Sodium Selenite Supplementation in Patients With Head and Neck Cancer

Study Overview
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Brief Summary
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The micronutrient selenium is an essential trace element in the human body. There are more than 25 proteins in the human body contain selenium, such as glutathione peroxidase and selenoprotein, which regulate the body's antioxidant and anti-inflammatory properties. Previous literatures had shown cancer patients have lower serum selenium concentrations than normal people, and lower serum selenium levels may be associated with increased cancer mortality. More than 50% of patients with locally advanced head and neck cancer are malnourished before treatment, and these patients often have deficiency of trace elements, including selenium. In these malnourished patients, they may have to endure increased treatment toxicity and treatment interruption when receiving standard concurrent chemoradiotherapy (CCRT). Interruption of treatment may lead to reduced therapeutic efficacy and compromised survival and recurrence rate. Several small studies have investigated whether oral administration of sodium selenite in patients with head and neck cancer undergoing radiation therapy can improve side effects and affect survival rates, but the results are inconsistent. Our study will use the intravenous form of sodium selenite (Zelnite®) to investigate the effect of selenium on the treatment outcomes of locally advanced head and neck cancer patients undergoing CCRT, such as therapy-related toxicities, quality of life, changes in selenium concentration in blood, nutritional, inflammation and immune markers, and tracking long-term survival and recurrence rates.

Detailed Description
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Selenium is an essential trace element for humans. It is involved in redox regulation, antioxidant functions, membrane integrity, and protection against DNA injury. In both animal models and human studies, it has been shown that selenium has cancer-protective effects and cytoprotective activities. Some mechanisms have been proposed to explain the anti-cancer effects of selenium, which include the antioxidant properties by selenoproteins, induction of conjugating enzymes that detoxify carcinogens, enhancement of the immune response, alterations in DNA methylation and blockage of the cell cycle to allow DNA repair. There has been conflicting response regarding selenium supplementation on the reduction of toxicity, antitumor efficacy and their quality of life in patients receiving radiotherapy. In the studies by Kiremidjian-Schumacher et al. and Elango et. al, sodium selenite supplementation was shown to significantly enhance cell-mediated immune responsiveness and improve defense systems in head and neck cancer patients. Micke et al. and Zimmerman et al. demonstrated the quality of life of patients suffering from head and neck cancer with lymphedema significantly improved after selenium supplementation. In the study by Büntzel et al., selenium supplementation reduced the radiation-associated side-effects of dysphagia developments in patients with head and neck cancer patients. However, some studies showed negative response of selenium supplementation in head and neck cancer patients. Weijl et al. showed oral selenium supplementation did not show improvement in cisplatin-induced toxicity or response rate in cancer patients. In the study by Mix et al., addition of oral selenium supplementation was well-tolerated but did not lower the incidence of severe mucositis or improve quality of life or survival outcomes in head and neck cancer patients undergoing concurrent chemoradiation (CRT). An early systematic review in Cochrane demonstrated there was still insufficient evidence to conclude efficacy of selenium in alleviating the side effects of chemotherapy or radiotherapy treatments. The aim of this study is to investigate the effect of intravenous selenium supplementation on the treatment outcome of head and neck patients undergoing CCRT (toxicities, quality of life, overall survival, progression-free survival), selenium concentration changes during CCRT, and its correlation with nutritional, inflammation and immune markers.

Official Title
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The Role of Sodium Selenite Supplementation in Patients With Locally Advanced Head and Neck Cancer Undergoing Concurrent Chemoradiotherapy

Conditions
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Head and Neck Squamous Cell Carcinoma, Selenium, Sodium Selenite

Intervention / Treatment
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* Dietary Supplement: Zelnite®
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological proven head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharynx, larynx, or metastatic cervical lymphadenopathy of unknown primary origin) who were scheduled for adjuvant or primary concurrent chemoradiotherapy (CCRT). American Joint Committee on Cancer 8th edition stage III, IVA, and IVB patients. Age 20-75 years old. Adequate hematopoietic or organ function (leukocyte count ≥ 3.0 x 109/L, hemoglobin ≥ 10 g/dL, platelet count ≥ 100 x109/L, serum bilirubin level ≤ 1.5 mg/dL, alanine aminotransferase (ALT) and aspartate aminotransferase levels (AST) ≤ 3 x upper limit of normal, and serum creatinine level ≤ 1.6 mg/dL or creatinine clearance ≥ 60 mL/min/1.73m2). ECOG performance status grade≦2. Subjects understand this study, agree to join this study and are able to sign the written inform consent form. Exclusion Criteria: Nasopharyngeal cancer. History of selenium allergy or intolerance. Received selenium supplementation in recent 1 month. Uncontrolled infection - according to PI diagnosis Heart failure - New York Heart Association class IV Impaired liver function (serum total bilirubin > 2 x upper limit of normal (ULN), ALT and/or AST > 5 x ULN). Impaired renal function: serum creatinine > 1.5 x ULN. Inadequate bone marrow function (white blood cell count < 2,500 / mm3 (<2.5 x 10^9/L), platelets < 100,000 / mm3 (< 100 x 10^9/L) and hemoglobin < 10 g/dL).

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sodium selenite<br>200μg/d intravenous sodium selenite was dissolved in 100 ml 0.09% NaCl run 30 minutes, will be given on day 1-5, day 8-12, day 15-19, day 22-26, day 29-33, day 36-40, day 43-47 during concurrent chemoradiotherapy. | Dietary Supplement: Zelnite®<br>* 2pc intravenous Zelnite® will be given for 7 weeks (5 days/week).<br>|
| Placebo Comparator: Placebo<br>100 ml intravenous 0.09% NaCl run 30 minutes, will be given on day 1-5, day 8-12, day 15-19, day 22-26, day 29-33, day 36-40, day 43-47 during concurrent chemoradiotherapy. | Dietary Supplement: Placebo<br>* Placebo will be given for 7 weeks (5 days/week).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities | Mucositis, pharyngitis, dermatitis, xerostomia, fatigue, infection, and cytopenia by Common Terminology Criteria for Adverse Events version 5 (CTCAE v5.0) | Week 1 to Week 8 | 
| Pain assessment | Visual analogue scale (VAS): score ranges 0-10 (higher value indicates worse outcome) | Week 1 to Week 8 | 
| Quality of life changes | European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module (EORTC QLQ-HN43), reported in mean values (higher value indicates worse outcome) | Week 1 to Week 8 | 
| Serum concentration changes of selenium | Serum levels of selenium during concurrent chemoradiotherapy | Week 1 to Week 8 | 
| Changes of albumin | Serum albumin (g/dL) changes during concurrent chemoradiotherapy | Week 1 to Week 12 | 
| Changes of transferrin | Serum transferrin (mg/dL) changes during concurrent chemoradiotherapy | Week 1 to Week 12 | 
| Changes of total cholesterol | Total cholesterol (mg/dL) changes during concurrent chemoradiotherapy | Week 1 to Week 12 | 
| Change of interferon-γ (IFNγ) | IFNγ (pg/mL) changes during concurrent chemoradiotherapy | Week 1 to Week 8 | 
| Changes of tumor necrosis factor-α (TNFα) | TNFα (pg/mL) changes during concurrent chemoradiotherapy | Week 1 to Week 8 | 
| Changes of interleukin-2 (IL-2) | IL-2 (pg/mL) changes during concurrent chemoradiotherapy | Week 1 to Week 8 | 
| Changes of interleukin-6 (IL-6) | IL-6 (pg/mL) changes during concurrent chemoradiotherapy | Week 1 to Week 8 | 
| Changes of granzyme B | Granzyme B (pg/mL) changes during concurrent chemoradiotherapy | Week 1 to Week 8 | 
| Immune cells changes during concurrent chemoradiotherapy | By using Maxpar Direct Immune Profiling Assay to identify 30 subsets of immune cells | Week 1 to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival |  | 0 to 3 years | 
| Overall survival |  | 0 to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sodium selenite, Selenium, chemoradiotherapy, head and neck cancer