Propofol vs Sevo for Paediatric Tumor Surgery

Study Overview
=================
Brief Summary
-----------------
Background: Retrospective studies and meta-analyses have shown a reduction in 5-year survival following inhalational based compared to propofol based total intravenous (TIVA) anaesthesia for cancer surgery. To date there have been no prospective trials published which evaluate the effect of anaesthetic technique on circulating tumour cells (CTC), oxidative stress, and recurrence rate following cancer surgery. Children with cancer often require surgery for tumour excision as well as for other diagnostic and therapeutic procedures. To date there has been no prospective randomized controlled trial evaluating the optimal anaesthetic technique for surgery on children with cancer. Aim: This is a pilot study in paediatric patients who require surgery for tumour excision. The aim is to investigate the effect of sevoflurane inhalational versus propofol intravenous anaesthesia on expression of hypoxia-inducible factor 1 (HIF-1), circulating tumour cells, DNA damage and biomarkers of immunity and inflammation in patients before and after tumour surgery. The patients will be followed up for up to 5 years for tumour recurrence after surgery. Method: This will be a single-blinded randomized controlled trial. One hundred children undergoing tumour excision surgery at the Hong Kong Children's Hospital will be recruited and randomized to receive TIVA or inhalational anaesthesia. Baseline, intraoperative and postoperative blood will be taken for tests of immunity and inflammatory markers, DNA damage and circulating tumour cells. Patients would be followed up to 3 years for tumour recurrence and survival.

Detailed Description
-----------------
Surgical resection is the main modality of treatment for many solid tumors. Despite successful tumor resection, some patients develop local recurrence or metastasis, causing morbidities and mortality. In recent years, there is growing interest in the pathophysiology of recurrence or metastasis. It is believed that the recurrence is caused by the liberation of circulating tumor cells during surgical manipulation of the tumors and the vascular invasive properties of the tumor cells. Perioperative events, such as surgical stress and anaesthesia may have immunomodulating effects, causing growth or inhibition of circulating tumor cells, which affect disease relapse. There is growing evidence that propofol is anti-inflammatory while sevoflurane is pro-inflammatory and their potential roles in cancer recurrence attract researchers' attention. In adults, there is increasing number of researches showing that propofol may improve patient outcomes in terms of disease survival, when compared to sevoflurane. However, such evidence in paediatric population is lacking. This study aims to compare the effects of propofol based intravenous anaesthesia with inhalation anaesthesia with sevoflurane on perioperative biomarkers of inflammation, circulating tumor cells and disease free survival in 3 years. 100 patients will be recruited for this single blinded randomised controlled trial. They will receive general anaesthesia in Hong Kong Children's Hospital for their primary tumor excision surgery. 50 patients will be randomised to sevoflurane group and 50 patients will be randomised to propofol group. They will receive standardised anaesthetic management in terms of death or anaesthesia, pain management, fluid or thermoregulation management. Sevoflurane group subjects will receive inhalational sevoflurane as main anaesthetic, while propofol group subjects will receive intravenous propofol. These patients will have 4 blood tests collected for analysis for biomarkers of inflammation, DNA damage, oxidative stress and circulating tumor cells. baseline: once patients have intravenous access established intraoperative: when the tumor is deemed resected by surgeons immediately postop: after wound closure 24 hours postop Early postoperative period follow up will look for wound recovery, sepsis, and time to start chemotherapy and need for second look operation for wound complication. Patients will also followed up for 3 years for tumor recurrence and disease survival.

Official Title
-----------------
The Effects of Propofol Based Intravenous vs Sevoflurane Inhalation Anaesthesia on Inflammation and Circulating Tumor Cells in Paediatric Tumor Surgery - a Pilot Study

Conditions
-----------------
Solid Tumor, Carcinoma, Malignancy, Cancer

Intervention / Treatment
-----------------
* Drug: propofol
* Drug: sevoflurane


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients coming for elective primary solid tumor resection for curative intent in Hong Kong Children's Hospital AND patients > 5kg AND patients within age limit Exclusion Criteria: Autoimmune / Chronic inflammatory diseases e.g. Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) etc. Current Steroid therapy Surgery for tumour removal in the past year Allergy to Propofol intraoperative use of nitrous oxide Patient susceptible to Malignant Hyperthermia Patients / parents / legal guardians showing preference in anaesthetic techniques during recruitment process

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: single blind controlled trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sevoflurane group<br>patients in this group will receive inhalation anaesthesia with sevoflurane at Minimal Alveolar Concentration 0.7-1.3 as the main anaesthetic to achieve Bispectral Index 40-60. Other anaesthetic management will be standardised. | Drug: sevoflurane<br>* sevoflurane at Minimal Alveolar Concentration 0.7-1.3 as the main anaesthetic to achieve Bispectral Index 40-60.<br>* Other names: ultane, sevorane;|
| Active Comparator: propofol group<br>patients in this group will receive intravenous propofol using Target Controlled Infusion 'Paedfusor' model 2-5 as the main anaesthetic to achieve Bispectral Index 40-60. Other anaesthetic management will be standardised. | Drug: propofol<br>* intravenous propofol using Target Controlled Infusion 'Paedfusor' model 2-5 as the main anaesthetic to achieve Bispectral Index 40-60<br>* Other names: Diprivan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| difference in Hypoxia Inducible Factor-1 gene expression | pg/mL | intraoperative to postoperative 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| difference in levels of Interleukin-6 | pg/mL | intraoperative to postoperative 24 hours | 
| difference in levels of Tumor Necrosis Factor-alpha | pg/mL | intraoperative to postoperative 24 hours | 
| difference in levels of high sensitivity C reaction protein | mg/L | intraoperative to postoperative 24 hours | 
| difference in levels of DNA damage (Comet Assay) | %T (percent tail) | intraoperative to postoperative 24 hours | 
| difference in levels of Glutathione Peroxidase | μg/mL | intraoperative to postoperative 24 hours | 
| difference in levels of Superoxide dismutase | units/ml | intraoperative to postoperative 24 hours | 
| difference in levels of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) | ng/mL | intraoperative to postoperative 24 hours | 
| difference in levels of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) | ng/mL | intraoperative to postoperative 24 hours | 
| difference in the quantity of circulating tumor cells (CTC) | cells/100 µL | intraoperative to postoperative 24 hours | 
| cancer free survival at 1 and 3 years | percent | intraoperative to postoperative 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cancer surgery, circulating tumor cells, propofol, sevoflurane, paediatric