Abstract
Objectives
This study aimed to evaluate the effectiveness of topical application of olive oil either to delay chemotherapy induced oral mucositis (OM) or to alleviate its severity in Acute Lymphoblastic Leukemia children.
Materials and methods
a randomized controlled clinical trial was conducted at Hematology-Oncology Department of Children’s Hospital of Damascus University, Syria. 24 children suffering from acute lymphoblastic leukemia aged between 4 and 6 years old were randomly assigned into two groups, olive oil and sodium bicarbonate 5% (12 in each group).
Preventive protocol started two days before the induction of chemotherapeutic drugs. Topical application was done by a sterilized spongeous stick in order to swab tongue, buccal mucosa, floor of the mouth, lips and hard palate, as those tissues of the mouth are susceptible to chemotherapy induced OM [1]. The study period was within induction and consolidation phases of chemotherapy. Oral mucosa was assessed weekly up to eight weeks by two external investigators using the World Health Organization grading scale.
Results
Data was analyzed using Mann-Whitney U test. Based on the observed results, (OM) grades were with less severity in olive oil group than in sodium bicarbonate group with statistically significant difference reported from the 2 nd week of study phase. In addition, Mann-Whitney U test demonstrated that patients in olive oil group started (OM) later than those in sodium bicarbonate group with statistically significant difference (p = 0.022). As a result, olive oil retarded the beginning of oral mucositis (OM) compared with sodium bicarbonate.
Conclusions
olive oil can be used topically on oral tissues to prevent chemotherapy induced (OM) in acute lymphoblastic leukemia children.
1
Introduction
Cancer is the second common reason of children fatality after accidents. Among malignant diseases, acute leukemia is the most common childhood cancer. Acute lymphoblastic leukemia (ALL) comprises about 75% of all leukemic conditions with the peak incidence occurs between the ages of 2–5 years old .
Chemotherapy is the most effective way in cancer management. However, it has many side effects that can harm children’s quality of life. Chemotherapy drugs may have significant undesirable effects on healthy tissues that have high mitotic rates, like the gastrointestinal tract mucosa and bone marrow .
Oral mucositis (OM) is one of the most annoying complications that can result from chemotherapeutic treatment . Oral mucositis (OM) develops after a series of biological events that take place throughout the different cellular compartments of the mucosa although the clinical symptoms of mucositis are the result of epithelial injury only . Ulceration stage is considered the last stage of pathobiology of mucositis before healing process begins . Discomfort, pain and burning sensation are the most important oral complications resulting from the ulceration stage and starts approximately ten days after the induction of chemotherapeutic drugs .
To prevent chemotherapy-induced oral mucositis (OM), different therapeutic agents have been used, including conventional oral hygiene protocol, anti-inflammatory agents, antimicrobial agents, cryotherapy, antiseptic agents, vitamins, cytokines and natural herbs, etc .
Olive oil is extracted from the olive, a species from the Oleaceae family . An animal study confirmed that topical use of olive oil has a radio-protective and chemo-protective effect. This can be due to its antioxidant, anti-inflammatory and antimicrobial properties .
Sodium bicarbonate solution acts as a mechanical cleanser on oral tissues, neutralizes the production of acid in the mouth and acts as an antiseptic to help prevent infections .
To the best of our knowledge, this study was the first trial that investigates the effectiveness of topical application of olive oil in the prevention of chemotherapy induced oral mucositis (OM) in pediatric patients.
2
Materials and methods
2.1
Study design
This study was a randomized controlled clinical trial conducted on 22 children suffering from acute lymphoblastic leukemia (ALL) aged between 4 and 6 years old. They were recruited from Hematology-Oncology Department of Children’s Hospital of Damascus University. The trial was approved by the Research Ethics Committee of Faculty of Dentistry of Damascus University and was registered at the Australian New Zealand Clinical Trials Registry (ANZCTR) ( trial id: ACTRN12618001931268 ), after having Universal Trial Number (UTN) U1111-1223-9672 .
Sample size was calculated according to previous similar study using the G*Power software (v. 3.1) (Franz Faul, Universität Kiel, Germany). The significant level was set at 0.05 and statistical power of study was set at 90%. It was estimated that 20 patients were required to demonstrate an effect size (0.85). Total sample size was raised by 20% to avoid any possible dropout of participants (24 patients).
The trial was a triple blinded one in which the patients, guardians, administrators and the investigators have no idea about the preventive agent they are used.
As computer-based methods for randomization are more reliable and easier to use than manual methods. Therefore, a random allocation list was carried out using https://www.randomizer.org/ .
This triple blinded randomized controlled clinical trial was designed and conducted according to the CONSORT statement over a period of 12 months from May 2018 to May 2019.
Inclusion Criteria of participants:
- 1.
Children with acute lymphoblastic leukemia aged between 4 and 6 years.
- 2.
Children have not received chemotherapy or radiotherapy before sampling.
- 3.
Children have intact oral mucosa.
Exclusion criteria of participants:
- 1.
Known sensitivity to olive oil.
- 2.
Presence of any gingival or oral ulceration or mucositis.
- 3.
Taking of any antiviral or antifungal therapy and/or any other agents for oral mucositis (OM) before enrollment in the study.
2.2
Clinical procedure
A signed informed consent was obtained from one guardian of each patient before the study.
Enrolled patients were in the high-risk group of Acute Lymphoblastic Leukemia to ensure that all participants will receive the same protocol of chemotherapy. All patients who fulfilled the inclusion criteria were randomly assigned into one of two groups, 12 children each.
Group 1: olive oil taken directly from a local distributor in Syria. It was stored in dark containers at room temperature through the study phase.
Group 2: Sodium bicarbonate 5% solution as a control group.
Regardless of the preventive agent used, all participants started the application two days before the induction of chemotherapeutic drugs. According to American Academic of Pediatric Dentistry (AAPD), children were instructed to brush their teeth before each application . Topical application was done two times daily by a sterilized disposable spongeous stick ( Fig. 1 ). Preventive agents were supplied in 200 ml glass containers that were colored with some attractive drawings in order to help in blinding ( Fig. 1 ).
For each application, a new stick was immersed into one of the agents and 5 ml was applied to tongue, buccal mucosa, lips and hard palate by the help of the Hospital’s nurses who have been informed that participants are not allowed to eat or drink for 1 h after the application .
A checklist paper posted in each participant’s room and the nurses did two checks every day (one check for each application) in order to monitor adherence of participants to the intervention.
2.3
Follow-up evaluations
The follow-up was done once weekly for eight weeks (during the induction and consolidation phases of chemotherapy) by two experienced external blinded investigators (Oral Medicine specialists).
Although there are many scales to quantify the injury of oral mucosa, the most common used one is the World Health Organization (WHO) grading scale, which combines clinical features with the patient’s ability to eat or drink . This scale classify oral mucositis (OM) as shown in Table 1 .
| Grade | Description |
|---|---|
| 0 | None |
| 1 | Oral soreness, erythema |
| 2 | Erythema, ulcers, solid diet tolerated |
| 3 | Ulcers, liquid diet only |
| 4 | Oral alimentation impossible |
The investigator assessed (OM) according to (WHO) oral mucositis (OM) grading scale. The follow-up was done weekly to assess if the intervention delayed (OM) appearance also.
Figs. 2–5 show (OM) grades according to (WHO) grading scale as presented in participants of the present study.
2.4
Statistical analysis
After using Kolmogorov–Smirnov test to determine if data were molded by a normal distribution, the test showed that data are not distributed normally. Therefore, Mann-Whitney U test was used to determine if there was a statistically significant difference between olive oil group and sodium bicarbonate group.
In this study, the level of significance (p-value) was set at 0.05 and the statistical analysis was performed using the IBM SPSS software v. 23 (IBM Corp., Armonk, USA).
Intra-examiner reproducibility and inter examiner reliability for (OM) diagnosis was calculated by cohen’s kappa test. The kappa for intra-examiner agreement and inter examiner reliability was 0.90.
3
Results
Of the 24 randomized patients, only 22 participants completed the phase of treatment (8 weeks) with 11 patients in each group. Dropouts in both groups occurred as a consequence of fatality of 2 patients before they completed the study phase. ( Fig. 6 ) shows the CONSORT flow diagram of the progress through the phases of this parallel-randomized trial.
Therefore, a total of 22 (12 male and 10 female) patients were enrolled in the study. The mean ages of the olive oil and sodium bicarbonate groups were 5.4 and 5.2 years, respectively. Male comprised 54.5% of the olive oil group and of the sodium bicarbonate group. Participants’ characteristics are summarized within Table 2 .
| Olive oil (N = 11) | Sodium bicarbonate (N = 11) | |
|---|---|---|
| Male | 6 (54.5%) | 6 (54.5%) |
| Female | 5 (45.45%) | 5 (45.45%) |
| Mean of age (year) | 5.4 years | 5.2 years |
Each participant was assessed weekly up to eight weeks by recording the degree of oral mucositis. Study results showed that grade (0) OM was with the highest percentage in olive oil group during the eight weeks. In addition, there is no grade (4) OM in olive oil group. The percentage of each OM grade weekly up to the eight week in olive oil group and sodium bicarbonate group are demonstrated in Tables 3 and 4 , respectively. ( Fig. 7 ) shows the change in degree of OM weekly in both groups.
| Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 7 | Week 8 | |
|---|---|---|---|---|---|---|---|---|
| Grade 0 | 100% | 100% | 90.91% | 81.81% | 81.81% | 72.73% | 72.73% | 90.91% |
| Grade 1 | 0% | 0% | 9.09% | 18.18% | 18.18% | 9.09% | 18.18% | 0% |
| Grade 2 | 0% | 0% | 0% | 0% | 0% | 18.18% | 0% | 0% |
| Grade 3 | 0% | 0% | 0% | 0% | 0% | 0% | 9.09% | 9.09% |
| Grade 4 | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% |
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