Oral cavity cancer accounts for nearly 200 400 new cases and 145 400 deaths worldwide (Torre et al., 2015). Currently, it is the sixth most common malignancy in Asia, and the age-standardized incidence rate in China is 1.97 per 100 000 men and 1.71 per 100 000 women (Curado et al., 2008). In China, the 5-year age-standardized survival rate of oral cavity cancer was 67%, which was higher than that of other countries (Sankaranarayanan et al., 2010). Previous studies have shown that multiple factors might affect the progression of oral cavity cancer (Petti et al., 2013; Guha et al., 2014; Gupta and Johnson, 2014; Galeone et al., 2015; Gong et al., 2015; Li et al., 2015; Zhang et al., 2015b; Ye et al., 2016) and that the association between coffee intake and the risk of oral cavity cancer is inconsistent.
Coffee is a commonly consumed hot beverage, and it is a modifiable factor of several diseases because it is rich in antioxidants, which might play an important role in the progression of upper aerodigestive cancer (IARC, 1995). Several studies have already shown the effects of the anticarcinogenic constituents in coffee (Daglia et al., 2000; Cavin et al., 2002; Rogers et al., 2007). Numerous observational studies have revealed the associations between coffee intake and the risk of oral cavity cancer. However, the results were inconsistent. As such association was not validated; the potential effects of coffee intake in the general population remain to be assessed. Therefore, this meta-analysis aimed to comprehensively examine previous observational studies to elucidate the association between coffee intake and the risk of oral cavity cancer. Stratified analyses based on year of publication, country where the study was conducted, and cancer types according to study design, were also carried out.
Materials and methods
Data sources, search strategy, and selection criteria
This review was conducted and is reported according to the meta-analysis of observational studies using the epidemiology protocol (Stroup et al., 2000). Observational studies were carried out to investigate whether the association between coffee intake and the risk of oral cavity cancer was eligible for this meta-analysis without restriction in language and status. Electronic databases, including PubMed, Embase, and Cochrane Library, were searched for studies conducted up to September 2018, and the following search terms were used: (Coffee or caffeine or beverages or drink or lifestyle) AND (Mouth or oral or jaws or ostium or buccal or oropharyngeal or oropharynx) AND (Neoplasms or cancer or carcinoma or tumor or adenoma). The details of the search strategy in PubMed are shown in Supplementary Material 1 (Supplemental digital content 1, http://links.lww.com/EJCP/A234). Manual searches of the reference lists of eligible studies were performed to identify any new eligible studies. The study selection process was based on populations, study design, exposure, comparison categories, and outcome variables.
Two reviewers independently conducted the literature search, and any disagreement was resolved via a group discussion until a consensus was reached. The inclusion criteria of this meta-analysis are listed as follows: (i) study design: case–control or cohort studies; (ii) exposure and control: studies that reported various categories versus low coffee intake alone; and (iii) outcomes: the effect estimates with corresponding 95% confidence intervals (CIs) for the risk of oral cavity cancer. Reviews, editorials, and letters to the editor were excluded because of the lack of relevant data.
Data collection and quality assessment
The data collected from the included studies were listed as follows: first author’s surname, year of publication, country where the study was conducted, study design, assessment of exposure, sample size, age, percentage of male participants, comparisons, cancer types, study period, adjusted factors, and effect estimates with 95% CI. If the study reported several adjusted effect estimates, we selected those that were maximally adjusted for potential confounders. The quality of the included studies was evaluated using the Newcastle–Ottawa Scale (NOS), which was based on selection (four items), comparability (one item), and outcome (three items). The star system for the evaluation of included studies ranged from 0 to 9 (Wells et al., 2009). Data collection and quality assessment were performed by two independent reviewers, and inconsistency was adjudicated based on the original study by the corresponding author.
The association between coffee intake and the risk of oral cavity cancer in each individual study was obtained as effect estimates and their corresponding 95% CI. The first category of coffee intake was high coffee intake, and the middle categories were pooled if reported as intermediate coffee intake using the fixed effect model more than once (DerSimonian and Laird, 1986). Then, the results of the association between high or intermediate versus low coffee intake and the risk of oral cavity cancer were calculated using the random-effects model (Ades et al., 2005). Heterogeneity across the included studies was calculated using the I2 and Q statistics, and an I2 value more than 50.0% was considered significantly heterogeneous (Higgins et al., 2003; Deeks et al., 2008). Sensitivity analyses for high or intermediate versus low coffee intake according to study design were conducted by sequentially removing a single study from the overall analysis (Tobias, 1999). Subgroup analyses were carried out according to study design based on year of publication, country where the study was conducted, and cancer types and univariate meta-regression analyses were performed to evaluate the heterogeneity between subgroups (Thompson and Higgins, 2002). Publication biases according to study design were conducted using qualitative and quantitative methods, which included funnel plots, Egger (Egger et al., 1997), and Begg (Begg and Mazumdar, 1994) test results. The inspection level was two sided, and a P value less than 0.05 was considered statistically significant. All statistical analyses were conducted using the STATA software (version 10.0; Stata Corporation, College Station, Texas, USA).
The electronic searches identified 1643 records, and after the first screening, 1592 studies were excluded because of irrelevant and duplicate topics. The remaining 51 studies were selected for further detailed evaluations, and 32 were excluded because of the following reasons: lack of information about coffee intake (n = 19), inclusion of other cancers (n = 8), and lack of sufficient data or review (n = 5). Finally, 14 case–control and five cohort studies were selected for the present meta-analysis (Franco et al., 1989; La Vecchia et al., 1989; Franceschi et al., 1992; Mashberg et al., 1993; Pintos et al., 1994; Stensvold and Jacobsen, 1994; Bundgaard et al., 1995; Takezaki et al., 1996; Tavani et al., 2003; Rodriguez et al., 2004; Heck et al., 2008; Naganuma et al., 2008; Ren et al., 2010; Biazevic et al., 2011; Tverdal et al., 2011; Hsu et al., 2012; Hildebrand et al., 2013; Radoi et al., 2013; Oze et al., 2014). New eligible studies were observed by the manual search of the reference lists of the retrieved studies. Figure 1 shows the results of the study selection process, and Table 1 depicts the summary of the baseline characteristics of the included studies.
In total, 6456 patients with oral cavity cancer who were recruited from 14 case–control and five cohort studies were included in this meta-analysis. The study included articles that were published from 1989 to 2014, and the percentage of male participants ranged from 44.5 to 100.0%. Fourteen studies were conducted in western countries, and the remaining five were carried out in eastern countries. Fifteen studies have reported the incidence of oral and pharyngeal cancer, the remaining four that of oral cavity cancer. The quality of the studies was assessed using the NOS scale. Moreover, four, three, and five studies had a star of 8, 7, and 6, respectively, and the remaining seven studies had a star of 5.
High versus low coffee intake
After pooling all the included studies, high coffee intake was found to be associated with a reduced risk of oral cavity cancer compared with the lowest category of coffee intake (OR: 0.68; 95% CI: 0.56–0.82; P < 0.001; Fig. 2) in both case–control (OR: 0.70; 95% CI: 0.55–0.90; P = 0.006) and cohort studies (OR: 0.65; 95% CI: 0.48–0.87; P = 0.004). A significant heterogeneity was observed in the pooled result from all the studies (I2: 60.3%; P < 0.001) or case–control studies (I2: 65.6%; P < 0.001), whereas moderate heterogeneity was found in the pooled result from cohort studies (I2: 46.9%; P = 0.110). Results of the sensitivity analyses indicated that the pooled results from the case–control or cohort studies did not change after excluding any particular study (Supplementary Material 2, Supplemental digital content 2, http://links.lww.com/EJCP/A235). The subgroup analysis indicated that the results were statistically significant if pooled from case–control studies published in 2000 or thereafter, those conducted in eastern countries, and those that reported about the incidence of oral and pharynx cancer (Table 2). Furthermore, the subgroup analysis of the pooled result from cohort studies indicated a significant association between high coffee intake and the risk of oral cavity cancer in most subsets. However, no significant association was observed when the results were pooled from studies published before 2000 (Table 2). No significant publication biases were observed in the association between high versus low coffee intake and the risk of oral cavity cancer in case–control studies (P value for Egger: 0.544; P value for Begg: 0.661) and cohort studies (P value for Egger: 0.273; P value for Begg: 0.462; Supplementary Material 3, Supplemental digital content 3, http://links.lww.com/EJCP/A236).
Intermediate versus low coffee intake
A total of 18 studies have reported about the association between intermediate coffee intake and the risk of oral cavity cancer. The summary result has indicated that intermediate coffee intake was significantly associated with a reduced risk of oral cavity cancer (OR: 0.85; 95% CI: 0.77–0.94; P = 0.002; Fig. 3), and such association was observed in case–control studies (OR: 0.86; 95% CI: 0.76–0.98; P = 0.021) but not in cohort studies (OR: 0.83; 95% CI: 0.67–1.02; P = 0.071). We noted a substantial heterogeneity in the pooled results from cohort studies (I2: 54.2%; P = 0.068) and moderate heterogeneity in the pooled results from all studies (I2: 33.7%; P = 0.081) or case–control studies (I2: 27.3%; P = 0.169). Sensitivity analyses indicated that the pooled results from case–control or cohort studies varied because of marginal 95% CI (Supplementary Material 2, Supplemental digital content 2, http://links.lww.com/EJCP/A235). Subgroup analyses indicated that intermediate coffee intake has a protective effect against oral cavity cancer based on case–control studies published in 2000 or thereafter and those conducted in western countries (Table 2). Moreover, a significant association between intermediate coffee intake and oral cavity cancer in cohort studies was observed in studies conducted in eastern countries (Table 2). No significant publication bias was observed in the association between intermediate versus low coffee intake and the risk of oral cavity cancer in case–control studies (P value for Egger: 0.135; P value for Begg: 0.360) or cohort studies (P value for Egger: 0.588; P value for Begg: 1.000; Supplementary Material 3, Supplemental digital content 3, http://links.lww.com/EJCP/A236).
This systematic review and meta-analysis based on observational studies assessed any potential associations between high or intermediate coffee intake and the risk of oral cavity cancer. This quantitative meta-analysis included 6456 patients with oral cavity cancer from 14 case–control and five cohort studies, with participants having different characteristics. We found that high or intermediate versus low coffee intake might have protective effects against oral cavity cancer. These significant associations might be affected by study design, year of publication, and country where the study was conducted.
The quality of the included studies was evaluated using the NOS scale, which was based on a selection, comparison, and outcome subscale that included eight items. The comparison subscale was not fully reported in several studies, and the outcome subscale for adequate follow-up duration and rate was not reported in most of the included studies. These factors might account for the heterogeneity among the included studies. A subgroup analysis according to the quality of the study was not conducted because of double standard for the evaluation of case–control and cohort studies.
Several systematic reviews and meta-analyses have already reported on the relationship between coffee intake and the risk of oral cavity cancer. Turati et al. (2011) have conducted a meta-analysis based on 1 cohort and 8 case–control studies showing that high versus low coffee intake was associated with a reduced risk of oral cavity/pharyngeal cancer, and this association might differ according to country (European, American, and Asian). Miranda et al. (2017) have revealed an inverse association between coffee intake and oral/pharyngeal cancers, with high coffee intake mainly having a protective effect against pharyngeal cancer. Zhang et al. (2015a) have conducted a meta-analysis of 12 studies indicating that high versus low coffee intake has a protective effect against oral cancer, a significant association was observed in individuals in Europe, whereas no significant association was noted between coffee intake and oral cancer in the USA. The meta-analysis of 11 case–control and 4 cohort studies conducted by Li et al. (2016), has suggested that high coffee intake has a protective effect against oral cancer, and this association was observed in case–control as well as cohort studies. However, the limitations regarding the previous meta-analyses were as follows: (i) all studies conducted a comparison on the association between high versus low coffee intake and subsequent risk of oral cavity cancer, whereas the median categories of coffee intake were not included. (ii) Stratified analyses based on potential confounders in the pooled results according to study design were not conducted. (iii) Lastly, stratified analyses based on reported cancer types were not calculated in previous meta-analyses. Therefore, we conducted a meta-analysis of observational studies to explore any potential relationship between coffee intake and the risk of oral cavity cancer.
The summary results indicated that high or intermediate versus low coffee intake has a preventive effect against oral cavity cancer. However, several previous studies did not obtain consistent results. Franco et al. (1989) have shown that taking at least six or two to five cups of coffee was not associated with the risk of oral cavity cancer. Pintos et al. (1994) have indicated that high, but not moderate coffee intake was associated with an increased risk of oral and pharyngeal cancer. Furthermore, Bundgaard et al. (1995) have shown that participants who were coffee drinkers were not significantly at higher risk of oral cavity cancer than those who were not. Tverdal et al. (2011) have not found any significant association between coffee intake and the risk of oral and pharyngeal cancers. Potential reasons for the lack of significant associations include the following: (i) oral and pharyngeal cancers are rare in young individuals, and the risk of oral and pharyngeal cancers could be biased by body mass index, which could affect the power and width of 95% CI. Moreover, (ii) the recall bias of case–control studies might bias the association between coffee intake and oral and pharyngeal cancers, which include the recall bias in smoking habits and alcohol intake.
Subgroup analyses were conducted to explore the association between coffee intake and oral cavity cancer for the pooled results from case–control or cohort studies in patients with specific characteristics. We noted that intermediate coffee intake was not associated with the risk of oral cavity cancer in the pooled results from cohort studies. case–control studies are more likely encumbered with recall bias and associated with overestimated pooled results. Furthermore, case–control or cohort studies were correlated with different evidence level, which was associated with the reliability of pooled results. The relationship between coffee intake and oral cavity cancer could be affected by the year of publication and country where the study was conducted because of these factors are correlated to lifestyle habits, which play an important role on the progression of oral cavity cancer.
The limitations of this meta-analysis are highlighted as follows: (i) the adjusted factors were different among the included studies, which might have affected the reported incidence of oral cavity cancer; (ii) mostly case–control studies were included, which might have introduced uncontrolled biases; (iii) data about the mean age of the included participants and the prevalence of oral cavity cancer among different age groups were not available in most of the included studies; (iv) publication bias might have existed because this meta-analysis was based on published observational studies; and (v) current analysis based on pooled data and detailed subgroup analyses was not conducted.
The findings of this meta-analysis indicate that high or intermediate versus low coffee intake might be associated with a reduced risk of oral cavity cancer irrespective of the study design (case–control or cohort study). However, these need to be validated in further large-scale prospective cohort studies.
Conflicts of interest
There are no conflicts of interest.
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