Low-level laser therapy in the prevention and treatment of oral mucositis

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Oral mucositis refers to the cytotoxic effects of therapies for malignancy such as chemotherapy and/or radiotherapy which cause erythematous and ulcerative lesions of the oral mucosa.1 The incidence of oral mucositis ranges from 20-40% in patients receiving chemotherapy, 60-85% in patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning and almost 100% of patients with head and neck squamous cell carcinoma receiving radiotherapy. Oral mucositis causes dysphagia, reduces nutritional intake, causes pain and reduces patient quality of life.2

Low-level laser therapy (LLLT) involves applying light energy which is absorbed by cytochromes and porphyrins in mitochondria. The light activates cells and promotes proliferation and differentiation, accelerating a regenerative process.  LLLT has been shown to have anti-inflammatory and analgesic effects.3 Therefore, this systematic review and meta-analysis aimed to evaluate the prophylactic and therapeutic effects of LLLT in patients who might or have developed oral mucositis during chemotherapy or radiotherapy.

Methods

Database searches were conducted in Medline, Embase, Cochrane Library, Web of Science, Clinicaltrials, CINAHL, SCOPUS and LILACS.  Only studies published in English were selected. Articles without full-texts or relevant data were excluded. The risk of bias was assessed using the Jadad scale and allocation concealment assessed separately.

The primary prophylactic outcome was the overall incidence of severe oral mucositis in the study population; this was also the primary outcome of the effect of LLLT. Secondary prophylactic outcomes included the incidence of oral mucositis at any grade, the incidence of severe oral mucositis at the most anticipated periods (6 weeks of chemoradiotherapy/radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) and day 10 of HSCT or chemotherapy).

The primary therapeutic outcome was the number of patients with severe oral mucositis after 7-day treatment with LLLT. The duration of severe oral mucositis was the secondary outcome. Oral mucositis was evaluated by the World Health Organisation scale, the Radiation Therapy Oncology Group scale, the National Cancer Institute Common Terminology Criteria and the Tardieu scale. The pooled effects of these trials were defined by the relative risk and weighted mean difference standardized difference depending on the type of data. Heterogeneity, publication bias and subgroup analysis were conducted.

Results

  • 29 papers reporting 30 trials with a total of 1616 patients were included in the review.
  • The studies were conducted in 8 countries with 14 in Brazil.
  • 10 studies were published between 2014 and 2018 and the earliest publication was in 1997.
  • Prophylactic LLLT was used in 26 studies and therapeutic LLLT in 6 studies.
  • Almost two thirds of studies (19) included patients who underwent HSCT or chemotherapy and others included patients with HNSCC undertaking radiotherapy or chemoradiotherapy.
  • Using the GRADE system, the quality of studies was assessed as moderate to high.
  • The Egger’s test proved there was no publication bias (P> 0.05).

Prophylactic outcomes

Incidence of severe oral mucositis

  • 22 studies (1190 patients; 593 Test, 597 Control) reported the incidence of severe oral mucositis during the treatment of haematological disorders or HNSCC.
  • Meta-analysis indicated that LLLT significantly reduced the risk of severe oral mucositis (Risk ratio= 0.40 (95%CI; 0.28-0.57). Significant results were also reported for the following groups: HSCT, chemotherapy and for age in both adults and children.
  • Intervention groups that received red laser, infrared laser, laser of high energy dentistry or low energy density and intraoral laser irradiation had a lower risk of severe oral mucositis compared with the control groups (all P values <0.01).
  • Patients receiving LLLT daily were also at low risk of severe oral mucositis (P <0.01) however patients who received LLLT every 2 days did not have a significantly reduced risk of severe oral mucositis.

Incidence of oral mucositis at any grade

  • 15 studies reported the incidence of any oral mucositis with patients assigned to the LLLT (449 patients) or control group (451 patients).
  • LLLT reduced the incidence of oral mucositis of any grade to 90% (95% CI 0.81-1.00; P=0.06). Subgroup analysis indicated significance in the chemotherapy group (RR 0.73; 95% CI 0.55-0.96; P = 0.03) but not in the radiotherapy or chemoradiotherapy groups.

Therapeutic outcomes

  • No significant outcomes were reported in the remission of severe oral mucositis.
  • The LLLT treated group (175 patients) showed a significant reduction in the duration of severe oral mucositis, weighted mean difference (WMD) = -5.81 days (95%CI; -9.34 to -2.28)

Conclusions

The authors concluded: –

…Prophylactic LLLT is effective in preventing oral mucositis in patients receiving chemotherapy or radiotherapy and that therapeutic LLLT is effective in reducing severe oral mucositis duration.

Comments

This systematic review and meta-analysis provides insight into the role of LLLT in the treatment and prophylaxis of oral mucositis. This meta-analysis undertook a range of statistical sub-group analyses for each of their research questions enabling them to determine the effect of LLLT on oral mucositis across a range of parameters such as different cancer treatments and patient ages. There must be caution on the interpretation of the results with the small number of high-quality studies included and the individual studies being small in patient cohort numbers. Moreover, the Jadad score for quality assessment is not recommended by Cochrane as it fails to account for allocation concealment and places emphasis on reporting rather than conduct.

Links

Primary Paper

Peng J, Shi Y, Wang J, Wang F, Dan H, Xu H, Zeng X. Low-level laser therapy in the prevention and treatment of oral mucositis: a systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020 Jun 5:S2212-4403(20)31021-X. doi: 10.1016/j.oooo.2020.05.014. Epub ahead of print. PMID: 32624448.

Other references

  1. Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am. 2008 Jan;52(1):61-77, viii. doi: 10.1016/j.cden.2007.10.002. PMID: 18154865; PMCID: PMC2266835.
  1. Zahn KL, Wong G, Bedrick EJ, Poston DG, Schroeder TM, Bauman JE. Relationship of protein and calorie intake to the severity of oral mucositis in patients with head and neck cancer receiving radiation therapy. Head Neck. 2012 May;34(5):655-62. doi: 10.1002/hed.21795. Epub 2011 Jun 20. PMID: 21692134.
  1. Avci, P., Gupta, A., Sadasivam, M., Vecchio, D., Pam, Z., Pam, N., & Hamblin, M. R. (2013). Low-level laser (light) therapy (LLLT) in skin: stimulating, healing, restoring. Seminars in cutaneous medicine and surgery, 32(1), 41–52.

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