Volatile Anaesthesia and Perioperative Outcomes Related to Cancer: The VAPOR-C Trial

Study Overview
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Brief Summary
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VAPOR-C is a randomised study of the impact of IV versus inhaled anaesthesia (propofol versus sevoflurane) and lidocaine versus no lidocaine on duration of disease free survival inpatients with either colorectal or non small cell lung cancer.

Detailed Description
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VAPOR-C is a pragmatic, event-driven, randomised controlled trial, with a single blind 2x2 factorial design for sevoflurane/propofol and for intravenous lidocaine infusion / no lidocaine infusion. This trial is designed to test for superiority in disease free survival (DFS) of propofol (total intravenous anaesthesia -TIVA) over sevoflurane (inhalational volatile anaesthesia) and intravenous lidocaine over no lidocaine in patients undergoing surgery for colorectal or non small cell lung cancer (NSCLC). The combination of two cancer types will help address the need to demonstrate the effects of anaesthetic technique across cancers to inform generalisable anaesthesia guidelines. Both NSCLC and colorectal cancer are important for this study due to high incidence rate, many longer-term survivors, and importantly the high risk of local or distant recurrence despite complete surgical resection. In addition, the study will collect additional data in a nested cohort related to the exploratory objectives. The study aims to recruit 3,500 patients in Australia, New Zealand, Canada, United States and Europe.

Official Title
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Volatile Anaesthesia and Perioperative Outcomes Related to Cancer: The VAPOR-C Trial

Conditions
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Colonic Cancer, Rectal Cancer, Non Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Sevoflurane
* Drug: Propofol
* Drug: Lidocaine IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 18 years or older at screening Has provided written informed consent for the trial Patient with American Joint committee on Cancer (AJCC) 8th edition Stage I-III colorectal cancer or Stage I-IIIa NSCLC, as confirmed by histological or cytological diagnosis. In cases where a histological diagnosis is not possible, suspected diagnosis through imaging techniques is acceptable. Patient has an American Society of Anaesthesiologists (ASA) score of 1 to 3 Scheduled to receive elective, surgical resection with curative intent Surgery expected to last ≥2 hours and expected to require ≥2 nights hospital stay Able to comply with protocol requirements and follow-up procedures Exclusion Criteria: Confirmed or suspected allergy to propofol, sevoflurane or intravenous lidocaine Patient with significant liver disease (with elevated International Normalised Ratio (INR) or bilirubin and/or low albumin; i.e. Childs-Pugh Score >Class A; Patient at personal or familial risk of malignant hyperthermia or porphyria Patient with a history of other malignancies within the past 5 years. However, patients with malignancies managed with curative therapy and considered to be at low risk of recurrence such as treated skin basal cell carcinoma, squamous cell carcinoma, malignant melanoma ≤1.0mm without ulceration, localised thyroid cancer, cervical carcinoma in situ or prior malignancies with high likelihood of cure (e.g. low grade prostate and breast cancer) may be included in the study Patient has distant metastases Patient with an actual body weight less than 45kg Patients taking the following drugs that are moderate-strong inhibitors of the CYP1A2 and CYP3A4 metabolic pathways within 72 hours prior to surgery: Antibiotics - 'mycin' class: Clarithromycin, Telithromycin, Azithromycin, Erythromycin Antibiotics - 'floxacin' class Ciprofloxacin (exception: can be used preoperatively within a bowel prep regime), Norfloxacin, Levofloxacin, Sparfloxacin Antibiotics - other: Chloramphenicol, Isoniazid Antifungals: Fluconazole, Itraconazole, Ketoconazole, Posaconazole, Voriconazole Antiretrovirals: Atazanavir; Darunavir; Indinavir; Lopinavir; Nelfinavir; Ombitasvir, Paritaprevir, Ritonavir and Saquinavir. Antidepressants/ADHD: Fluvoxamine, Enoxacine. Calcium-channel blockers: Diltiazem, Verapamil Monoclonal Antibodies: Ceritinib, Idelalisib, Lonafarnib, Tucatinib. Other strong cytochrome P450 3A4 inhibitors: Cimetidine, Cobicistat; grapefruit juice, Mifepristone, Nefazodone.

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an event-driven, international multicentre, randomised controlled trial with a 2x2 factorial design. Patients with stage I-III colorectal cancer or stage I-IIIa NSCLC are eligible and will be randomised in the ratio of 1:1:1:1 using permuted block randomisation with stratification by cancer type (Colon, Rectal or NSCLC), and by site to receive either 1) sevoflurane maintenance anaesthesia and lidocaine infusion or 2) sevoflurane maintenance anaesthesia; or 3), propofol maintenance anaesthesia and lidocaine infusion or 4), propofol maintenance anaesthesia .
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Sevoflurane + intravenous lidocaine | Drug: Sevoflurane<br>* Inhaled anaesthetic used for maintenance of anaesthesia, dosed as per standard practice<br>Drug: Lidocaine IV<br>* 1.5mg/kg loading dose over 20 minutes, followed by an infusion of 2mg/kg/hr up to 4 hours and 1.5mg/kg/hour thereafter. Bolus and maintenance dosages of lidocaine will be per actual body weight and capped at a maximum of 100 kg.<br>|
| Active Comparator: B<br>Sevoflurane | Drug: Sevoflurane<br>* Inhaled anaesthetic used for maintenance of anaesthesia, dosed as per standard practice<br>|
| Active Comparator: C<br>Propofol TIVA + intravenous lidocaine | Drug: Propofol<br>* Intravenous anaesthetic used for induction and maintenance of anaesthesia<br>Drug: Lidocaine IV<br>* 1.5mg/kg loading dose over 20 minutes, followed by an infusion of 2mg/kg/hr up to 4 hours and 1.5mg/kg/hour thereafter. Bolus and maintenance dosages of lidocaine will be per actual body weight and capped at a maximum of 100 kg.<br>|
| Active Comparator: D<br>Propofol TIVA | Drug: Propofol<br>* Intravenous anaesthetic used for induction and maintenance of anaesthesia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of disease free survival (DFS) with propofol-TIVA versus sevoflurane | The study will collect endpoint data for each participant on time of disease progression. This will be used to compare disease free survival across arms. | Until 3 years from participant index surgery date | 
| Comparison of disease free survival (DFS) with lidocaine compared with no lidocaine | The study will collect endpoint data for each participant on time of disease progression. This will be used to compare disease free survival across arms. | Until 3 years from participant index surgery date | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of overall survival (OS) with propofol-TIVA versus sevoflurane | The study will collect endpoint data for each participant on survival status. This will be used to compare overall survival across arms. | Until 3 years from participant index surgery date | 
| Days alive and at home with propofol-TIVA versus sevoflurane | Data will be collected at thirty days post surgery regarding date of discharge from hospital and survival status. This is then used to calculate number of days alive and at home (i.e. out of hospital) and compare across arms. | 30 days post surgery | 
| Overall survival with intravenous lidocaine versus no lidocaine | The study will collect endpoint data for each participant on survival status. This will be used to compare overall survival across arms. | Until 3 years from participant index surgery date | 
| Days alive and at home with intravenous lidocaine versus no lidocaine | Data will be collected at thirty days post surgery regarding date of discharge from hospital and survival status. This is then used to calculate number of days alive and at home (i.e. out of hospital) and compare across arms. | 30 days post surgery | 
| Comparison of post-operative complications with propofol-TIVA versus sevoflurane | Short term postoperative morbidity assessed by the Post Operative Morbidity Scale (POMS) with Clavien-Dindo severity grading. POMS is an 18-item tool that addresses nine domains of morbidity relevant to the post-surgical patient . The severity in each POMS domain will then be graded according to the Clavien-Dindo Classification on the basis of treatment applied to correct each respective complication , and captures complications within 5 grades. | 5 days post surgery or at discharge if earlier | 
| Comparison of post-operative complications with intravenous lidocaine versus no lidocaine | Short term postoperative morbidity assessed by the Post Operative Morbidity Scale (POMS) with Clavien-Dindo severity grading. POMS is an 18-item tool that addresses nine domains of morbidity relevant to the post-surgical patient . The severity in each POMS domain will then be graded according to the Clavien-Dindo Classification on the basis of treatment applied to correct each respective complication , and captures complications within 5 grades. | 5 days post surgery or at discharge if earlier | 
| Comparison of chronic post surgical pain with propofol-TIVA versus sevoflurane | Pain measured using the Brief Pain Inventory Short Form. Patient reported pain on a scale of 0 to 10 where 0 is no pain and 10 is worst pain. Pain measured using the Neuropathic Pain Questionnaire. Patient reported neuropathic pain on a scale of 0 to 100 where 0 is no pain and 100 is worst pain. | At 90 days and 12 months post surgery | 
| Comparison of chronic post surgical pain with intravenous lidocaine versus no lidocaine | Pain measured using the Brief Pain Inventory Short Form. Patient reported pain on a scale of 0 to 10 where 0 is no pain and 10 is worst pain. Pain measured using the Neuropathic Pain Questionnaire. Patient reported neuropathic pain on a scale of 0 to 100 where 0 is no pain and 100 is worst pain. | At 90 days and 12 months post surgery | 
| Safety profile of propofol-TIVA versus sevoflurane | Toxicities measured using CTCAE V 5 .0 | during surgery until discharge from Post Anaesthetic Care Unit (PACU) or within the first 4 hours of ICU admission | 
| Safety Profile intravenous lidocaine versus no lidocaine | Toxicities measured using CTCAE V 5 .0 | during surgery until discharge from Post Anaesthetic Care Unit (PACU) or within the first 4 hours of ICU admission | 
| Concomitant medication use with propofol-TIVA versus sevoflurane | From 2 weeks prior to surgery up to Day 5 post-surgery administration of relevant medications will be recorded | 5 days post anaesthesia | 
| Concomitant medications use with intravenous lidocaine versus no lidocaine | From 2 weeks prior to surgery up to Day 5 post-surgery administration of relevant medications will be recorded | 5 days post anaesthesia | 
| Health utility with propofol-TIVA versus sevoflurane | The EQ-5D-5L is a standardised instrument for use as a measure of health outcome and is applicable to a wide range of health conditions and treatments. This five item scale covers the following dimensions (5D): mobility, self-care, usual activities, pain/discomfort and anxiety/depression, with each dimension having five levels (5L). The use of the EQ-5D-5L will enable utility valuations to be estimated for health states experienced. | At 30 days, 90 days and every 12 months post surgery up to 3 years | 
| Health utility with intravenous lidocaine versus no lidocaine | The EQ-5D-5L is a standardised instrument for use as a measure of health outcome and is applicable to a wide range of health conditions and treatments. This five item scale covers the following dimensions (5D): mobility, self-care, usual activities, pain/discomfort and anxiety/depression, with each dimension having five levels (5L). The use of the EQ-5D-5L will enable utility valuations to be estimated for health states experienced | At 30 days, 90 days and every 12 months post surgery up to 3 years |