Globally, head and neck cancer accounts for ~900,000 cancer cases and >40,000 deaths annually (1). In the United States, head and neck cancer accounts for ~4% of all cancers and incidence varies depending on sex and ethnicity (2,3). Risk factors include alcohol and tobacco consumption and viral infections (4). Other than surgical treatment, chemotherapy and radiation therapy remain the mainstay treatment for patients diagnosed with head and neck cancer and can be used independently or in conjunction with surgery (5). Although chemotherapy and radiation therapy can be used for treatment of cancer, these are associated with side effects such as nausea, vomiting, hair loss, loss of appetite and oral mucositis (OM) (6,7). Cytotoxic effects of anticancer therapy cause inflammatory changes in the oral mucosal epithelial cells leading to painful, multiple lesions in the oral cavity (8,9). A total of 30-40% of patients with cancer treated with chemotherapy develop mucositis; this incidence increases to 90% for patients with head and neck cancer treated with radiotherapy + chemotherapy (10,11). Mucositis occurs during chemotherapy and lasts for a few weeks following the completion of the treatment (12,13). Physical discomfort during eating and drinking impairs nutritional status of patients, affecting their physical and psychological state, as well as their quality of life (14). OM is associated with bacteraemia, increased inpatient hospital duration and mortality (15,16). Keratinocyte growth factor was shown to be effective in decreasing the duration of radiation-induced OM (RIOM), prolonging the time to develop RIOM and decreasing the incidence of RIOM in patients with head and neck cancer (17).

The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology (MASCC/ISOO) performed a systematic review to identify interventions found to be most effective for the prevention, treatment and alleviation of OM symptoms (18). Basic oral care, use of anti-inflammatory agents (such as benzydamine mouthwash), intraoral photobiomodulation using low-level laser therapy, anaesthetics, analgesics, vitamins, minerals and nutritional supplements (such as glutamine, zinc, supersaturated calcium phosphate rinse, vitamin E, selenium, folinic acid and calcitriol) are recommended for mucositis (17). Several studies have showed the benefit of oral zinc supplementation in the prevention of OM in patients with cancer receiving chemotherapy and radiation (14,17,19,20).

Zinc is naturally present in saliva, dental plaque and hard tissues. Supplementation with zinc is effective against oral conditions, for example, gingivitis, periodontitis, halitosis and others. Zinc deficiency is associated with poor oral and periodontal health (21-23). Zinc is involved in numerous processes associated with immunity, growth and development, and it is implicated in wound healing and has anti-inflammatory properties (23,24). Zinc is administered orally or parenterally as zinc sulphate (22.5 mg elemental zinc/100 mg), zinc acetate (30 mg elemental zinc/100 mg), or zinc oxide (80 mg elemental zinc/100 mg) for therapeutic purposes (25). A meta-analysis of five studies by Tian et al (26) showed that oral zinc sulphate failed to decrease the incidence of chemotherapy-induced OM or relieve the chemotherapy-induced OM grade. In addition, zinc sulphate did not show a beneficial effect in decreasing the incidence and grade of RIOM in a meta-analysis of four randomized controlled trials by Shuai et al (27). Chaitanya et al (28) conducted a meta-analysis with 10 studies to assess the effect of oral zinc on OM incidence and severity in patients undergoing chemotherapy, radiation therapy or combined chemo-radiation therapy (28); zinc did not decrease the prevent OM but decreased its severity.

The present study assessed evidence from available randomized controlled trials (RCTs) and prospective studies evaluating the effectiveness of zinc supplementation vs. placebo or control treatments on the incidence of OM in patients undergoing chemotherapy, radiation therapy or a combined approach.

OM is a serious and common side effect of chemotherapy and radiation therapy and it is reported to affect ~40% of patients receiving chemotherapy and 100% of patients treated with radiation therapy (37,38). Pain, physical and psychological distress, reduced nutritional intake and decreased quality of life are negative outcomes associated with OM along with increased hospital stay and medical expenditure (33). Despite the high occurrence of OM in patients with cancer, specifically those with head and neck cancer, there is no specific treatment available for the prevention and treatment of OM. Antioxidant agents (amifostine, glutamine, oral zinc supplements, vitamin E and N-acetyl-cysteine), inhibitors of inflammation and cytokine production (turmeric, clonidine tablets, benzydamine oral rinses and pentoxifylline), natural agents (honey, manuka oils, aloe vera gel, chamomile mouthwash, and Chinese traditional herbs), probiotics and physical interventions (low-level laser therapy, oral cryotherapy and Oral hygiene care) are some therapies that are under investigation for mucositis prevention (11).

The present study aimed to provide an up-to-date meta-analysis of the effect of oral zinc supplementation on the incidence of OM in patients undergoing chemotherapy, radiation therapy and combined chemoradiation therapy. The current results indicated that oral zinc administration caused a significant decrease in incidence of OM in patients receiving cancer therapy. However, when stratified by the type of cancer therapy (chemotherapy, radiation or a combinatorial approach), zinc supplementation did not cause a significant decrease in OM incidence. The present results were in agreement with the results of Tian et al (26), which was conducted on patients undergoing chemotherapy only, and meta-analysis by Shuai et al (27) on patients receiving chemotherapy. Favourable effects of zinc when all studies were pooled could be attributed specifically to the studies by Gholizadeh et al (20) and Anandhi et al (29) that enrolled a higher number of patients. The high heterogeneity of the overall meta-analysis and subgroups can be attributed to differences in methodology, such as dose of chemotherapy and radiation, patient baseline characteristics, such as sex and age, zinc dose, type and severity of cancer and follow-up times. The type of anticancer agent, doses and number of cycles and treatment timing are known to influence mucositis incidence and severity (11). A total of four studies in the current meta-analysis (18,20,29,36) showed a significant decrease in OM incidence following zinc supplementation compared with the placebo or control group. These studies were performed on patients receiving chemotherapy or combined chemoradiotherapy across different types of cancer including head and neck cancer and leukaemia. Results in favour of zinc in studies by Gholizadeh et al (20) and Rambod et al (18) can also be attributed to normal dose chemotherapy in these studies whereas in the study by Mansouri et al (31) a high-dose chemotherapy regimen was used, which may have led to the lack of effect of zinc supplementation. Results in favour of the control group were also observed in the study by Gorgu et al (30), which could be associated with lower zinc dosage (25 mg four times/day) compared with other studies in which the dose of zinc was 15-220 mg two or three times per day. Watanabe et al (36) used polaprezinc (zinc-L-carnosine) in the treatment group, which has been shown to improve 5-fluorouracil-induced OM and mucosal ulceration in animal models (39,40). It is important to note that only two studies with patients with leukaemia and pharyngeal cancer were included in the present meta-analysis. The present study showed a significant benefit of zinc supplementation in decreasing incidence of OM compared with an active comparator, azulene oral rinse, which could be attributed to both the form of zinc used and the mode of administration (oral rinse as compared with the majority of other studies in which capsules of zinc salts were given). No definite conclusions on the effectiveness of zinc supplementation on OM incidence could be drawn from the studies that showed the positive effects of zinc. The dose of zinc was 30-220 mg three times daily and the radiation dose was 60-70 Gy with various chemotherapeutic agents and lengths of treatment ranging from 2 to 9 weeks. This makes it difficult to determine the dose or regimen of zinc supplementation that should be used concurrently with radiation treatment or chemotherapy, indicating that the response of patients to the beneficial effects of zinc varies based on the type of cancer, its location and antineoplastic agents used, and does not depend only upon the zinc form, dosage or duration of treatment.

Criteria/scale to assess OM differed between the studies, with the RTOG and WHO scale being the most widely used. Meta-analysis showed that the type of scale used did not have any effect on results obtained in favour of zinc. The high heterogeneity in each subgroup was attributed to methodological differences between the studies. However, there is no standard scale to assess the incidence or grade of the severity of OM. The commonly used WHO scale is based on objective assessment, such as the presence of erythema or ulceration and the OM assessment scale is based on quantitative assessment of ulceration dimension (11). The absence of a standardized scale makes it difficult to compare the severity of OM. Although OM incidence is judged by trained individuals, assessment may differ between the studies and therefore results should be interpreted with caution. The absence of a high number of trials in patients with cancer other than head and neck cancer limits the ability to understand the effects of zinc supplementation on different types and stages of cancer.

Limitations of the present meta-analysis are associated with the low number of eligible studies and small patient population size, making it difficult to assess the effect of zinc dose, chemotherapy and radiation dose and duration of treatment on OM outcome. Furthermore, the lack of details provided on the chemotherapeutic regimens or radiation doses and duration of treatments in the majority of the included trials makes it difficult to draw a definitive conclusion regarding circumstances in which zinc supplementation would be beneficial.

Further studies with larger sample sizes are needed to confirm the effectiveness of zinc supplementation in decreasing the incidence of OM. The studies published and included in the present meta-analysis are too heterogeneous to make any definite conclusion on the effectiveness of oral zinc. Additionally, since the effects of zinc supplantation were highly variable between the studies, it is important to investigate other therapies that may consistently alleviate the suffering of patients with cancer undergoing chemotherapy.