Oral Leukoplakia Clinical Trial
Official title:
Evaluation of Effect of Topical Melatonin in Treatment of Oral Leukoplakia: A Randomized Placebo Controlled Study
Oral leukoplakia is the most commonly occurring oral premalignant disorder. It has an overall
prevalence rate of 1-4% with highest prevalence rate of 10.54% in Asian countries. The
management of leukoplakia includes conventional as well as surgical modalities. The
conventional approaches include Beta Carotene, Lycopene, ascorbic acid, alpha tocopherol,
retinoids. But, no significant results are documented on regression rate and prevention of
recurrence of the lesions.
Melatonin chemically N-acetyl-5-methoxytryptamine is a hormone produced in the pineal gland.
It is synthesized from the amino acid, tryptophan. The basic physiological function of
melatonin is to control day night cycle and hence is commonly used in insomnia, jet lag and
some other psychological disorders.
Melatonin has a potent antioxidant effect and other actions such as modulation of cell cycle
and induction of apoptosis, inhibition of telomerase activity, inhibition of metastasis,
prevention of circadian disruption, anti-angiogenesis and stimulation of cell differentiation
To date, no treatment modality has demonstrated its clear superiority for leukoplakia. There
are many pathways by which melatonin can be used beneficially for management oral
leukoplakia.
The World Health Organization (W.H.O). defines oral potentially malignant disorders (OPMDs)
as "A histologically proven lesion that is associated with a significantly increased risk of
malignant transformation."Oral leukoplakia is the most commonly occurring oral potentially
malignant disorder. According to World Health Organisation (WHO), it is defined as
"predominantly white plaques of questionable risk having excluded other known diseases or
disorders that carry no increased risk for cancer."Leukoplakia has a prevalence rate of 1-4%
in the world and 0.2% to 5.2% in Indian Subcontinent, with a malignant transformation rate
(MTR) of 0.13% to 10%.
The risk factors include- a) Smokeless and smoking tobacco b) Ultraviolet radiation c)
Associated infections like candida, Human papilloma virus (HPV), Epstein Bar Virus (EBV) d)
Synergistic effects of alcohol e) Epithelial atrophy due to conditions like syphilis, vitamin
deficiencies, iron deficiencies f) trauma.
There are mainly two types of leukoplakia- homogenous and non-homogenous. When widespread or
multiple patches of leukoplakia are noted, the term proliferative verrucous leukoplakia (PVL)
is used. The homogenous leukoplakias have a lower risk of malignant transformation (0.6%-5%)
as compared to non-homogenous (20-25%), while its highest for PVL (61%). The MTR is also high
in lesions of size more than 200 mm, tongue and floor of mouth, female patients, old age,
severe dysplasia, HPV and candida associated and DNA Aneuploidy.The presence of dysplasia in
the lesions of leukoplakia increases the incidence of malignancy by 30 %.
On exposure to carcinogens, tissue cells proliferate and shrink the cytosolic capacity as an
adaptation which can be appreciated as hyperplasia of epithelium in histological sections.
The persistence of irritant factor leads to cellular degeneration and atrophy, thus further
progressing into irreversible cell damages, leading to apoptosis, genetic damages and
malignant transformation. There are many studies which suggest the role of reactive oxygen
species and reactive nitrogen species in the initiation and progression of carcinogenesis.
The generation of oxidative stresses further lead to DNA damage in later stages. Studies are
also done which shows decrease in the serum superoxide dismutase, glutathione reductase,
glutathione peroxidase and catalase in the patients of leukoplakia.
It is a well-established fact that, oral cancer development is a two-step process which
constitutes the emergence of premalignant disorders and their subsequent conversion into
cancer. The asymptomatic nature of leukoplakia makes the scenario more difficult as they go
unnoticed, leading to their diagnosis only in the stages of malignant conversion. Medical as
well as surgical management of cancer causes a deterioration in quality of life of patients
due to potentially harmful side effects. Thus, more focus is necessary for chemoprevention of
leukoplakia lesions at the premalignant stages thereby preventing its malignant
transformation.
The management of leukoplakia includes both conventional as well as surgical modalities. The
conventional approaches include Beta Carotene, Lycopene, ascorbic acid, alpha tocopherol,
retinoids. But, no significant results are documented on regression rate and prevention of
recurrence of the lesions. Other treatment modalities under the experimental trials include
extracts of green tea, inhibitors of cyclo-oxygenase 2, epidermal growth factors, peroxisome
proliferator. However, there is no generally approved standard systemic therapy so far. Local
surgical procedures include photodynamic therapy, laser therapy, cryotherapy and excision.
Melatonin chemically N-acetyl-5-methoxytryptamine is a hormone produced in the pineal gland.
It is synthesised from the amino acid, tryptophan. The basic physiological function of
melatonin is to control day night cycle and hence is commonly used in insomnia, jet lag and
some other psychological disorders.
Melatonin has been proved to exert oncostatic properties through various mechanisms like
potent antioxidant effect, antiproliferative functions, stimulation of anticancer immunity,
antiangiogenic effects, modulation of oncogene expression and anti-inflammatory. It also
exhibits anti candidal and radioprotective effect on the oral mucosa. Thus, melatonin may be
helpful in treatment of oral leukoplakia.
Therefore, this study intends to evaluate the effect of topical application of melatonin on
clinical response as well as on histopathological and immunohistochemistry findings of
leukoplakia.
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