Epidural Anesthesia-analgesia and Long-term Outcome

Elderly Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03012945
• Other study ID #: PUCRP201101-1
• Status: Completed
• Phase: N/A
• Start date: November 1, 2014
• Est. completion date: September 30, 2019

Study information

• Verified date: July 2020
• Source: Peking University First Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1802
• Est. completion date: September 30, 2019
• Est. primary completion date: September 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Elderly
• Epidural Anesthesia
• Long-term Outcome
• Malignant Tumor
• Neoplasms
• Surgical Resection

Intervention

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.
• 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.

Locations

Country	Name	City	State
China	Beijing Hospital	Beijing
China	Beijing Shijitan Hospital	Beijing
China	Peking University First Hospital	Beijing	Beijing
China	Peking University People's Hospital	Beijing
China	Peking University Third Hospital	Beijing

Sponsors (6)

Lead Sponsor	Collaborator
Peking University First Hospital	Beijing Hospital, Beijing Shijitan Hospital, Peking University, Peking University People's Hospital, Peking University Third Hospital

Country where clinical trial is conducted

China, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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):1331-9. — View Citation

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. — View Citation

O'Riain SC, Buggy DJ, Kerin MJ, Watson RW, 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):244-9. — View Citation

Sessler DI. Long-term consequences of anesthetic management. Anesthesiology. 2009 Jul;111(1):1-4. doi: 10.1097/ALN.0b013e3181a913e1. — View Citation

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. Review. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall survival after surgery (cancer patients).	Time from surgery to the date of all-cause death.	Up to median 5 years after surgery.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Primary	Overall survival after surgery.	Time from surgery to the date of all-cause death.	Up to median 5 years after surgery.
Secondary	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.
Secondary	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.
Secondary	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.