2.4 Data extraction
Firstly, LJY and HC review the titles and abstracts to assess the eligibility. Then, when the articles appear to meet included criteria, they will be retrieved in full and independently considered for inclusion by the 2 members. The third author (XEL) will resolve disagreements in opinion of studies for inclusion and the reasons for excluded studies will be recorded.
Data from included full-text articles will be extracted by 2 reviewers (WQC and LJY). The basic information and data for the specific outcomes, such as first author, publication year, age of participants, sample size, details of interventions, and outcomes of interest, are extracted on the basis of the standard data extraction form designed by XT which was used in our previous systematic reviews and meta-analyses (seen as supplemental Table, http://links.lww.com/MD/C654). Disagreements about the extraction of the basic information and data will be resolved through discussion.
2.5 Quality assessment of individual study
The 2 independent reviewers are assigned to evaluate the risk of bias from 7 domains, including randomization sequence generation, allocation concealment, blinding of participants, blinding of study personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other bias with the Cochrane risk of bias assessment tool. A study will be assigned a risk level of “high risk of bias,” “unclear risk of bias,” or “low risk of bias” according to the match level between the actual information and the evaluation criteria. Any discrepancies between the 2 reviewers will be resolved through 3rd-party adjudication.
2.6 Statistical analysis
Meta-analysis will be performed when the identified studies are comparable. To calculate the pooled effects, the continuous data will be recorded as mean difference (MD) with 95% confidence intervals (CIs) and the dichotomous data will be extracted as relative risk (RR) with 95% CIs. At the same time, traditional pairwise meta-analysis will be conducted based on the random-effect model, which incorporates within and between studies heterogeneity, to estimate the summarized RR and 95% CIs. The Chi-squared method and the I2 statistic will be adopted to test the heterogeneity and the proportion of the overall variation that is attributable to between study heterogeneity.[29,30] All analyses will be conducted using the RevMan 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2013, Copenhagen, Denmark) and Stata 12 (StataCorp, College Station, TX).
Given possible important heterogeneity among the included studies, subgroup analyses and meta-regression analyses are perhaps used to explore the possible sources. Subgroup analyses are planned in accordance with chemoradiotherapy and assessment scales of oropharyngeal mucositis. Sensitivity analyses may be used by analyzing only studies considered at low risk of bias. When the number of studies in the meta-analysis is more than 10, the funnel plot is necessary to be performed for identifying publication bias.
2.7 Subgroup and sensitivity analyses
In the case of possible important heterogeneity, we will explore the possible sources using subgroup and meta-regression analyses. Subgroup analyses are planned for dose of radiotherapy and control regimes. Sensitivity analyses are planned for prevention of radiotherapy-induced oropharyngeal mucositis by analyzing only studies considered at low risk of bias.
2.8 Publication bias
For single outcome, we will draw the funnel plot to identify publication bias if the number of studies analyzed is more than 10. Moreover, we will also perform the Egger linear regression test to quantitatively detect the symmetric or a symmetric of funnel plot.
The definition of head and neck cancer has not yet been identified all around the world. In this study, we will adopt the definition of head and neck cancer which was defined by the International Agency for Research on Cancer (IRAC) in 2014. Within the head and neck, the major anatomical sites involve the nasal cavity, nasopharynx, oral cavity, oropharynx, larynx, and hypopharynx. With rapid population growth and aging worldwide, the rising prominence of head and neck cancer has been an important public health problem. Radiotherapy with or without chemotherapy has been the primary option in the treatment of head and neck cancer. However, radiotherapy inevitably brings about short- and long-term side effects because of the cytotoxic effect. Oropharyngeal mucositis is considered as one of the most stressful side effects of head and neck irradiation. Mucositis-associated pain significantly impairs oral functions such as deglutition and taste, resulting in the nutritional problems. The severe oropharyngeal mucositis can decrease the quality of sleep, and disturb phonation and aspiration. Besides, severe oropharyngeal mucositis also increases the risk of infections and the hospitalization. Hence, it is worthwhile to find effective intervention to prevent or minimize oropharyngeal mucositis during the course of radiotherapy.
Although published studies have come up with plenty of different methods to prevent and treat radiation-induced oropharyngeal mucositis, the effect of these interventions has not been completely identified and the prophylaxis of oropharyngeal mucositis is still an unsolved problem. Published evidences exactly demonstrated that zinc is the important element for multiple cellular activities and the regulation of immune system. Moreover, zinc works as an organelle stabilizer and a stabilizer of the structure of DNA, RNA, and ribosome, which can accelerate wound healing.[15,19] So some researchers tried to confirm the benefit of zinc in preventing radiation-induced mucositis in the head and neck cancer. To date, 4 studies explored the benefit but the different results were published. Three studies showed zinc could reduce the incidence and severity of mucositis in patients with head and neck cancer undergoing radiotherapy with or without chemotherapy.[9,20,22] But Gorgu et al found that zinc sulfate prophylaxis did not reduce incidence of mucositis. Therefore, the efficacy of zinc to prevent radiation-induced oropharyngeal mucositis remains controversial. Although several meta analyses about cancer treatment-induced oropharyngeal mucositis were published, these articles did not include the complete studies and perform the subgroup to clearly clarify the effect for prophylaxis with oral zinc sulfate against radiation-induced oropharyngeal mucositis in patients with head and neck cancer.[34,35]
The present study will be the first systematic review and meta-analysis to elucidate current evidence of the efficacy of zinc to prevent radiation-induced oropharyngeal mucositis in the head and neck cancer. It will highlight that further exploration is needed to inform recommendations of radiation-induced oropharyngeal mucositis.
3.1 Ethics and dissemination
Ethics approval and patient written informed consent will not be required because all analyses in the present study will be performed based on data from published studies. The systematic review and meta-analysis will be submitted to a peer reviewed scientific journal for publication.
Ting Shuai, Xu Tian, and Xiu-E Li conceived the study and developed the study criteria. Li-juan Yi and Hui Chen searched the literature and Xu Tian designed the data extraction form. Ting Shuai wrote the protocol. Xiu-E Li and Wei-Qing Chen revised the manuscript. All authors have read, and approved the final manuscript.
Conceptualization: Ting Shuai, Xu Tian.
Data curation: Ting Shuai, Li-Juan Yi, Hui Chen.
Formal analysis: Ting Shuai, Hui Chen.
Investigation: Li-Juan Yi, Xu Tian.
Methodology: Ting Shuai, Li-Juan Yi, Xu Tian.
Resources: Hui Chen.
Supervision: Xiu-E Li.
Validation: Xiu-E Li.
Writing – original draft: Ting Shuai, Xu Tian.
Writing – review & editing: Wei-Qing Chen, Xiu-E Li.
. McGuire S. World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015. Adv Nutr 2016;7:418–9.
. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;0:1–31.
. De Sanctis V, Bossi P, Sanguineti G, et al. Mucositis in head and neck cancer
patients treated with radiotherapy
and systemic therapies: Literature review and consensus statements. Crit Rev Oncol Hematol 2016;100:147–66.
. Moslemi D, Nokhandani AM, Otaghsaraei MT, et al. Management of chemo/radiation-induced oral mucositis in patients with head and neck cancer
: a review of the current literature. Radiother Oncol 2016;120:13–20.
. Belgioia L, Bacigalupo A, Alterio D, et al. Management of oropharyngeal mycosis in head and neck cancer
occurring during (chemo) radiotherapy
: an Italian radio-oncologist survey. Tumori 2015;101:312–7.
. Naidu MU, Ramana GV, Rani PU, et al. Chemotherapy-induced and/or radiation therapy-induced oral mucositis–complicating the treatment of cancer. Neoplasia (New York, N Y) 2004;6:423–31.
. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer
with or without chemotherapy: a systematic literature review. Radiother Oncol 2003;66:253–62.
. Sutherland SE, Browman GP. Prophylaxis of oral mucositis in irradiated head-and-neck cancer patients: a proposed classification scheme of interventions and meta-analysis of randomized controlled trials. Int J Radiat Oncol Biol Phys 2001;49:917–30.
. Moslemi D, Babaee N, Damavandi M, et al. Oral zinc sulphate and prevention of radiation-induced oropharyngealmucositis in patients with head and neck cancers: a double blind, randomized controlled clinical trial. Int J Radiat Res 2014;12:235–42.
. Kam AY, McMillan AS, Pow EH, et al. A preliminary report on patient acceptance of a novel intra-oral lubricating device for the management of radiotherapy
-related xerostomia. Clin Oral Investig 2005;9:148–53.
. La RPA, Epstein JB, Trotti A, et al. Complications of radiation therapy for head and neck cancers. Cancer Nurs 2002;25:461–7.
. Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 2003;98:1531–9.
. Motallebnejad M, Akram S, Moghadamnia A, et al. The effect of topical application of pure honey on radiation-induced mucositis: a randomized clinical trial. J Contemp Dent Pract 2008;9:40–7.
. Sciubba JJ, Goldenberg D. Oral complications of radiotherapy
. Lancet Oncol 2006;7:175–83.
. Rambod M, Pasyar N, Ramzi M. The effect of zinc sulfate
on prevention, incidence, and severity of mucositis in leukemia patients undergoing chemotherapy. Eur J Oncol Nurs 2018;33:14–21.
. Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol 2015;27:159–64.
. Garofalo JA, Erlandson E, Strong EW, et al. Serum zinc, serum copper, and the Cu/Zn ratio in patients with epidermoid cancers of the head and neck. J Surg Oncol 1980;15:381–6.
. Gruber S, Frings K, Kuess P, et al. Protective effects of systemic dermatan sulfate treatment in a preclinical model of radiation-induced oral mucositis. Strahlenther Onkol 2018;194:675–85.
. Ertekin MV, Koc M, Karslioglu I, et al. The effects of oral zinc sulphate during radiotherapy
on anti-oxidant enzyme activities in patients with head and neck cancer
: a prospective, randomised, placebo-controlled study. Int J Clin Pract 2004;58:662–8.
. Mosalaei A, Nasrolahi H, Ahmadloo N, et al. Effect of oral zinc sulphate in preventionof radiation induced oropharyngealmucositis during and after radiotherapyin patients with head and neck cancers. Middle East J Cancer 2010;1:69–76.
. Gorgu S, Ilknur A, Sercan O, et al. The effect of zinc sulphate in the prevention of radiation induced oral mucositis in patents with head and neck cancer
. Int J Radiation Res 2013;111–6.
. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review
and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ (Clinical research ed ) 2015;350:g7647.
. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org
. Sonis ST. Method and apparatus for assessing oral mucositis, WO, 2005.
. Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy
. Int J Radiat Oncol Biol Phys 2000;47:13–47.
. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151:264–9.
. Wang L, Shuai T, Wang YY, Cao H. The effect of traditional Chinese medicine washing combined with massage for neonatal jaundice: a meta-analysis. TMR Integr Nur 2017;1:36–44.
. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7:177–88.
. Bowden J, Tierney JF, Copas AJ, et al. Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics. BMC Med Res Methodol 2011;11:41.
. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58.
. Palma PS, Delgado RM. Practical considerations on detection of publication bias. Gac Sanit 2006;20:10–6.
. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.
. Gautam AP, Fernandes DJ, Vidyasagar MS, et al. Effect of low-level laser therapy on patient reported measures of oral mucositis and quality of life in head and neck cancer
patients receiving chemoradiotherapy–a randomized controlled trial. Support Care Cancer 2013;21:1421–8.
. Alterio D, Jereczek-Fossa BA, Fiore MR, et al. Cancer treatment-induced oral mucositis. Anticancer Res 2007;27:1105–25.
. Lee S. Mineral derivatives in alleviating oral mucositis during cancer therapy: a systematic review
. PeerJ 2015;3:e765.
head and neck cancer; oropharyngeal mucositis; radiotherapy; systematic review; zinc sulfate
Supplemental Digital Content
Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.