Abstract
Background/Aim: Oral mucositis (OM) is a common and serious side effect of cancer treatment. The incidence of chemotherapy-induced OM in pediatric patients can reach up to 91.5% and has a major impact on patients’ quality of life. The aim of the study was to assess the efficacy of current interventions and agents for the management of OM in children undergoing chemo/radiotherapy or hematopoietic stem cell transplantation (HSCT). Materials and Methods: A systematic search of randomized controlled trials (RCTs) was conducted in the MEDLINE and Scopus databases from January 2000 until March 2023. Thirty-four randomized studies meeting the inclusion criteria were identified and five RCTs investigating the efficacy of Low Level Laser Therapy (LLLT) intervention or the agent honey were included in the meta-analysis. Results: The meta-analysis of two RCTs indicated that topical application of honey on oral mucosa was effective in shortening the mean duration of hospital stay in children with severe OM (MD=−4.33, p=0.002). However, LLLT was not found to be effective for the prevention or treatment of OM grade ≥II (RR=0.99, p=0.99). Moreover, the therapeutic application of LLLT did not show significant benefit for lower risk of OM grade ≥II (RR=0.48, p=0.58). Conclusion: Various interventions and agents were examined in the present study for the management of OM. Honey could be a promising candidate for the treatment of OM in pediatric patients. Further high-quality RCTs are required to enhance our findings.
Oral mucositis (OM), also referred to as stomatitis, is a common and serious complication of chemotherapy, and/or radiotherapy in patients undergoing cancer treatment or hematopoietic cell transplant (HSCT) for malignant or non-malignant diseases (1). This condition affects approximately 40% of patients receiving conventional chemotherapy and 60%-85% patients undergoing high-dose chemotherapy for bone marrow transplantation (2, 3). Research has indicated that up to 90% of patients receiving a combination of chemo- and radiotherapy for head and neck cancer will experience OM, and 19% of them will require admission to hospital for management (3). Furthermore, the incidence of chemotherapy-induced OM in children is higher than adults and can reach up to 80%-91.5%, depending on the underlying primary disease and treatment regimen (4, 5).
The duration of chemotherapy-induced OM among children persists for around three weeks and is clinically manifested with severe pain, difficulty in swallowing (dysphagia), weight loss and a significant decline in the patients' overall quality of life. OM often leads to inability of alimenting, necessitating the administration of total parenteral nutrition or gastrostomy tube placement to achieve feeding. Consequently, the length of hospital stay is prolonged, leading to increased inpatient costs (6). Moreover, the presence of ulcerative stomatitis is potentially complicated with secondary infections involving pathogens, such as Herpes simplex virus and Candida species, and in case of chemotherapy-induced neutropenia, patients face a heightened risk of life-threatening sepsis. It is estimated that severe OM (grade III-IV) can increase mortality by 40% (7).
Toxicity grading of OM is clinically assessed with various tools. Two of the commonly-used scales are the World Health Organization (WHO; Grade I: soreness±erythema, grade II: erythema, ulcers; patients’ ability to swallow solid foods, grade III: ulcers with extensive erythema; patients not being able to swallow solid foods, and grade IV: mucositis to the extent that alimentation is not possible) and Common Toxicity Criteria Scale of the National Cancer Institute (NCI-CTC; 0=none; 1=painless ulcers, erythema, or mild soreness in the absence of lesions; 2=painful erythema, edema or ulcers, but able to eat; 3=painful erythema, edema or ulcers, requiring intravenous hydration; 4=requires parenteral or enteral nutrition support) (8). These two grading scales are considered similar as they identically assess the damage of oral mucosa and the patient’s ability to eat.
The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) published in 2014 guidelines for the treatment of OM (1). These guidelines are presented as recommendations in favor or against an intervention (evidence level I-II) and suggestions in favor or against an intervention (evidence level III-V) (1). Furthermore, MASCC/ISOO published in 2020 a review of 45 studies (including 21 randomized controlled trials) that demonstrates interventions and agents for the management of OM in pediatric and young patients. These studies have included oral hygiene protocols, cryotherapy, low level laser therapy (LLLT), honey, analgesics (e.g., morphine), antiseptics (e.g., chlorhexidine), anti-inflammatory agents (e.g., benzydamine), growth factors (e.g., palifermin) and other treatments (9).
Many studies have been conducted in adult patients or a mixed population for the management of OM, but only a limited number of them have enrolled children and young individuals (10-16). The present study aimed to assess the efficacy of current interventions and agents for the prevention and treatment of OM specifically in pediatric patients.
Material and Methods
The protocol of the systematic review and meta-analysis was registered on PROSPERO (http://www.crd.york.ac.uk, study ID: CRD42023452934).
Search strategy. A systematic review of the literature was performed on MEDLINE via PubMed and Scopus databases until March 2023 using the MeSH terms: (“chemother*”[Text Word] OR “radiother*”[Text Word] OR “autolog*”[Text Word] OR “transplan*”[Text Word]) AND (“child” [MeSH Terms] OR pediatr*[Text Word] OR infant* [Text Word] OR adolescen* [Text Word]) AND (“mucositis”[MeSH Terms] OR “stomatitis/chemically induced”[MeSH Terms] OR mucositis [Text Word] OR stomatitis [Text Word]).
Study selection. Two independent reviewers (CSA, PP) carried out separately a systematic search for study selection. The PRISMA statement was used to report the study selection process as seen in Figure 1 (17).
PRISMA analysis of study selection process.
A study was included only if 1) the full-text version of the article was available; 2) publication year was from January 2000 until March 2023; 3) it was written in English language; 4) it was a randomized controlled trial (RCT) that presented the efficacy of at least one intervention or agent for the prevention or treatment of OM compared to placebo or another intervention or agent; 5) it included only pediatric patients; 6) grading of OM was evaluated with WHO or NCI-CTC scale; 7) the number of patients with OM was reported.
A study was excluded if: 1) it presented duplicate data with another study from the same center (the RCT with the greater number of patients was included in the data analysis); 2) the number of patients with OM was zero or not reported.
Data extraction. Data extraction included the following variables for each eligible study: principal investigator, year of publication, study design, origin and period of the study, number of patients, age of patients, type of intervention or agent, type of cancer or disease, type of treatment, definition of OM, follow-up period regarding the development of OM, number of patients with OM or length of hospital stay due to OM in each group. The Jadad scale was used for the assessment of the RCTs included in the qualitative synthesis (18), while the Cochrane Risk of Bias tool (19) was used for the RCTs included to the meta-analysis.
Data analysis. A meta-analysis was performed on the following outcomes: 1) efficacy of LLLT for the prevention or treatment of OM grade ≥II; 2) efficacy of LLLT for the treatment of OM grade ≥II; 3) efficacy of honey regarding the length of hospital stay due to severe OM (grade ≥III). The program Review Manager 5.4 (Cochrane Collaboration, Nordic Cochrane Centre) was used for statistical analysis. The Mantel–Haenszel method was applied for the calculation of pooled risk ratio (RR) for 1) and 2) outcomes. The pooled mean difference (MD) was calculated for (3) outcome with 95% confidence interval (CI). Statistical heterogeneity among studies in each analysis was calculated using the I2 method (p<0.10, significant heterogeneity). The random effects model was applied.
Results
Thirty-four RCTs were eligible for qualitative analysis from systematic search of the literature regarding the management of OM in pediatric patients. The characteristics of the included studies are presented in Table I. Various interventions and agents were found to be examined for the prevention and treatment of OM using WHO or NCI-CTC scale. For this reason, four categories of studies were created depending on the intervention or agent that was proposed: 1) LLLT; 2) Honey; 3) Growth factors; 4) Other interventions/agents.
Characteristics of the included studies in qualitative synthesis.
Low level laser therapy. LLLT intervention was investigated in eleven studies (20-30). The primary aim of seven studies was to examine the efficacy of LLLT in the prevention (21) or the treatment (20, 23-25, 27, 30) of OM compared to sham laser (placebo) or no intervention in children receiving chemotherapy for cancer or undergoing HSCT. Two RCTs focused on the efficacy of photodynamic therapy (PDT) (22) or the combination of PDT and LLLT (26) compared to LLLT in the treatment of chemotherapy-induced OM in pediatric patients with cancer. One RCT compared topical application of Andiroba oil on oral mucosa with LLLT in the treatment of OM in children with cancer and found a significant reduction in the severity of OM in andiroba oil group (28). One RCT compared three different setting of LLLT for the treatment of chemotherapy-induced OM and showed no difference between groups (29). From the above RCTs, Gobbo et al. (23) suggested that LLLT was effective in reducing OM severity (grade <III) on the seventh day of evaluation (p=0.01) and Karaman et al. (24) concluded that average OM grade was lower in LLLT group at the seventh day of evaluation. The percentage of events (p=0.029) and mean duration (p=0.004) of OM were lower in LLLT group according to Kuhn et al. (25) and a significant decline in OM with LLLT (p=0.003) was marked as reported by Reyad et al. (27). Furthermore, significant regression of OM was observed in LLLT group compared to sham laser group at the seventh day of evaluation in the study of Vitale et al. (30) and the combination of PDT and LLLT had a significant grater effect compared with LLLT intervention in reducing the severity of OM (p=0.005) in the study of Medeiros-Filho et al. (26). However, other pediatric studies found no significant benefit from the application of LLLT. Specifically, Amadori et al. (20) concluded that LLLT was not associated with a lower percentage of events of chemotherapy-induced OM (p=0.07) while Cruz et al. (21) found no significant benefit of LLLT in the prevention of OM in children receiving chemotherapy or HSCT (p=0.208). Moreover, Ribeiro da Silva et al. (22) reported no significant difference between PDT and LLLT for the treatment of chemotherapy-induced OM in pediatric patients.
Honey. Topical application of honey on oral mucosa was examined in two studies (31, 32). These studies evaluated the efficacy of honey for the management of OM in pediatric patients with cancer receiving chemotherapy (31) or chemotherapy/radiotherapy (32). The first RCT concluded that there was a statistically significant shorter recovery time in children with OM grade II-III that were admitted to hospital for evaluation and follow-up (31). It is noted that according to OM grading, patients with severe OM (grade ≥III) have difficulty in alimenting and, therefore, hospitalization is required. The second RCT found a significant shorter length of hospital stay due to severe OM (32). A mixture of honey, beeswax, and olive oil-propolis extract (HOPE) was effective for reducing recovery time due to OM grade III (p=0.0012) but no difference was found between HOPE and honey group (p=0.6108) as reported by Abdulrhman et al. (31). Furthermore, there was a significant absolute risk reduction of severe OM in honey group (p=0.02) according to Al Jaouni et al. (32).
Growth factors. Growth factors were investigated in four studies (33-36). Cesaro et al. (33) compared pegfilgrastim and filgrastim for the treatment of OM in pediatric patients with cancer undergoing autologous peripheral blood stem cell transplant (PBSCT) and found no significant difference in the percentage of events of OM grade (p=0.2) and OM duration (p=0.7). Additionally, TGF-β2 enriched feeding and oral rinse did not reduce the duration of chemotherapy-induced OM grade III-IV compared to placebo group in children with cancer according to de Koning et al. (34). Lucchese et al. (35) succeeded to show the efficacy of palifermin in the prevention of OM grade IV (p=0.005) and reduction of the duration of severe OM (p=0.04) in pediatric patients with acute lymphoblastic leukemia (ALL) receiving HSCT. Finally, Tsurusawa et al. (36) found no significant benefit of lenograstim prophylaxis for the prevention of chemotherapy-induced OM in pediatric patients with B-cell non-Hodgkin lymphoma.
Other interventions and agents. Other heterogenous interventions and agents were explored in seventeen studies (37-53). Alkhouli et al. (37) indicated that the prophylactic application of aloe vera on oral mucosa was associated with less severe chemotherapy-induced OM during the second week of treatment (p=0.001) and occurred later (p=0.001) compared to the sodium bicarbonate group in children with ALL. Additionally, the application of oral solution Verbascoside/PVP/sodium hyaluronate reduced the median of OM grading on eighth day in pediatric patients with ALL (p=0.038), as reported by Bardellini et al. (38). Cheng et al. (39) demonstrated the superiority of chlorhexidine over benzydamine for treating chemotherapy-induced OM grade II (4) while Cubukçu et al. (40) suggested that debridement effectively reduced severe OM on the sixth day of evaluation in children with cancer receiving chemotherapy. Eghbali et al. (41) reported that sugar-free gum was associated with a significant lower percentage of events of chemotherapy-induced OM grade I-II, but no difference was found on severe OM in the same study. Similarly, Gandemer et al. (42) noted that prophylactic use of fluoride-containing sugar-free gum did not decrease the percentage of events (p=0.67) or the median duration (p=0.54) of severe OM in children receiving chemotherapy. However, this agent was effective in reducing OM grade I-IV (p=0.03) when less toxic chemotherapy regiments were administrated (42). Prophylactic calcitriol supplementation did not reduce the percentage of events (p=1) and the severity of OM (p=0.54) and did not shorten the median length of hospital stay (p=0.8) in children with Fanconi anaemia undergoing HSCT, according to Hamidieh et al. (43). Although, baseline Vitamin D level was significantly associated with complete resolution of OM (p=0.03) and recovery from severe OM (p=0.04) in the same study. Oral supersaturated calcium phosphate rinse was not superior over oral saline rinse for the prevention of chemotherapy-induced OM (p=0.12) in pediatric patients as stated to the study of Immonen et al. (44). Moreover, Kamsvåg et al. (53) found no significant effect of oral cryotherapy in reducing the incidence of severe OM in children undergoing HSCT. Oral application of vitamin E and pycnogenol were effective in the treatment of OM compared to oral application of glycerin (p<0.001), but there was not significant improvement of OM between vitamin E group and pycnogenol group (p=0.0988), according to Khurana et al. (45). The administration of vitamin A supplementation had no benefit for the prevention of overall OM (p=1) and severe OM (p=0.27) in children receiving HSCT in the study of Pattanakitsakul et al. (46). Raphael et al. (47) found no significant difference between supersaturated calcium phosphate oral rinse and placebo for shorter duration of OM (p=0.069) in children undergoing chemotherapy or HSCT. Furthermore, prophylaxis with bovine colostrum supplementation significantly reduced the peak severity of OM in children receiving chemotherapy for ALL (p=0.02) as reported by Rathe et al. (48). Schmid et al. (49) concluded that parental nutrition did not shorten mean length of hospital stay compared to intravenous fluids in pediatric patients with chemotherapy-induced OM grade IV (p=0.817). Sener et al. (50) reported significant lower OM index value with Vitamin E oral care solution compared to chlorhexidine or honey oral care solution in children treated in an intensive care unit. Honey was superior to chlorhexidine in reducing the OM index value in the same study. Oral application of vitamin E did not result in a lower mean score of doxorubicin-induced OM in pediatric patients with cancer, according to Sung et al. (51). Finally, prophylactic administration of oral glutamine reduced the duration of hospital stay (p=0.005) and the percentage of events of OM (p=0.001) in children with ALL receiving high-dose methotrexate in the study of Widjaja et al. (52).
Outcomes. This systematic review identified a total of thirty-four studies, but only LLLT and honey categories provided enough studies for data analysis and meta-analysis synthesis (54). The results of the analysis regarding the management of OM in pediatric patients are the following:
Among the eleven studies accessing the efficacy of LLLT, only three of them (21, 25, 27) provided data regarding the number of patients with OM grade ≥II. Consequently, quantitative analysis was feasible only for these studies. It is important to note that OM grade II is more symptomatic compared to OM grade I, as the ulcers on oral mucosa cause pain and discomfort to the patient. The data analysis included 121 pediatric patients, 28 patients in each arm (LLLT vs. control group) of Cruz et al. study (21), 22 patients in each arm (LLLT vs. control group) of Reyad et al. study (27) and a total of 21 patients (9 patients in LLLT group vs 12 patients in control group) in Kuhn et al. study (25). The risk of bias summary of the RCTs included to the meta-analysis is presented in Figure 2. The meta-analysis of three studies (21, 25, 27) involving a total of 121 children demonstrated that LLLT did not significantly reduce the risk of OM grade ≥II compared to no intervention (RR=0.99, 95%CI=0.26-3.76, p=0.99; I2=72%, Figure 3). By excluding one of the above studies (21) which focused on the prevention of OM involving patients without OM at the beginning of the trial, no significant difference between the two groups (LLLT and no intervention) was observed regarding the risk of OM grade ≥II (RR=0.48, 95%CI=0.04-6.20, p=0.58; I2=86%, Figure 4).
Risk of bias summary for LLLT intervention showing the assessment of each risk of bias item for each included study. (+)=Low risk of bias; (?)=Unclear risk of bias; (−)=High risk of bias. LLLT: Low level laser therapy.
Forest plot showing the efficacy of LLLT for the prevention or treatment of OM grade ≥II. OM: Oral mucositis.
Forest plot showing the efficacy of LLLT for the treatment of OM grade ≥II. OM: Oral mucositis.
Two studies investigated the efficacy of topical application of honey on oral mucosa compared to no intervention (control group) regarding the mean duration of hospital stay in children with OM grade ≥III (31, 32). The data analysis included 66 pediatric patients, 13 patients in each arm (honey vs. control group) of Abdulrhman et al. study (31) and 20 patients in each arm (honey vs. control group) of Al Jaouni et al. study (32). The risk of bias summary of the RCTs included to the meta-analysis is presented on Figure 5. The meta-analysis of the above studies showed a statistically significant reduction in the mean duration of hospital stay for the honey group [MD=−4.33, 95%CI=− 7.02-−1.64, p=0.002; I2=76%, Figure 6]. This conclusion is further supported by the findings of Abdulrhman et al. (31) for OM grade II which recorded faster recovery time for honey group (p=0.0017).
Risk of bias summary for agent honey showing the assessment of each risk of bias item for each included study. (+)=Low risk of bias; (?)=Unclear risk of bias; (−)=High risk of bias.
Forest plot showing the efficacy of honey regarding the mean duration of hospital stay due to severe OM (grade ≥III). OM: Oral mucositis.
Discussion
This systematic review and meta-analysis of RCTs with pediatric patients investigated current interventions/agents for the management of OM and supports the role of topical application of honey for the management of severe OM. One previous meta-analysis of RCTs and non-RCTs involving pediatric and young adult patients with cancer supported the role of LLLT in the prevention and treatment of OM (55). One meta-analysis of RCTs including pediatric and young adult patients with cancer found only a trend for a lower incidence of OM in LLLT group compared to no intervention on 7th-10th day of evaluation (16). Another meta-analysis of RCTs and non-RCTs with children undergoing cancer treatment showed no significant difference in decreasing the percentage of events of OM when LLLT was applied (56). The same meta-analysis showed a significant benefit of palifermin in reducing the percentage of events severity, and duration of severe OM in children with cancer (56). Topical application of honey on oral mucosa was also found to be effective in shortening the recovery time due to OM in one meta-analysis involving children receiving radio/chemotherapy (15).
The present meta-analysis of two RCTs that included 66 pediatric patients undergoing radio/chemotherapy demonstrated a significant benefit of honey on shorter hospital stay in children with severe OM (p=0.002). Honey has a significant role in medicine, and it is popular for its anti-inflammatory, antioxidant, and antimicrobial activity. The anti-inflammatory effect is due to the reduction of plasma prostaglandin E2 concentration through inhibition of cyclooxygenase 1 or/and 2 and the antibacterial effect is due to its high viscosity since it contains high concentration of sugars and low water content, creating a protective barrier to prevent infection. In addition, the presence of organic acids (mainly gluconic acid) creates an acidic environment (pH=3.2-4.5) which is hostile for bacteria that grow mostly at pH 6.5-7.5 (57, 58). The antioxidant activity is attributed to its content of polyphenols and ascorbic acid and the activity of glucose oxidase. Hydrogen peroxide (H2O2) is also an important in vivo antioxidant agent which is produced when the enzyme glucose oxidase that is activated during the dilution of honey acts on endogenous glucose (57, 59). All these properties of honey promote wound healing by enhancing epithelialization and minimizing scar tissue (60).
The present study also found no significant benefit when LLLT was applied for the management (prevention or treatment) (p=0.99) and the treatment (p=0.58) of OM grade ≥II in children. These meta-analyses of RCTs included 121 and 65 pediatric patients, respectively. However, further larger RCTs in children are needed to verify these findings. LLLT has been found to be effective for the prevention and management of OM in adult patients and a mixed population according to recent meta-analyses (10, 61, 62). Mechanics of LLLT’s effectiveness on OM are not fully understood, but researchers found that it has significant anti-inflammatory and analgetic effects. LLLT triggers the production of growth factors, fibroblast proliferation and angiogenesis, and induces the release of endorphins (63). The commonly used parameters of LLLT are wavelength 632.8-685 nm, power 10-60 mW, fluence 1.8-3.0 J/cm2, and total energy 0.8-3.0 J (64). Although, LLLT is well studied for its role to the management of OM in adults, it is an expensive intervention and requires special training.
Study limitations. We presented the findings of RCTs concerning two different interventions, LLLT and honey compared to a control group, and even though it seems that honey provides significantly better results than LLLT, the results of the two meta-analyses are not comparable. The comparison for LLLT concerns the differentiation in the outcome between LLLT and no intervention group with a cut off value II toxicity grade of OM, while the comparison between honey and no intervention group, is conducted with a cut off value of III. This restriction is related to the way the patients in the included studies are grouped and therefore, any alteration is not feasible. Another limitation observed in the analysis regarding honey is that the actual number of episodes of severe OM is not stated by the study of Al Jaouni et al. (32), only the number of patients with a reported episode of severe OM that equals 4 in honey group and 11 in control group. Still, considering a minimum of 1 episode per patient, the inference does not change, and the benefit of the honey-based intervention remains statistically significant with an expected mean difference equal or greater than 3.5 units.
Conclusion
The results of the meta-analysis demonstrate that LLLT had no significant benefit for lower risk of OM grade ≥II in pediatric patients. Topical application of honey on oral mucosa was effective in shortening the mean duration of hospital stay in children with severe OM. We conclude that honey is a potent agent for the treatment of severe OM in children. However, further RCTs are needed to investigate the role of honey in less severe OM and explore more interventions and agents for the management of OM in pediatric patients with cancer.
Acknowledgements
This article is a revised research paper of CSA thesis for Master of Sciences (MSc) Program “General Pediatric Subspecialties: Clinical and Research” at the School of Medicine, Division of Health Sciences, National and Kapodistrian University of Athens, Greece.
Footnotes
Authors’ Contributions
CSA, CY, IK, PP contributed to study conception and design; CSA, PP performed the literature search, data extraction, risk-of-bias, and data analysis; CSA drafted the manuscript. All Authors reviewed and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest.
- Received December 5, 2023.
- Revision received January 22, 2024.
- Accepted February 6, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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