A cluster randomized controlled trial to evaluate the efficacy of esophageal and gastric cancer screening in mortality reduction in a non-high-incidence area: methodology and initial results

Introduction

Esophageal cancer (EC) and gastric cancer (GC) are common malignancies worldwide, responsible for 1.7 million estimated new cases and 1.3 million new deaths in 2020 (1). In China, EC and GC accounted for approximately 50% of global cases and deaths in 2020, imposing a heavy burden on public health (1). Because of the lack of typical early symptoms, many individuals are initially diagnosed with EC or GC in advanced stages, which may compromise treatment effectiveness and ultimately lead to a dismal prognosis (2). The overall 5-year survival rates of Chinese EC and GC patients are only 30.3% and 35.1%, respectively (3). However, the rates of early-stage EC and GC can be improved substantially to about 86% and 90%, respectively (4-6). Thus, there is a need to promote early detection and treatment of these malignancies to improve prognosis and reduce mortality.

Endoscopy-based screening programs for EC and GC have been implemented in several endemic countries such as Japan and South Korea, showing clinical benefits and mortality reduction (7-9). China has organized a series of endoscopic screening programs for upper gastrointestinal cancer in high-risk populations, with endoscopic examination of the esophagus and stomach at one time. Due to the high incidence and mortality rates of EC and GC in rural areas, the Cancer Screening Program in Rural Areas was launched in high-incidence rural areas in 2005. Such national programs subsequently expanded to Huai River Basin in 2007 (the Cancer Screening Program in Huai River Areas) and non-high-incidence urban areas in 2012 (the Cancer Screening Program in Urban Areas) (10). Currently, the Cancer Screening Program in Rural Areas has been reported to cover more than 200 counties and screen over 1.86 million high-risk individuals, making great advances in the early detection and treatment of upper gastrointestinal cancer.

Previous studies have demonstrated the effectiveness of endoscopic screening for EC and GC in high-incidence areas, which can result in an increase in early detection and a reduction in mortality (11-13). A 10-year follow-up study showed that the cumulative mortality and incidence of esophageal squamous cell carcinoma were significantly lower in the endoscopic screening group compared with the control group without screening (14). Such findings indicate the importance of endoscopic screening for prevention and control of EC and GC in high-incidence areas. However, considering its invasiveness and high cost, endoscopic screening for EC and GC may be not appropriate for the broad application in low- to intermediate-incidence areas (15). Accordingly, in such areas, risk-stratification assessment is recommended to identify subgroups with different risk levels for EC and GC, and high-risk individuals can be subsequently invited to undergo endoscopy (16,17). The endoscopy-based strategy seems to be reasonable for early detection, but evidence on the effectiveness of this approach in non-high-incidence is still insufficient. Therefore, a multi-center cluster randomized controlled trial (RCT) of EC and GC screening was carried out in 3 high-incidence areas and 4 non-high-incidence areas in China in 2015 (18). As part of the national study, a community-based RCT was launched in Luoshan County, one of the 4 non-high-incidence areas, to evaluate the efficacy of endoscopic screening for EC and GC in mortality reduction, and the feasibility of the risk assessment in combination with endoscopic examination in non-high-incidence rural areas. Herein, we reported the baseline characteristics of study participants, endoscopy compliance and its associated factors, and the detection rates as well as the treatment rates of EC and GC in the first-round screening. We present the following article in accordance with the CONSORT reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4052/rc).

Methods

Study design

We prospectively conducted a community-based cluster RCT. A total of 33 eligible villages in Luoshan County in Henan Province served as the allocation units (clusters) in this trial. We excluded clusters if they underwent endoscopic screening in the last 3 years, or were unwilling to participate. The 33 clusters were assigned randomly to the intervention or control group in a 1:1 ratio. Enrollment began in May 2015 and was completed by July 2017, and then follow-up would last at least 10 years. The study was approved by the independent ethics committee of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No. 2015SQ00223). The trial was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and there were no substantial changes to the methods after trial commencement. As part of the multi-center study, more details of this trial can be found in previous literature (18,19).

Randomization and masking

Randomization was performed on the basis of cluster. Villages rather than individuals were regarded as units of randomization, and were allocated to the intervention (N=17) or control (N=16) group by a computer-generated randomization list. Local health workers enrolled participants and completed the allocation in accordance with the group assignment. Researchers, local health workers, and study participants could not be blinded to randomization procedures.

Participant eligibility

Local residents in the eligible villages were considered for inclusion according to the following criteria: aged 40–69 years old, with no history of cancer, being in good physical and mental condition, and having undergone no endoscopic examinations in the past 3 years. Residents who were not willing to undergo endoscopic screening, or had severe diseases that might interfere with participation, were excluded from the trial. Sample size calculation has been described in detail previously (18). After describing the study, local health workers obtained written informed consent from participants.

Interventions

The interventions pertain to the individual level. All the participants in this trial were invited to complete a standardized questionnaire during face-to-face interviews, and underwent physical examination including measurement of height, weight, and blood pressure. The questionnaire covered demography, personality and mental health, behavioral habits, dietary habits, family history of cancer, disease history, and clinical symptoms of EC and GC. Only participants in the intervention group were evaluated to determine whether they were at high risk of upper gastrointestinal cancer by the questionnaire assessment. The assessment criteria has been reported elsewhere (19,20). In brief, participants would be defined as “high-risk individuals” if they met any 2 of items (I)–(III) or any 1 of (IV)–(VI): (I) smoking more than 20 cigarettes per day for at least 10 years; (II) drinking 28 g ethanol or more per day for at least 10 years; (III) eating moldy, salted, or fried food at least once per week; (IV) family history of upper gastrointestinal cancer; (V) upper gastrointestinal symptoms including dysphagia, chest/back pain during swallowing, nausea/vomiting/belching, heartburn/acid regurgitation/abdominal distention, inappetence, epigastric pain, melena, and unexplained weight loss; (VI) personal history of upper gastrointestinal diseases such as reflux esophagitis and gastritis.

High-risk individuals in the intervention group were invited to undergo endoscopic examination in the designated hospitals. Some routine tests were carried out to detect human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and syphilis. Standard upper endoscopic examination was then performed by experienced physicians according to the technical proposal for the upper gastrointestinal cancer screening project. The esophagus and stomach were examined visually, and chromoendoscopy with Lugol’s iodine staining or indigo carmine dye would be performed to diagnose suspicious lesions in the esophagus or stomach if necessary. Only positive or suspicious lesions were targeted for biopsy, and pathological diagnosis was then determined independently by 2 experienced pathologists. Positive cases were defined as follows: esophageal severe dysplasia, esophageal carcinoma in situ, EC, gastric high-grade dysplasia, and GC. Among these, esophageal severe dysplasia, esophageal carcinoma in situ, gastric high-grade dysplasia, and stage I EC/GC were considered as early-stage cases.

Follow-up

Outcomes were assessed by both passive and active follow-up annually. Passive follow-up was conducted for all the participants, and data were collected through databases of cancer registries, medical records, death surveillance, and medical insurance. Positive cases identified at baseline and passive follow-up would be interviewed via telephone or home visit by trained health workers. Participants with precancerous lesions would receive an endoscopic reexamination. Specifically, participants with esophageal mild dysplasia were required to undergo a reexamination every 3 years, and those with esophageal moderate dysplasia, cardia or gastric low-grade dysplasia, severe intestinal metaplasia, or severe atrophic gastritis were required to undergo a reexamination every year.

Outcomes

Outcomes were measured at the individual level. The primary outcomes were EC and GC mortality. The secondary outcomes comprised the detection rate (the proportion of positive cases among participants undergoing endoscopy), the early detection rate (the proportion of cases in stage 0/I among all the positive cases), and the treatment rate (the proportion of positive cases receiving clinical treatment). There were no changes to outcomes after the trial commenced.

Statistical analysis

Baseline characteristics of participants were reported for the intervention and control groups. Student’s t test was employed to compare 2 groups with respect to continuous variables, and the Chi-square test or Fisher’s exact test was performed for categorical variables. To explore factors potentially involved in endoscopy compliance (the proportion of participants undergoing endoscopy among high-risk individuals), univariate logistic regression analyses were performed, and variables with P<0.1 were selected for subsequent multivariate analysis. A multivariate regression model was then developed to estimate odds ratios (ORs) as well as 95% confidence intervals (CIs). Statistical analyses were conducted using R v3.6.1, and a two-sided P value of <0.05 was considered statistically significant.

Results

Enrollment and participant characteristics

Between May 2015 and July 2017, a total of 23,917 individuals from 33 villages attended the baseline survey, with 12,475 allocated to the intervention group (17 villages) and 11,442 allocated to the control group (16 villages). Of these, 264 were excluded owing to personal cancer history (N=146), received endoscopy examinations in the past 3 years (N=93), age nonconformity (N=12), or erroneous data (N=13). Finally, 23,653 individuals were eligible for inclusion in the analysis, with 12,402 in the intervention group and 11,251 in the control group (Figure 1).

Figure 1 Participant flow diagram of the trial.

Baseline characteristics including age, gender, marital status, smoking, and strong adaptability were well balanced between the trial groups (P>0.05). The average (± SD) age of participants was 52.1 (±7.8). About 51.3% of participants were men, and the majority of participants (94.2%) were married. A total of 80.2% of participants never smoked. In addition, most participants (92.9%) reported that they had strong adaptability. Other variables on sociodemographic characteristics and risk factors are reported in Table 1.

Endoscopy compliance and its associated factors

In the intervention group, 12,402 participants finished the questionnaire. Of these, 6,286 (50.7%) were estimated as high-risk individuals and were invited to receive endoscopic examination. There were ultimately 2,719 participants undergoing endoscopy. The compliance rate of endoscopy was 43.3%.

To explore factors associated with endoscopy compliance, we performed univariate logistic regression analyses based on variables presented in Table 1. Significant variables (P<0.1) were then incorporated into a multivariate logistic regression model. As shown in Table 2, the results demonstrated that participants aged 50–59 and 60–69 years were more likely to undergo endoscopy than those aged 40–49 years (OR =1.38, 95% CI: 1.22–1.56, P<0.001; OR =1.82, 95% CI: 1.58–2.10, P<0.001). Compared with males, females showed higher endoscopy compliance (OR =1.38, 95% CI: 1.24–1.54, P<0.001). Participants who completed primary school, middle school, or college and above had a higher probability of attending endoscopy than those with no schooling (OR =1.41, 95% CI: 1.15–1.74, P=0.001; OR =1.68, 95% CI: 1.34–2.11, P<0.001; OR =2.70, 95% CI: 1.27–5.88, P=0.011). Regarding personality and mental health, participants that did not have a type A personality or strong adaptability, or those with depression were less likely to accept endoscopic examination (OR =0.78, 95% CI: 0.69–0.87, P<0.001; OR =0.78, 95% CI: 0.64–0.95, P=0.016; OR =0.54, 95% CI: 0.35–0.80, P=0.003). Furthermore, participants with a personal history of gastric and duodenal ulcers or superficial gastritis were more prone to undergo endoscopy (OR =1.38, 95% CI: 1.18–1.62, P<0.001; OR =1.16, 95% CI: 1.03–1.30, P=0.014). Positive associations were observed between upper gastrointestinal symptoms and endoscopy compliance. Participants with heartburn, acid regurgitation, and abdominal distention tended to attend endoscopic screening (OR =1.38, 95% CI: 1.22–1.56, P<0.001). Likewise, participants with nausea, vomiting, and belching showed greater odds of endoscopy compliance (OR =1.43, 95% CI: 1.28–1.60, P<0.001), and those with dysphagia or epigastric pain exhibited similar results (OR =1.57, 95% CI: 1.12–2.20, P=0.008; OR =1.38, 95% CI: 1.24–1.53, P<0.001).

Esophageal and gastric cancer detection

Among participants receiving endoscopy examination, a total of 1,784 (65.6%) participants underwent pathological biopsy due to positive or suspicious lesions. There were 20 positive cases detected, with a detection rate of 0.74%. The pathological distribution of all the lesions is shown in Table 3. Out of the 36 cases with esophageal lesions, 6 were reported as positive cases (0.22%), including 3 cases of EC and 3 cases of severe dysplasia. Moreover, 19 cases with esophageal precancerous lesions were detected (0.70%), with 7 moderate dysplasia cases and 12 mild dysplasia cases. Other abnormal esophageal pathology results included 1 case of moderate esophagitis and 10 cases of basal cell hyperplasia. With regard to the 1,623 cases with stomach lesions, 15 were identified as positive cases (0.55%), including 12 cases of GC and 3 cases of high-grade dysplasia. The 64 cases with stomach precancerous lesions (2.35%) consisted of 28 low-grade dysplasia cases and 36 severe atrophic gastritis cases. Other abnormal stomach pathology results included 128 cases of moderate atrophic gastritis, 88 cases of mild atrophic gastritis, and 1,328 cases of non-atrophic gastritis.

Clinical stage and treatment of positive cases

Clinical stage and treatment information of positive cases are shown in Table 4. Out of the 20 positive cases, 8 (40.0%) were in the early stage. The early detection rates for EC and GC were 50.0% and 33.3%, respectively. Additionally, the overall treatment rate for positive cases was 90.0%. For EC, all the 6 (100.0%) positive cases received clinical treatment. For GC, 13 cases received treatment, with a treatment rate of 86.7%.

Discussion

The efficacy and feasibility of endoscopy-based screening for EC and GC in non-high-incidence rural areas of China are not clear. Here, we conducted a cluster RCT with at least 10 years of follow-up and reported the baseline findings. After the questionnaire assessment was completed, high-risk individuals in the intervention group were invited to undergo endoscopic examination, with a compliance rate of 43.3%. Multivariate logistic regression analysis showed that several factors including age, gender, education, personality and mental health, and upper gastrointestinal diseases or symptoms might affect endoscopy compliance. The detection rate for positive cases of EC or GC was 0.74%, and of the positive cases, 40.0% were in the early stage. Furthermore, the overall treatment rate for positive cases was 90.0%. Our findings may offer important clues for optimal screening strategies for EC and GC in non-high-incidence areas of China.

For upper gastrointestinal cancer screening programs implemented in high-incidence areas of China, all the local participants are regarded as high-risk individuals and are invited to undergo endoscopy. However, owing to the invasiveness and high cost of this technique, participants in non-high-incidence areas are first risk-stratified with a standardized questionnaire, and only those evaluated as high-risk individuals are advised to attend endoscopic examination. As a result, we found that about half (50.7%) of the participants completing the risk assessment were estimated as high-risk individuals, while the detection rate for positive cases of EC or GC was low (0.74%). These results suggest that the risk assessment tool used in non-incidence areas may not accurately distinguish risk levels, and further risk stratification methods need to be developed to identify high-risk individuals. Numerous studies have indicated that multiple biomarkers such as tumor-associated antigens, autoantibodies, miRNAs, and methylated DNA markers exhibit good performance for the early detection and diagnosis of EC and GC (21-26). Thus, the combination of epidemiological risk factors (obtained by the questionnaire) and promising biomarkers, which may be used to develop risk prediction models, may help to optimize the risk stratification and improve screening efficacy.

In this study, the endoscopy compliance rate of high-risk individuals in the intervention group was 43.3%, which was relatively lower than that in high-incidence areas of China such as Feicheng, Linzhou, and Cixian (14,27,28). One of the possible reasons was the differences in awareness of upper gastrointestinal cancer screening among these areas (29). For decades, upper gastrointestinal cancer prevention and control programs, along with publicity and education, have been implemented in high-incidence areas (20). Numerous studies such as risk factor research, general population nutrition intervention trials, dysplasia population nutrition intervention trials, and chemoprevention trials have been also performed in these areas (30-38). Such efforts not only resulted in a decrease in incidence (30), but also probably increased the awareness of cancer prevention. Thus, there is a need to enhance social mobilization campaigns and health education on cancer prevention and screening in non-high-incidence areas. Moreover, we found that some factors were significantly associated with endoscopy compliance. As a result, elderly individuals and females were more likely to undergo endoscopic examination. This is probably because such populations prefer to attend education sessions and follow healthcare advice (39). Another prominent factor associated with endoscopy compliance was educational attainment, with relatively well-educated individuals more prone to attend endoscopy. This may be because individuals with higher education have greater awareness and knowledge of cancer prevention (40). We also observed that participants that did not have a type A personality or strong adaptability, or those with depression showed lower endoscopy compliance, which is a reflection that negative personality or mental health issues probably affect health-related behaviors. Furthermore, participants with upper gastrointestinal symptoms (dysphagia, epigastric pain, heartburn, acid regurgitation and abdominal distention, nausea, vomiting, and belching) or a personal history of upper gastrointestinal diseases (gastric and duodenal ulcers, superficial gastritis) tended to participate in endoscopic screening. Part of the reason may be that these individuals have a relatively more urgent need to seek medical help for upper gastrointestinal problems and thus accept endoscopy. Based on these findings, targeted education, especially targeting males, individuals aged 40–49 years, those with lower education levels, or those with negative personality traits, will be important for the improvement of endoscopy compliance.

The detection rates for positive cases of EC and GC were 0.22% and 0.55%, respectively, which were lower than those in high-incidence areas in previous studies (27,41). The reasons may include differences in the prevalence of upper gastrointestinal cancer between these areas, and a lack of endoscopy training or experience in non-high-incidence areas (42). This also suggests that the risk assessment needs to be improved to identify high-risk individuals more efficiently.

Despite the large community-based RCT design with long-term follow-up and quality implementation processes, our study still has several limitations. First, the trial was only part of a multi-center study, which might affect the generalizability of the research findings. Second, selection bias due to nonparticipation in the recruitment and endoscopy screening processes probably influenced the validity of the results. Further analyses will be performed in our subsequent study to investigate and adjust for potential selection bias.

Overall, our study is a cluster community-based RCT of EC and GC screening in a non-high-incidence area of China, with a total of 23,917 participants included in the trial. The preliminary results described baseline recruitment, endoscopy participation and its associated factors, detection of positive cases, and treatment rates. The findings highlight the need to develop efficient risk assessment in non-high-incidence areas, and indicate the importance of improving endoscopy compliance partly through targeted education. Follow-up of study participants is progressing, which is expected to offer further clues as to the efficacy of endoscopy-based screening for EC and GC and the feasibility of this screening strategy in non-high-incidence areas.

Acknowledgments

We gratefully acknowledge the team at the National Cancer Center and all the staff as well as the participants in this study for their support and contribution to this work.

Funding: This study was funded by the Special Fund for Health Research in the Public Interest (No. 201502001).

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-4052/rc

Trial Protocol: Available at https://atm.amegroups.com/article/view/10.21037/atm-22-4052/tp

Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-22-4052/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4052/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the independent ethics committee of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No. 2015SQ00223). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). All participants provided written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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