Oxidative Stress and Inflammation Biomarkers in Surgically Treated Patients With Laryngeal Cancer

Quality of Life Clinical Trial

Official title:

Oxidative Stress and Inflammation Biomarkers in Correlation to Postoperative Pain Modulation in Surgically Treated Patients With Laryngeal Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05857202
• Other study ID #: 754/5
• Status: Recruiting
• Start date: September 1, 2022
• Est. completion date: October 30, 2023

Study information

• Verified date: May 2023
• Source: Clinical Centre of Serbia
• Contact: Ana D Jotic, MD, PHD
• Phone: +381 63 7789825
• Email: anajotic[@]yahoo.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: October 30, 2023
• Est. primary completion date: September 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• patients with all stages of diagnosed and operable laryngeal squamocellular carcinoma (T1-T4, N0-N2)

Exclusion Criteria:

• 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
• the inability to provide informed consent.

Related Conditions & MeSH terms

• Inflammation
• Interleukins
• Laryngeal Cancer
• Laryngeal Neoplasms
• Oxidative Stress Induction
• Pain Management
• Pain, Postoperative
• Quality of Life

Intervention

Drug:
• Analgesics, Opioid
Drugs were given immediately after the surgery, and correlation between analgesic use and parameters of oxidative stress and inflammation was assessed.
• Analgesics, Non-Narcotic
Drugs were given immediately after the surgery, and correlation between analgesic use and parameters of oxidative stress and inflammation was assessed.

Locations

Country	Name	City	State
Serbia	Clinic for otorhinolaryngology and maxillofacial surgery, Clinical Center of Serbia	Belgrade
Serbia	Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade	Belgrade

Sponsors (2)

Lead Sponsor	Collaborator
Clinical Centre of Serbia	Faculty of Medicine, University of Belgrade

Country where clinical trial is conducted

Serbia, 

References & Publications (12)

Hinther A, Nakoneshny SC, Chandarana SP, Wayne Matthews T, Dort JC. Efficacy of postoperative pain management in head and neck cancer patients. J Otolaryngol Head Neck Surg. 2018 May 2;47(1):29. doi: 10.1186/s40463-018-0274-y. — View Citation

Karkkainen J, Selander T, Purdy M, Juvonen P, Eskelinen M. Patients with Increased Levels of the Oxidative Stress Biomarker SOD1 Appear to Have Diminished Postoperative Pain After Midline Laparotomy: A Randomised Trial with Special Reference to Postoperat — View Citation

Liu D, Liu H, Wu J, Gong B. Effects of Thoracic Paravertebral Blockon Inflammatory Response, Stress Response, Hemodynamics and Anesthesia Resuscitation inGallbladder Carcinoma. Cell Mol Biol (Noisy-le-grand). 2022 Feb 28;68(2):171-177. doi: 10.14715/cmb/2 — View Citation

Liu Q, Xu K. Evaluation of some cellular biomarker proteins, oxidative stress and clinical indices as results of laparoscopic appendectomy for perforated appendicitis in children. Cell Mol Biol (Noisy-le-grand). 2020 Jun 5;66(3):197-203. — View Citation

Niklander SE, Murdoch C, Hunter KD. IL-1/IL-1R Signaling in Head and Neck Cancer. Front Oral Health. 2021 Aug 26;2:722676. doi: 10.3389/froh.2021.722676. eCollection 2021. — View Citation

Purdy M, Karkkainen J, Kokki M, Anttila M, Aspinen S, Juvonen P, Kokki H, Pulkki K, Rantanen T, Eskelinen M. Does Rectus Sheath Block Analgesia Alter Levels of the Oxidative Stress Biomarker Glutathione Peroxidase: A Randomised Trial of Patients with Canc — View Citation

Rettig TC, Verwijmeren L, Dijkstra IM, Boerma D, van de Garde EM, Noordzij PG. Postoperative Interleukin-6 Level and Early Detection of Complications After Elective Major Abdominal Surgery. Ann Surg. 2016 Jun;263(6):1207-12. doi: 10.1097/SLA.0000000000001 — View Citation

Salzman R, Kankova K, Pacal L, Tomandl J, Horakova Z, Kostrica R. Increased activity of superoxide dismutase in advanced stages of head and neck squamous cell carcinoma with locoregional metastases. Neoplasma. 2007;54(4):321-5. — View Citation

Si HB, Yang TM, Zeng Y, Zhou ZK, Pei FX, Lu YR, Cheng JQ, Shen B. Correlations between inflammatory cytokines, muscle damage markers and acute postoperative pain following primary total knee arthroplasty. BMC Musculoskelet Disord. 2017 Jun 17;18(1):265. d — View Citation

Sies H, Berndt C, Jones DP. Oxidative Stress. Annu Rev Biochem. 2017 Jun 20;86:715-748. doi: 10.1146/annurev-biochem-061516-045037. Epub 2017 Apr 24. — View Citation

Uz U, Eskiizmir G. Association Between Interleukin-6 and Head and Neck Squamous Cell Carcinoma: A Systematic Review. Clin Exp Otorhinolaryngol. 2021 Feb;14(1):50-60. doi: 10.21053/ceo.2019.00906. Epub 2021 Feb 1. — View Citation

Xi MY, Li SS, Zhang C, Zhang L, Wang T, Yu C. Nalbuphine for Analgesia After Orthognathic Surgery and Its Effect on Postoperative Inflammatory and Oxidative Stress: A Randomized Double-Blind Controlled Trial. J Oral Maxillofac Surg. 2020 Apr;78(4):528-537 — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	7 days
Primary	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.	7 days
Primary	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.	7 days
Primary	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.	7 days
Primary	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.	7 days
Primary	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.	7 days