The effectiveness of the Mucosept for the treatment of radiotherapy-induced oral mucositis in head and neck cancer patients: A multicenter randomized controlled trial

Introduction

Oral mucositis (OM) is one of the earliest and most common consequences of chemotherapy and radiotherapy in patients with cancer [1]. Often, the course of OM is accompanied by painful symptoms that disrupt the processes of sleep, eating, verbal and social communication, which leads to a deterioration of the psycho-emotional state, a decrease in the quality of life (QOL) [2, 3], as well as an extremely undesirable suspension of basic cancer therapy [4, 5].

Despite the complexity of the etiological and pathogenetic mechanisms of the OM development, the probability and nature of its course is largely determined by the type of cancer therapy. According to S.T. Sonis, chemotherapy-induced OM is characterized by a faster and shorter period of the disease (up to two weeks) in comparison with the radiotherapy-induced OM the duration of which can reach five weeks (when receiving a dose of 2 Gy daily) [6, 7]. In this connection, head and neck cancer patients undergoing radiotherapy are more vulnerable to the occurrence of OM with a severe course (in 65% of cases) [8, 9]. The condition of such patients is worsened by changes in the composition and ratio of oral microbiota, which are assigned to be the etiological factors of the OM. However, in the scientific literature there is no consolidated opinion regarding this aspect [10]. Nevertheless, it is known that bacterial colonization of ulcers contributes to increased severity of OM and delayed healing [11]. Also, changes in the composition and functional behavior of oral biofilms can induce local or even systemic infections and diseases [12—16]. In this connection, measures aimed at the prevention and treatment of diseases induced by cancer therapy through oral microbiota normalization are of particular importance [17].

Basic oral care (BOC) is the primary recommendation for patients of this category. The BOC includes a complex of measures: patient education (including individual oral hygiene training), professional oral care, as well as the selection and prescription of oral care agents. Oral care agents are represented by a wide variety: from simple and affordable substances (sodium bicarbonate, chlorhexidine, natural compositions etc.) to medicines (for example, benzidamine hydrochloride) or their combinations [18]. Such diversity of agents and the absence of a specific oral care protocol is a consequence of insufficient evidence of effectiveness or intolerance of components [19, 20].

Thus, the question of finding an agent with analgesic, antiseptic and anti-inflammatory effects, capable of modulating the oral microbiota and contributing to the repair of damaged soft tissues remains an urgent objective in helping cancer patients with OM.

A natural agent mouthwash “Mucocept” (Patent RU No. 2810839, effective from 31.01.2023) is proposed for the prevention and treatment of OM induced by chemotherapy and/or radiotherapy for which microbiological efficacy has been determined [21]. Phytocomposite “Mucosept” is a sachet powder with crushed components mixed in equal proportions (10 g each): Achillea millefolium (herba), Acorus calamus (radix), Arctium lappa (radix), Betula pendula (folium), Bidens pilosa (herba), Calendula officinalis (flos), Chelidonium majus (herba), Epilobium angustifolium (folium), Glycyrrhiza glabra (radix), Inonotus obliquus (fungus), Matricaria recutita (flos), Mentha spicata (herba), Plantago major (folium), Tanacetum parthenium (flos), Vaccinium vitis-idaea (folium).

The aim of the study was to assess the effect of the “Mucosept” on head and neck cancer patients’ quality of life with manifestations of radiotherapy-induced oral mucositis.

Materials and methods

General study design

Null hypothesis was formulated as: the quality of life of head and neck cancer patients using “Mucosept” does not differ from the patients who do not use it. Null hypothesis testing involved a comparative analysis of various aspects of quality of life in head and neck cancer patients who were using “Mucosept” (experimental group) with patients who were not using it (control group).

Criteria for inclusion, non-inclusion and exclusion of patients in the study were compiled to ensure the homogeneity of the sample size. The control measurements timing was established in accordance with the patients’ baseline (T₀) and after their one-month follow-up (T₁). The T₀ data was intended to verify the study groups' initial homogeneity and the T₁ data was intended to verify the null hypothesis. Informed Consent Statement was obtained prior to the patients’ inclusion in the study.

Dental measures in the control group corresponded to the basic oral care recommendations received during their comprehensive rehabilitation. The patients included in the experimental group also followed the BOС recommendations and in addition received the phytocomposite “Mucosept”.

Calculation of sample size

In accordance with the study design, we assumed the use of the t-test method (differences between two independent samples) to test the null hypothesis, as well as the homogeneity of sample size at the T₀ study stage. The sample size was calculated in the G*Power program (Heinrich Heine Universität, Dusseldorf, Germany) where the following parameters were set: 0.05 (significance, α); 0.80 (power, 1−β); 0.80 (effect size, Cohen’s d). Based on this, the required sample size corresponded to 42 patients (21 patients in each group).

Study group formation

The following requirements were determined for the patients’ inclusion in the study: over 18 years old; diagnosed head and neck cancer; oral mucositis of the 3rd grade (WHO scale for oral mucositis [22]); undergoing radiotherapy; ECOG Performance Status Scale grade 0 or 1 [23].

The non-inclusion criteria in the study were: the presence of indications or the use of removable dentures; systemic diseases in the stage of exacerbation or decompensation; mental or psychogenic diseases in the medical history; cancer recurrence; allergic history; radical surgical interventions; participation in other studies; synchronous or metachronous malignant neoplasm; prescribed treatment for oral mucositis other than sodium bicarbonate 5%.

Patients were distributed randomly in the ratio of 1:1.

Quality of life measurement

The quality of life was assessed using the EORTC QLQ-HN43 questionnaire which differs from the previous version (QLQ-HN35) by improved psychometric properties [24]. The official Russian version of the questionnaire, as well as instructions for results calculation were provided by the developers (EORTC AISBL, Brussels, Belgium) upon request for this study.

The questionnaire was converted to digital format with the possibility of access via the web-interface. The first data collection (T₀) was carried out in the presence of researchers who provided technical advice on using the web-interface in case of difficulties. The second data collection (T₁) involved remote communication.

Statistical analysis

Considering the insignificance of cultural and linguistic differences among the populations in the research centers areas, as well as the acceptable robustness of EORTC QLQ-HN, a separate statistical analysis of data with following meta-analysis from each center was not necessary [24, 25].

Independent-samples t-test was assumed to be the main statistical criterion for assessing the statistically significant differences. The obtained data were preliminarily checked for the possibility of their processing with a parametric criterion, for which an equal variation test (Levene's test) was performed. In the case of variance inequality (p<0.05), the choice of a nonparametric statistical criterion (Mann—Whitney U test, Welch's t-test or Yuen—Welch's test) was assumed.

Results

The study included 42 patients (19 men and 23 women, average age 56.43±7.32 years).

The first assessment of QOL was performed at the control period T₀ stage, after the formation of a sample size and randomization of patients into study groups. The variances of QOL at this stage, in the study groups for each scale were determined to be equivalent (p>0.05). Statistically significant intergroup differences in scale indicators were not revealed (t-test, p>0.05; the details of the results are presented in Table).

At the second stage of the QOL control assessment (T₁), after 1 month patients' follow-up, there were no cases of exclusion (n=42). According to the results of the intergroup statistical analysis, significant differences in following scales were revealed: Pain in the mouth (PA), Swallowing (SW), Dry mouth and sticky saliva (DR) and Speech (SP) (p<0.05).

Discussion

The null hypothesis assumed that there were no statistically significant differences between the study groups in the level of quality of life, which includes the most important aspects (scales) for cancer patients. Statistical differences found in the scales of PA, SW, DR and SP allow us to reject the null hypothesis. It is important to note that these scales are closely related to the oral health, and therefore, it can be assumed that changes in these scales are impacted by a local factor.

Thus, F. Mohammadi et al. determined that the use of zinc chloride and sodium bicarbonate can improve the quality of life of cancer patients undergoing chemotherapy [26]. Despite the fact that the sample size included patients undergoing only radiotherapy, in the control group there was also an improvement in the quality of life indicators, especially with respect to the scales of PA, SW, TE, DR, SE and SP. However, since the issue of intragroup changes in QOL was not included in the objectives of the current study, the revealed trend can only be used as a hypothesis for further study of the BOC impact on the quality of life of cancer patients undergoing only radiotherapy.

Thus, it can be concluded that within the framework of this study, the most significant factor determining the outcome of quality of life measurement is assigned to oral care agents, and the revealed statistical differences between the groups can be explained by the use of “Mucosept”.

A comparison of indicators by scales with a statistical difference (T₁) corresponds to a higher level of quality of life in the experimental group, in which the patients' BOC was supplemented with phytocomposite. It is worth noting that the study design did not assume the phytocomposite effectiveness assessment in the case of its isolated use, in consequence of which other results may be obtained due to the lack of possible synergy between “Mucosept” and sodium bicarbonate. The study of various BOC agents’ interaction is an interesting question, in particular, in the context of the continuation of this work.

The revealed best efficiency in the experimental group, in our opinion, is due to the multicomponent nature of “Mucosept”, which provided multidirectional actions of each component, that most explains the obtained results.

The differences in the PA and SW scales are consistent with the data of other researchers (including clinical ones) regarding: Matricaria recutita [27, 28], Plantago major [29], as well as Tanacetum parthenium [30], in which the effectiveness of OM symptoms reduction in cancer patients is determined due their analgesic properties. The obtained results are also due to the anti-inflammatory and regenerative properties of Epilobium angustifolium, owing to the activation of inhibition of neutrophil elastase [31, 32], the excess of which leads to tissue damage and aggravation of the OM severity [33].

Based on the literature data, it can be concluded that the improvement of PA, SW and DR indicators is primarily due to antioxidant properties of Achillea millefolium [34], Acorus calamus [35, 36], Arctium lappa [37], Betula pendula [38], Bidens pilosa [39], Calendula officinalis [40], Chelidonium majus [41], Glycyrrhiza glabra [42], Inonotus obliquus [43, 44], Mentha spicata [45] and Vaccinium vitis-idaea [46].

Improved speech (SP) in both study groups may be a consequence of patients' adaptation. However, a statistically significant difference in SP indicators in the experimental group shows a positive effect of “Mucosept”. In our opinion, the obtained results may partly be due to the strong antioxidant properties of the phytocomposition, that made it possible to reduce oxidative stress, which is of great importance in the development of radio-induced oral mucositis and salivary hypofunction [7, 47]. Oxidative stress reduction could contribute to normal salivation, thereby improving the quality of speech [48, 49].

Despite the fact that problems with teeth (TE scale) are also directly related to the oral cavity and its condition, the lack of statistical differences between the groups, in our opinion, is due to insufficient time for accumulation and manifestation of positive or negative effects. It should be borne in mind that the period from the measures start within the framework of the BOC (patient education, professional oral care) to the patients’ inclusion in the study did not exceed 1 month.

Taste and smell perversions are associated with damage to any structure of the nervous system (central nervous system, receptors, etc.), as a result of radiotherapy [50]. In this case, the BOC cannot protect or restore the disrupted functions, which explains the lack of statistical differences in this scale (SE scale).

Problems with opening the mouth in patients undergoing cancer therapy are associated with the accumulation of radiation exposure and the development of radiation-induced trismus [51]. This complication is delayed [48, 52] and slowly developing, and its manifestation occurs during the post-radiation therapy period [53]. This fact explains the absence of an intergroup difference in OM-scale, since at the time of the control measurement (T₁) the accumulation of radiation exposure and the time from the start of radiotherapy was insufficient for the manifestation of noticeable symptoms.

S. Singer et al. [24] determined the relatively limited reliability of the SC and SN scales during repeated measurement (test-retest) for a period of one week. We could not find other studies evaluating the reliability of SC and SN for a longer period between measurements, and therefore, the interpretation of the obtained results on these scales may be incorrect.

From our point of view, the state of oral health in relation to the BI, SO, ANX, SX, WL scales does not play a priority role, since the indicators of these scales are determined by a variety of other factors, among which it is difficult to accurately determine the contribution of the BOC agents' impact. B.A. Rhoten et al. identify two main groups of factors that determine the self-perception of the body image — disfigurement (for example, a change in the face configuration) and dysfunction, which are the result of not only local complications, such as impaired verbal communication, food chewing, but also their general condition (weakness, fatigue, etc.) [54]. J.M. Patterson et al. concluded that age and social status play a decisive role in SO indicators [55]. The anxiety level is determined not only by physiological, but also by psychosocial problems [56]. Thus, the determination of the local BOC agents' effect is a separate research issue that requires the formation of more specific criteria for the patients' inclusion in order to exclude interfering factors.

The informativeness of SH, SK, CO, WO, NE indicators does not allow to correctly judge the effectiveness of the phytocomposite, since the issues of these scales do not affect the area of the BOC agents' action. In our opinion, any significant differences in the indicators of these scales could be prerequisites for considering systemic side effects, which, however, was not revealed during the study.

The limitation of this study is the short observation period, which does not allow us to judge the long-term effects of the phytocomposite use. In our study, we did not take into account the cumulative radiation dose and radiotherapy regimen at the time of patients' inclusion in the study, which might be a factor reducing the homogeneity of the sample size and the power of the study. When including patients in the studies, we also did not take into account the patients' social status, which might have an impact on the success of individual oral hygiene training. When including patients in the study, we did not detail the patients' oral health status according to hygienic parameters, the presence and condition of fixed dentures, fillings, which may also be the reason for a decrease in the power of the study. The presented study is associated with a large effect of the sample size, therefore, in order to increase the level of evidence of the obtained results, it is necessary to conduct a similar study with a large sample size.

Conclusions

Taking into account the limitations of the study, we can conclude about the positive effect of the phytocomposition “Mucosept” on the quality of life of head and neck cancer patients with concomitant complication in the form of oral mucositis induced by radiation therapy.