pain and implications for the analgesic effects of low-level laser therapy (LLLT). BACKGROUND: LLLT is used in the treatment of pain, and laser-induced neural inhibition has been proposed as a mechanism. To date, no study has systematically evaluated the effects of LI on peripheral nerve, other than those related to nerve repair, despite the fact that experimental studies of LI on nerves have been conducted over the past 25 years. METHODS: We searched computerized databases and reference lists for studies of LI effects on animal and human nerves using a priori inclusion and exclusion criteria. RESULTS: We identified 44 studies suitable for inclusion. In 13 of 18 human studies, pulsed or continuous wave visible and continuous wave infrared (IR) LI slowed conduction velocity (CV) and/or reduced the amplitude of compound action potentials (CAPs). In 26 animal experiments, IR LI suppressed electrically and noxiously evoked action potentials including pro-inflammatory mediators. Disruption of microtubule arrays and fast axonal flow may underpin neural inhibition. CONCLUSIONS: This review has identified a range of laser-induced inhibitory effects in diverse peripheral nerve models, which may reduce acute pain by direct inhibition of peripheral nociceptors. In chronic pain, spinal cord changes induced by LI may result in long-term depression of pain. Incomplete reporting of parameters limited aggregation of data.

Low-level laser therapy (LLLT) attenuates RhoA mRNA expression in the rat bronchi smooth muscle exposed to tumor necrosis factor-alpha.

Low-level laser therapy (LLLT) has been found to produce anti-inflammatory effects in a variety of disorders. Bronchial smooth muscle (BSM) hyperreactivity is associated with increased Ca+2 sensitivity and increased RhoA mRNA expression. In the current study, we investigated if LLLT could reduce BSM contraction force and RhoA mRNA expression in tumor necrosis factor-alpha (TNF-alpha)-induced BSM hyperreactivity. In the study, 112 male Wistar rats were divided randomly into 16 groups, and BSM was harvested and suspended in TNF-alpha baths for 6 and 24 h, respectively. Irradiation with LLLT was performed with a wavelength of 660 nm for 42 s with a dose of 1.3 J/cm2. This LLLT dose was administered once in the 6-h group and twice in the 24-h group. LLLT significantly decreased contraction force in BSM at 6 h (TNF-alpha + LLLT: 11.65+/-1.10 g/100 mg of tissue) (F=3115) and at 24 h (TNF-alpha+ LLLT: 14.15+/-1.1 g/100 mg of tissue) (F=3245, p<0.05) after TNF-alpha, respectively, when compared to vehicle-bathed groups (control). LLLT also significantly decreased the expression of RhoA mRNA in BSM segments at 6 h (1.22+/-0.20) (F=2820, p<0.05) and 24 h (2.13+/-0.20) (F=3324, p<0.05) when compared to BSM segments incubated with TNF-alpha without LLLT irradiation. We conclude that LLLT administered with this protocol, reduces RhoA mRNA expression and BSM contraction force in TNF-alpha-induced BSM hyperreactivity.

Low-level laser irradiation (InGaAlP-660 nm) increases fibroblast cell proliferation and reduces cell death in a dose-dependent manner.

BACKGROUND AND OBJECTIVE: Impaired cell metabolism and increased cell death in fibroblast cells are physiological features of chronic tendinopathy. Although several studies have shown that low-level laser therapy (LLLT) at certain parameters has a biostimulatory effect on fibroblast cells, it remains uncertain if LLLT effects depend on the physiological state. STUDY DESIGN/MATERIAL AND METHODS: High-metabolic immortal cell culture and primary human keloid fibroblast cell culture were used in this study. Trypan blue exclusion and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test were used to determine cell viability and proliferation. Propidium iodide stain was used for cell-cycle analysis by flow cytometry. Laser irradiation was performed daily on three consecutive days with a GaAlAs 660-nm laser (mean output: 50 mW, spot size 2 mm(2), power density =2.5 W/cm(2)) and a typical LLLT dose and a high LLLT dose (irradiation times: 60 or 420 s; fluences:150 or 1050 J/cm(2); energy delivered: 3 or 21 J). RESULTS: Primary fibroblast cell culture from human keloids irradiated with 3 J showed significant proliferation by the trypan blue exclusion test (p < 0.05), whereas the 3T3 cell culture showed no difference using this method. Propidium iodide staining flow cytometry data showed a significant decrease in the percentage of cells being in proliferative phases of the cell cycle (S/g(2)/M) when irradiated with 21 J in both cell types (hypodiploid cells increased). CONCLUSIONS: Our data support the hypothesis that the physiological state of the cells affects the LLLT results, and that high-metabolic rate and short- cell-cycle 3T3 cells are not responsive to LLLT. In conclusion, LLLT with a dose of 3 J reduced cell death significantly, but did not stimulate cell cycle. A LLLT dose of 21 J had negative effects on the cells, as it increased cell death and inhibited cell proliferation.

Low-Level Laser Irradiation (InGaAlP-660 nm) Increases Fibroblast Cell Proliferation and Reduces Cell Death in a Dose-Dependent Manner

Background and Objective: Impaired cell metabolism and increased cell death in fibroblast cells are physiologicalfeatures of chronic tendinopathy. Although several studies have shown that low-level laser therapy (LLLT) atcertain parameters has a biostimulatory effect on fibroblast cells, it remains uncertain if LLLT effects depend on thephysiological state. Study Design/Material and Methods: High-metabolic immortal cell culture and primaryhuman keloid fibroblast cell culture were used in this study. Trypan blue exclusion and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test were used to determine cell viability and proliferation. Propidiumiodide stain was used for cell-cycle analysis by flow cytometry. Laser irradiation was performed daily onthree consecutive days with a GaAlAs 660-nm laser (mean output: 50mW, spot size 2mm2, power density»2.5W=cm2) and a typical LLLT dose and a high LLLT dose (irradiation times: 60 or 420 s; fluences:150 or1050 J=cm2; energy delivered: 3 or 21 J). Results: Primary fibroblast cell culture from human keloids irradiated with3 J showed significant proliferation by the trypan blue exclusion test ( p<0.05), whereas the 3T3 cell cultureshowed no difference using this method. Propidium iodide staining flow cytometry data showed a significantdecrease in the percentage of cells being in proliferative phases of the cell cycle (S=g2=M) when irradiated with 21 Jin both cell types (hypodiploid cells increased). Conclusions: Our data support the hypothesis that the physiologicalstate of the cells affects the LLLT results, and that high-metabolic rate and short- cell-cycle 3T3 cells are notresponsive to LLLT. In conclusion, LLLT with a dose of 3 J reduced cell death significantly, but did not stimulatecell cycle. A LLLT dose of 21 J had negative effects on the cells, as it increased cell death and inhibited cellproliferation.

The effect of low-level laser irradiation (In-Ga-Al-AsP - 660 nm) on melanoma in vitro and in vivo.

BACKGROUND: It has been speculated that the biostimulatory effect of Low Level Laser Therapy could cause undesirable enhancement of tumor growth in neoplastic diseases. The aim of the present study is to analyze the behavior of melanoma cells (B16F10) in vitro and the in vivo development of melanoma in mice after laser irradiation. METHODS: We performed a controlled in vitro study on B16F10 melanoma cells to investigate cell viability and cell cycle changes by the Tripan Blue, MTT and cell quest histogram tests at 24, 48 and 72 h post irradiation. The in vivo mouse model (male Balb C, n = 21) of melanoma was used to analyze tumor volume and histological characteristics. Laser irradiation was performed three times (once a day for three consecutive days) with a 660 nm 50 mW CW laser, beam spot size 2 mm(2), irradiance 2.5 W/cm(2) and irradiation times of 60s (dose 150 J/cm(2)) and 420s (dose 1050 J/cm(2)) respectively. RESULTS: There were no statistically significant differences between the in vitro groups, except for an increase in the hypodiploid melanoma cells (8.48 +/- 1.40% and 4.26 +/- 0.60%) at 72 h post-irradiation. This cancer-protective effect was not reproduced in the in vivo experiment where outcome measures for the 150 J/cm(2) dose group were not significantly different from controls. For the 1050 J/cm(2) dose group, there were significant increases in tumor volume, blood vessels and cell abnormalities compared to the other groups. CONCLUSION: LLLT Irradiation should be avoided over melanomas as the combination of high irradiance (2.5 W/cm(2)) and high dose (1050 J/cm(2)) significantly increases melanoma tumor growth in vivo.

Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials.

BACKGROUND: Neck pain is a common and costly condition for which pharmacological management has limited evidence of efficacy and side-effects. Low-level laser therapy (LLLT) is a relatively uncommon, non-invasive treatment for neck pain, in which non-thermal laser irradiation is applied to sites of pain. We did a systematic review and meta-analysis of randomised controlled trials to assess the efficacy of LLLT in neck pain. METHODS: We searched computerised databases comparing efficacy of LLLT using any wavelength with placebo or with active control in acute or chronic neck pain. Effect size for the primary outcome, pain intensity, was defined as a pooled estimate of mean difference in change in mm on 100 mm visual analogue scale. FINDINGS: We identified 16 randomised controlled trials including a total of 820 patients. In acute neck pain, results of two trials showed a relative risk (RR) of 1.69 (95% CI 1.22-2.33) for pain improvement of LLLT versus placebo. Five trials of chronic neck pain reporting categorical data showed an RR for pain improvement of 4.05 (2.74-5.98) of LLLT. Patients in 11 trials reporting changes in visual analogue scale had pain intensity reduced by 19.86 mm (10.04-29.68). Seven trials provided follow-up data for 1-22 weeks after completion of treatment, with short-term pain relief persisting in the medium term with a reduction of 22.07 mm (17.42-26.72). Side-effects from LLLT were mild and not different from those of placebo. INTERPRETATION: We show that LLLT reduces pain immediately after treatment in acute neck pain and up to 22 weeks after completion of treatment in patients with chronic neck pain. FUNDING: None.