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Support Care Cancer (2011) 19:1069–1077DOI 10.1007/s00520-011-1202-0 A systematic review with meta-analysis of the effectof low-level laser therapy (LLLT) in cancer therapy-inducedoral mucositis Jan Magnus Bjordal & Rene-Jean Bensadoun &Jan Tunèr & Lucio Frigo & Kjersti Gjerde &Rodrigo AB Lopes-Martins Received: 26 August 2010 / Accepted: 30 May 2011 / Published online: 10 June 2011# Springer-Verlag 2011 Results We found 11 randomised placebo-controlled trials Purpose The purpose of this study is to review the effects with a total of 415 patients; methodological quality was of low-level laser therapy (LLLT) in the prevention and acceptable at 4.10 (SD±0.74) on the 5-point Jadad scale. The treatment of cancer therapy-induced oral mucositis (OM).
relative risk (RR) for developing OM was significantly (p= Methods A systematic review and meta-analysis of randomised 0.02) reduced after LLLT compared with placebo LLLT (RR= placebo-controlled trials of LLLT performed during chemother- 2.03 (95% CI, 1.11 to 3.69)). This preventive effect of LLLT apy or radiation therapy in head and neck cancer patients.
improved to RR=2.72 (95% CI, 1.98 to 3.74) when onlytrials with adequate doses above 1 J were included. For J. M. Bjordal (*) treatment of OM ulcers, the number of days with OM grade 2 Centre for Evidence-Based Practice, or worse was significantly reduced after LLLT to 4.38 (95% Bergen University College-HiB, CI, 3.35 to 5.40) days less than placebo LLLT. Oral mucositis Moellendalsvn. 6, severity was also reduced after LLLT with a standardised 5009 Bergen, Norwaye-mail: [email protected] mean difference of 1.33 (95% CI, 0.68 to 1.98) over placeboLLLT. All studies registered possible side-effects, but they were not significantly different from placebo LLLT.
Service d'Oncologie Radiothérapique, Conclusions There is consistent evidence from small high- CHU de Poitiers, BP 577, 86021 Poitiers Cedex, France quality studies that red and infrared LLLT can partly prevent development of cancer therapy-induced OM. LLLT also Grängesberg Dental Clinic, significantly reduced pain, severity and duration of symp- Grängesberg, Sweden toms in patients with cancer therapy-induced OM.
L. FrigoUniversity of Cruzeiro do Sul, Keywords Low-level laser therapy. Oral mucositis .
Sao Miguel Paulista, SP, Brazil Cancer. Chemotherapy. Radiation therapy K. GjerdeDepartment of Clinical Odontology, University of Bergen,Bergen, Norway R. A. Lopes-Martins Oral mucositis (OM) is a serious and acute side-effect for Institute of Biomedical Sciences, University of São Paulo (USP), patients undergoing cancer therapy. The frequency of its São Paulo, Brazile-mail: [email protected] appearance varies with therapy and cancer type up to 100%in oral cancer patients receiving adjuvant chemotherapy or R. A. Lopes-Martins radiotherapy [, ].
Centro de Pesquisa Clínica em Biofotônica Aplicada às Ciências OM has great impact on a patient´s well-being. It may da Saúde, Universidade Nove de Julho,São Paulo, Brazil necessitate modifications of treatment planning, suspension Support Care Cancer (2011) 19:1069–1077 recommended in treatment guidelines [, Recommendednonpharmacological treatments are oral care with mouthrinse] and cryotherapy []. The latter may also be used for theprevention of OM occurrence. Pharmacological agents havelargely been used for palliative care and pain relief, and someare recommended by consensus in spite of lacking scientificevidence from randomised controlled trials. These pharma-cological agents include patient-controlled analgesia withmorphine in transplant patients with hematological malig-nancies and topical anaesthetics like lidocaine alone, or incombination with diphenhydramine []. More recently,pharmacological focus has been directed towards theprevention of ulceration and the drug palifermin, a humankeratinocyte growth factor that stimulates the prolifer-ation, migration, and differentiation of epithelial cells and isrecommended in patients undergoing stem cell transplanta-tions. In addition, amifostine is thought to inhibit harmfulreactive oxygen species release but the scientificevidence for this drug is sparse. More recently, pharmaco-logical focus has been directed towards the prevention of Fig. 1 Quorum flow chart showing the stages of the reviewing ulceration (palifermin and amifostine) but no single inter- process and the number of studies filtered out at each stage vention yet serves as a panacea for all phases of OM.
Low-level laser therapy (LLLT) is a local application of a of therapy, need for opioid analgesics, and/or require enteral monochromatic, narrow-band, coherent light source. LLLT is or parenteral nutrition with an impact on patient's survival recommended as a treatment option for OM in the MASCC ]. The additional cost of OM treatment for cancer guidelines but with limitations due to heterogeneous laser patients can be considerable [].
parameters and a lack of dosage consensus in the LLLT Many interventions have been used in OM management, literature. The action of LLLT is disputed, but a cytoprotective but only a handful of interventions have sufficient scientific effect before and during oxidative stress has been observed support from positive results in controlled clinical trials to be after pre-treatment with LLLT There is some support Table 1 Trial characteristics First column identifies trial by first author's last name and the publication year. Other columns represent: sample size (type of cancer therapy),laser wavelength in nm, laser output in mW, spot size in cm2 , dose in Joules, irradiation time per point, outcomes reported including mucositisseverity scales (WHO or OMI), pain and duration of OM in days and dichotomized overall results given by: (+) significantly in favour of LLLT or(−) non-significant between LLLT and placebo

Support Care Cancer (2011) 19:1069–1077 Table 2 Trial methodological quality scored with an "x" if the methodological criterion is fulfilled Withdrawals handled The first column identifies each trial by first author's last name and last two digits of the publication year. The total methodological score (Jadadscale max. score=5) for each trial is given in the last column for this protective LLLT effect in humans too ], and a as advised by Dickersin et al. [] for randomised possible therapeutic window has also been identified for an controlled clinical trials. Keywords were: low-level laser anti-inflammatory effect of red and infrared LLLT ].
therapy, low-intensity laser therapy, low-energy laser ther- Evidence-based treatment guidelines have been forwarded apy, phototherapy, HeNe laser, IR laser, GaAlAs, GaAs, from the World Association for Laser Therapy (WALT) diode laser, NdYag, oral mucositis, and cancer. Hand searching was also performed in national physiotherapy doses of LLLT have been identified for osteoarthritis [], and medical journals from Norway, Denmark, Sweden, tendinopathies [], and neck pain With the increasing Holland, England, Canada, and Australia. Additional body of randomised controlled trials, there seems to be a information was gathered from LLLT researchers in the need for systematically reviewing the literature and quantify possible LLLT effects of LLLT in both prevention andtreatment of cancer therapy-induced OM.
Inclusion criteria The randomised controlled trials were subjected to the Materials and methods following six inclusion criteria: Literature search 1. Diagnosis: oral mucositis in cancer patients induced after chemotherapy or radiation therapy A literature search was performed on Medline, Embase, 2. Treatment: LLLT with wavelengths of 632–1,064 nm, Cinahl, PedRo, and the Cochrane Controlled Trial Register treating the mucosa of the oral cavity Fig. 2 Forest plot showing themeta-analysis results forprevention of OM occurrence byLLLT dose compared withplacebo. Trial results plotted onthe right-hand side indicateeffects in favour of LLLT, andthe combined effects are plottedas black diamonds for dosesabove 1 J, below 1 J and overallregardless of dose, respectively

Support Care Cancer (2011) 19:1069–1077 Fig. 3 Forest plot showing themeta-analysis results forprevention of OM occurrence byLLLT wavelengths comparedwith placebo. Trial resultsplotted on the right-hand sideindicate effects in favour ofLLLT, and the combined effectsare plotted as black diamondsfor red wavelengths(630–670 nm), infraredwavelengths (780–830 nm), andoverall regardless ofwavelength, respectively(published online only) 3. Design: randomised parallel group design or crossover 5. Subgroup analyses were planned for (1) doses of <1 J and >1 J (minimum dose according to WALT guidelines 4. Blinding: outcome assessors should be blinded for other inflammatory conditions), (2) red and infrared 5 Control group: receiving identical placebo laser wavelengths with their anticipated optimal dose ranges 6. Specific endpoints for prevention of oral mucositis (1–4 J for red wavelengths and 3–8 J for infrared above a certain grade, oral mucositis severity, duration in days, and pain intensity A statistical meta-analysis software package developed by Cochrane Collaboration (Revman 5.0.22) was usedfor the statistical calculations. If heterogeneity was 1. The relative risk (RR) over placebo for preventing present in heterogeneity tests, a random effects model occurrence of oral mucositis above a certain grade (0– was used for calculations. If heterogeneity was absent, a fixed effects model was used for calculation of the overall 2. The effect of LLLT on the severity of oral mucositis measured by the Oral Mucositis Index (OMI) or WHOscales were calculated as the SMD versus placebo.
Analysis of bias, including methodological quality, funding 3. The effect of LLLTon the duration of days oral mucositis source, and patient selection was calculated as the weighted mean difference versusplacebo Positive bias direction, caused by flaws in trial 4. The effect of LLLT on pain intensity was calculated as methodology, funding source the standardised mean difference (SMD) versus placeboand labelled after Cohen [as "poor" (0.2–0.5), Trials were subjected to methodological assessments by the "good" (0.5–0.8), or "very good" (>0.8) 5-point Jadad checklist [For-profit funding sources Fig. 4 Forest plot showing the meta-analysis results for duration of LLLT, and the combined effect including variance is plotted as a black OM after LLLT compared with placebo as a weighted mean difference.
diamond at the bottom of the forest plot Trial results plotted on the right-hand side indicate effects in favour of

Support Care Cancer (2011) 19:1069–1077 Fig. 5 Forest plot showing the meta-analysis results for LLLT effect results plotted on the right-hand side indicate effects in favour of on OM severity compared with placebo as a standardised mean LLLT, and the combined effect including variance is plotted as a black difference (combines results from different OM severity scales). Trial have been shown to affect trial conclusions in a positive severity. The characteristics of the included trials and laser direction [which made us include an analysis of parameters are listed in Table .
funding sources. Methodological assessments were madeindependently according to the Jadad 5-point scale by two Methodological quality of the authors (JMB and RABLM).
The assessors gave similar methodological gradings for allthe included studies, and a consensus meeting was not needed. Methodological quality was high for the includedstudies with a mean score of 4.10 (SD±0.74). The Literature search and exclusion procedure individual method scores are given in Table .
The literature search revealed 149 papers for oral mucositis Funding sources analysis and laser therapy. Thirty-three were regarded as potentiallyrelevant papers. Of these, nine studies were reviews and six Laser manufacturers were acknowledged for support in two studies were case studies while another three were animal trial reports [One trial report explicitly stated that studies. Three controlled studies were excluded for lack of no conflicts of interest existed ] while another trial stated randomization while one study lacked a placebo-control that funding came from an independent non-profit source group ]. The exclusion/inclusion procedure is described ]. Six trials did not explicitly mention conflicts of according to the ] Quorum standard in Fig.
interest in their trial reports. But none of the affiliations and The final sample consisted of 11 randomised placebo- addresses in these reports indicated industry involvement.
controlled trials published from 1997 until 2009 with a total Double checking the "Instructions to Authors" in the of 415 patients []. The OMI was used in seven trials journals in which these trial reports appeared, revealed that and the WHO was used in one trial as measures of OM the journals demanded declarations from the authors about Fig. 6 Forest plot showing the subgroup meta-analysis results for right-hand side indicate effects in favour of LLLT, and the combined infrared LLLT doses of ≤2 J or >2 J of the effect on OM severity effect including variance is plotted as a black diamond (published compared with placebo as a standardised mean difference (combines results from different OM severity scales). Trial results plotted on the

Support Care Cancer (2011) 19:1069–1077 Fig. 7 Forest plot showing the meta-analysis results for LLLT effect the right-hand side indicate effects in favour of LLLT, and the on pain compared with placebo as a standardised mean difference combined effect including variance is plotted as a black diamond (combines results from different pain scales). Trial results plotted on (published online only) possible conflicts of interest before publication. For this Effect on duration of oral mucositis reason, the lack of mention has been accepted by theauthors as a lack of conflicts of interest, rather than Five studies presented data for this outcome, and LLLT undeclared conflicts of interest. In total, bias from for- reduced significantly the number of days with oral profit funding sources occurred in just two of 11 papers mucositis grade 2 or worse with 4.38 (95% CI, 3.35 to which the authors consider has negligible influence on the 5.40) days. The results for each individual study and the review conclusion.
combined results are summarised in Fig.
Relative risk for occurrence of cancer therapy-induced OM Effect on mucositis severity Six trials presented seven different comparisons of contin- Six studies started LLLT before OM ulcers occurred and uous data for mucositis severity. As the trials used different presented categorical data for the risk of developing OM mucositis index scales, the combined results were calculat- above a certain grade (OM grades 0, 1, 2) during cancer ed as the SMD. The combined SMD effect size was 1.33 therapy. There was a significant preventive effect of LLLT (95% CI, 0.68 to 1.98) and heterogeneity was present (p< with a relative risk at 2.03 (95% CI, 1.11 to 3.69) less for 0.0001 and I2=81%). The results for each trial and the cancer therapy-induced OM to occur. The analysis revealed combined effect size are presented in Fig.
significant heterogeneity (I2=54%, p=0.03) between trials,and the results are summarised in Fig.
Dose analyses of anticipated optimal dose ranges Analysis of irradiation parameters revealed that one study ] had given a lower dose (0.18 J) than theminimum recommended WALT dose of 1 J. After sub- A subgroup analysis of anticipated optimal dose ranges for red grouping trials with doses above 1 J, heterogeneity and infrared wavelengths on OM severity, revealed that disappeared (I2=16%, p=0.31). The relative risk for infrared wavelengths (6 J in both trials) gave an SMD at 2.17 preventing OM to occur increased to 2.72 (95% CI, 1.98 (95% CI, 1.48 to 2.86) without signs of heterogeneity between to 3.74). The results for each study subgrouped by their trials (I2=0% and p=0.89). A dose of 2 J with an infrared timing of LLLT subgroups and the total RR are presented wavelength was ineffective SMD 0.38 (95% CI, −0.19 to 0.96) in reducing mucositis severity. The dose analyses arepresented in Fig. Subgroup analysis of LLLT wavelength effectson the relative risk for occurrence of OM after LLLT Effect on pain relief The subgroup analysis revealed no heterogeneity between Four trials reported continuous data on pain intensity from trials with anticipated optimal doses for the red (630– different scales. The combined analysis revealed a signif- 670 nm) and the infrared (780–830 nm) subgroups, icant effect of LLLT with an SMD at 1.22 (95% CI, 0.19 to respectively (p>0.21 and I2<32%), and there were no 2.25) but also significant heterogeneity caused by one trial significant wavelength differences in relative risks between ]. Removal of this study restored homogeneity (I2=0% red and infrared at 2.72 (95% CI, 1.98 to 3.74) and infrared and p=0.58), but reduced the effect size to 0.61 (95% CI, at 3.48 (95% CI, 1.79 to 6.75).
0.29 to 0.94) (see Fig. ).
Support Care Cancer (2011) 19:1069–1077 Table 3 Summarised recommended treatment parameters Minimum no. days to start LLLT before cancer therapy Side effects of LLLT previous studies found no significant differences betweenred wavelengths in this range ]. For infrared wave- All the studies investigated possible side-effects, but none lengths, 830 nm was used in all trials but one underdosed found side-effects or adverse effects beyond those reported trial []. Doses were also fairly consistent across trials for placebo LLLT. Five trials reported explicitly that LLLT ranging from 1 to 6 J except the underdosed trial finding was well tolerated among patients.
no significant effect from a dose 0.18 J. Treatment timesper point varied considerably with the variation in laseroutputs, but at least 17 s of irradiation per point was need to achieve beneficial results (median, 50 s). The number oftreatment session varied from 3 to 30 in this material, but This systematic review has revealed moderate to strong this heterogeneity must be seen in conjunction with the evidence for the efficacy of LLLT in cancer therapy- heterogeneity in durations of chemotherapy and radiation induced OM. A possible limitation to our findings is the therapy regimens. Our interpretation is that LLLT needs to small sample size of the included trials. Our finding is be performed at least every other day for the duration of partly contradicting a Cochrane review [] which was chemotherapy and radiation therapy regimens, or as long recently updated [Our review deviates from their as OM ulcers are present. The trials which aimed at the conclusions because we have included more studies and prevention of OM started LLLT at 7 days before chemo- subgroup analyses by dose range and wavelengths. The therapy/radiation therapy regimens. It should be a target overall scientific quality of the trials was methodologically for future trials to compare treatment start at different acceptable, but the heterogeneous treatment procedures timepoints before cancer therapy to avoid unnecessary and dosing may cause confusion. In the MASCC guide- lines, the evidence behind LLLT is characterized as From the evidence, we propose a fairly simple procedure promising, but it is added that conflicting evidence with for diode lasers for prevention and treatment of cancer large operator variability and expensive equipment (gas therapy-induced OM. LLLT should be performed with a red lasers) limits more widespread clinical use []. The lasers or infrared diode laser with outputs of 10–100 mW in a used in the studies reviewed are relatively inexpensive stationary manner (not scanning). The parameters are diode lasers (from $2,500) with low optical outputs (10– summarised in Table .
100 mW), which have substituted the older more expen- In manifested OM, lesions and inflammatory areas sive gas lasers from the early LLLT trials [After should be specifically targeted for irradiation. Our reviewing the apparent discrepancies of the material, our findings relate well to the emerging LLLT evidence of subgroup analyses revealed plausible causes for the few optimal doses in inflammatory conditions such as conflicting results. A common misunderstanding in the rheumatoid arthritis [] and acute postoperative pain LLLT literature is caused by reporting clinical doses for ]. It is also interesting to note that the variety of diode lasers with small spot sizes in Joules/cm2 rather than different cancer therapies involved in the included trials in Joules. If the spot size is very small, then the irradiation did not seem to seriously interfere with the beneficial time will be very short. This led to under-dosing in one of effects of LLLT. How LLLT efficacy compares with the the included trials, where they irradiated for 3 s per point efficacy of pharmacological agents in OM, is outside the WALT recommends that doses in clinical studies scope for this review but this should certainly be a topic for should be reported in Joules instead of Joules/cm2. LLLT future research. In terms of side-effects, LLLT was well wavelengths and doses were fairly homogeneous in the tolerated and no serious incidents or withdrawals due to other studies. Red wavelengths from 633 to 685 nm, and treatment intolerance were reported.
Support Care Cancer (2011) 19:1069–1077 9. Lalla RV, Sonis ST, Peterson DE (2008) Management of oral mucositis in patients who have cancer. Dent Clin North Am52:61–77, viii We conclude that there is moderate to strong evidence in 10. Elting LS, Shih YC, Stiff PJ, Bensinger W, Cantor SB, Cooksley favour of LLLT applied with doses of 1–6 J per point in the C (2007) Economic impact of palifermin on the costs of oropharyngeal area in cancer patients receiving chemotherapy hospitalization for autologous hematopoietic stem-cell transplant: or radiation therapy. There are limitations to the material in analysis of phase 3 trial results. Biol Blood Marrow Transplant 13(7):806–813 terms of small sample size in the included trials. However, the 11. Hwang WY, Koh LP, Ng HJ, Tan PH, Chuah CT, Fook SC et al (2004) material was consistently in favour of LLLT in both in the A randomized trial of amifostine as a cytoprotectant for patients prevention of OM occurrences and reductions of severity, receiving myeloablative therapy for allogeneic hematopoietic stem pain, and duration of OM ulcers.
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