An observational study in Oxidative Stress Induction, Laryngeal Cancer and Interleukins, sponsored by Clinical Centre of Serbia. Recruiting at 2 sites in Serbia. Open to participants aged 18 Years to 85 Years. Per ClinicalTrials.gov, last updated 2023-05-12.
Sponsored by Clinical Centre of Serbia · Observational
A experimental interventional prospective study will include patients with squamocellular carcinoma of the larynx surgically treated at the tertiary referral center. Clinical and demographic characteristics of the patients would be noted. The visual analog scale (VAS), Brief Pain Inventory questionnaire, Diagnosing Neuropathic Pain 4 (DN4) and Pain Detect Questionnaire were used for pain assessment. Questionnaire Quality of Life in Head and Neck Cancer Patients (QLQ - H\&N35) was used to assess the quality of life in patients with surgically treated laryngeal carcinoma. The type and consumption of analgesics used after surgery was monitored. The analgesics were used according to WHO Ladder. Blood samples ware taken from the patients for the analysis of oxidative stress parameters and inflammation parameters before the operative treatment and after the operative treatment (1-2 postoperative day and 9-10 postoperative day). The concentrations of interleukin 1 (IL-1) and 6 (IL-6), glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1) and malondialdehyde (MDA) in the serum were determined.
The aim of the study will be to assess concentrations of inflammatory biomarkers (IL-1, IL-6) and oxidative stress factors (MDA, SOD, GPKS1) in postoperative course in surgically treated patients with laryngeal carcinoma and in possible complication occurrence. Also, their correlation to type and dosage of used analgesics, to pain assessment questionnaire scores and QOL questionnaire scores in surgically treated patients with laryngeal carcinoma will be assessed.
Patient selection
A experimental interventional prospective study would include 100 patients with squamocellular carcinoma of the larynx surgically treated in the period from October 2022 to February 2023 at the tertiary referral center. This study was approved by the Institutional Ethics Committee (745/5-22), and all patients signed the informed consent form prior to their inclusion in the study. The diagnosis of laryngeal carcinoma was confirmed by otorhinolaryngological clinical examination and laryngomicroscopic examination of the larynx with the biopsy and histopathologic examination of the tissue. Additional diagnostics (chest radiography and computed tomography of the neck and ultrasonography of the abdomen) were performed to determine the TNM stage of the disease. Study included patients with all stages of operable laryngeal carcinoma (T1-T4, N0-N2), without previous treated malignancies. Exclusion criteria were inoperable malignant disease, presence of distant metastases, previously treated malignancies, presence of neurological or other severe comorbidities which prevent surgical treatment, the presence of neurological or other severe physical and metabolic comorbidities, substance abuse, and the inability to provide informed consent.
The modality of treatment for every patient was decided on the institutional Oncological Board (consisting of a radiotherapist, head and neck surgeons, an oncologist, and a histopathologist). Open surgical treatment involved resection of the tumor (cordectomy, partial or total laryngectomy) with or without some form of the neck dissection in case of cervical lymphadenopathy. Demographic, clinical and histopathological characteristics (age and gender, tobacco use, histopathological tumor grade, TNM classification, and therapy modality) were noted.
Quality of life assessment
Questionnaire Quality of Life in Head and Neck Cancer Patients (QLQ - H\&N35) was used to assess the quality of life in patients with surgically treated laryngeal carcinoma.
Pain assessment
The visual analog scale (VAS) was used for pain assessment. Scores were based on self-reported measures of pain severety that are recorded with a mark placed at one point along the length of a 10-cm line that represents a continuum between the two ends of the scale (0 cm on the left end of the scale marks ''no pain'' and 10 cm on the right end of the scale marks ''the worst pain'').
Brief Pain Inventory questionnaire, Diagnosing Neuropathic Pain 4 (DN4) and Pain Detect Questionnaire were used for quality assessment of postoperative pain
Postoperative analgesia
The type and consumption of analgesics used after surgery was monitored. The analgesics were used according to WHO Ladder: (1) for mild to moderate pain, a non-opioid (acetaminophen or non-steroid anti-inflammatory drug , NSAID) with or without an adjuvant; (2) for moderate or severe pain, a non-opioid with an opioid for moderate pain and (3) an opioid for moderate to severe pain not combined with another agent.
Measurement of the Oxidative Stress and Inflammatory Parameters
Blood was taken from the patients for the analysis of oxidative stress parameters and inflammation parameters before the operative treatment and after the operative treatment (1-2 postoperative day and 9-10 postoperative day). The concentrations of interleukin 1 (IL-1) and 6 (IL-6), glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1) and malondialdehyde (MDA) in the serum were determined by coated enzyme-linked immunosorbent assay (ELISA) kits, according to the manufacturer's instructions (Elabscience, Wuhan, China). The ELISA kits for determination of concentrations of IL-1 and IL-6 were based on the Sandwich ELISA principle, with plates pre-coated with an antibody specific to human cytokines. The optical density (OD) was measured spectrophotometrically at 450 nm, using a Multiskan EX plate reader (Thermo Fisher Scientific, Vantaa, Finland). The concentration of analytesin of the tested samples was calculated by comparing the OD of the samples to the standard curve created with GraphPad Prism 9.0 software (GraphPad Software Inc., San Diego, CA, USA).
Statistical analysis
Categorical data was described by absolute and relative numbers (in percentages), while numerical data was reported as arithmetic mean and standard deviation or median and interquartile range (IQR), depending on the data distribution. The normality was evaluated using mathematical (Shapiro-Willk, skewness and kurtosis, and coefficient of variation) and graphical (histogram, box plot) methods. For the evaluation of changing of pain intensity, parameters of oxidative stress, and biomarkers of inflammation Friedman test was applied with Wilcoxon signed rank test as post-hoc testing method. For analyzing the association between pain intensity (VAS), parameters of oxidative stress, and biomarkers of inflammation Spearman's rank correlation coefficient was used, because variables didn't have normal distribution. In order to evaluate all possible factors that influence the level of oxidative stress expressed as SOD and MDA levels, linear regression analysis (enter method) was performed reporting regression coefficient B, 95% confidence level (CI) of B, and p value. Univariate analysis was done first, and all significant factors were combined in multivariate models. All statistical methods were considered significant if p value was less or equal 0.05. The analysis was performed in IBM SPSS ver. 26.
The study would include 100 patients with squamocellular carcinoma of the larynx surgically treated at the tertiary referral center. The diagnosis of laryngeal carcinoma was confirmed by otorhinolaryngological clinical examination, laryngomicroscopic examination with the biopsy and histopathologic examination. Additional diagnostics (chest radiography and computed tomography of the neck and ultrasonography of the abdomen) were performed to determine the TNM stage of the disease.
The modality of surgical treatment was decided on the institutional Oncological Board and involved resection of the tumor (cordectomy, partial or total laryngectomy) with or without some form of the neck dissection in case of cervical lymphadenopathy.
Exclusion Criteria:
Operated laryngeal cancer patients who were administered non narcotic drugs postoperative for pain management
Drug: Analgesics, Non-Narcotic
Operated laryngeal cancer patients who were administered non narcotic and opioids postoperative for pain management
Drug: Analgesics, Opioid · Drug: Analgesics, Non-Narcotic
Operated laryngeal cancer patients who were administered opioids postoperative for pain management
Drug: Analgesics, Opioid
Drugs were given immediately after the surgery, and correlation between analgesic use and parameters of oxidative stress and inflammation was assessed.
Drugs were given immediately after the surgery, and correlation between analgesic use and parameters of oxidative stress and inflammation was assessed.
Correlation between inflammatory marker IL-1 and pain intensity
A positive correlation between concentration of inflammatory marker IL-1 and pain intensity (VAS score) in postoperatively in surgically treated patients with laryngeal cancer is expected. The concentrations of inflammatory parameters IL-1 (pg/mL) in the blood serum were determined by ELISA kits, according to the manufacturer's instructions. Pain intensity would be assessed using the visual analog scale (VAS). Scores were based on self-reported measures of pain severity recorded with a mark placed at one point along the length of a 10-cm line that represents a continuum between the two ends of the scale (0 mm on the left end of the scale marks ''no pain'' and 100mm on the right end of the scale marks ''the worst pain''). Correlation would be calculated with Spearman's rank correlation coefficient.
Time frame: 7 days
Correlation between inflammatory marker IL-6 and pain intensity
A positive correlation between concentration of inflammatory marker IL-6 and pain intensity (VAS score) in postoperatively in surgically treated patients with laryngeal cancer is expected. The concentrations of inflammatory marker IL-6 (pg/mL) in the blood serum were determined by ELISA kits, according to the manufacturer's instructions. Pain intensity would be assessed using the visual analog scale (VAS). Scores were based on self-reported measures of pain severity recorded with a mark placed at one point along the length of a 10-cm line that represents a continuum between the two ends of the scale (0 mm on the left end of the scale marks ''no pain'' and 100mm on the right end of the scale marks ''the worst pain''). Correlation would be calculated with Spearman's rank correlation coefficient.
Time frame: 7 days
Correlation between inflammatory marker CRP and pain intensity
A positive correlation between concentration of inflammatory marker CRP and pain intensity (VAS score) in postoperatively in surgically treated patients with laryngeal cancer is expected. The concentrations of inflammatory marker CRP (ng/mL) in the blood serum were determined by ELISA kits, according to the manufacturer's instructions. Pain intensity would be assessed using the visual analog scale (VAS). Scores were based on self-reported measures of pain severity recorded with a mark placed at one point along the length of a 10-cm line that represents a continuum between the two ends of the scale (0 mm on the left end of the scale marks ''no pain'' and 100mm on the right end of the scale marks ''the worst pain''). Correlation would be calculated with Spearman's rank correlation coefficient.
Time frame: 7 days
Correlation between oxidative stress marker MDA and pain intensity
A positive correlation between concentration of oxidative stress marker MDA and pain intensity (VAS score) in postoperatively in surgically treated patients with laryngeal cancer is expected. The concentrations of oxidative stress marker MDA (ng/mL) in the blood serum were determined by ELISA kits, according to the manufacturer's instructions. Pain intensity would be assessed using the visual analog scale (VAS). Scores were based on self-reported measures of pain severity recorded with a mark placed at one point along the length of a 10-cm line that represents a continuum between the two ends of the scale (0 mm on the left end of the scale marks ''no pain'' and 100mm on the right end of the scale marks ''the worst pain''). Correlation would be calculated with Spearman's rank correlation coefficient.
Time frame: 7 days
Correlation between anti- oxidative stress marker SOD and pain intensity
A negative correlation between concentration of anti-oxidative stress marker SOD and pain intensity (VAS score) in postoperatively in surgically treated patients with laryngeal cancer is expected. The concentrations of anti-oxidative stress marker SOD (pg/mL) in the blood serum were determined by ELISA kits, according to the manufacturer's instructions. Pain intensity would be assessed using the visual analog scale (VAS). Scores were based on self-reported measures of pain severity recorded with a mark placed at one point along the length of a 10-cm line that represents a continuum between the two ends of the scale (0 mm on the left end of the scale marks ''no pain'' and 100mm on the right end of the scale marks ''the worst pain''). Correlation would be calculated with Spearman's rank correlation coefficient.
Time frame: 7 days
Correlation between anti- oxidative stress marker GPX1 and pain intensity
A negative correlation between concentration of anti- oxidative stress marker GPX1 and pain intensity (VAS score) in postoperatively in surgically treated patients with laryngeal cancer is expected. The concentrations of anti-oxidative stress marker GPX1 (pg/mL) in the blood serum were determined by ELISA kits, according to the manufacturer's instructions. Pain intensity would be assessed using the visual analog scale (VAS). Scores were based on self-reported measures of pain severity recorded with a mark placed at one point along the length of a 10-cm line that represents a continuum between the two ends of the scale (0 mm on the left end of the scale marks ''no pain'' and 100mm on the right end of the scale marks ''the worst pain''). Correlation would be calculated with Spearman's rank correlation coefficient.
Time frame: 7 days
Plan to share: Yes — Available and ethical compliant patients data will be submitted to the data repository
Supporting information: Study protocol, Sap, Icf
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Clinical Centre of Serbia