Neoplasms

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Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Oral Squamous Cell Carcinoma

Central Nervous System Depressants

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Melatonin

Antioxidants

Protective Agents

The group received standard treatment with the oral administration of Melatonin

The group received standard treatment with the oral administration of Placebo

The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.

Melatonin 20 MG Oral Capsule

The administration of placebo capsule in addition to neoadjuvant chemotherapy

Placebo oral capsule

Diani Kartini, MD

Backgrounds

Squamous cell carcinoma of the oral cancer (OSCC) is the sixth most common malignancy. Surgery is the mainstay of treatment for oral cancers. In locally advanced and unresectable oral cancer, surgery presents challenges primarily because the head and neck region have many critical structures that can be damaged by tumor or treatment. Damage to the critical structures can result in significant structural, cosmetic and functional deficits that negatively impact quality of life.

Use of NC was found to achieve resectability in 39% of locally advanced unresectable oral cancers. Patil et al. reported response rate with the three drugs regimen (TPF) for NC was 32% and 27,37% for two drugs regimen (TP). The overall response rate in the TPF group was significantly higher than that in the PF group, both in the induction-chemotherapy phase and after locoregional therapy (33,3% vs 19,9%, p = 0,004). Chemoresistancy has become the challenge in OSCC treatment affecting tumor response to chemotherapy.

Hypoxic microenvironment found in OSCC is marked by the high expression of HIF-1α. CD44 and CD133 as a cancer stem cells marker in head and neck (HNSCC) and miR-210 known as hypoxamiR has been reported to contribute chemoresistancy. As hypoxia inarguably one of the main causes of chemoresistancy, it is agreeable to use melatonin as an antioxidant to reduce the hypoxic condition in tumor microenvironment. Melatonin, a potent endogenous antioxidant agent is proven to have an oncostatic effect, was given in expect to reduce the tumor hypoxic condition so that it would increase the tumor response on NC. Majority of the clinical study use oral melatonin given once daily in 20 mg dose as the minimal dose to yield anti-tumor effects.

The purpose of this study is to prove the effectiveness of melatonin to increase clinical response in locally advanced OSCC patients when treated with NC. The effect of melatonin in reducing tumor hypoxia will be seen through its effect in decreasing the gene expressions of HIF-1α, miR-210, CD44, and CD133.

Methods

Study Design

This study is a double blind, randomized clinical trial using placebo as comparison running from June 2017 to July 2018 . Locally advanced OSSC (stage IVA and IVB) patients that will receive NC were included in the study. Fifty patients treated at two centres (RSCM and RSKD) were randomly allocated into two arms. Twenty-five patients received melatonin combined with three regiment NC (Taxane, Cisplatin, and 5-FU) and the other received placebo with NC. However only 25 out of 50 patients had completed the study protocol (13 patients in melatonin arm and 12 in placebo arm)

Evaluation of Clinical Response

The clinical response were assessed by evaluating pre-treatment and post treatment MRI with the aid of RECIST 1.1. First, it is necessary to estimate the overall tumor burden at baseline (target and non-target lesion) and use this as a comparator for subsequent measurement. The tumor response then being determined according to the definition criteria according to RECIST 1.1, as follows: Complete response (CR) is the disappearance of all target lesions. Partial response (PR) means there is at least 30% decrement in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) means there is at least a 20% increment in the sum of diameters of target lesions or an absolute increment of at least 5 mm. Stable disease (SD) is when there is neither a sufficient shrinkage nor sufficient increment of target lesion. Patients who categorized as PR and CR undergone surgery while those with SD and PD undergone core biopsy.

Genes expression examination

The primer for HIF-1α miR210, CD44, and CD133 genes amplification was design using a Primer Quest Tool IDT software. The total sequence of each gene attained from GenBank data source: National Centre for Biotechnology Information (NCBI). The steps of gene expression examination are RNA isolation, cDNA synthesis, and absolute quantification qPCR. qPCR result was analyzed based on the gene expression concentration compare to the pre-determined standard curve (positive control) of each genes.

Statistical analysis

The data was analysed with statistics software SPSS 20. Saphiro Wilk was used to test data normal distribution. Data with normal distribution and with p \> 0,05 presented in mean +- standard deviation (SD). Data with abnormal data distribution presented in median (minimal and maximal value). The statistical difference of gene concentration level (numerical data) between melatonin and placebo was analysed using normality test of Saphiro Wilk. Data with normal distribution was tested using unpaired-T test, while data with abnormal distribution was tested using Mann Whitney. Statistically significant different stated as p \< 0,05.

one group receive standard treatment with melatonin, while the other group receive standard treatment with placebo

Melatonin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma

Effect of Melatonin in Combination With Neoadjuvant Chemotherapy to HIF-1⍺, CD44, CD133, and miR-210 Expression and Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma (OSCC)

Clinical Response is measured using RECIST 1.1. criteria. CR (Complete response) is defined as disappearance of all target lesion, and pathological lymph node showing reduction of its shortest axis to less than 10 mm. PR (Partial response) is defined as reduction of total target lesion diameter at least by 30%. PD (Progressive disease) is defined as total target lesion diameter increased in size atleast by 20% or 5 mm OR occurence of one new lesion. SD (Stable disease) is defined as absence of reduction or increasing of target lesion. Patients with PR and CR are considered as positive response. Patients with SD and PD are considered as negative response.

Expression of HIF-1⍺ is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.

Expression of miR-210 is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.

Expression of CD44 is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.

Expression of CD133 is measured at the initial period of the study (baseline) and after 3 neoadjuvant chemotherapy cycles are completed using qRT-PCR Absolute Quantification. Change was calculated from two time points as the value at the later time point minus the value at the earlier time point.

Indonesia University

Lecturer, Staff of Oncology Division of Department of Surgery, Principal Investigator

The group received standard treatment with the oral administration of Melatonin

Melatonin 20 MG Oral Capsule: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.

The group received standard treatment with the oral administration of Placebo

Placebo oral capsule: The administration of placebo capsule in addition to neoadjuvant chemotherapy

Placebo

Participants who received Melatonin (treatment arm) who finished study protocol

Melatonin Group

Participants who received Placebo (control arm) who finished study protocol

Placebo Group

Total

Age, Customized

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Indonesia

Region of Enrollment

Tumor Location

Stage of patients is performed referring to 8th edition 2017 American Joint Committee on Cancer (AJCC) Staging based on TNM (Primary tumor, Regional lymph nodes, Distant metastasis). Patients with Stage IVa is in general considered to have a better outcome than those of having Stage IVb.

Stage

Keratinized/non-keratinized

Differentiation

Grade

Medication adherence

There is a significant number of participants that are enrolled at the initial period of study but did not complete the whole study protocol due to various reasons, therefore statistical power of this study becomes lowered.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Melatonin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma	NCT04137627	Oral Squamous C... Neoadjuvant Che...	Melatonin 20 MG... Placebo oral ca...	-	Indonesia University
Melatonin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma	NCT04137627	Oral Squamous C... Neoadjuvant Che...	Melatonin 20 MG... Placebo oral ca...	-	Indonesia University

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