Oral mucositis is a well-documented side effect of chemotherapy (Dental Elf – 7th Aug 2019) with the buccal mucosa, dorsal tongue, floor of mouth and soft palate commonly affected sites. The pathogenesis of oral mucositis involves an initiation stage which is cellular DNA damage caused by the antineoplastic agents generating reactive oxygen species. The message generation phase triggers a cascade of events causing cell apoptosis and damaging connective tissue. In the signal amplification phase, different signalling pathways are activated by pro-inflammatory cytokines causing clinical erythema and oedema in the oral mucosa. This progresses to ulceration and then finally tissue healing. The frequency of oral mucositis ranges from 51.7% to 75% of patients receiving chemotherapy.
The aim of this systematic review and meta-analysis was to identify the potential risk factors associated with the development of oral mucositis in paediatric patients.
An electronic database search of PubMed/Medline, Embase, Scopus and Web of Science were conducted up to 31st January 2021. Inclusion criteria included studies in English only, patients aged from 0-19 years undergoing antineoplastic therapy protocols for the treatment of different baseline diseases. Studies were excluded if they were reviews, letters to the editor, conference papers, book chapters, unpublished data, animal studies and monographs. Studies were also excluded if at least address one of the following was observed: risk factors associated with development of oral mucositis, patients with previous head and neck radiotherapy and if the primary endpoint was not oral mucositis.
- 19 studies were included in this systematic review (4 were included for quantitative analysis).
- Studies were conducted in Brazil, China, Turkey, Italy, France, Canada, Morocco, Australia and the Netherlands.
- There were 11 cohort, 6 case control, 1 cross sectional and 1 multicentre randomised control study.
- The mean patient age was 7.96 years (range 0-18 years).
- The following scales for OM assessment were used: World Health Organisation (n=8), National Cancer Institute (n=4), Oral Assessment Guide (n=2), the Mouth and Throat Soreness Related and Mucositis Quality of Life Scale (MTS-OMQoL) (n=1). 3 studies did not report which scale they used.
- Risk factors for oral mucositis:
- Chemotherapeutic agents. This was the main risk factor reported with 8 of 19 studies reporting on this. A range of agents were reported.
- Underlying disease. 4 studies considered this as a risk factor for oral mucositis. These included haematological malignancies, solid tumours, lymphoma, germinal tumours and an undifferentiated nasopharyngeal carcinoma.
- Specific individual factors. This included low body weight, nausea/vomiting, previous oral mucositis, anxiety levels and oral mucositis on days 8 and 9 of chemotherapy cycles.
- Haematological, liver and renal parameters. 8 studies identified these as risk factors including neutropenia, low white blood cell count, high platelet count and high levels of creatinine, alanine aminotransferase and aspartate aminotransferase. High levels of total and indirect bilirubin were also risk factors of oral mucositis.
- Genetic profile and biomarker factors. 4 articles identified gene variants and biomarkers as predictive for oral mucositis. Genes included MDR1, ABCB1, ABCC4 and XRCC1 genes. High concentrations of IL-6, IL-8 and IFN-C) and low levels of LL-37 in patients with acute leukaemia were associated as a risk factor for higher levels of oral mucositis.
- Oral microbiota. 4 studies investigated this and reported candida, herpes simplex type 1 and unspecified bacterial infections were considered risk factors for oral mucositis.
- For the meta-analysis, 4 studies comparing group that used high risk chemotherapy including methotrexate and low risk chemotherapy without methotrexate were included. The groups that underwent high risk chemotherapy had a 2.79 fold increased risk of developing oral mucositis (of more severe grades) (95% CI: 1.36 to 5.70) compared to the low risk group. The studies showed significant heterogeneity (I2=89%, p<0.00001).
- The risk of bias was assessed using the JBI critical appraisal tools and the studies did not identify possible confounding factors or adequate statistical analysis.
The authors concluded:-
…chemotherapeutic agents (MTX and associations), the gene variants related to the course of OM and the diverse oral microbiota are points that deserve special attention when considering the risk factors for developing OM….
This systematic review highlights the range of risk factors for oral mucositis in children undergoing treatment with antineoplastic therapy. Whilst these risk factors may highlight susceptibility to oral mucositis, it is worth acknowledging the context that studies report 80-100% of all children undergoing chemotherapy will experience some degree of mucositis (Attina et al 2021; Miller et al 2012). Furthermore, children with haematological malignancies will experience mucositis more frequently than those with solid tumours.
de Farias Gabriel A, Silveira FM, Curra M, Schuch LF, Wagner VP, Martins MAT, da Silveira Matte U, Siebert M, Botton MR, Brunetto AT, Gregianin LJ, Martins MD. Risk factors associated with the development of oral mucositis in pediatric oncology patients: Systematic review and meta-analysis. Oral Dis. 2021 Mar 28. doi: 10.1111/odi.13863. Epub ahead of print. PMID: 33774891.
Attinà G, Romano A, Maurizi P, D’Amuri S, Mastrangelo S, Capozza MA, Triarico S, Ruggiero A. Management of Oral Mucositis in Children With Malignant Solid Tumors. Front Oncol. 2021 Mar 30;11:599243. doi: 10.3389/fonc.2021.599243. PMID: 33859935; PMCID: PMC8042390.
Miller MM, Donald DV, Hagemann TM. Prevention and treatment of oral mucositis in children with cancer. J Pediatr Pharmacol Ther. 2012 Oct;17(4):340-50. doi: 10.5863/1551-6776-17.4.340. PMID: 23413048; PMCID: PMC3567887.
Dental Elf – 7th August 2019