Epidural Anesthesia-analgesia and Long-term Outcome

Study Overview
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Brief Summary
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Surgical resection is one of the most important treatments for resectable cancer; on the other hand, cancer recurrence and/or metastasis are the major reasons of treatment failure. The development of recurrence/metastasis after cancer surgery mostly depends on the balance between the immunity of human body and the capability of implantation, proliferation and neovascularization of the residual cancer. Preclinical and retrospective clinical studies suggest that anaesthetic management may affect the long-term outcomes after cancer surgery. The investigators hypothesize that use of epidural anesthesia-analgesia may improve long-term survival in elderly patients after major surgery for cancer.

Detailed Description
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Surgical resection is the main treatment for potentially curable solid organ cancer. However, it is unavoidable that some cancer cells are disseminated into the circulatory or lymphatic system during surgery. And quite a number of patients develop cancer recurrence and/or metastasis after surgery, which are associated with poor long-term outcomes. The development of cancer recurrence and/or metastasis after surgery is mostly dependent on the balance between the anti-tumor immune function of the human body and the ability of implantation, proliferation and neovascularization of the residual cancer cells. Multiple surgical factors may influence the balance between the anti-cancer immune function and cancer recurrence. For example, the presence of the primary cancer inhibits angiogenesis, whereas cancer resection eliminates this safeguard against angiogenesis; surgical manipulation releases cancer cells into the circulation; surgery-related stress response inhibits natural killer (NK) cell activity and can promote the development of cancer metastasis; local and systemic release of growth factors during surgery may also promote cancer recurrence both locally and at distant sites. Available studies showed that general anaesthesia/anesthetics may influence the cellular immune function and long-term outcomes. For example, it was found that ketamine and thiopental, but not propofol, suppressed NK cell activity; all three drugs caused a significant reduction in NK cell number; isoflurane and halothane inhibit interferon (IFN) stimulation of NK cell cytotoxicity; nitrous oxide interferes with DNA, purine, and thymidylate synthesis and depresses neutrophil chemotaxis; opioids have been reported to suppress cell-mediated and humoral immunity. Considering the potential harmful effects of general anesthesia/anesthetics, there is an increasing interest on the effect of regional anaesthesia. Retrospective studies investigating the relationship between epidural anesthesia and outcome after cancer surgery gave different results. In a meta-analysis, regional anesthesia is associated with improved survival (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.74-0.96, P = 0.013), but not cancer recurrence/metastasis (HR 0.88, 95% Cl 0.64-1.22, P = 0.457). The investigators hypothesize that combined use of epidural anesthesia may produce favorable effects on the long-term survival in elderly patients undergoing major cancer surgery.

Official Title
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Impact of Epidural Anesthesia-analgesia on Long-term Outcome in Elderly Patients After Surgery: 5-year Follow-up of a Multicenter Randomized Controlled Trial

Conditions
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Elderly, Malignant Tumor, Surgical Resection, Epidural Anesthesia, Long-term Outcome

Intervention / Treatment
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* Drug: Combined epidural-general anesthesia
* Drug: General anesthesia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Elderly patients (age 60-90 years); Scheduled to undergo noncardiac thoracic or abdominal surgery with an expected duration of 2 hours or longer. For those who undergo thoracoscopic or laparoscopic surgery, the expected length of incision must be 5 centimeters or more; Agree to receive patient-controlled postoperative analgesia. Exclusion Criteria: Refuse to participate; Previous history of schizophrenia, epilepsy or Parkinson disease, or unable to complete preoperative assessment due to severe dementia, language barrier or end-stage disease; History of myocardial infarction or stroke within 3 months before surgery; Presence of any contraindication to epidural anesthesia and analgesia, including abnormal vertebral anatomy, previous spinal trauma or surgery, severe chronic back pain, coagulation disorder (prothrombin time or activated partial prothrombin time longer than 1.5 times of the upper normal limit, or platelet count of less than 80 * 10^9/L), local infection near the site of puncture, and severe sepsis; Severe heart dysfunction (New York Heart Association functional classification 3 or above), severe hepatic insufficiency (Child-Pugh grade C), or severe renal insufficiency (serum creatinine of 442 umol/L or above, with or without serum potassium of 6.5 mmol/L or above, or requirement of renal replacement therapy); Any other conditions that are considered unsuitable for study participation.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 90 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined epidural-general anesthesia<br>Patients assigned to this group (experimental group) receive combined epidural-general anesthesia and postoperative patient-controlled epidural analgesia. | Drug: Combined epidural-general anesthesia<br>* Combined epidural-general anesthesia and postoperative epidural analgesia. General anesthesia is performed as that in the general anesthesia group. Epidural anesthesia is performed with ropivacaine. Epidural analgesia is performed with a mixture of ropivacaine and sufentanil.<br>* Other names: Combined epidural-general anesthesia and postoperative epidural analgesia;|
| Active Comparator: General anesthesia<br>Patients assigned to this group (control group) receive general anesthesia and postoperative patient-controlled intravenous analgesia. | Drug: General anesthesia<br>* General anesthesia and postoperative intravenous analgesia. General anesthesia is performed with propofol induction and propofol and/or sevoflurane maintenance. Intravenous analgesia is performed with morphine.<br>* Other names: General anesthesia and postoperative intravenous analgesia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival after surgery. | Time from surgery to the date of all-cause death. | Up to median 5 years after surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cancer-specific survival after surgery. | Time from surgery to the date of cancer-specific death. Patients who die from other causes will be censored at the time of death. | Up to median 5 years after surgery. | 
| Recurrence-free survival after surgery. | Time from surgery to the date of cancer recurrence/metastasis or all-cause death, whichever come first. | Up to median 5 years after surgery. | 
| Event-free survival after surgery. | Time from surgery to the first date of cancer recurrence/metastasis, new onset cancer, new serious non-cancer disease, or death from any cause. | Up to median 5 years after surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elderly, Cancer surgery, Epidural anesthesia and analgesia, Long-term survival