Vagus Nerve Preservation and Chronic Cough in Non-small Cell Lung Cancer Surgery

Study Overview
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Brief Summary
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Lung cancer is the leading cause of cancer death worldwide. Surgical resection is the main treatment for resectable non-small-cell lung cancer (NSCLC), and lobectomy with systemic mediastinal lymph node dissection is the standard surgical method. However, a significant number of patients experience postoperative chronic cough; it is observed in about 60% of patients during the first year of outpatient clinic follow-up, and persistently lasts in about 24.7-50% during the 5 year follow-up period. Several studies showed the association between vagus nerve and chronic cough. The bronchopulmonary vagal afferent C-fibers are responsible for cough, chest tightness and reflex bronchoconstrictions. It is expected that during the mediastinal lymph node dissection, the inevitable injuries to the pulmonary branch of vagus nerve is largely responsible for development of chronic cough. In other words, preservation of pulmonary branch of vagus nerve may reduce the incidence of chronic cough and relevant detrimental effects on quality of life. Therefore, this prospective, randomized and controlled clinical study, aims to evaluate the effect of vagus nerve preservation on postoperative chronic cough in patients undergoing lobectomy with mediastinal lymph node dissection. In addition, the feasibility and oncologic safety of preserving pulmonary branch of vagus nerve during mediastinal lymph node dissection with minimally invasive surgery compared with conventional mediastinal lymph node dissection with minimally invasive surgery will also be investigated. This trial will provide a new basis for oncologically feasible, safe and effective new surgical technique for mediastinal lymph node dissection in patients with early lung cancer undergoing minimally invasive surgery. Furthermore, the preventive effect of vagus nerve preservation on incidence of chronic cough will be objectively be proven and thus help to broaden the current knowledge of the role of vagus nerve and postoperative chronic cough.

Official Title
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Prospective Randomized Controlled Study on the Effects of Vagus Nerve Pulmonary Branch Preservation During Video-assisted Thoracic Surgery Lobectomy in Non-small Cell Lung Cancer: Can it Decrease Postoperative Cough and Pulmonary Complications

Conditions
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Cough, Lung Cancer, Vagus Nerve Injuries

Intervention / Treatment
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* Procedure: Pulmonary branch of vagus nerve preserved
* Procedure: Pulmonary branch of vagus nerve not preserved


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects clearly understand the purpose of the study, are willing and able to comply with the requirements to complete the study, and can sign the informed consent. Clinically suspicious of non-small cell lung cancer or tissue confirmed preoperatively Clinical stage T1-3/N0-1/M0 Preoperative ECOG performance status 0-1 Preoperative ASA class I-III Preoperative pulmonary function test FEV1 ≥ 60%, DLCO ≥ 60% Patients expected to achieve R0 (complete resection) via simple lobectomy and mediastinal lymph node dissection Exclusion Criteria: Patients who smoked within 2 weeks prior to operation Patients who received antitussives and expectorants 2 weeks prior to operation Patients who are pregnant or breast feeding Patients with severe or uncontrolled psychological disorders Patients with severe pulmonary adhesion Patients who are ineligible for minimally invasive surgery; thoracotomy conversion Patients diagnosed with other malignancies within 2 years prior to operation Patients who received chemotherapy or radiotherapy within 6 months prior to operation Patients suspicious of clinical N2 or received neoadjuvant therapy prior to operation Patients with cough-related diseases; COPD, asthma, ILD, GERD Patients suspicious of lymph node metastasis/invasion around vagus nerve during the preoperative clinical staging evaluation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 214 patients will be divided into two groups. Control group (N=107): Effort to preserve the pulmonary branch of vagus nerve preservation is not made in this group during mediastinal lymph node dissection Treatment group (N=107): Effort to preserve the pulmonary branch of vagus nerve preservation is made in this group during mediastinal lymph node dissection
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pulmonary branch of vagus nerve preserved<br>Pulmonary branch of vagus nerve is preserved during the mediastinal lymph node dissection using minimally invasive surgery | Procedure: Pulmonary branch of vagus nerve preserved<br>* During the mediastinal lymph node dissection using minimally invasive surgery, efforts to preserve the pulmonary branch of vagus nerve is made.<br>|
| Experimental: Pulmonary branch of vagus nerve not-preserved<br>Pulmonary branch of vagus nerve is not preserved during the mediastinal lymph node dissection using minimally invasive surgery | Procedure: Pulmonary branch of vagus nerve not preserved<br>* During the mediastinal lymph node dissection using minimally invasive surgery, efforts to preserve the pulmonary branch of vagus nerve is not made/ can be severed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qualitative measurement of postoperative cough | Cough Visual Analog Scale (VAS) will be used for survey. The Cough VAS is a numeric scale from 0-10 scale, with 0 indicating that patient experiences no distress from cough and 10 indicating severe distress from cough. | Preoperative day | 
| Qualitative measurement of postoperative cough | Cough Visual Analog Scale (VAS) will be used for survey. The Cough VAS is a numeric scale from 0-10 scale, with 0 indicating that patient experiences no distress from cough and 10 indicating severe distress from cough. | Postoperative day (discharge day, an average of 1 week) | 
| Qualitative measurement of postoperative cough | Cough Visual Analog Scale (VAS) will be used for survey. The Cough VAS is a numeric scale from 0-10 scale, with 0 indicating that patient experiences no distress from cough and 10 indicating severe distress from cough. | Postoperative 1 month follow up at outpatient clinic | 
| Qualitative measurement of postoperative cough | Cough Visual Analog Scale (VAS) will be used for survey. The Cough VAS is a numeric scale from 0-10 scale, with 0 indicating that patient experiences no distress from cough and 10 indicating severe distress from cough. | Postoperative 2 month follow up at outpatient clinic | 
| Qualitative measurement of postoperative cough | Cough Visual Analog Scale (VAS) will be used for survey. The Cough VAS is a numeric scale from 0-10 scale, with 0 indicating that patient experiences no distress from cough and 10 indicating severe distress from cough. | Postoperative 6 month follow up at outpatient clinic | 
| Qualitative measurement of postoperative cough | Cough Visual Analog Scale (VAS) will be used for survey. The Cough VAS is a numeric scale from 0-10 scale, with 0 indicating that patient experiences no distress from cough and 10 indicating severe distress from cough. | Postoperative 12 month follow up at outpatient clinic | 
| Quantitative measurement of postoperative cough | The Korean version of the Leicester Cough Questionnaire will be used for survey. Comparison of preoperative and and postoperative change in objective cough frequency and quality of life among patients using the Leicester Cough Questionnaire, which is a 7 point Likert scale with a minimum value of 1 indicating chronic cough impacts participant life all of the time and a maximum value of 7 indicating chronic cough impacts participant life none of the time. | Preoperative day | 
| Quantitative measurement of postoperative cough | The Korean version of the Leicester Cough Questionnaire will be used for survey. Comparison of preoperative and and postoperative change in objective cough frequency and quality of life among patients using the Leicester Cough Questionnaire, which is a 7 point Likert scale with a minimum value of 1 indicating chronic cough impacts participant life all of the time and a maximum value of 7 indicating chronic cough impacts participant life none of the time. | Postoperative day (discharge day, an average of 1 week) | 
| Quantitative measurement of postoperative cough | The Korean version of the Leicester Cough Questionnaire will be used for survey. Comparison of preoperative and and postoperative change in objective cough frequency and quality of life among patients using the Leicester Cough Questionnaire, which is a 7 point Likert scale with a minimum value of 1 indicating chronic cough impacts participant life all of the time and a maximum value of 7 indicating chronic cough impacts participant life none of the time. | Postoperative 1 month follow up at outpatient clinic | 
| Quantitative measurement of postoperative cough | The Korean version of the Leicester Cough Questionnaire will be used for survey. Comparison of preoperative and and postoperative change in objective cough frequency and quality of life among patients using the Leicester Cough Questionnaire, which is a 7 point Likert scale with a minimum value of 1 indicating chronic cough impacts participant life all of the time and a maximum value of 7 indicating chronic cough impacts participant life none of the time. | Postoperative 2 month follow up at outpatient clinic | 
| Quantitative measurement of postoperative cough | The Korean version of the Leicester Cough Questionnaire will be used for survey. Comparison of preoperative and and postoperative change in objective cough frequency and quality of life among patients using the Leicester Cough Questionnaire, which is a 7 point Likert scale with a minimum value of 1 indicating chronic cough impacts participant life all of the time and a maximum value of 7 indicating chronic cough impacts participant life none of the time. | Postoperative 6 month follow up at outpatient clinic | 
| Quantitative measurement of postoperative cough | The Korean version of the Leicester Cough Questionnaire will be used for survey. Comparison of preoperative and and postoperative change in objective cough frequency and quality of life among patients using the Leicester Cough Questionnaire, which is a 7 point Likert scale with a minimum value of 1 indicating chronic cough impacts participant life all of the time and a maximum value of 7 indicating chronic cough impacts participant life none of the time. | Postoperative 12 month follow up at outpatient clinic | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum TRPA1, TRPV1, bradykinin, PGE2 measurements | Measurement of TRPA1 (ng/mL), TRPV1 (ng/mL), bradykinin (pg/mL), PGE2 (pg/mL) (released from C-fibers) via enzyme-linked immunosorbent assay (ELISA) test to quantitatively measure the injures of the vagus nerve during the mediastinal lymph node dissection. | Preoperative day | 
| Serum TRPA1, TRPV1, bradykinin, PGE2 measurements | Measurement of TRPA1 (ng/mL), TRPV1 (ng/mL), bradykinin (pg/mL), PGE2 (pg/mL) (released from C-fibers) via enzyme-linked immunosorbent assay (ELISA) test to quantitatively measure the injures of the vagus nerve during the mediastinal lymph node dissection. | Postoperative 1 day | 
| Serum TRPA1, TRPV1, bradykinin, PGE2 measurements | Measurement of TRPA1 (ng/mL), TRPV1 (ng/mL), bradykinin (pg/mL), PGE2 (pg/mL) (released from C-fibers) via enzyme-linked immunosorbent assay (ELISA) test to quantitatively measure the injures of the vagus nerve during the mediastinal lymph node dissection. | Postoperative 2 month follow up at outpatient clinic | 
| Pulmonary function test | Routine PFT (FEV1%, FEV1/FVC%) check to evaluate the effects of vagus nerve preservation in pulmonary function | Preoperative day | 
| Pulmonary function test | Routine PFT (FEV1%, FEV1/FVC%) check to evaluate the effects of vagus nerve preservation in pulmonary function | Postoperative 1 month follow up at outpatient clinic | 
| Pulmonary function test | Routine PFT (FEV1%, FEV1/FVC%) check to evaluate the effects of vagus nerve preservation in pulmonary function | Postoperative 2 month follow up at outpatient clinic | 
| Pulmonary function test | Routine PFT (FEV1%, FEV1/FVC%) check to evaluate the effects of vagus nerve preservation in pulmonary function | Postoperative 6 month follow up at outpatient clinic | 
| Pulmonary function test | Routine PFT (FEV1%, FEV1/FVC%) check to evaluate the effects of vagus nerve preservation in pulmonary function | Postoperative 12 month follow up at outpatient clinic | 
| Incidence of postoperative pulmonary complications, hospital stay and readmission, ICU care |  | from admission for operation to until the date of first documented postoperative complication or readmission, whichever came first), assessed up to 30 days | 
| Histopathologic review of the total number of mediastinal lymph node dissected | Total number of dissected mediastinal lymph nodes and metastatic lymph nodes will be analyzed. Patient's preoperative clinical N stage and pathologic N stage will be compared; if pathologic N stage is higher than that of the clinical N stage, it will be considered as nodal upstaging. | through study completion, an average of 1 year |