Neoplasms

Digestive System Diseases

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Esophageal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

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Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Capsule sponge cytology examination coupled with H\&E staining analysed for the presence of atypia and p53 immunohistochemistry

Capsule sponge

Reza Malekzadeh, MD

The aim of this study is to assess the effects of implementation of a non-endoscopic esophageal cancer-screening program on outcomes of interest in an asymptomatic high-risk population in Golestan Province, Iran. Study population will be recruited in two arms. In the intervention arm, cytological examination of the esophagus will be performed using a capsule sponge device. Subjects in the control arm will receive no intervention. All participants will be followed for 5 years. The outcomes of interest, including the incidence of esophageal cancer as well as mortality rates, will be compared between the two groups.

Background:

Esophageal cancer (EC) is the 8th most common cancer and the 6th most common cause of death from cancer worldwide. Golestan province located in Northern Iran has been known as a high-risk area for esophageal squamous cell carcinoma (ESCC). Recent reports suggest an increasing rate of esophageal adenocarcinoma (EAC) in this region as well. Designing and implementing of screening programs may be effective for controlling these cancers. The investigators aim to develop a screening program for esophageal cancer in this region. The pilot phase of this project, the Golestan EC Screening Program (GESP), was conducted during 2011 and 2012 among 300 asymptomatic participants of Golestan Cohort Study (GCS), which is a prospective population-based cohort of 50,045 individuals, aged 40-75 years at baseline, in the eastern half of Golestan Province, Iran. The initial results of the GESP project showed a low participation rate for endoscopic screening. In other words, endoscopic ESCC screening was not feasible in our population, suggesting the need for a non-endoscopic screening method. Further results of the GESP project suggested that capsule sponge cytology is a feasible and valid primary method for ESCC screening in this region. Because of the promising findings of the GESP project, it has been decided to start the main phase of the EC screening program, called the "Non-endoscopic EC Screening Program in Northern Iran (NESP)". The aim of this study is to assess the effects of implementation of a non-endoscopic EC screening program on outcomes of interest in an asymptomatic high-risk population in Golestan Province, Iran.

Methods:

For sample size calculations, the investigators considered different scenarios based on the published literature and unpublished data. The prevalence of high grade dysplasia in the general population of Golestan has been estimated to be 1.4-3.6%. The sensitivity of cytological detection of esophageal squamous dysplasia (ESD) was predicted to be about 46% based on studies from China, and 60-100% based on studies from Iran, and according to previous studies, 27-65% of ESD lesions progress to invasive ESCC without treatment. The investigators used a rather conservative assumption to calculate sample size: a dysplasia prevalence of 1.5%, a 60% sensitivity for the sponge cytology, and a 2% progression to invasive ESCC in the screened (and treated) group vs. 40% in the untreated group. The investigators also assumed a power of 90%, a mean cluster size of 28 based on the PolyIran study (CV=0.84%), and an intra-class correlation (ICC) of 0.01. Based on these assumptions the investigators will need 4980 people in each arm. So, the investigators need to enroll 9,960 GCS participants \> 50 years old. Estimating a 20% lack of consent, the final invitation lists of NESP project will consist of 12000 GCS participants including 6000 subjects in the intervention (capsule sponge) arm and 6000 subjects in the control arm.

A list of 12000 subjects from GCS participants will be prepared. Sampling will be done using a cluster randomization method. Each village will be considered as a cluster. Clusters will randomly be allocated into two groups, the intervention group (group 1) and the control group (group 2). Capsule sponge examination will be performed for all subjects in intervention clusters. But, participants in control clusters will be enrolled without capsule sponge examination. Both intervention and control subjects will be offered endoscopy if they develop upper GI symptoms according to current clinical practice.

The process of data collection and sampling will be performed at the community level. The NESP enrollment team will go to healthcare houses located in each village and data collection and sampling will be done there.

After obtaining informed consent, a structured questionnaire including data on demographic, socioeconomic status and medical history will be completed for each subject. Subjects will also be asked to fill in a quality of life (QOL) questionnaire. The investigators will use the validated Persian version of the WHOQOL-BREF questionnaire which was basically developed by the WHO.

Then the capsule sponge examination will be performed for each subject in the community clinic after an overnight fast. The cytological specimen will be placed in preservative fluid and transferred to the histopathology lab.

Cytological specimens will be processed into paraffin blocks, and slides will be prepared from each paraffin block and will be stained using the hematoxylin and eosin (H\&E) method. Cytological examination of the capsule sponge H\&E slides will be done by expert pathologists.

The result will be reported according to the Bethesda system. All subjects with cytological diagnosis of atypia will be referred to Atrak clinic (a central clinic for upper gastrointestinal disease in Gonbad, Iran) for endoscopic examination. Endoscopic examination with Lugol's iodine staining will be performed by previously described methods and biopsies will be taken from abnormal lesions. Histological examination of endoscopic biopsy samples will be done by expert pathologists. If the results of the endoscopic examination show high-grade dysplasia or cancer, the subject will be referred for treatment. These subjects will be treated with endoscopic mucosal resection (EMR) and/or radiofrequency ablation (RFA).

Participants will be followed annually according to the protocol of the GCS follow-up. Each subject will annually be contacted by a telephone call, and questions about the subject's vital status and cancer incidence will be asked from the subject or a first-degree relative. In addition, official data on subject's vital status will be obtained from the death registry unit in the Department of Health of Golestan University of Medical Sciences. Data on cancer incidence in the study subjects will also be obtained from the Golestan population-based cancer registry.

Both groups will be followed for 5 years. At the end of the study, the QOL questionnaire will be completed again for all available subjects.

The risk of developing outcomes will be compared between the intervention and control groups. Odds ratios and 95% confidence intervals (CI) will be calculated. Survival analysis will be done to assess survival rates in the sponge and control groups. The log rank test will be used to compare the survival rates between the two groups. Hazard ratios and 95% CI will be calculated for different variables using Cox regression analysis. Changes in QOL scores during the 5 year follow-up period will be compared between the sponge and control groups.

Non-endoscopic EC Screening Program in Northern Iran

Non-endoscopic Esophageal Cancer Screening Program in Northern Iran

Number of participants with Histologically-confirmed esophageal squamous cell carcinoma will be identified in both intervention and control arms

Number of Death from Esophageal Squamous Cell Carcinoma will be identified in both intervention and control arms

Number of Death from all causes will be identified in both intervention and control arms

Number of participants with Histologically-confirmed esophageal adenocarcinoma will be identified in both intervention and control arms

Number of participants with Histologically-confirmed gastric cardia adenocarcinoma will be identified in both intervention and control arms

Change in Quality of life will be identified in both intervention and control arms

National Cancer Institute (NCI)

International Agency for Research on Cancer

University of Cambridge

Golestan University of Medical sciences

Tehran University of Medical Sciences

Carcinoma

Carcinoma, Squamous Cell

Esophageal Squamous Cell Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

This part of the study will have an active prospective recruitment of patients. Recruitment will involve three patient populations:

1. Patients with ESCC
2. Patients at high risk for ESCC
3. Healthy controls

Following inclusion in the study, subjects will be asked to complete a behavior questionnaire, have blood collected, and undergo a capsule-sponge procedure followed by diagnostic gastroscopy using advanced imaging with biopsies. During gastroscopy, additional tissue samples will be collected for research purposes. These samples, along with cytological specimens from the capsule-sponge, will be analyzed to assess the diagnostic accuracy of biomarkers in the diagnosis of esophageal squamous neoplasia.

The capsule-sponge is a minimally-invasive sampling device consisting of a polyurethane sponge compressed in a cellophane capsule attached to a string. When swallowed, the capsule dissolves in the stomach, releasing the cell collection sponge that expands to 3 cm in diameter. Next, a nurse or qualified medical technician retrieves the sponge by pulling back on the string and retracting it through the mouth. During extraction, the rough texture on the surface of the sponge collects epithelial cells in the cardia and along the entire length of the esophagus.

Capsule-sponge

Wladyslaw Januszewicz, M.D., PhD

Jaroslaw Regula, M.D., PhD

Esophageal squamous cell carcinoma accounts for \~90% of the nearly half-million annual incident cases of esophageal cancer worldwide. The high costs and invasiveness of upper endoscopy constitute a limitation in providing adequate surveillance for at-risk individuals, including those with previous head and neck cancer. The ANGELA study is a prospective evaluation of the minimally-invasive capsule-sponge device, coupled with tissue biomarkers (p53-immunohistochemistry), to detect squamous neoplasia in high-risk individuals.

Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer worldwide, accounting for nearly 90% of the 456,000 incident cases of esophageal cancer each year. Overall, it is the seventh most common malignancy and the sixth most common cause of cancer-related mortality, with a high incidence rate in eastern to central Asia and eastern and southern Africa. This cancer is more common in men (\~70%), and the main risk factors include cigarette smoking, alcohol consumption, poor oral hygiene, the ingestion of caustic agents, and nutritional deficiencies. Additionally, an increased risk of ESCC following curative treatment of head and neck cancer (HNC) has been well-documented in the literature, with a lifetime incidence ranging between 3.8% and 14.9% in prospective observational studies. The carcinogenesis of ESCC is sequential and preceded by several precancerous stages, including low-grade intraepithelial neoplasia (LG-IEN) and, subsequently, high-grade intraepithelial neoplasia (HG-IEN).

Although the prognosis of ESCC is extremely poor, with 5-year survival below 20%, it dramatically improves if the disease is detected at an early stage. Consequently, mass screening in high-incidence regions is being widely debated. However, population-wide screening presents a large challenge in terms of cost-effectiveness and manpower, as currently, a potential screening regime for ESCC would rely on endoscopic examination with biopsies, which remains the gold standard for ESCC diagnosis. Furthermore, since around 80% of all ESCCs occur in economically less-developed regions, newer, cheaper, and less invasive diagnostic tools are highly warranted.

The capsule-sponge is a novel, minimally-invasive device that collects cells from the esophagus to produce a pseudo-biopsy suitable for routine laboratory analysis. In addition, tissue biomarkers such as p53 immunohistochemistry (p53-IHC) and molecular testing, including copy number assays to detect aneuploidy, can be applied. There is extensive data on the use of this technology for early diagnosis of Barrett's esophagus (precursor to adenocarcinoma), which has now reached wide clinical implementation in the UK National Health Service. Building on the promising pilot data, the current study aims to expand further our previously developed clinical assay for early detection of esophageal squamous neoplasia using the capsule-sponge device coupled with biomarkers and machine learning technologies.

In this prospective trial, we plan to recruit patients within three risk groups for ESCC: 1. healthy controls; 2. high-risk individuals (previous head-and-neck cancer/ESCC); and 3. patients with known early ESCC. Each patient will undergo a high-definition endoscopy and a capsule-sponge examination. The biomarker assay, including p53-IHC and shallow whole genome sequencing, will be tested within the capsule-sponge samples and compared with the final endoscopic diagnosis. Machine learning algorithms will be applied to digitalized cytology to detect atypical cells and regions of p53-IHC overexpression. Lastly, we will extract microbial DNA from capsule-sponge samples to assess any taxonomic diversity within the three risk groups for ESCC.

We hope to develop a novel, effective, and affordable diagnostic assay that, coupled with a minimally-invasive capsule-sponge device, could be implemented in a clinical setting, improving the early detection of ESCC and, eventually, patient outcomes.

Single Group Assignment A prospective cohort study

Early Detection of Esophageal Squamous Cancer With the Capsule Sponge Device

Early Detection of Esophageal Squamous Cell Carcinoma With the Capsule Sponge Device Coupled With Molecular Biomarkers and Machine Learning

Data obtained through this study may be provided to qualified researchers with academic interest in esophageal cancer. Data or samples shared will be coded. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party.

Sensitivity (%) and Specificity (%) of the capsule-sponge device in identifying patients with early squamous neoplasia (LG-IEN, HG-IEN, ESCC) as compared to the upper endoscopy with biopsies (gold standard)

% of Participants that have scored the Cytosponge experience of at least 6 points on a 0 to 10 Visual Analogue Scale (VAS) acceptability scale whereby 0 denotes "worst experience in life" and 10 denotes "best experience in life".

Within this outcome, we will clarify the optimal depth of sequencing, and we will then perform shallow whole genome sequencing (sWGS) on the samples collected in the training phase to input the copy-number variation (CNV) into the classification algorithm and evaluate the output as compared with the diagnosis of the patient. This will enable us to refine the classifications with the ultimate aim of using them predictively in a testing phase.

To assess the utility of machine learning-based approaches to assist pathological assessment of the capsule-sponge samples for the applicability of the technology at scale. We will test the feasibility of applying the artificial intelligence (AI)-based technology onto digitalized capsule-sponge samples. The assessment will comprise of AI training phase and a validation period.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Non-endoscopic EC Screening Program in Northern Iran	NCT02311712	Esophageal Canc...	Capsule sponge	50 Years -	Tehran University of Medical Sciences
Early Detection of Esophageal Squamous Cancer With the Capsule Sponge Device	NCT06418516	Esophageal Canc... Head and Neck C... Squamous Cell C...	Capsule-sponge	18 Years -	Centre of Postgraduate Medical Education
Non-endoscopic EC Screening Program in Northern Iran	NCT02311712	Esophageal Canc...	Capsule sponge	50 Years -	Tehran University of Medical Sciences
Early Detection of Esophageal Squamous Cancer With the Capsule Sponge Device	NCT06418516	Esophageal Canc... Head and Neck C... Squamous Cell C...	Capsule-sponge	18 Years -	Centre of Postgraduate Medical Education

Spots Global Cancer Trial Database for capsule sponge