Melatonin Effect in Combination With Neoadjuvant Chemotherapy to Clinical Response in Locally Advanced Oral Squamous Cell Carcinoma
Condition: Oral Squamous Cell Carcinoma; Neoadjuvant Chemotherapy
MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
Intervention: Melatonin 20 MG Oral Capsule; Placebo oral capsule
Intervention description: The administration of Melatonin 20 mg in addition to neoadjuvant chemotherapy to observe the antioxidant and onco-static effect.; The administration of placebo capsule in addition to neoadjuvant chemotherapy
Intervention MeSH terms: Melatonin
Phase: Phase 3
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: one group receive standard treatment with melatonin, while the other group receive standard treatment with placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: double-blind masking
Enrollment: 50.0
Sex: All
Healthy volunteers: No
Keywords: Melatonin; Locally Advanced Oral Squamous Cell Carcinoma; Neoadjuvant Chemotherapy

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