HIV and Other Risk Factors for Esophageal Squamous Cell Carcinoma in Malawi

Study Overview
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Brief Summary
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The primary purpose of this single-center, case-control, non-interventional study is to determine risk factors which contribute to the development of esophageal squamous cell carcinoma (ESCC) at Kamuzu Central Hospital (KCH) and St. Gabriel Hospital (SGH) in Malawi.

Detailed Description
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RATIONALE FOR RESEARCH The Rift Valley of Africa is a 'hot spot' for ESCC, yet little is known about the etiology of this disease in Sub-Saharan Africa. In Malawi, ESCC is the third commonest cancer nationwide behind Kaposi sarcoma and cervical carcinoma. Among cancers that are not classically HIV-related, ESCC has the highest incidence in Malawi. The ESCC burden recorded in the national cancer registry is also likely an underestimate, as many cases may go undiagnosed and unregistered. Additionally, few data are available on the epidemiology of ESCC in Malawi, and underlying reasons for high frequency of the disease are largely unknown. This knowledge gap is a major barrier to public health prevention efforts. Given that survival after ESCC diagnosis is dismal in Malawi (12% at 1 year), developing evidence-based prevention efforts is paramount. The proposed study will make a significant contribution to existing literature from Malawi and Sub-Saharan Africa in several important respects. First, previous epidemiologic studies of ESCC in Malawi have been limited by challenges with appropriate control selection, which may have limited the validity of their findings. Secondly, our study will include prospective clinical follow-up of confirmed ESCC cases as they receive treatment under local conditions to provide accurate survival estimates. Thirdly, biospecimens from consenting patients will permit etiology and pathogenesis studies to understand mechanisms of ESCC development, which can be correlated with high-quality clinical and epidemiologic data. Finally, we plan to coordinate with other ESCC researchers in eastern and southern Africa to harmonize data collection, and help create a regional consortium in which Malawi can be a founding member and active participant. Primary Objective: Identify demographic and environmental risk factors for ESCC through a case-control study implemented at KCH and SGH. Hypothesis: Modifiable risk factors contribute significantly to ESCC. These include polycyclic aromatic hydrocarbon (PAH) exposure from various sources, excessively hot beverages, dietary factors such as maize fumonisin and low selenium, and HIV infection. Secondary Objective: Identify common genetic and epigenetic alterations in germline and somatic DNA associated with ESCC development. Hypothesis: Recurring genetic and epigenetic alterations can facilitate risk stratification, development of early detection biomarkers, and identification of novel treatment strategies. Procedures After informed consent and study enrollment, subjects will be interviewed using a structured questionnaire and provide biological samples including saliva, blood, urine, and toenail clippings. Esophageal biopsies will be taken for diagnostic confirmation and to support molecular studies. If patients suspected to have ESCC are enrolled but then pathologically confirmed to have an alternate diagnosis, they will be withdrawn. HIV testing will be offered to all participants, and CD4, HIV RNA, and ART status documented for HIV-infected participants. Exposures will be measured using the questionnaire and laboratory analyses of saliva, blood, urine, and toenail samples. We will collect information on: demographic characteristics; HIV status; tobacco and drug use; alcohol consumption; medical history; family history of cancer; indoor air pollution; occupational history; diet, cooking, and food preservation; beverage history including temperature; farming; signs and symptoms of upper gastrointestinal disease; oral health; anthropometric indices; and reproductive history. To examine correlates with patient outcomes, telephone follow-up to assess vital status will be done every 3 months until 2 years from enrollment. Biological samples will be stored in freezers and transferred to the US only for assays that are currently unavailable in Malawi. Laboratory testing will include serum selenium level, blood and urine testing for PAH exposure, tumor immunohistochemistry assays, salivary DNA isolation for genetic studies, and molecular profiling of ESCC tumors. Analysis Sample size will include 300 ESCC cases and 300 controls; 66-68 case control pairs will be enrolled per year, over 3 years, assuming a response rate of 75% in the endoscopy clinic. With 300 case-control pairs, estimated statistical power for an exposure with control population prevalence of 10% and OR 2.0 is 81%, using alpha level 0.05, with higher power for higher control exposure rates and odds ratios. Expected prevalence for key exposures (tobacco and alcohol, hot tea, PAH exposure, selenium deficiency, HIV) is 10-50% in the control population. To assess epidemiologic risk factors for ESCC, we will use logistic regression to estimate odds ratios and 95% confidence intervals for each exposure, while controlling for possible confounders. Survival estimates will be generated using Kaplan-Meyer curves to estimate overall survival at 6, 12 and 24 months.

Official Title
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LCCC 1608 - HIV and Other Risk Factors for Esophageal Squamous Cell Carcinoma in Malawi

Conditions
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Esophageal Squamous Cell Carcinoma

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cases Inclusion Criteria All patients > 18 years of age diagnosed with histologically confirmed ESCC are eligible to be a case regardless of sex or place of residence. Diagnosis of ESCC (histologically confirmed) Subject able to understand and provide written consent in English or Chichewa Able to understand and comply with study procedures for the entire length of the study Controls Inclusion Criteria All patients > 18 years of age without a history of esophageal cancer or esophageal squamous dysplasia, a history of other cancer, or upper gastrointestinal diseases are eligible to be controls, regardless of age, sex, or place of residence Subject able to understand and provide written consent in English or Chichewa Able to understand and comply with study procedures for the entire length of the study Exclusion Criteria: Cases Exclusion Criteria Healthcare provider determines it is unsafe to perform a biopsy Mental impairment which precludes provision of informed consent Patients who are unable to provide their past medical history Controls Exclusion Criteria All patients > 18 years of age with a history of esophageal cancer or esophageal squamous dysplasia, a history of other cancer, or upper gastrointestinal diseases are ineligible to be controls Patients with significant difficulty swallowing Mental impairment which precludes provision of informed consent Patients who are unable to provide their past medical history

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 300 esophageal cases<br>diagnosed with histologically confirmed ESCC | |
| 300 patient controls<br>without a history of esophageal cancer or esophageal squamous dysplasia, a history of other cancer, or upper gastrointestinal diseases | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk factors for ESCC - HIV Infection | To identify risk factors for ESCC through a case-control study implemented at a national teaching hospital, specifically focused on the following exposures: HIV infection, PAH exposure, Dietary factors including fumonisin and selenium, Scalding hot beverages and foods, Tobacco and alcohol consumption | 2 years | 
| Survival estimates after ESCC diagnosis in Malawi. | To assess survival after ESCC diagnosis in Malawi. | 2 years | 
| Risk factors for ESCC - HIV Infection | To identify risk factors for ESCC through a case-control study implemented at a national teaching hospital, specifically focused on the following exposures: HIV infection | 2 years | 
| Risk factors for ESCC - PAH exposure | To identify risk factors for ESCC through a case-control study implemented at a national teaching hospital, specifically focused on the following exposures: PAH exposure | 2 years | 
| Risk factors for ESCC - Dietary factors including fumonisin and selenium | To identify risk factors for ESCC through a case-control study implemented at a national teaching hospital, specifically focused on the following exposures: Dietary factors including fumonisin and selenium | 2 years | 
| Risk factors for ESCC - Scalding hot beverages and foods, | To identify risk factors for ESCC through a case-control study implemented at a national teaching hospital, specifically focused on the following exposures: Scalding hot beverages and foods | 2 years | 
| Risk factors for ESCC - Tobacco and alcohol consumption | To identify risk factors for ESCC through a case-control study implemented at a national teaching hospital, specifically focused on the following exposures: Tobacco and alcohol consumption | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The common somatic genetic and epigenetic alterations in ESCC tumors from Malawi. | To identify and characterize common somatic genetic and epigenetic alterations in ESCC tumors from Malawi. | 2 years | 
| The germline genetic and epigenetic alterations associated with susceptibility to ESCC. | To identify and characterize germline genetic and epigenetic alterations associated with susceptibility to ESCC. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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risk factors, case-control study