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Investigating the Association Between Microbiota and Esophageal/Oropharyngeal Cancer

Primary Purpose

Microbial Colonization, Esophageal Cancer, Oropharyngeal Neoplasms

Status
Recruiting
Phase
Not Applicable
Locations
Taiwan
Study Type
Interventional
Intervention
Oral swab test
Sponsored by
National Cheng-Kung University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional screening trial for Microbial Colonization

Eligibility Criteria

20 Years - 99 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Eligible participants included patients aged ≥ 20 years with oropharyngeal cancer, esophageal cancer, or dyspeptic patients without cancer.

Exclusion Criteria:

  • Patients with other cancer than esophageal cancer or oropharyngeal cancer.
  • Patients with bleeding tendency, such as platelet < 50k, PTinr > 2, or using anti-coagulants.
  • Patients with use of antibiotics within the past 2 weeks

Sites / Locations

  • National Cheng-Kung University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Esophageal cancer group

Oropharyngeal cancer group

Synchronous cancer group

Control group

Arm Description

patients aged ≥ 20 years with esophageal cancer

patients aged ≥ 20 years with oropharyngeal cancer

patients aged ≥ 20 years with synchronous oropharyngeal cancer and esophageal cancer

patients aged ≥ 20 years with symptoms of dysphagia without cancer

Outcomes

Primary Outcome Measures

To analyze the similarity of microbiota distribution between the buccal field and the esophageal area in the same patient
We will send one patient's oral swab and esophageal mucosal tissue for screening microbiota by sequencing 16S rRNA (measured as percentage abundance per microbial species and differences in percentage abundance between the esophagus and mouth). In order to compare the similarity of microbiota between mouth and esophagus. The raw tags of data will be transformed into high-quality clean tags through the QIIME quality control process. Both alpha- and beta-diversity will be calculated with QIIME software and display with R software. We will use the Ace index to assess the richness of OTUs community and the Shannon index to assess the evenness of community diversity. Weighted UniFrac will be implemented to manifest the phylogenetic relationship of beta-diversity. To find out different genera of bacterial composition between groups, the student's t-test will be employed.

Secondary Outcome Measures

To analyze the distribution difference of microbiota among the patients with esophageal cancer/oropharyngeal cancer and non-cancer control
The study will compare the microbiota by sequencing 16S rRNA (measured as percentage abundance per microbial species and differences in percentage abundance between the control group and cancer group). In order to compare the difference of microbiota among esophageal cancer patients, oropharyngeal cancer patients, synchronous cancer patients, and non-cancer control. The raw tags of data will be transformed into high-quality clean tags through the QIIME quality control process. Both alpha- and beta-diversity will be calculated with QIIME software and display with R software. We will use the Ace index to assess the richness of OTUs community and the Shannon index to assess the evenness of community diversity. Weighted UniFrac will be implemented to manifest the phylogenetic relationship of beta-diversity. To find out different genera of bacterial composition between groups, the student's t-test will be employed.

Full Information

First Posted
March 16, 2022
Last Updated
June 21, 2023
Sponsor
National Cheng-Kung University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05412628
Brief Title
Investigating the Association Between Microbiota and Esophageal/Oropharyngeal Cancer
Official Title
Investigating the Association, Disease Mechanism, and Clinical Application Between Microbiota and Oropharyngeal and Esophageal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 15, 2022 (Actual)
Primary Completion Date
February 14, 2024 (Anticipated)
Study Completion Date
February 14, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cheng-Kung University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Background: Esophageal cancer commonly occurs in middle-aged man. It is ranked to the 6th common cancer and 5th cancer-related death in Taiwanese male, and sometimes co-exist with oropharyngeal cancer, which impacts our national economics and productivity a lot. To improve the prognosis of esophageal cancer, we should contribute to early diagnosis and improved treatment of the disease. Recent studies showed oral and esophageal dysbiosis may lead to oropharyngeal and esophageal cancer. Aim: To investigate whether oral microbiota is similar to esophageal microbiota. To investigate whether oral microbiota can be a non-invasive biomarker of oropharyngeal cancer, esophageal cancer, synchronous cancer and chemoradiation resistance. And whether probiotic supplement can improve oral/esophageal dysbiosis in order to prevent esophageal cancer. Study design: This study compares the oral/esophageal microbiota composition between oropharyngeal cancer cases, esophageal cancer cases, synchronous cancer cases and non-cancer controls. In addition, the link between oral and esophageal microbiota will be explored. The study will identify the microbiota related with esophageal cancer development. We will also validate the effect of probiotic supplementation on improving oral/esophageal dysbiosis. Expected result and significance: Examination of oral microbiota has the potential to become a non-invasive tool for oropharyngeal cancer, esophageal cancer, and synchronous cancer. Probiotic supplementation has the potential to improve oral dysbiosis.
Detailed Description
Esophageal cancer is one of the most common gastrointestinal malignant diseases worldwide with an estimated 456,000 incident cases annually. Esophageal cancer has a poor prognosis and high mortality rate. The 5-year survival rate is around 15%-25%. The treatment options of esophageal cancer can be divided into curative treatment and palliative treatment, while endoscopy, surgery and chemoradiotherapy were involved. However, 60-70% patients diagnosed with esophageal cancer are not eligible for curative treatment. In these patients, chemoradiotherapy is the standard for unresectable esophageal cancer, but the treatment outcome remains poor. In the literatures, the complete response rate of chemoradiotherapy in advanced esophageal cancer was about 20%, and the 2-year overall survival rate was 40%. Therefore, early detection and prediction of esophageal cancer are needed. Besides, the inconsistency of treatment effect of chemoradiotherapy may indicate some differences of esophageal cancer microenvironment among the patients. Finding out the affecting factors of microenvironment may help the decision making of treatment options and the prediction of disease prognosis. Furthermore, if we can change the affecting factors in microenvironment, we may be able to prevent the esophageal cancer formation or progression. Esophageal tumor initiation is associated with environmental exposures, chronic inflammation, and immune cells. Several genetic and environmental factors play key roles in the formation and progression of esophageal cancer. Refluxed gastric and bile acids induce chronic inflammation and the development of intestinal metaplasia (Barrett's esophagus), which is the precursor lesion to esophageal adenocarcinoma. Toxic agent like tobacco and alcohol can cause direct esophageal injury and production of reactive oxygen species (ROS). ROS production causes direct DNA damage and tumor-initiating mutations. Besides, some literatures had reported the possible correlation with microbiota and cancer formation. Commensal bacteria (the microbiota) normally live in the gastrointestinal tract with host cell. Disruption of the relationship (dysbiosis) can influence the metabolism, tissue development, and immune response, which may cause damage to epithelial barriers, inflammation, and inducing DNA and pro-oncogenic signaling, leading to carcinogenesis in the gastrointestinal tract. The role of microbiota in the esophagus has not been widely investigated. Increasing of gram-negative bacteria increases the production of lipopolysaccharide (LPS), leading to inflammation and increased gastric reflux. The gut microbiota is associated with nutrition, the immune system, and defense of the host. It produces short chain fatty acids via anaerobic fermentation of dietary fibers in the intestine. Compared with healthy individuals, the abundance of short chain fatty acids -producing bacteria decreased and the abundance of lipopolysaccharide (LPS) -producing bacteria increased in esophageal cancer patients. Butyrate, one of the short chain fatty acids, decreases LPS-induced cytokine expression and NF-κB activation in lamina propria mononuclear cells. Esophageal microbiota theoretically plays a role in esophageal carcinogenesis. Esophageal cancer is composed of esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC). In esophageal adenocarcinoma, a decrease of Firmicutes, and an increase of Proteobacteria, Lactobacillus fermentum, and Tannerella forsythia have been reported. In esophageal squamous cell carcinoma, a reduction of Streptococcus species and an increase of Fusobacterium nucleatum and Porphyromonas gingivalis were observed. In Taiwan, patients with primary oropharyngeal cancer had ten times the risk of second esophageal cancer compared to the general population, and vice versa. Some specific bacteria may be associated with the co-existence of oropharyngeal cancer and esophageal cancer. However, diet is one of the most potent factors in determining microbiome integrity. Owing to the dietary difference between easterners and westerners, the dominant microbiota affecting esophageal cancer may be different. Finding out the esophageal cancer-associated specific bacteria of microbiota in Taiwan is important for further research and application for our patients. Previously, some microorganisms could not be cultured, which would make the microbiota detection incomplete. Nowadays, 16S ribosomal RNA (16S rRNA) sequences had replaced the culture methods in detection of microbiota. In our study, we aim to compare the microbiota among healthy individuals, patients with esophageal cancer, oropharyngeal cancer, and concurrent esophageal cancer with oropharyngeal cancer in Taiwan. Through the comparison, we may find the potential risky microbiota for cancer formation or progression in Taiwan.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Microbial Colonization, Esophageal Cancer, Oropharyngeal Neoplasms, Synchronous Neoplasm

7. Study Design

Primary Purpose
Screening
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Esophageal cancer group
Arm Type
Experimental
Arm Description
patients aged ≥ 20 years with esophageal cancer
Arm Title
Oropharyngeal cancer group
Arm Type
Experimental
Arm Description
patients aged ≥ 20 years with oropharyngeal cancer
Arm Title
Synchronous cancer group
Arm Type
Experimental
Arm Description
patients aged ≥ 20 years with synchronous oropharyngeal cancer and esophageal cancer
Arm Title
Control group
Arm Type
Placebo Comparator
Arm Description
patients aged ≥ 20 years with symptoms of dysphagia without cancer
Intervention Type
Diagnostic Test
Intervention Name(s)
Oral swab test
Other Intervention Name(s)
Esophageal mucosal tissue biopsy
Intervention Description
In this study, we will perform tissue biopsy at esophageal tumor site in esophageal cancer patients and perform random biopsy at middle esophagus in patients without esophageal cancer. Besides, we will take oral swab in all participants.
Primary Outcome Measure Information:
Title
To analyze the similarity of microbiota distribution between the buccal field and the esophageal area in the same patient
Description
We will send one patient's oral swab and esophageal mucosal tissue for screening microbiota by sequencing 16S rRNA (measured as percentage abundance per microbial species and differences in percentage abundance between the esophagus and mouth). In order to compare the similarity of microbiota between mouth and esophagus. The raw tags of data will be transformed into high-quality clean tags through the QIIME quality control process. Both alpha- and beta-diversity will be calculated with QIIME software and display with R software. We will use the Ace index to assess the richness of OTUs community and the Shannon index to assess the evenness of community diversity. Weighted UniFrac will be implemented to manifest the phylogenetic relationship of beta-diversity. To find out different genera of bacterial composition between groups, the student's t-test will be employed.
Time Frame
1 week
Secondary Outcome Measure Information:
Title
To analyze the distribution difference of microbiota among the patients with esophageal cancer/oropharyngeal cancer and non-cancer control
Description
The study will compare the microbiota by sequencing 16S rRNA (measured as percentage abundance per microbial species and differences in percentage abundance between the control group and cancer group). In order to compare the difference of microbiota among esophageal cancer patients, oropharyngeal cancer patients, synchronous cancer patients, and non-cancer control. The raw tags of data will be transformed into high-quality clean tags through the QIIME quality control process. Both alpha- and beta-diversity will be calculated with QIIME software and display with R software. We will use the Ace index to assess the richness of OTUs community and the Shannon index to assess the evenness of community diversity. Weighted UniFrac will be implemented to manifest the phylogenetic relationship of beta-diversity. To find out different genera of bacterial composition between groups, the student's t-test will be employed.
Time Frame
1 week

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Eligible participants included patients aged ≥ 20 years with oropharyngeal cancer, esophageal cancer, or dyspeptic patients without cancer. Exclusion Criteria: Patients with other cancer than esophageal cancer or oropharyngeal cancer. Patients with bleeding tendency, such as platelet < 50k, PTinr > 2, or using anti-coagulants. Patients with use of antibiotics within the past 2 weeks
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Hsueh-Chien Chiang, M.D.
Phone
2353535
Email
scion456scion@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Jenn-Wei Chen, Ph.D
Phone
2353535
Email
jc923@mail.ncku.edu.tw
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wei-Lun Chang, M.D. Ph.D
Organizational Affiliation
National Cheng-Kung University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Cheng-Kung University Hospital
City
Tainan
State/Province
Other (Non U.s.)
ZIP/Postal Code
704
Country
Taiwan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hsueh-Chien Chiang
Phone
2353535
Email
scion456scion@gmail.com

12. IPD Sharing Statement

Plan to Share IPD
Yes
Citations:
PubMed Identifier
28648400
Citation
Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet. 2017 Nov 25;390(10110):2383-2396. doi: 10.1016/S0140-6736(17)31462-9. Epub 2017 Jun 22.
Results Reference
result
PubMed Identifier
26923327
Citation
Lin EW, Karakasheva TA, Hicks PD, Bass AJ, Rustgi AK. The tumor microenvironment in esophageal cancer. Oncogene. 2016 Oct 13;35(41):5337-5349. doi: 10.1038/onc.2016.34. Epub 2016 Feb 29.
Results Reference
result
PubMed Identifier
22344232
Citation
Yang L, Francois F, Pei Z. Molecular pathways: pathogenesis and clinical implications of microbiome alteration in esophagitis and Barrett esophagus. Clin Cancer Res. 2012 Apr 15;18(8):2138-44. doi: 10.1158/1078-0432.CCR-11-0934. Epub 2012 Feb 16.
Results Reference
result
PubMed Identifier
31466948
Citation
Snider EJ, Compres G, Freedberg DE, Khiabanian H, Nobel YR, Stump S, Uhlemann AC, Lightdale CJ, Abrams JA. Alterations to the Esophageal Microbiome Associated with Progression from Barrett's Esophagus to Esophageal Adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2019 Oct;28(10):1687-1693. doi: 10.1158/1055-9965.EPI-19-0008. Epub 2019 Aug 29.
Results Reference
result
PubMed Identifier
29196415
Citation
Peters BA, Wu J, Pei Z, Yang L, Purdue MP, Freedman ND, Jacobs EJ, Gapstur SM, Hayes RB, Ahn J. Oral Microbiome Composition Reflects Prospective Risk for Esophageal Cancers. Cancer Res. 2017 Dec 1;77(23):6777-6787. doi: 10.1158/0008-5472.CAN-17-1296.
Results Reference
result
PubMed Identifier
28562351
Citation
Lee KD, Wang TY, Lu CH, Huang CE, Chen MC. The bidirectional association between oral cancer and esophageal cancer: A population-based study in Taiwan over a 28-year period. Oncotarget. 2017 Jul 4;8(27):44567-44578. doi: 10.18632/oncotarget.17818.
Results Reference
result
PubMed Identifier
34733778
Citation
Zhou J, Sun S, Luan S, Xiao X, Yang Y, Mao C, Chen L, Zeng X, Zhang Y, Yuan Y. Gut Microbiota for Esophageal Cancer: Role in Carcinogenesis and Clinical Implications. Front Oncol. 2021 Oct 18;11:717242. doi: 10.3389/fonc.2021.717242. eCollection 2021.
Results Reference
result

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Investigating the Association Between Microbiota and Esophageal/Oropharyngeal Cancer

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