Low level laser therapy (Photobiomodulation therapy) for breast cancer-related lymphedema: a systematic review

Methods

Clinical trials were searched in PubMed, AMED, Web of Science, and China National Knowledge Infrastructure up to November 2016. Two reviewers independently assessed the methodological quality and adequacy of LLLT (PBM) in these clinical trials. Primary outcome measures were limb circumference/volume, and secondary outcomes included pain intensity and range of motion. Because data were clinically heterogeneous, best evidence synthesis was performed.

Results

Eleven clinical trials were identified, of which seven randomized controlled trials (RCTs) were chosen for analysis. Overall, the methodological quality of included RCTs was high, whereas the reporting of treatment parameters was poor. Results indicated that there is strong evidence (three high quality trials) showing LLLT (PBM) was more effective than sham treatment for limb circumference/volume reduction at a short-term follow-up. There is moderate evidence (one high quality trial) indicating that LLLT (PBM) was more effective than sham laser for short-term pain relief, and limited evidence (one low quality trial) that LLLT (PBM) was more effective than no treatment for decreasing limb swelling at short-term follow-up.

Conclusions

Based upon the current systematic review, LLLT (PBM) may be considered an effective treatment approach for women with BCRL. Due to the limited numbers of published trials available, there is a clear need for well-designed high-quality trials in this area. The optimal treatment parameters for clinical application have yet to be elucidated.

Discussion

The primary aim of this systematic review was to evaluate the effectiveness of LLLT (PBM) in the management of BCRL. Findings support the use of LLLT (PBM) for treating women with BCRL. Based upon the best evidence synthesis, the current review provided strong evidence (three high quality trials) favoring LLLT (PBM) over sham in terms of reduction in limb edema at short-term follow-up. For other comparisons, this review provided moderate evidence (one high quality trial) favoring LLLT (PBM) over sham for short-term pain relief, and limited evidence (one low quality trial) favoring LLLT (PBM) over no treatment for decreasing limb swelling at a short-term follow-up.

As a relatively novel therapeutic tool for the treatment of BCRL, LLLT (PBM) has gained increasing popularity since its approval by the United States Food and Drug Administration in 2007. Over the past two decades, seven RCTs [46–52] and four observational studies [44, 45, 54, 55] have been published in this area. Since RCTs are considered as the gold standard of contemporary medical research, the current systematic review generated conclusions about effectiveness of LLLT (PBM) based on the seven included RCTs. It is encouraging to note that the methodological quality of identified RCTs was ‘high’ in accordance with the PEDro scale (over 5/10); findings of this review were considered to be robust. Nevertheless, there was extensive study heterogeneity in treatment protocols, comparators, outcome measures, and follow-up periods. Due to a limited number of included studies, a head-to-head comparison to determine a superior LLLT (PBM) treatment regime was not possible. Future research into this area is suggested, which could provide evidence to guide development of an optimal LLLT (PBM) therapy regime for symptom management of BCRL.

This is the first systematic review applying best evidence synthesis to comprehensively evaluate the therapeutic value of LLLT (PBM) for BCRL. Findings from the review have strengthened conclusions of previous reviews [15, 36, 37], and confirmed the effectiveness of LLLT (PBM) in the treatment of BCRL. While two previous reviews [15, 36] showed favorable results of LLLT (PBM) in reduction of limb volume and tissue hardness, it was argued that these reviews lacked formal analysis methodology, thus reliability of the conclusions was unclear. Smoot et al. conducted a meta-analysis [37] to synthesize evidence from intervention studies, and concluded that there was moderate-strength evidence supporting the use of LLLT (PBM) in the management of BCRL. Although this review was rated as ‘moderate quality’ (6/11) according to the Assessment of Multiple Systematic Reviews (AMSTAR) criteria (a validated instrument for quality assessment of systematic reviews) [56], clinical appropriateness of pooling study results irrespective of control comparisons (lack of subgroup analysis) may limit the validity of the review conclusions.

Sham laser was typically set as a control arm in the included RCTs. Although the use of sham laser well satisfied the methodology requirement of double blinding to investigate the specific effects of LLLT (PBM), rationale for clinical utility of a novel treatment intervention (for instance, LLLT (PBM)) is best demonstrated against an accepted standard (best) therapy. This review found conflicting evidence regarding the effectiveness of LLLT (PBM) over conventional treatments, including manual lymphatic drainage, pneumatic compression therapy and compression bandage [49–51], on limb circumference and pain intensity. Another systematic review evaluating a series of conservative therapies has demonstrated that LLLT (PBM) yielded a similar percentage of volume reductions (approximately 11%) to compression garment or bandage [57]. Previous research suggested that wearing a compression garment alone results in a moderately significant reduction in BCRL [58]. Considering the intractable nature of BCRL, an integrative treatment package, in which LLLT (PBM) is used in addition to compression garment, may be a reasonable clinical option, and deserves further investigation through well-designed high quality RCTs.

Despite the clear statement by the WALT advocating standards of reporting of parameters when conducting studies involving laser therapy [53], there still seems to be inadequate information provided by authors of such studies. This is not uncommon and other systematic reviews have also highlighted these failures [59, 60]. Heterogeneity of the parameters used in the included studies and variable methods of application, along with differences in treatment regimes, all contribute to the difficulties of pooling information to make definitive statements regarding this use of LLLT (PBM) for BCRL. That being said, the normal genesis of treatment guidelines will result in many studies that show variation or contradictory results. Until patterns are recognized on a consistent basis across studies, the window of effective parameters cannot be identified. From all 11 studies included in this review, infrared wavelengths (808-905 nm) have been most commonly employed to date, and reported energy densities in the range of 1.5 J/cm²–2.4 J/cm² have delivered positive outcomes. In comparison, effective energy densities for tendinopathy range from 1.8 J/cm² to 19.2 J/cm² depending upon the location of the tendon [59]. The reported frequency and duration of treatment is however too varied to make any strong statements, but a minimum of 4 weeks seems to be required.

The current review has adopted robust methodology to minimize the risk of bias. Firstly, it implemented most of the items listed in the AMSTAR checklist [56], therefore has a high methodological quality score (internal validity) of 9/11 (two points were missing because of the lack of a priori review protocol registry and an assessment of publication bias due to the qualitative analysis methodology). Secondly, in terms of the external validity, reporting of this review strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [61] to ensure research replication. Thirdly, for data synthesis, subgroup analyses stratified by control comparisons and outcome measures were performed to address the influence of clinical (as well as statistical) heterogeneity. Fourthly, conclusions of the review were synthesized from seven RCTs with high methodology quality.

The primary limitation of this systematic review derived from the small number of included studies and lack of conclusions regarding the longer-term effects of LLLT (PBM) for BCRL management. Findings of this review suggest future well-designed fully powered RCTs are needed to inform the superiority of different LLLT (PBM) interventions, and determine an optimal treatment protocol for this therapy.