Perioperative Dexmedetomidine and Long-term Survival After Cancer Surgery

Study Overview
=================
Brief Summary
-----------------
Along with aging population, cancer incidence and mortality are increasing. However, despite advances in oncology and surgery, long-term survival of cancer patients is far from optimal. Dexmedetomidine is a highly selective alpha 2 adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. Studies showed that perioperative use of dexmedetomidine reduces delirium and some non-delirium complications after surgery. In long-term follow-up studies of older patients who, for other reasons, were randomized to receive either dexmedetomidine or placebo during intra- or postoperative period, dexmedetomidine use was associated with improved long-term survival. This multicenter randomized trial aims to investigate the effect of perioperative dexmedetomidine on long-term outcomes in older patients undergoing cancer surgery.

Detailed Description
-----------------
Along with aging population, cancer incidence and mortality are increasing. Surgical resection remains the mainstay treatment for solid organ cancer. However, despite advances in oncology and surgery, long-term survival of cancer patients is far from optimal. For example, the 5-year survival rate of cancer patients is about 36.9% in China, and the survival rate decreases for about 10% each year in older patients after cancer surgery. How to improve long-term survival after cancer surgery remains an urgent problem to be solved. Cancer death usually occur after cancer recurrence or metastasis. The development of cancer recurrence or metastasise after surgical resection depends on the balance between the anti-cancer defense function of host and the invasiveness of residual cancer cells. Studies showed that surgery, while resecting cancer mass, also releases cancer cells into the circulation. Surgical stress also impairs cell-mediated immunity and promote cancer growth. Dexmedetomidine is a highly selective alpha 2 adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. Studies showed that intraoperative use of dexmedetomidine reduces anesthetic and opioid consumption and relieves surgery-related stress response and inflammation. Studies also showed that perioperative use of dexmedetomidine reduces delirium, a commonly occurred complication in older patients, and some non-delirium complications after surgery. The effect of perioperative dexmedetomidine on long-term outcomes after cancer surgery remains unclear. In a long-term follow-up of older patients who were randomized to receive either low-dose dexmedetomidine or placebo during intensive care unit stay, dexmedetomidine use was associated with improved survival within 2 years. In a recent long-term follow-up of older patients who were randomized to receive either dexmedetomidine or placebo during surgery, dexmedetomidine use was associated with improved recurrence-free survival. The investigators hypothesize that perioperative use of dexmedetomidine may improve long-term survival after cancer surgery. This multicenter randomized trial aims to investigate the effect of perioperative dexmedetomidine on long-term outcomes in older patients undergoing cancer surgery.

Official Title
-----------------
Impact of Perioperative Dexmedetomidine on Long-term Survival in Older Patients After Cancer Surgery: a Multicenter Randomized Trial

Conditions
-----------------
Elderly, Cancer Surgery, Dexmedetomidine, Long-Term Survivors

Intervention / Treatment
-----------------
* Drug: Dexmedetomidine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Aged 60 years or older. Scheduled to undergo radical surgery for cancer under general anesthesia, with an expected surgical duration of 2 hours or longer. Required patient-controlled intravenous analgesia after surgery. Exclusion criteria: Inability to communicate preoperatively due to visual, auditory, verbal. or other reasons. Surgery for breast cancer or intracranial tumor. Preoperative severe sinus bradycardia (<50 beats per minute), sick sinus syndrome，or second-degree or above atrioventricular block without pacemaker. Severe hepatic dysfunction (Child-Pugh class C). Severe renal dysfunction (requirement of renal replacement therapy before surgery). Enrolled in other clinical studies.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

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

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

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine group<br>A loading dose of dexmedetomidine (0.6 μg/kg) will be administered over 10-15 minutes before anaesthesia induction, followed by a continuous infusion at a rate of 0.5 μg/kg/h till 1 hour before the end of surgery. Patient-controlled dexmedetomidine supplemented sufentanil analgesia will be provided after surgery: the formula contains a mixture of sufentanil (1.25 μg/ml) and dexmedetomidine (1.25 μg/ml), diluted with normal saline to a total volume of 160 ml; the analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time of 8 minutes. | Drug: Dexmedetomidine<br>* A loading dose of dexmedetomidine (0.6 μg/kg) will be administered over 10-15 minutes before anaesthesia induction, followed by a continuous infusion at a rate of 0.5 μg/kg/hr till 1 hour before the end of surgery. Patient-controlled dexmedetomidine supplemented sufentanil analgesia will be provided after surgery: the formula contains a mixture of sufentanil (1.25 μg/ml) and dexmedetomidine (1.25 μg/ml), diluted with normal saline to a total volume of 160 ml; the analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time of 8 minutes.<br>* Other names: Dexmedetomidine hydrochloride;|
| Placebo Comparator: Control group<br>Volume-matched normal saline will be administered in the same rate and volume for the same duration as in the dexmedetomidine group during anesthesia. Patient-controlled sufentanil analgesia will be provided after surgery: the formula contains sufentanil (1.25 μg/ml), diluted with normal saline to a total volume of 160 ml; the analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time of 8 minutes. | Drug: Placebo<br>* Volume-matched normal saline will be administered in the same rate and volume for the same duration as in the dexmedetomidine group during anesthesia. Patient-controlled sufentanil analgesia will be provided after surgery: the formula contains sufentanil (1.25 μg/ml), diluted with normal saline to a total volume of 160 ml; the analgesic pump is set to administer a background infusion at a rate of 1 ml/h, with patient-controlled bolus of 2 ml each time and a lockout time of 8 minutes.<br>* Other names: Normal saline;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival after surgery | Time interval from index surgery to cancer recurrence/metastasis/progression or all-cause death, whichever comes first. | Up to 3 years after surgery of the last enrolled patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of postoperative delirium. | Delirium will be assessed with the 3D-Confusion Assessment Method (3D-CAM) or CAM for the Intensive Care Unit (CAM-ICU) twice daily during the first 4 postoperative days. | During the first 4 postoperative days. | 
| Incidence of cognitive dysfunction at 6 months and 1 year postoperatively. | Cognitive function will be assessed with the Telephone Montreal Cognitive Assessment (T-MoCA; scores range from 0 to 22, with higher score indicating better function) before surgery and at 6 months and 12 months after surgery. A T-MoCA score reduction of 1 standard deviation (SD) or more from baseline will be considered occurrence of cognitive dysfunction. | At 6 months and 1 year postoperatively. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Older patients, Cancer surgery, Dexmedetomidine, Long-term survival