Epidural Anesthesia-analgesia and Long-term Outcome

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

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.

Study Overview

• Status: Completed
• Conditions: Elderly; Long-term Outcome; Malignant Tumor; Epidural Anesthesia; Surgical Resection
• Intervention / Treatment: Drug: Combined epidural-general anesthesia; Drug: General anesthesia

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1802
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100044
    • Peking University People's Hospital
  • Beijing, China, 100730
    • Beijing Hospital
  • Beijing, China, 100191
    • Peking University Third Hospital
  • Beijing, China, 100038
    • Beijing Shijitan Hospital
  • Beijing
    • Beijing, Beijing, China, 100034
      • Peking University First Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Combined epidural-general anesthesia; Patients assigned to this group (experimental group) receive combined epidural-general anesthesia and postoperative patient-controlled epidural analgesia.	Drug: Combined epidural-general anesthesia; 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.; Other Names: Combined epidural-general anesthesia and postoperative epidural analgesia
ACTIVE_COMPARATOR: General anesthesia; Patients assigned to this group (control group) receive general anesthesia and postoperative patient-controlled intravenous analgesia.	Drug: General anesthesia; 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.; Other Names: General anesthesia and postoperative intravenous analgesia

What is the study measuring?

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
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.
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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival after surgery (cancer patients).	Time from surgery to the date of all-cause death.	Up to median 5 years after surgery.
Event-free survival after surgery (cancer patients).	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.
Cognitive function (3-year survivors).	Cognitive function is assessed with the modified Telephone Interview for Cognitive Status (TICS-m; a 12-item questionnaire that assesses global cognitive function by verbal communication via telephone. The score ranges from 0 to 50, with higher score indicating better function).	At the end of the 3rd year after surgery.
Cancer-specific survival after surgery (cancer patients).	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 (cancer patients).	Time from surgery to the date of cancer recurrence/metastasis or all-cause death, whichever come first.	Up to median 5 years after surgery.
Quality of life (3-year survivors).	Quality of life is assessed with the World Health Organization Quality of Life-brief version (WHOQOL-BREF; a 24-item questionnaire that assesses the quality of life in physical, psychological, social relationship and environmental domains. The score ranges from 0 to 100 for each domain, with higher score indicating better function).	At the end of the 3rd year after surgery.

Collaborators and Investigators

• Sponsor: Peking University First Hospital
• Collaborators: Peking University; Peking University People's Hospital; Peking University Third Hospital; Beijing Hospital; Beijing Shijitan Hospital, Capital Medical University
• Investigators: Principal Investigator: Dong-Xin Wang, MD, Peking University First Hospital

Publications and helpful links

General Publications

• Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann Surg Oncol. 2003 Oct;10(8):972-92. doi: 10.1245/aso.2003.02.007.
• Yamaguchi K, Takagi Y, Aoki S, Futamura M, Saji S. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann Surg. 2000 Jul;232(1):58-65. doi: 10.1097/00000658-200007000-00009.
• Sessler DI. Long-term consequences of anesthetic management. Anesthesiology. 2009 Jul;111(1):1-4. doi: 10.1097/ALN.0b013e3181a913e1. No abstract available.
• Buggy DJ, Smith G. Epidural anaesthesia and analgesia: better outcome after major surgery?. Growing evidence suggests so. BMJ. 1999 Aug 28;319(7209):530-1. doi: 10.1136/bmj.319.7209.530. No abstract available.
• Melamed R, Bar-Yosef S, Shakhar G, Shakhar K, Ben-Eliyahu S. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures. Anesth Analg. 2003 Nov;97(5):1331-1339. doi: 10.1213/01.ANE.0000082995.44040.07.
• Mitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects of volatile anesthetics on cytokine release in human peripheral blood mononuclear cells. Int J Immunopharmacol. 1995 Jun;17(6):529-34. doi: 10.1016/0192-0561(95)00026-x.
• Markovic SN, Knight PR, Murasko DM. Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane. Anesthesiology. 1993 Apr;78(4):700-6. doi: 10.1097/00000542-199304000-00013.
• Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 2002 Aug 1;62(15):4491-8.
• Beilin B, Martin FC, Shavit Y, Gale RP, Liebeskind JC. Suppression of natural killer cell activity by high-dose narcotic anesthesia in rats. Brain Behav Immun. 1989 Jun;3(2):129-37. doi: 10.1016/0889-1591(89)90013-5.
• Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. J Neuroimmunol. 2002 Aug;129(1-2):18-24. doi: 10.1016/s0165-5728(02)00165-0.
• O'Riain SC, Buggy DJ, Kerin MJ, Watson RWG, Moriarty DC. Inhibition of the stress response to breast cancer surgery by regional anesthesia and analgesia does not affect vascular endothelial growth factor and prostaglandin E2. Anesth Analg. 2005 Jan;100(1):244-249. doi: 10.1213/01.ANE.0000143336.37946.7D.
• Chen WK, Miao CH. The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. PLoS One. 2013;8(2):e56540. doi: 10.1371/journal.pone.0056540. Epub 2013 Feb 20.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2014
• Primary Completion (ACTUAL): September 30, 2019
• Study Completion (ACTUAL): September 30, 2019

Study Registration Dates

• First Submitted: December 31, 2016
• First Submitted That Met QC Criteria: January 5, 2017
• First Posted (ESTIMATE): January 6, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 8, 2020
• Last Update Submitted That Met QC Criteria: July 6, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Elderly; Cancer surgery; Epidural anesthesia and analgesia; Long-term survival
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics
• Other Study ID Numbers: PUCRP201101-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will be provided on request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No