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.

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.

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.

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.

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.

Effect of low level laser therapy on bronchial hyper-responsiveness.

The objective of this study was to investigate whether low level laser therapy (LLLT) could reduce bronchial hyper-responsiveness (BHR) induced by tumour necrosis factor-alpha (TNF-alpha) modulating the metabolism of inositol phosphate (IP) in bronchial smooth muscle cells (BSMCs). The study was on 28 Wistar rats, randomly divided into four groups. Irradiation (1.3 J/cm(2)) was administered 5 min and 4 h after bronchial smooth muscle (BSM) had been suspended in TNF-alpha baths, and the contractile response-induced calcium ion (Ca(2+)) sensitization was measured. The BSMCs were isolated, and the IP accumulation was measured before and after TNF-alpha immersion in the groups that had been irradiated or not irradiated. BSM segments significantly increased contraction 24 h after TNF-alpha immersion when exposed to carbachol (CCh) as Ca(2+), but it was significantly reduced by 64% and 30%, respectively, after laser treatment. The increase in IP accumulation induced by CCh after TNF-alpha immersion was reduced in the BSMCs by LLLT. The dose of 2.6 J/cm(2) reduced BHR and IP accumulation in the rats' inflammatory BSMCs.

A systematic review with procedural assessments and meta-analysis of low level laser therapy in lateral elbow tendinopathy (tennis elbow).

BACKGROUND: Recent reviews have indicated that low level level laser therapy (LLLT) is ineffective in lateral elbow tendinopathy (LET) without assessing validity of treatment procedures and doses or the influence of prior steroid injections. METHODS: Systematic review with meta-analysis, with primary outcome measures of pain relief and/or global improvement and subgroup analyses of methodological quality, wavelengths and treatment procedures. RESULTS: 18 randomised placebo-controlled trials (RCTs) were identified with 13 RCTs (730 patients) meeting the criteria for meta-analysis. 12 RCTs satisfied half or more of the methodological criteria. Publication bias was detected by Egger's graphical test, which showed a negative direction of bias. Ten of the trials included patients with poor prognosis caused by failed steroid injections or other treatment failures, or long symptom duration or severe baseline pain. The weighted mean difference (WMD) for pain relief was 10.2 mm [95% CI: 3.0 to 17.5] and the RR for global improvement was 1.36 [1.16 to 1.60]. Trials which targeted acupuncture points reported negative results, as did trials with wavelengths 820, 830 and 1064 nm. In a subgroup of five trials with 904 nm lasers and one trial with 632 nm wavelength where the lateral elbow tendon insertions were directly irradiated, WMD for pain relief was 17.2 mm [95% CI: 8.5 to 25.9] and 14.0 mm [95% CI: 7.4 to 20.6] respectively, while RR for global pain improvement was only reported for 904 nm at 1.53 [95% CI: 1.28 to 1.83]. LLLT doses in this subgroup ranged between 0.5 and 7.2 Joules. Secondary outcome measures of painfree grip strength, pain pressure threshold, sick leave and follow-up data from 3 to 8 weeks after the end of treatment, showed consistently significant results in favour of the same LLLT subgroup (p < 0.02). No serious side-effects were reported. CONCLUSION: LLLT administered with optimal doses of 904 nm and possibly 632 nm wavelengths directly to the lateral elbow tendon insertions, seem to offer short-term pain relief and less disability in LET, both alone and in conjunction with an exercise regimen. This finding contradicts the conclusions of previous reviews which failed to assess treatment procedures, wavelengths and optimal doses.

Effects of low-level laser therapy and eccentric exercises in the treatment of recreational athletes with chronic achilles tendinopathy.

BACKGROUND: Eccentric exercises (EEs) are recommended for the treatment of Achilles tendinopathy, but the clinical effect from EE has a slow onset. HYPOTHESIS: The addition of low-level laser therapy (LLLT) to EE may cause more rapid clinical improvement. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 52 recreational athletes with chronic Achilles tendinopathy symptoms were randomized to groups receiving either EE + LLLT or EE + placebo LLLT over 8 weeks in a blinded manner. Low-level laser therapy (lambda = 820 nm) was administered in 12 sessions by irradiating 6 points along the Achilles tendon with a power density of 60 mW/cm(2) and a total dose of 5.4 J per session. RESULTS: The results of the intention-to-treat analysis for the primary outcome, pain intensity during physical activity on the 100-mm visual analog scale, were significantly lower in the LLLT group than in the placebo LLLT group, with 53.6 mm versus 71.5 mm (P = .0003) at 4 weeks, 37.3 mm versus 62.8 mm (P = .0002) at 8 weeks, and 33.0 mm versus 53.0 mm (P = .007) at 12 weeks after randomization. Secondary outcomes of morning stiffness, active dorsiflexion, palpation tenderness, and crepitation showed the same pattern in favor of the LLLT group. CONCLUSION: Low-level laser therapy, with the parameters used in this study, accelerates clinical recovery from chronic Achilles tendinopathy when added to an EE regimen. For the LLLT group, the results at 4 weeks were similar to the placebo LLLT group results after 12 weeks.

An investigation into the effect of electrode placement of transcutaneous electrical nerve stimulation (TENS) on experimentally induced ischemic pain in healthy human participants.

INTRODUCTION: It is claimed that transcutaneous electrical nerve stimulation (TENS) operates via a segmental mechanism by reducing ongoing transmission and sensitization of nociceptive dorsal horn neurons. Hence, TENS electrodes are usually placed at the site of pain. OBJECTIVE: This study compared TENS administered at the site of experimentally induced ischemic pain (ipsilateral forearm) with TENS administered at a location not related to pain (contralateral lower leg). METHODS: Ten healthy, pain free volunteers took part in a cross-over study during which ischemic pain was induced in the nondominant arm using a modified version of submaximal effort tourniquet technique. Pain intensity was taken at 1-minute interval/s for 5 minutes while receiving TENS either at the ipsilateral arm or contralateral leg. RESULTS: There were no statistically significant differences in pain intensity or McGill Pain Questionnaire ratings between TENS given at the arm compared with the leg. DISCUSSION: Taken at face value, the findings suggest that TENS effects were nonspecific and that electrode location does not affect outcome. However, this study should be seen as a call for further research rather than a definitive conclusion.

Low-level laser therapy (GaAs lambda = 904 nm) reduces inflammatory cell migration in mice with lipopolysaccharide-induced peritonitis.

OBJECTIVE: This study was designed to study the effect of an infrared low-level laser (GaAs lambda = 904 nm, 4 mW) on inflammatory cell migration in lipopolysaccharide (LPS)-induced peritonitis in mice. BACKGROUND DATA: It has been suggested that red wavelengths of low-level laser therapy (LLLT) can exert anti-inflammatory effects, but little is known about the anti-inflammatory effects of infrared lasers. Peritonitis is a potentially life-threatening inflammatory condition that may be suitable for studying anti-inflammatory effects of infrared lasers. METHODS: Sixty male mice were randomly divided into five groups, and one group was given an intraperitoneal sterile saline injection. In the remaining four groups, peritonitis was induced by an intraperitoneal LPS injection. Animals in three of the LPS groups were irradiated at a single point over the peritoneum with doses of 3 J/cm(2), 7.5 J/cm(2), and 15 J/cm(2), respectively. The fourth group injected with LPS was an LPS-control group. RESULTS: At 6 hours after injection the groups irradiated with doses of 3 J/cm(2) and 7.5 J/cm(2) had a reduced number of neutrophil cells in the peritoneal cavity compared with the LPS-control group, and there were significant differences between the number of neutrophils in the peritoneal cavity between the LPS-control group and groups irradiated with doses of 3 J/cm(2) (-42%) and 7.5 J/cm(2) (-70%). In the group irradiated with 15 J/cm(2), neutrophil cell counts were lower than, but not significantly different from, LPS controls (-38%; p = 0.07). At 24 hours after injection, both neutrophil and total leukocyte cell counts were lower in all the irradiated groups than in the LPS controls. The 3-J/cm(2) exposure group showed the best results at 24 hours, with reductions of 77% in neutrophil and 49% in leukocyte counts. CONCLUSION: Low-level laser therapy (904 nm) can reduce inflammatory cell migration in mice with LPS-induced peritonitis in a dose-dependent manner.