Barrett's Esophagus Clinical Trial
Official title:
The Renin-angiotensin System (RAS) in Barrett's Esophagus as Future Biomarkers for Dysplasia and Cancer? A Randomized Controlled Trial
Barrett`s esophagus (BE) is the major esophageal pre-neoplastic lesion in which dysplastic
transformations eventually can lead to cancer development. Today, the only way for early
detection of pre-neoplastic lesions is an endoscopic surveillance programme with tissue
sampling for histopathology, the latter being the only validated biomarker for esophageal
adenocarcinoma (EAC)-risk available. New biomarkers are warranted for better patient
selection before inclusion into BE surveillance programmes.
Epidemiologic studies have demonstrated suppressed numbers of cancer prevalence in cohorts
being under different medical treatment. In a British epidemiological study 2007 Sjöberg et
al noted a lower prevalence of EAC among patients treated with antihypertensive drugs
interfering with the renin-angiotensin system (RAS) such as AT1R-blockers and
ACE-inhibitors. The last decade this endocrine signalling system has been proven to be
involved in pathological conditions such as inflammation, wound-healing and even cancer, in
several organ systems.
Earlier reports from the investigators laboratory indicate the existence of a local RAS in
the esophageal wall musculature and in the squamous mucosa. In the investigators latest
explorative study, the investigators discovered the altered expression of "classical" RAS
components in BE with and without dysplasia (unpublished results).
By a possible alteration in RAS-related protein-expression in BE with increasing grade of
dysplasia towards EAC, the investigator may have a possible "pathway" leading to biomarkers
for cancer-development. Furthermore, the already well-known anti-hypertensive drugs
ACE-inhibitors and AT1R-blockers may interfere with the risk of malignancy in BE. The
investigators therefore wish to test, in an exploratory prospective randomized
placebo-controlled setting, whether RAS-related protein-expressions in BE are altered by the
addition of RAS-suppressant pharmaceuticals. In the same manner the investigators wish to
see if the expressions of well-known biomarkers for cancer and inflammation are altered.
Barrett`s esophagus (BE) is the major esophageal pre-neoplastic lesion in which dysplastic
transformations eventually can lead to cancer development. Early detection of high-grade
dysplasia (HGD) or intramucosal cancer is of fundamental value for the patient. The
minimally invasive endoscopic resection- and ablation-techniques available are curative. In
patients with invasive cancer far more invasive resection-techniques are required which are
associated with severe post-operative morbidity, mortality and poor overall survival. Today,
the only way for early detection of pre-neoplastic lesions is an endoscopic surveillance
programme with tissue sampling for histopathology, the latter being the only validated
biomarker for esophageal adenocarcinoma (EAC)-risk available. In an unselected BE-population
the risk of developing EAC is low, 0.12% annually. In patients with BE and low-grade
dysplasia (LGD) the number of EAC is 5,1 per 1000 person-years according to a large Danish
cohort-study. New biomarkers are warranted for better patient selection before inclusion
into BE surveillance programmes.
Epidemiologic studies have demonstrated suppressed numbers of cancer prevalence in cohorts
being under different medical treatment. Anti-inflammatory, lipid-lowering and
anti-hypertensive drugs are mentioned. In a British epidemiological study 2007 Sjöberg et al
noted a lower prevalence of EAC among patients treated with antihypertensive drugs
interfering with the renin-angiotensin system (RAS) such as AT1R-blockers and
ACE-inhibitors. Wegman-Ostrosky et al linked RAS to the "Hallmarks of cancer" by RAS
directly affecting tumor and stromal cells, and indirectly by affecting vascular cells in
angiogenesis.
RAS is known to be involved in fluid and electrolyte homeostasis and in hemodynamic
regulation. The last decade this endocrine signalling system has been proven to utilise
tissue-based character, being involved in pathological conditions such as inflammation,
wound-healing and even cancer, in several organ systems.
The "classical" signalling pathway of RAS, when angiotensin II (AngII) is being formed by
the help of angiotensin converting enzyme (ACE) and its affinity to the membrane-bound
receptors (angiotensin II type 1 and 2 receptors (AT1R and AT2R)), is now being challenged
by the discovery of "alternative" pathways with enzymes and receptors, making the picture
more diverse.
Reports from the investigators laboratory indicate the existence of a local RAS in the
esophageal wall musculature and in the squamous mucosa. This was further explored by
Björkman et al 2013, showing that some RAS-components are significantly altered in patients
with erosive reflux disease when compared to healthy volunteers. In the investigators latest
explorative study, the investigators discovered the altered expression of "classical" RAS
components in BE with and without dysplasia (unpublished results).
By a possible alteration in RAS-related protein-expression in BE with increasing grade of
dysplasia towards EAC, the investigators may have a possible "pathway" leading to biomarkers
for cancer-development. Furthermore, the already well-known anti-hypertensive drugs
ACE-inhibitors and AT1R-blockers may interfere with the risk of malignancy in BE. The
investigators therefore wish to test, in a exploratory prospective randomized
placebo-controlled setting, whether RAS-related protein-expressions in BE are altered by the
addition of RAS-suppressant pharmaceuticals. In the same manner the investigator wish to see
if the expressions of well-known biomarkers for cancer and inflammation are altered.
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Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science
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