Introduction

Chemotherapy and radiotherapy are cancer treatment modalities commonly associated with adverse effects, such as inappetence, nausea, vomiting, and mucositis [1]. Oral mucositis (OM), an inflammatory lesion of the mucosa, manifests within 7 to 10 days after cancer treatment [2] and occurs in 40 to 80% of patients treated with chemotherapy and in practically all those submitted to radiotherapy in the head and neck region [3].

Clinically, oral mucositis appear as mild erythema in the non-keratinised mucosa and progress to ulcers with extremely painful symptoms [3, 4]. They can compromise functions such as speech and swallowing, which reduce the quality of life of the patients [4, 5] and become limiting factors in cancer treatment, as it may be interrupted [6].

Different strategies have been indicated for the treatment of mucositis, such as low-level laser treatment, rinsing with morphine [7]; adequate oral hygiene, the use of antiseptics, analgesics, anti-inflammatories [8]; and cryotherapy [5]. These aim to utilise the palliative effect in the control of pain; however, there is still a need for more studies that evaluate the effectiveness of alternative interventions [9].

The use of natural products represents an alternative that should be investigated due to their anti-inflammatory action with less possibility of adverse side effects [10], less toxicity, and more affordable costs [11]. The search for such products is increasing in the face of the limitations of conventional medicine [12] and the appreciation of healthier lifestyle habits associated with the use of natural products [13].

The therapeutic activities of medicinal plants are validated through ethnopharmacological surveys, laboratory tests, and clinical trials, which are considered the gold standard for the analysis of therapeutic interventions [14]. By grouping, organising, and evaluating the results of clinical trials through systematic review, it is possible to evaluate the natural products used to treat OM.

The systematic analysis of publications makes it possible to recognise the natural products with the best results and, with this, to indicate their clinical use as well as to direct future research [15].

Materials and methods

Study design

A systematic review was carried out following the PRISMA protocol under registration number CRD 42,019,118,673 (PROSPERO).

Clinical question

The clinical question based on the PICO strategy (Table 1) was the following: “Which medicinal plants are effective in the treatment of OM induced by cancer treatment?”.

Table 1 Description of the PICO strategy used in the development of the clinical question
Full size table

Search strategy

The searches in the databases were carried out on 10/27/2018 and followed the strategy described in (Table 2).

Table 2 Database search strategy
Full size table

Inclusion criteria

The inclusion criteria were the following: randomised clinical trials or non-randomised clinical trials; patients with OM induced by cancer treatment; and treatments performed with medicinal plants.

Exclusion criteria

The exclusion criteria were the following: literature reviews; clinical trials without a control group; in vitro studies; and in vivo animal studies.

Article selection and data extraction

The selection of articles was independently carried out by two reviewers. The Kappa index was calculated after reading 10% of the papers (0.82). The inclusion criteria were applied to select the titles and abstracts, which were included based on the eligibility criteria. The differences were resolved by consensus between the two researchers.

Bias risk assessment

The risk of bias assessment was performed in randomised clinical trials using the Cochrane manual (Review Manager) [16]. The evaluated items were the following:

  • Selection bias: the generation of random sequence and allocation hiding

  • Performance bias: the blinding of participants and professionals

  • Detection bias: the blinding of outcome evaluators

  • Friction bias: incomplete outcomes

  • Reporting bias: the reporting of selective outcomes

  • Other biases

Analysis of the results

The results were analysed using the Cochrane manual evaluation method [17] for randomised clinical trials.

Results

The search strategy illustrated in the PRISMA flowchart (Fig. 1) identified 1064 studies whose titles and abstracts were evaluated according to the inclusion criteria. Of this total, 51 works were pre-selected and read in full. After the complete reading, 27 studies were excluded after applying the exclusion criteria, such as the absence of a control group, literature reviews, and design of the study conducted in vivo (animals) and in vitro.

Fig. 1
figure 1

PRISMA flowchart for inclusion of articles in the systematic review

Full size image

For qualitative analysis, 24 articles were selected and included in this systematic review. The articles included are described in chronological order in Table 3. The total sample consisted of 1296 patients undergoing treatment for OM with medicinal plants. Fourteen clinical trials evaluated only one plant species. The most widely used plant extracts were Matricaria chamomilla [18,19,20], Aloe vera [21, 22], Isatis indigotica Fort [23], Olea europaea [24], Calendula officinalis [25], Curcuma longa [26], Glycyrrhiza glabra [27], Achillea millefolium [28], Morus nigra L. [29], Zataria multiflora [30], and Plantago major [31].

Table 3 Clinical trials included in the systematic review in chronological order of publication
Full size table

The action of herbal medicines on mucositis lesions was evaluated in 6 clinical trials that used the following products: Mucotrol™ [32], Qingre liyan [33], SAMITAL® [34], Mucosyte biopharm [35], CHIN [36], and Faringel [37]. The other studies (4) used the following plant compounds to treat oral mucositis: essential oils of manuka and kanuka [38], thyme tea with mint (sage tea thyme peppermint hydrosol) [39], Matricaria chamomilla with Mentha peperita [40], and Alcea digitata Alef with Malva sylvestris [41].

The countries that presented the largest number of publications on the use of plant extracts in the treatment of mucositis were Iran [22, 25, 27, 28, 30, 40, 41] and Italy [34, 35, 37]. Other countries that carried out works with natural products were Brazil [19, 20], the USA [18, 21], India [26, 32], China [33, 36], Turkey [29, 39], New Zealand [38], Taiwan [23], Iraq [24], and Spain [31].

In the present study, there were limitations regarding the evaluation of the data analysis of the primary studies. As for the existence of publication bias, one of the great limitations of systematic reviews, there is the possibility that studies with negative results, mainly of small size, have not been published. The high heterogeneity among the studies, mainly regarding the plant species, did not allow for the realisation of the meta-analysis; thus, the qualitative analysis was carried out.

Bias risk assessment

Bias risk assessment was performed in clinical trials following the criteria of the Cochrane manual [17]. The risk of selection bias has not been identified in the studies. The performance bias resulting from the blinding of participants and professionals was identified as a limiting factor and was reported in the study by Wang et al. [36]. The blinding of outcome evaluators was described in 82.14% (23/24) of the studies evaluated. The evaluation of incomplete outcomes was considered uncertain in all studies analysed. Figure 2 presents the assessment of the risk of bias performed by the Review Manager program (RevMan 5.3).

Fig. 2
figure 2

Assessment of the risk of bias in clinical trials

Full size image

Discussion

OM, commonly manifested in patients undergoing cancer treatment, is considered the most severe non-haematological complication of cancer therapy [5, 42] and can be become a limiting factor in cancer treatment [4, 5]. Its treatment consists of relieving painful symptoms and preventing the spread of infections since the lesions are a gateway for pathogenic microorganisms [8].

The search for products of plant origin to treat OM has been carried out in several countries, mainly in Iran and Italy. There are several factors that propagate the practice of phytotherapy, such as the high cost of allopathic drugs, the search for less aggressive products, and the appreciation of healthier lifestyle habits [13].

Among the 893 works identified in the electronic databases, only 24 met the inclusion criteria and underwent qualitative analysis. Most of the studies (n = 14, 58.3%) evaluated the action of treatments carried out with a single plant species. The plant species found were the following: Matricaria chamomilla [18,19,20], Aloe vera [21, 22], Isatis indigotica Fort [23], Olea europaea L. [24], Calendula officinalis [25], Curcuma longa [26], Glycyrrhiza glabra [27], Achillea millefolium [28], Morus nigra L. [29], Zatara multiflora [30], and Plantago major [31].

Vegetable compounds were evaluated in four clinical trials that used the combination of essential oils of manuka and kanuka [38], salvia, thyme and mint tea [39], chamomile with mint [40], and Alcea digitata Alef with Malva sylvestris [41].

Herbal medicines were evaluated in 6 (25%) of the 24 articles included Mucotrol™ [32], Qingre liyan [33], SAMITAL® [34], Mucosyte biopharm [35], CHIN [36], and Faringel [37].

The pioneering study on the use of medicinal plants in the treatment of mucositis was carried out in the USA with Matricaria chamomilla (chamomile) by Fidler et al. [18]. Chamomile, whose action initially did not show favourable and significant results [18], currently shows its beneficial action on mucositis lesions [43]. The incidence and duration of OM were lower in patients who underwent treatment with a mouthwash manipulated with 1% chamomile extract [19], and the treatment performed with cryotherapy made with chamomile infusion reduced the duration and severity of the lesions [20].

The use of the mouthwash manipulated with the combination of chamomile and mint resulted in a shorter duration of lesions and a lower degree of severity of OM, according to the National Cancer Institute scale [40]. Chamomile is considered a promising alternative treatment for OM [43].

Aloe vera has antibacterial, antifungal, anti-inflammatory, antioxidant, and anti-tumour pharmacological action [44]. Its beneficial effects are attributed to the polysaccharides present in its pulp, which is widely used as a medicine and cosmetic [45]. The action of Aloe vera in the treatment of OM has presented divergent results between studies [21, 22]; therefore, its indication is still questionable.

The species Isatis indigotica Fort, a plant of traditional Chinese medicine, has as main components indigo, indirubin, organic acids, nucleosides, glucosinolates, lignans, ceramides, steroids, and polysaccharides [46]. It has multiple pharmacological properties, such as antiviral, anti-cancer, and antibacterial properties [47]. When carrying out an analysis of the degree of severity of OM, patients undergoing treatment with Isatis indigotica Fort extract had less severe lesions and less difficulty swallowing [23].

The extract of Olea europaea L., manipulated from the olive leaf, is marketed as a natural supplement for its multiple benefits, such as its antioxidant activity and antimicrobial action, which helps in the treatment of various infectious diseases [48], and its anti-inflammatory action [49]. Its use reduced the severity of OM lesions (Oral Mucositis Assessment Scale scale) and reduced the levels of Interleukin 1 beta (IL-1β) and Tumour Necrosis Factor-Alpha (TNF-α) [24].

Calendula officinalis, popularly known as daisy, is used in folk medicine for its anti-inflammatory action in the treatment of wounds, minor burns, bruises, skin rashes and stomach ulcers, or inflammation of the oral and pharyngeal mucosa [50]. Other important pharmacological activities are its antioxidant, antimicrobial, and healing activities. The biological activity of each extract is due to its constituents, including terpenoids, flavonoids, phenolic acids, carotenoids, coumarins, quinones, volatile oils, amino acids, and lipids [51]. Its use reduced the intensity and degree of OM [25].

Curcuma longa (curcumin), also called saffron, has anti-inflammatory, antimicrobial, antioxidant, and antineoplastic properties [52]. It is used to treat a variety of diseases because of its actions related to wound healing and the increase in the amount of collagen [53]. The treatment performed for OM reduced its degree of severity [26].

Glycyrrhiza glabra, popularly known as licorice or regaliz, is a species of flowering plant belonging to the Fabaceae family. It has sweet roots rich in glycyrrhizin, from which syrup is extracted. It is used in herbal medicine in many Asian and European countries, with effectiveness in the treatment of cough, peptic ulcer, constipation, and other viral infections [54]. The constituents of the Glycyrrhiza extracts have anti-inflammatory effects that result in the inhibition of inflammatory cytokines, such as IL-6, IL-1β, and TNF-α. [55]. In the treatment of OM, patients showed an improvement in painful symptoms [27], but Glycyrrhiza glabra should be used with caution since it can present important side effects, such as hypertension and secondary disorders induced by hypokalaemia [56].

Achillea millefolium, popularly known as yarrow or thousand leaves, is an important species in the Asteraceae family and is used in the treatment of gastrointestinal disorders, hepatobiliary disorders, gynaecological disorders, inflammation, and wound healing [57]. Treatment with milefolium extract reduced the degree of severity of OM after 7 and 14 days [28].

The species Morus nigra L. (blackberry) is rich in secondary metabolites, such as flavonoids, and is associated with important biological activities with antioxidant and anti-inflammatory actions [58]. Blackberry molasses did not reduce the incidence or severity of OM [29].

The Zataria multiflora plant belongs to the Laminaceae family and is found in Iran, Pakistan, and Afghanistan. Traditionally, it is used as an antiseptic, anaesthetic, and antispasmodic because it has phenolic constituents, such as carvacrol, thymol, and eugenol [59]. Treatment with Zataria multiflora extract reduced the severity of OM on the OMAS and World Health Organization (WHO) scales [30].

The therapeutic plant Plantago major, popularly known as plantain, is a species of plantago of the Plantaginaceae family. They present bioactive flavonoid compounds, alkaloids, phenolics, glycosides, polysaccharides, and vitamins with healing, antiulcerative, anti-inflammatory, antioxidant, and anticancer effects [60]. In the treatment of OM, the Plantago major extract did not reduce the healing time or pain intensity [31].

The association of Alcea digitata Alef and Malva sylvestris, described in Persian medicine as mucilage plants, can be used for its anti-inflammatory and analgesic properties [61]. A. digitata and M. sylvestris reduced the degree of OM intensity (WHO scale) and promoted an improvement in the level of pain [41].

The essential oils of manuka (Leptospermum scoparium) and kanuka (kunzea ericoides), found in New Zealand, have anti-inflammatory, analgesic, and antimicrobial properties. Its treatment postponed the onset of the appearance of the first mucositis lesions [38]. The preventive action of thyme tea and pepper hydrosol reduced the incidence of OM [39].

Herbal medicines composed of more than one plant species and obtained by the pharmaceutical industry were part of the methodology of some studies included in the systematic review.

Mucotrol™ (Belker Pharmaceuticals, Geo Pharma, USA), an herbal medicine composed of sorbitol, magnesium stearate, Aloe vera sp., Acesulfame K, glycyrrhizin extract, and centella asiatica, promoted a reduction in the degree of severity of mucositis on the WHO scale. However, there was no significant difference in the Radiation Therapy Oncology Group (RTOG) scale [32].

The Chinese medicine by decoction Qinre liyan—QRLYD (Puji Pharmacy, Shaanxi, China) consists of los Lonicerae, Rhizoma belamcandae, Lasiosphaera seu calvatia, Radix astragali, Radix glehniae, Radix ophiopogonis, Radix trichosanthes, Radix scrophulariae, Rhizoma ligusticum wallichii, Herba agrimoniae, Rhizoma imperatae, and Radix glycyrrhizae. The QRLYD rinse did not improve the degree of severity of OM lesions [33].

The herbal medicine SAMITAL® (Indena SpA, Milan, Italy), whose botanical formulation contains multiple components (Vaccinium myrtillus, Macleaya cordata, and Echinacea angustifolia), was produced for the treatment of OM induced by chemotherapy and/or radiation therapy. SAMITAL® was analysed in two clinical phases by Bertoglio et al. [62] and Pawar et al. [34]. SAMITAL® reduced the degree of mucositis (WHO scale) and the number of lesions, as well as decreased the intensity of pain from the fourth day of treatment [34, 62].

Mucosyte (BIOPHARM, Milan, Italy) is a solution composed of verbascoside, polyvinylpyrrolidone, and sodium hyaluronate. In its formulation, it has anti-inflammatory and analgesic properties. Treatment with the herbal medicine Mucosyte reduced the degree of severity of the lesions and decreased the need for analgesics [35].

The herbal medicine Faringel® (Ca Di Group, Italy), composed of propolis, Aloe vera, calendula, chamomile, and honey, did not reduce the degree of severity of OM nor did it promote pain control [37].

The typical Chinese medicine plant compound, CHIN (modified Liangge San), promoted the protection of the mucosa by regulating the nuclear factor kappa B (NF-κB) signalling pathway and regulating the oral flora. It showed important anti-inflammatory activity, with a reduction in the degree of severity of OM lesions, and it improved the level of pain [36].

The risk of bias assessment followed the Cochrane Collaboration criteria for the development of systematic intervention reviews [17]. No risks were identified in controlled clinical trials in relation to the selection of participants as the groups were formed by cancer patients undergoing treatment. In 82.14% of the studies, the outcome evaluators were blind. The evaluation of incomplete outcomes was considered uncertain in all articles analysed.

The systematic review can have limitations like any other type of study. Possible sources of bias are mentioned, such as publication bias, where the published results are different from reality due to the non-publication of unfavourable findings or negative results [16]. Another limitation for this method is the impossibility to better detail each research since the papers lacked specific information described in the systematic review. The meta-analysis could not be carried out due to the high heterogeneity between the studies since several natural products were identified in different designs.

Evidence-based medicine assists healthcare professionals in treating and making clinical decisions for the most appropriate procedure, besides collaborating with future work [63]. In this systematic review, controlled clinical trials, considered the gold standard for the development of research in humans [64], were included in the qualitative analysis and provided the main natural products used to treat OM.

Final considerations

Matricaria chamomilla is a good alternative for complementary treatment of OM since the species has proven anti-inflammatory effects, and, despite the few clinical trials in humans, they do not point out any harmful effects to anyone using it.

Isatis indigótico [23], the rinse with olive leaf extract [24], Calendula officinalis [25], A. digitatae, and M. sylvestris [41] promoted improvement in mucositis lesions, but further studies are necessary since these plant species were analysed in small samples.

The herbal medicines Mucotrol™ [32] and QRLYD [33] promoted improvement in the degree of severity of mucositis. SAMITAL® [34] and MUCOSYTE [35] promoted a reduction in the degree of mucositis and better pain control. The Chinese decoction CHIN [36] promoted good pain control.