Clinical trial NCT03012945: Epidural Anesthesia-analgesia and Long-term Outcome
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Elderly
Malignant Tumor
Surgical Resection
Epidural Anesthesia
Long-term Outcome
Keywords: Elderly
Cancer surgery
Epidural anesthesia and analgesia
Long-term survival
Lead sponsor: Peking University First Hospital
Sponsor class: OTHER
Collaborators: name: Peking University People's Hospital
name: Peking University Third Hospital
name: Beijing Hospital
name: Beijing Shijitan Hospital, Capital Medical University
name: Peking University
First posted: 2017-01-06
Enrollment: 1802
Sex: ALL
Minimum age (years): 60
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival after surgery.
timeFrame: Up to median 5 years after surgery.
Secondary outcomes:
measure: Cancer-specific survival after surgery.
timeFrame: Up to median 5 years after surgery.
measure: Recurrence-free survival after surgery.
timeFrame: Up to median 5 years after surgery.
measure: Event-free survival after surgery.
timeFrame: Up to median 5 years after surgery.
Other outcomes:
measure: Overall survival after surgery (cancer patients).
timeFrame: Up to median 5 years after surgery.
measure: Cancer-specific survival after surgery (cancer patients).
timeFrame: Up to median 5 years after surgery.
measure: Recurrence-free survival after surgery (cancer patients).
timeFrame: Up to median 5 years after surgery.
measure: Event-free survival after surgery (cancer patients).
timeFrame: Up to median 5 years after surgery.
measure: Cognitive function (3-year survivors).
timeFrame: At the end of the 3rd year after surgery.
measure: Quality of life (3-year survivors).
timeFrame: At the end of the 3rd year after surgery.
Locations:
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Beijing
country: China
facility: Beijing Shijitan Hospital
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Peking University Third Hospital
city: Beijing
country: China
facility: Beijing Hospital
Study officials:
affiliation: Peking University First Hospital
name: Dong-Xin Wang, MD
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1097/00000658-200007000-00009.
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. doi: 10.1245/aso.2003.02.007.
citation: Sessler DI. Long-term consequences of anesthetic management. Anesthesiology. 2009 Jul;111(1):1-4. doi: 10.1097/ALN.0b013e3181a913e1. No abstract available.
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. doi: 10.1136/bmj.319.7209.530. No abstract available.
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):1331-1339. doi: 10.1213/01.ANE.0000082995.44040.07.
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. doi: 10.1016/0192-0561(95)00026-x.
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. doi: 10.1097/00000542-199304000-00013.
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.
citation: 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.
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. doi: 10.1016/s0165-5728(02)00165-0.
citation: 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.
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.