Brief Title
Cancer Chemoprevention by Metformin Hydrochloride in Oral Potentially Malignant Lesions
Official Title
Cancer Chemoprevention by Metformin Hydrochloride Compared to Placebo in Oral Potentially Malignant Lesions: A Randomized Clinical Trial (Part 1)
Brief Summary
Oral squamous cell carcinomas (OSCCs) are among the most common types of head and neck
cancers and are a major cause of significant morbidity. It was reported that 16- 62% of OSCCs
develop from premalignant lesions, which often presents clinically as white or red mucosal
patches known as leukoplakia and erythroplakia.
The role of miRNA in cancer has been established by many studies that have shown that miRNA
signatures (i.e., mRNA expression profiles) can be useful for classifying human cancers.
These studies have identified "cancer related miRNAs through investigating expression
profiles in matched normal and tumor tissues, as well as in body fluids.
Metformin, one of most widely prescribed oral hypoglycemic agents, has recently received
increased attention because of its potential anti-tumorigenic effects that are thought to be
independent of its hypoglycemic effects. Evans et al. first found an association between
metformin use and decreased cancer incidence.
The study will reveal whether Systemic Metformin hydrochloride treatment given to patients
with oral potentially malignant lesions improve the prognosis and prevent or at least reduce
the incidence of malignant transformation?
Detailed Description
The idea of identifying oral lesions with a precancerous nature, that is, in the sense of
pertaining to a pathologic process with an increased risk for future malignant development,
of course, is to prevent frank malignancy to occur in the affected area.
In 2005, WHO categorized any lesion or condition that may increase the risk of malignant
transformation as an 'oral potentially malignant disorder' (OPMD). Early detection of cancer
development from oral premalignant lesions (OPLs) plays an important role in successful
therapy. The management of OPMDs varies according to the type of lesion and often differs
between treatment centers. However, it remains unclear if excision of
leukoplakia/erythroplakia protects patients against the development of OSCC and no randomized
controlled trials have been performed to address this issue.
Various treatment modalities, such as systemic therapies and surgical removal, have been
suggested. The systemic therapies tested so far include retinoids, extracts of green tea,
inhibitors of cyclooxygenase-2 and of epidermal growth factor, and peroxisome
proliferator-activated receptor-c agonists, but there is no generally approved standard
systemic therapy regimen so far.
Local removal includes photodynamic therapy, laser therapy, cryotherapy and conventional
removal by scalpel, but no treatment has so far gained universal approval, no treatment has
so far been subjected to a randomized clinical trial (RCT), and no treatment has been shown
to prevent recurrence or significantly reduce malignant development in long-term follow-up
studies. It is well established that no treatment results in malignant development at an
annual rate of 2-3%.
The overall purpose of treatment therefore is to reduce this percentage. However, the
situation is to take responsibility for the welfare of the patients still is, as it has been
so far: despite treatment, in some types of lesions cancers do occur, so the important
question is whether the harm to patients by not treating or by treating them? Lack of
randomized clinical trials accounts for this persistent question, and while waiting for such
studies to be reported, it is necessary to reflect on the existing scenarios.
Field cancerization To explain why surgery may not always be beneficial, it has been
mentioned that the visible lesions may be surrounded by genetically altered, cancer
stigmatized epithelial cells unrevealed by routine clinical inspection and histological
examination. A possible outcome of such characteristics is obviously lacking resection of all
affected tissue with recurrence and development of carcinoma from residual genetically
altered cells.
Introduction to MicroRNA MicroRNAs (miRNAs) are non-coding regulatory RNA molecules of 19-25
nucleotides in length. miRNAs play a major role in maintaining tissue homeostasis by
regulating many processes such as cellular proliferation, differentiation, migration,
apoptosis, survival and morphogenesis.
It is estimated that the human genome may harbor up to 1,000 miRNAs. Although miRNAs are not
directly involved in encoding proteins, they are believed to control the expression of more
than one third of all protein coding genes present within the human genome. Historically,
miRNAs have been viewed as negative regulators of gene expression. Recent work by Vasudevan
et al., has, however, shown that a small subset of miRNAs within the human genome can also
enhance gene expression.
Role of miRNAs in cancer The role of miRNA in cancer has been reiterated and established by
many studies that have shown that miRNA signatures (i.e., mRNA expression profiles) can be
useful for classifying human cancers. These studies have identified "cancer related miRNAs"
through investigating expression profiles in matched normal and tumor tissues, as well as in
body fluids. In addition, a vast number of studies have shown that miRNAs can play a role in
regulating the expression of oncogenes and tumor suppressor genes, whereas others have shown
that miRNA gene deletion or mutation can lead cancer initiation, progression and metastasis.
Calin et al., were the first to demonstrate that a differential expression of miRNAs may
provide useful tools in the diagnosis and prognosis of human cancers.
MicroRNAs as diagnostic tools Many miRNAs are uniquely and differentially expressed in
certain tissues as compared with normal adjacent tissues. These small RNA molecules can have
diagnostic or prognostic value, as miRNA expression profiles reflect tumor origin, stage, and
other pathological factors. For example, the expression of miRNA let-7 is downregulated in
lung cancer but not in other cancers, such as breast or colon cancer. These observations
suggest that miRNAs can be used as biomarkers and diagnostic tools for cancer detection.
Moreover, miRNAs can function as accurate molecular markers also because they are relatively
stable and resistant to RNase degradation-probably due to their small size.
miR-21 and miR-200 seem to be particularly relevant to OSCC. Inhibition of miR-21 in tongue
cancer cells in vitro reduces survival and anchorage-independent growth. miR-21 increases
proliferation, migration and anchorage-independent growth of HNSCC cells in vitro and in
mouse models, thereby augmenting the oncogenic potential of these cells.
Detection of miRNAs in body fluids With the advances of molecular biological techniques and
the increasing knowledge of tumor pathogenesis, bio-markers are now considered as an
effective supplement, in conjunction to histological examination, for facilitating clinical
decision making. Extracellular miRNAs in serum, plasma, saliva and urine have recently been
shown to be associated with various pathological conditions, including cancer. Most of the
circulating miRNAs are included in lipid or lipoprotein complexes, such as apoptotic bodies,
micro vesicles or exosomes, rendering them inaccessible to degradation by RNAses. Lawrie and
colleagues were the first to observe elevated levels of miRNA-21 in serum samples collected
from large B-cell lymphoma patients.
Explanation for choice of comparators:
Control/comparator : Patients receiving the standard of care together with PLACEBO starch
tablets.
Management strategies for patients with OPLs fall into three categories: close observation,
surgical removal and ablation, and medical therapies. The mainstay of therapy is observation
using frequent clinical examinations. The frequency of examinations should be tailored to
individual patient factors such as the clinical appearance and stage of lesion; presence of
dysplasia; continued use of tobacco, alcohol, or Areca quid; reliability; and access to
medical care.
Study Phase
Phase 3
Study Type
Interventional
Primary Outcome
Clinical Outcomes
Secondary Outcome
Immunohistochemical analysis
Condition
Oral Cancer
Intervention
Metformin Hydrochloride 500 MG
Study Arms / Comparison Groups
Metformin-Group
Description: Metformin hydrochloride tablets 500 mg taken orally once daily for 3 months
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
62
Start Date
October 1, 2018
Completion Date
September 30, 2020
Primary Completion Date
September 30, 2019
Eligibility Criteria
Inclusion Criteria:
- Both genders with age range from 20 to 70 years.
- Patients able to return for the follow up visits and can perform oral hygiene
measures.
- Clinically diagnosed and histologically confirmed as having oral potentially malignant
lesions (Atrophic oral lichen planus, leukoplakia, erythroplakia and oral submucous
fibrosis).
- Patients agreed to sign a written consent after understanding the nature of the study
- Patients have diagnosed oral premalignant lesion/lesions and not yet turned into
malignancy
Exclusion Criteria:
- Diabetic patients (Diabetes Mellitus Type I & II)
- Patients have cardiovascular, lung, Renal, Liver diseases
- Patients on H2 blocker & proton pump inhibitors therapy as Ranitidine (affects
metformin absorption and clearance)
- Those with allergy or sensitivity to Metformin therapy or having any contraindication
for their use.
- Systemic and/or local systemic drug therapy within the last 3 months prior to the
start of the study
- Patients on steroidal or Non-steroidal anti-inflammatory drugs (NSAIDs) for at least
the last 6 months
- Patients on Antibiotics treatment for at least the last 2 months
- Patients on Retinoid, green tea supplements or another natural products therapy
- Patients with already diagnosed malignant lesion/lesions
- Pregnant or Lactating females
- Vulnerable groups as prisoners, mentally disabled, etc…
Gender
All
Ages
20 Years - 70 Years
Accepts Healthy Volunteers
No
Contacts
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Location Countries
Egypt
Location Countries
Egypt
Administrative Informations
NCT ID
NCT03685409
Organization ID
023836530
Responsible Party
Principal Investigator
Study Sponsor
Cairo University
Study Sponsor
, ,
Verification Date
September 2018