Honey for Managing Chemotherapy Side Effects

Understanding the Global Impact of Cancer and the Challenge of Oral Mucositis in Pediatric Patients

cancer remains one of the most significant health challenges worldwide, claiming nearly 10 million lives in 2020 alone. This statistic translates to one in six deaths, as reported by the World Health Organization (WHO) in 2022. Alarmingly, around 300,000 children aged 0–17 are diagnosed with various forms of cancer each year. While chemotherapy has proven effective for many cancer types, a critical concern arises from its impact on normal cells, leading to complications such as oral mucositis (OM). This condition is particularly prevalent among pediatric patients, with severe cases increasing mortality rates by nearly 40%. Oral mucositis manifests as acute inflammation of the oral mucosa, characterized by symptoms like hemorrhage, erythema, and edema. Studies indicate that children are at a significantly higher risk (45–80%) of developing OM compared to adults, largely due to their unique physiological responses, compliance issues, and compromised immune systems. The management of OM is essential not just for comfort but also for ensuring effective cancer treatment and improving survival rates. Current treatments for OM in adults include mucosal coating agents, analgesics, and cryotherapy, but options for pediatric patients are limited. Interestingly, cryotherapy has traditionally been deemed suitable only for older children who can cooperate. In recent years, honey has emerged as a promising adjunct treatment due to its healing, antibacterial, and antioxidant properties, making it a globally recognized natural remedy. Current evidence suggests that honey can be effectively utilized to manage chemotherapy-induced oral mucositis. Comprising approximately 200 natural substances, honey not only promotes tissue healing by stimulating immune responses but also provides a viable alternative to conventional treatments. Several studies have shown that both natural and commercially available honey can mitigate not just chemotherapy-induced OM but also complications arising from radiation and chemoradiation therapies. However, Manuka honey, despite its reputed benefits, has yielded mixed results, possibly due to its unique composition, including a high level of methylglyoxal, which is thought to be cytotoxic. Additionally, the distinct taste of Manuka honey, often described as bitter, has contributed to a high dropout rate among pediatric patients. Given the pressing need for effective interventions in managing OM in children, this report aims to compile compelling evidence supporting the use of honey in pediatric oncology to prevent and treat chemotherapy-induced oral mucositis. By synthesizing existing studies, we hope to pave the way for further research and clinical applications in this crucial area.

Research Approach for Evaluating Honey’s Efficacy in Treating Pediatric Oral Mucositis

In this comprehensive study, we meticulously selected published research focusing on the use of honey or honey-derived products in preventing and treating chemotherapy-induced oral mucositis among pediatric patients. Our criteria included randomized controlled trials (RCTs) and non-randomized controlled studies (NRSs) that specifically examined the role of honey or its derivatives in managing this condition within the pediatric population.

Research Databases and Methodology

To conduct a thorough search of English literature, we employed a range of targeted keywords, including honey, stomatitis, oral mucositis, oral ulcer, child, pediatric, adolescent, and chemotherapy. Our search was conducted across several reputable healthcare databases, including CINAHL, CENTRAL, EMBASE, and MEDLINE PubMed, spanning from April 2010 to April 2020. The gathered data underwent rigorous analysis using GraphPad PRISMA-8 software, based in California, USA. The review process utilized a comprehensive 27-item checklist to assess the quality of included studies, focusing on critical aspects such as reporting, external validity, and the potential for bias. The quality levels established by the Downs and Black scoring system classify studies as excellent (26–28), good (20–25), fair (15–19), or poor (14).

Defining the Study Population for Honey Intervention

Characteristics of the Pediatric Cancer Population

Our study specifically targeted children and adolescents aged 1–17 years who were diagnosed with cancer and experiencing chemotherapy-induced oral mucositis. The interventions investigated included various honey-based products, such as natural honey, commercially available honey, and honey ice cubes. These interventions were administered between the 7th and 14th days after the initiation of chemotherapy, coinciding with the peak onset of oral mucositis symptoms. In contrast, prophylactic treatments with honey were applied before chemotherapy commenced to prevent the onset of OM.

Evaluating Treatment Outcomes for Oral Mucositis

The primary outcomes of interest in our analysis included recovery time and the severity of oral mucositis. Given the variability in outcome measures across studies, we focused exclusively on those employing the National Cancer Institute – Common Toxicity Criteria (NCI-CTC) Table S1 and the scales endorsed by the World Health Organization (WHO). Details of these assessment scales are presented in Table S2.

Establishing Inclusion Criteria for Study Selection

This report encompasses studies that compare the effects of honey against routine oral care, no treatment, or alternative therapies for the prevention and management of oral mucositis. Data were gathered from published scientific evidence concerning children and adolescents aged 1–17 years with chemotherapy-induced oral mucositis or those undergoing chemotherapy treatment. We applied strict inclusion criteria, selecting RCTs and NRSs that specifically investigated the efficacy of honey products for patients with chemotherapy-induced oral mucositis in either preventative or curative contexts. All studies included in the review were published in English and available in full text prior to April 2020.

Criteria for Exclusion from the Study

We excluded patients younger than one year or older than 17 years, those unable to consume orally, individuals with known allergies to honey, confirmed co-infection, or diabetes diagnoses. A detailed outline of the exclusion criteria is presented in Table 1. Additionally, studies that utilized Manuka honey as an intervention were excluded due to concerns regarding its taste and high methylglyoxal content, which may contribute to adverse effects.

Data Extraction and Comprehensive Processing Methodology

Data were meticulously extracted from databases that aligned with the study’s objectives and systematically compiled in a Microsoft Excel format Table S3. Key extracted data comprised essential information, study characteristics, study design, participant demographics, intervention types, and outcome measures. A mini-review approach was adopted to compare the effects of treatments across different studies, particularly in RCTs where a larger patient population could reveal clinically significant differences. Unlike brief reviews, our narrative synthesis approach offered a more subjective analysis to avoid potential biases. Following the Centre for Reviews and Dissemination (CRD) guidelines (2009), we ensured that our methodology was both transparent and rigorous. Nevertheless, we recognized the inherent heterogeneity in study designs, cancer types, causes of OM, control arms, assessment scales, and overall methodologies. Consequently, our data synthesis was tailored to reflect these variances accurately, focusing on developing a comprehensive synthesis of the findings from included studies.

Intervention Types and Comparative Analysis

All experimental groups in the selected studies utilized honey as a primary intervention. Among these, two studies implemented natural honey,^26,27 while another two employed commercial honey,^12,28 and one study investigated a combination of honey and tulsi in ice cube form.²⁸ The herb tulsi is renowned for its strong anti-cancer, anti-inflammatory, and anti-stress properties, which can also protect DNA from radiation damage. With the exception of one study that divided participants into three groups, the majority of studies categorized patients into experimental and control groups.²⁷ Notably, the ice cube study did not include routine mouth care,²⁹ whereas the remaining three studies ensured that all experimental groups received routine mouth care alongside honey treatments.^26–28 One study opted for a routine practice involving analgesics and antiseptic gel along with honey instead of standard mouth care.¹² Control groups in three studies followed identical protocols to the experimental groups but did not incorporate honey, while other studies compared honey with Benzocaine 7.5% gel²⁷ and plain ice cubes.²⁹ Most studies administered honey more than three times a day, except the ice cube study, which applied honey five minutes prior to methotrexate (MTX) treatment.²⁹ Dosing varied, with two studies administering 0.5–1g honey/kg,^26,27 another study delivering 1–2mL per application,¹² while two studies did not specify honey dosage.^28,29

Assessment of Treatment Outcomes

All studies utilized oral mucositis assessment scales to evaluate the degree of OM and to measure the effectiveness of honey in both treatment and prevention contexts from various perspectives. Given the myriad of variables involved, drawing definitive conclusions proved challenging. Recovery time, defined as the number of days from the initiation of treatment until complete healing of all ulcers, was reported in four studies.^12,26–28 One study opted to report on hospitalization duration instead of recovery time.²⁸ In terms of OM severity, Bulut and Tüfekci conducted assessments before each chemotherapy session and on the 1st, 4th, 8th, 12th, 16th, and 21st days post-chemotherapy.²⁶ Meanwhile, Mishra and Nayak focused their assessments on OM occurrences from the start of MTX administration.²⁹ Assessment of severity in the ice cube study occurred on the 5th and 15th days following treatment initiation. Al Jaouni et al evaluated OM both before and after chemotherapy, as well as one week after chemotherapy began.²⁸ Singh et al monitored OM progression every other day from the initial enrollment until complete healing was achieved.¹²

Evaluating the Quality of Included Studies

All studies included in this review were rated as fair based on the Downs and Black assessment criteria established in 1998.²³ Specifically, the scores for Singh et al and Abdulrhman et al were 16 and 18,^12,27 while three other studies received a score of 17.^26,28,29 Detailed quality assessments for each included study are available in Table S4. Notably, all studies failed to adequately describe the participant selection process, raising questions about the representativeness of the chosen populations.^12,27,29 Bulut and Tüfekci and Abdulrhman et al successfully included nearly all relevant source populations meeting the inclusion criteria,^26,27 whereas Mishra and Nayak recruited nearly all participants undergoing MTX chemotherapy, which was limited by the small number of eligible children in the hematology and oncology department.²⁹ Consequently, it remains unclear whether participants from these studies are representative of the broader population, as convenience sampling may have been employed. Only two studies^12,26 utilized blinding for outcome assessors to mitigate personal bias,³⁰ and none of the studies blinded participants regarding the intervention received, which could impact the reliability of the findings. Furthermore, only three studies in this review were RCTs, and randomization into groups was executed.^27–29 However, none of the studies provided information on whether randomization was concealed from healthcare staff and patients.

Documented Effects of Honey Interventions on Oral Mucositis

All studies included in our review confirmed the effectiveness of honey in both preventing and treating oral mucositis among pediatric patients undergoing chemotherapy.^12,26–29 Due to the existing clinical and methodological heterogeneity, the actual results will be presented through a narrative synthesis approach. The P-value serves as a statistical measure to quantify the effect of honey application in this mini-review. Detailed characteristics of the experimental and control groups from each study are summarized in Table 2. Additionally, overall data concerning recovery time and the status of oral mucositis are compiled in Table 3.

Table 2 Detailed Characteristics of Participants Included in the Present Studies (Experimental and Control Groups)

Table 3 Characteristics of Recovery Time and the Severity of OM

Comprehensive Results from Selected Studies

A total of 51 original studies were identified through our electronic database searches, as illustrated in PRISM-8 (Figure 1). The sources included 8 results from CENTRAL, 9 from MEDLINE, 12 from CINAHL, 12 from EMBASE, and 10 from Web of Science. Upon reviewing each article, we excluded 16 studies that involved adults or non-cancer patients, as well as those that used propolis as an intervention, which did not align with our predefined inclusion criteria. Moreover, 7 additional studies were excluded for various reasons: three focused on radiation-reduced oral mucositis, one was a piece of grey literature lacking results, two were presented at symposiums without adequate information, and one study lacked full-text access S5.

Figure 1 The study selection process is presented as a PRISMA flow diagram. Notes: Adapted from: Page MJ, McKenzie JE, Bossuyt PM, Boutron I et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71. Creative Commons Attribution (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/legalcode).33

Detailed Characteristics of Participants in the Studies

In total, 51 studies were reviewed and published to date. Detailed participant data can be found in Table 2. None of the participants experienced oral mucositis during the prophylactic phase; however, participants at the treatment stage exhibited varying degrees of chemotherapy-induced OM, as shown in Table 2. While two studies focused solely on chemotherapy, one study specified the chemotherapy drug used, which was methotrexate (MTX). Additionally, one study included participants receiving a combination of chemotherapy and radiotherapy, but it failed to report the ratio of chemotherapy to radiotherapy.

Assessment of Recovery Time in Pediatric Patients

Three studies evaluated the effectiveness of honey by analyzing recovery time from oral mucositis. One study specifically assessed the duration of hospitalization for OM patients.²⁸ In the research conducted by Abdulrahman et al, children with grade II OM showed a recovery time of 3.6±0.8 days in the honey group, compared to 4.6±0.9 days in the control group, indicating a statistically significant difference (P=0.0017). For grade III OM, the recovery times were 5.4±1.11 days in the honey group versus 8.6±1.0 days in the control group, again showing significant differences (P=0.0001). Combining grades II and III, the recovery time averaged 4.25±1.25 days in the honey group while it was 6.20±2.47 days in the control group, highlighting a statistically significant faster healing process in those treated with honey (P=0.0005; statistical power of 96.2%). Bulut and Tüfekci documented a recovery duration of 4.869±4.341 days in the honey group before OM developed, contrasted with 14.857±2.905 days after OM was established, significantly shorter than the control group’s 19.282±1.805 days (p=0.000). Al Jaouni et al compared hospitalization durations between honey-treated and control groups, revealing a mean of 7±3 days for the honey group versus 13±5 days for the control group (p<0.001). Singh et al (2019) further illustrated that the median duration of OM in the honey group was 4 days (IQR: 4–6 days), compared to 6 days (IQR: 6–8 days) in the control group. Collectively, these findings underscore the significant advantage of honey in expediting recovery from oral mucositis (p<0.01).

Severity Assessment of Oral Mucositis

Four out of five studies included in our review assessed honey’s effectiveness by examining the severity of oral mucositis.^12,26,28,29 One particular study encompassed two honey groups.²⁶ The severity of OM exhibited a gradual decrease in the honey group (patients with grade III and V OM) by the fourth follow-up day (p<0.001). Initially, the severity of OM was notably higher in the honey group compared to the control group on day 4 (3.58±0.47 vs 1.79±1.08, p=0.000); however, by day 21, the OM severity had significantly diminished (0.14±0.36 vs 1.76±1.03, p=0.000). Remarkably, 92.9% of the children in the honey group achieved full recovery, with only 7.1% remaining at a mild level, while in the control group, only 5.1% fully recovered, with 71.8% at a mild level and 23.1% exhibiting severe OM. Notably, none of the children in the honey group developed severe OM after the eighth follow-up day. A significant difference was observed in recovery status between both groups (p<0.01), indicating that honey effectively reduces the severity of OM. Additionally, in the honey group (patients without OM before chemotherapy), OM severity was significantly lower compared to the control group (0.43±0.58 vs 1.79±1.08, p=0.000) on both day 4 and day 21 (0.17±0.38 vs 1.76±1.03, p=0.000). The control group experienced a gradual increase in OM severity on days 4, 8, and 12, followed by a slight decrease on days 16 and 21, with significant differences in OM severity across different follow-up days (p<0.001). Before the development of OM, 82.6% of children in the honey group achieved full recovery, while only 5.1% did so in the control group, with 71.8% remaining at a mild level and 23.1% experiencing severe OM. Notably, no children in the honey group developed severe OM, and recovery status differed significantly between the two groups (p<0.01).

Al Jaouni et al conducted their study with participants receiving honey treatment prior to the onset of OM.²⁸ While prophylaxis and treatment were not investigated separately, the incidence of grade III and V OM was significantly reduced in the honey group (20% in honey versus 55% in control; P=0.02). In a study by Mishra and Nayak, participants were also enrolled before the onset of OM.²⁹ The experimental group (honey and tulsi ice cubes) displayed a considerably lower incidence of OM compared to the control group (plain ice cubes), with 40% of children experiencing mild to moderate OM in the experimental group while 90% (65% mild-moderate and 25% severe) in the control group on day 5 (p<0.001). By day 15, all OM cases in the experimental group were classified as mild-moderate, with only 15% incidence in this group compared to 80% in the control group (p<0.001). The severity of OM was also significantly reduced in the experimental group relative to the control group (0.4±0.50 vs 1.75±0.96, p=0.001) on both day 5 and day 15 (0.15±0.36 vs 1.1±0.71, p=0.001). The rate of children achieving grade 0 OM differed significantly between both groups, with 50% on day 5 and 92% on day 7 in the honey group, contrasted with 8% on day 5 and 54% on day 7 in the control group (p<0.01). Notably, all children in the honey group recovered from OM by day 9, while those in the control group took until day 13.

In-depth Discussion on Honey’s Role in Pediatric Oral Mucositis Management

Our focus centered on the efficacy of oral care treatments utilizing honey products to manage chemotherapy-induced oral mucositis in pediatric patients. The evidence reviewed indicates that honey products confer significant benefits, notably reducing OM severity and accelerating healing processes. Honey has demonstrated effectiveness in treating grades I, II, and III of chemotherapy-induced OM, thereby preventing the progression to severe forms of OM in children. Notably, no adverse data have been reported regarding conventional honey