Clinical trial NCT04137627: Melatonin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Oral Squamous Cell Carcinoma
Neoadjuvant Chemotherapy
Keywords: Melatonin
Locally Advanced Oral Squamous Cell Carcinoma
Neoadjuvant Chemotherapy
Lead sponsor: Indonesia University
Sponsor class: OTHER
First posted: 2019-10-24
Enrollment: 50
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: one group receive standard treatment with melatonin, while the other group receive standard treatment with placebo
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Patients with locally advanced oral squamous cell carcinoma
2. Patients with locally advanced oral squamous cell carcinoma who are planned with neoadjuvant chemotherapy
3. Patients with locally advanced oral squamous cell carcinoma who are planned with neoadjuvant chemotherapy who have not received any definitive treatment modalities, including surgical resection and chemoradiation therapy before the study conducted
4. Patients who are willing to sign the informed consent form to be our subject participants
5. Karnofky \>50

Exclusion Criteria:

1. Patients who are already treated with definitive therapy for locally advanced oral squamous cell carcinoma
2. Patients who are not eligible to be treated with chemotherapy

Primary outcomes:
measure: Clinical Response as Measured by RECIST 1.1. Criteria
timeFrame: 1 Year
Secondary outcomes:
measure: Change in Expression of HIF-1⍺ as Measured by qRT-PCR Absolute Quantification
timeFrame: 1 Year
measure: Change in Expression of miR-210 as Measured by qRT-PCR Absolute Quantification
timeFrame: 1 Year
measure: Change in Expression of CD44 as Measured by qRT-PCR Absolute Quantification
timeFrame: 1 Year
measure: Change in Expression of CD133 as Measured by qRT-PCR Absolute Quantification
timeFrame: 1 Year
Other outcomes:
Locations:
city: Jakarta Pusat
country: Indonesia
facility: Faculty of Medicine, Universitas Indonesia
state: DKI Jakarta
Study officials:
affiliation: Indonesia University
name: Diani Kartini, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kartini D, Taher A, Panigoro SS, Setiabudy R, Jusman SW, Haryana SM, Abdullah M, Rustamadji P, Purwanto DJ, Sutandyo N, Suroyo I, Siregar BH, Maruli H, Sungkar S. 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. J Egypt Natl Canc Inst. 2020 Feb 28;32(1):12. doi: 10.1186/s43046-020-0021-0.