Effect of melatonin supplementation in combination with neoadjuvant chemotherapy to miR-210 and CD44 expression and clinical response improvement in locally advanced oral squamous cell carcinoma: a randomized controlled trial

Background: Squamous cell carcinoma of the oral cavity (OSCC) is the sixth most common malignancy. Surgery is
mainstay treatment for oral cancers. Surgery in locally advanced OSCC presents many challenges primarily because
the head and neck have critical structures that can be damaged by tumor or treatment. It is thought that
neoadjuvant chemotherapy (NC) in locally advanced OSCC is able to shrink tumor size. Chemoresistancy is a
problem due to hypoxic microenvironment characterized by increased expression of HIF-1α. It is also regulated by
miR-210 as well as increased expression of CD44 and CD133. Melatonin has a powerful antioxidant and oncostatic
effects that are expected to improve tumor hypoxia and clinical response. Fifty patients with OSCC were included
and randomized. miR-210 and CD44 expression were measured before and after intervention using qRT-PCR
absolute quantification, and clinical response was evaluated according to RECIST 1.1 criteria. This study aims to
determine the effect of melatonin in improving the clinical response of patients with locally advanced oral
squamous cell carcinoma (OSCC) after neoadjuvant chemotherapy to miR-210 and CD44 expression.
Results: Melatonin administration reduced miR-210 levels but not significant (p = 0.767). CD44 expression also
decreased in the melatonin group compared with placebo yet was not significant (p = 0.103). There was a decrease
in the expression of miR-210 and CD44 followed by a decrease in the percentage of residual tumor but not
significant (p = 0.114)
Conclusion: In OSCC, the addition of 20-mg melatonin to neoadjuvant chemotherapy (NC) reduced the expression
of miR-210 and CD44 and decreased the percentage of tumor residue; however, no statistically significant result
was observed.
Trial registration: This study is registered to ClinicalTrials.gov under trial registration number: NCT04137627 with
date of registration on October 22, 2019—retrospectively registered, accessible from: https://clinicaltrials.gov/ct2/
show/NCT04137627
Keywords: CD44, Clinical Response, Melatonin, OSCC, Tumor residue percentage