Impact of Anesthesia Maintenance Methods on Long-term Survival

Neoplasms Clinical Trial

Official title:

Impact of Inhalational Versus Intravenous Anesthesia Maintenance Methods on Long-term Survival in Elderly Patients After Cancer Surgery: a Randomized Controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02660411
• Other study ID #: 2015[869]-2
• Secondary ID: ChiCTR-IPR-15006
• Status: Completed
• Phase: N/A
• Start date: April 1, 2015
• Est. completion date: September 30, 2020

Study information

• Verified date: March 2022
• Source: Peking University First Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Surgery is one of the major treatment methods for patients with malignant tumor. And, alone with the ageing process, more and more elderly patients undergo surgery for malignant tumor. Evidence emerges that choice of anesthetics, i.e., either inhalational or intravenous anesthetics, may influence the outcome of elderly patients undergoing cancer surgery. From the point of view of immune function after surgery and invasiveness of malignant tumor cells, propofol intravenous anesthesia may be superior to inhalational anesthesia. However, the clinical significance of these effects remains unclear. Retrospective studies indicated that use of propofol intravenous anesthesia was associated higher long-term survival rate. Prospective studies exploring the effect of anesthetic choice on long-term survival in cancer surgery patients are urgently needed.

Description:

It is estimated that 234.2 million major surgical procedures are undertaken every year worldwide. Surgery is one of the major treatment methods for patients with malignant tumor. And, alone with the ageing process, more and more elderly patients undergo surgery for malignant tumor. However, evidence emerges that choice of anesthetics, i.e., either inhalational or intravenous anesthetics, may influence the outcome of elderly patients undergoing cancer surgery.

A. Effects of anesthetics on immune function after surgery

The choice of general anesthetics might influence human's immune function after surgery. An international multicenter team (NCT00418457) investigated the effects of propofol-paravertebral anesthesia vs sevoflurane-opioid anesthesia on the immune function in patients after breast cancer surgery. In a small sample size (n = 32) randomized controlled trail published in 2010, postoperative serum concentrations of interleukin (IL)-1 (protumorigenic cytokine) and matrix metalloproteinases (MMP)-3/9 (associated with cancer cell invasion and metastasis) were significantly lower (P = 0.003 and 0.011, respectively), whereas that of IL-10 (antitumorigenic cytokines) was significantly higher in the propofol group than in the sevoflurane group (P = 0.001). In another small sample size (n = 10) randomized controlled trail published in 2014, serum obtained from patients who received propofol anesthesia led to greater human donor natural killer (NK) cell cytotoxicity in vitro when compared with serum from those who received sevoflurane anesthesia. In a recent small sample size (n = 28) randomized controlled trial, the levels of NK and T helper cell infiltration in breast cancer tissue were significantly higher in patients receiving propofol anesthesia than those receiving sevoflurane anesthesia (P = 0.015 and 0.03, respectively).

Similar findings were reported in patients with other malignant tumors. In a small randomized controlled trial, 30 patients with non-small-cell lung cancer randomly received either propofol or isoflurane anesthesia. The results showed that cluster of differentiation (CD)4+CD28+ percentage (P < 0.0001) and the ratio of interferon-gamma:interleukin-4 (P = 0.001) all increased significantly with propofol but no change with isoflurane anesthesia; indicating that propofol promotes activation and differentiation of peripheral T-helper cells. In another randomized controlled trial, 60 patients undergoing surgery for tongue cancer surgery randomly received total propofol, mixed (propofol induction and sevoflurane maintenance) anesthesia or total sevoflurane anesthesia. The results showed that the percentages of CD3+, CD3+CD4+, and NK cells and the ratio of CD4+/CD8+ were significantly decreased in the two sevoflurane groups, but not in the total propofol group; suggesting that propofol has less effects on cellular immune response than sevoflurane. There are also studies that reported neutral results.

The above studies suggest that, when compared with inhalational anesthesia, propofol intravenous anesthesia may have favorable effects on the immune function in patients after cancer surgery. However, care must be taken when explaining these results: (1) the sample sizes of the available studies were small; (2) the relationship between postoperative immune function changes and long-term outcomes remains unclear.

B. Effects of anesthetics on invasiveness of malignant tumor

The effects of anesthetics on invasiveness of tumor cells were mainly tested in the experimental studies, i.e., tumor cells were incubated with anesthetics in the in vitro environment. In this aspect, propofol shows somewhat favorable effects. The results of Miao et al. showed that propofol stimulation decreased the expression of MMP-2 and -9 and subsequently decreased the invasive activity of human colon cancer cells, possibly via extracellular signal-regulated kinase 1/2 (ERK1/2) down-regulation mediated through the gamma-aminobutyric acid (GABA)-A receptor. The study of Wang et al. reported that propofol inhibited invasion and metastasis, and enhanced paclitaxel-induced apoptosis of ovarian cancer cells, possibly by suppressing the Slug expression. Ecimovic et al. also reported that propofol reduced migration in both estrogen receptor-positive and -negative breast cancer cells, possibly by suppressing the Neuroepithelial Cell Transforming Gene 1 (NET1) expression.

The reported effects of various inhalational anesthetics are conflicting. Huang et al. compared the effects of propofol and isoflurane on prostate cancer cells. The results showed that propofol, at clinical relevant concentration, inhibited the activation of hypoxia-inducible factor (HIF)-1 alpha, and partially reduced cancer cell malignant activities; whereas isoflurane raised HIF-1 alpha expression, and increased the probability of proliferation and migration. The study of Benaonana et al. reported similar results, i.e., isoflurane up-regulated the expression of HIFs, and increased the growth and malignant potential of renal cancer cells. On the other hand, sevoflurane and desflurane show opposite effects. Multiple studies found that sevoflurane inhibited the proliferation and migration, and induced apoptosis of lung cancer cells. Müller-Edenborn et al. also reported that volatile anesthetics (sevoflurane and desflurane) reduced invasion of colorectal cancer cells through down-regulation of matrix metalloproteinase-9.

So far, the clinical significance of anesthetics on the invasiveness of malignant tumors is still lacking.

C. Effect of anesthetics on long-term outcome after cancer surgery

Studies in this aspect are very limited. In the study of Enlund et al., 2838 patients who underwent breast cancer or colorectal cancer surgery were retrospectively analyzed, among them 1935 received sevoflurane anesthesia and 903 propofol anesthesia. The 1-year and 5-year survival rates were higher in propofol-anesthetized patients than in sevoflurane-anesthetized ones (differences in overall survival rate were 4.7%, P = 0.004 and 5.6%, P < 0.001, respectively). However, the differences were not statistically significant after adjusting for confounding factors. In a recent study, Wigmore et al. retrospectively investigated 11,395 patients after cancer surgery. After exclusions and propensity matching, 2,607 patients remained in each of the inhalational anesthesia group or total intravenous anesthesia group. The results showed that, after a median follow-up duration of 2.66 years (95% confidence interval [CI] 2.62-2.69), volatile inhalational anesthesia was associated with a higher risk for death after both univariate (HR 1.59, 95% CI 1.30-1.95) and multivariable analysis (HR 1.46, 95% CI 1.29-1.66).

However, in this aspect, long-term follow-up results of randomized controlled trials are still lacking. Prospective studies exploring the effect of anesthetic choice on long-term survival in cancer surgery patients are urgently needed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1228
• Est. completion date: September 30, 2020
• Est. primary completion date: September 29, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years to 90 Years

Eligibility

Inclusion Criteria:

• Participants will be included if they meet all the following criteria:

1. Age = 65 years and < 90 years;

2. Primary malignant tumor;

3. Do not receive radiation therapy or chemotherapy before surgery;

4. Scheduled to undergo surgery for the treatment of tumors, with an expected duration of 2 hours or more, under general anesthesia;

5. Agree to participate, and give signed written informed consent.

Exclusion Criteria:

• Patients will be excluded if they meet any of the following criteria:

1. Preoperative history of schizophrenia, epilepsy, parkinsonism or myasthenia gravis;

2. Inability to communicate in the preoperative period (coma, profound dementia, language barrier, or end-stage disease);

3. Critical illness (preoperative American Society of Anesthesiologists physical status classification = IV), severe hepatic dysfunction (Child-Pugh class C), or severe renal dysfunction (undergoing dialysis before surgery);

4. Neurosurgery;

5. Other reasons that are considered unsuitable for participation by the responsible surgeons or investigators (reasons must be recorded in the case report form).

Related Conditions & MeSH terms

• Aged
• Anesthesia, Inhalation
• Anesthesia, Intravenous
• Neoplasms
• Respiratory Aspiration
• Surgical Procedure, Operative
• Survival

Intervention

Drug:
• Sevoflurane
Sevoflurane will be administered by inhalation for anesthesia maintenance. The concentration of inhaled sevoflurane will be adjusted to maintain the BIS value between 40 and 60. Sevoflurane inhalational concentration will be decreased towards the end of surgery. Sevoflurane inhalation will be stopped at the end of surgery.
• Propofol
Propofol will be administered by intravenous infusion for anesthesia maintenance. The infusion rate of propofol will be adjusted to maintain the BIS value between 40 and 60. Propofol infusion rate will be decreased towards the end of surgery. Propofol infusion will be stopped at the end of surgery.

Locations

Country	Name	City	State
China	Beijing Shijitan Hospital	Beijing	Beijing
China	Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital	Beijing	Beijing
China	Peking University Cancer Hospital	Beijing	Beijing
China	University School and Hospital of Stomatology	Beijing	Beijing
China	The Third Xiangya Hospital of Central South University	Changsha	Hunan
China	Guizhou Provincial People's Hospital	Guiyang	Guizhou
China	Zhongda Hospital	Nanjing	Jiangsu
China	Cancer Hospital of Guangxi Medical University	Nanning	Guangxi
China	Shenzhen Second People's Hospital	Shenzhen	Guangzhou
China	Hebei Medical University Forth Hospital	Shijiazhuang	Hebei
China	Shaanxi Provincial People's Hospital	Taiyuan	Shanxi
China	Shanxi Province Cancer Hospital	Taiyuan	Shanxi
China	Tianjin Nankai Hospital	Tianjin
China	Tang-Du Hospital	Xi'an	Shaanxi
China	Affiliated Hospital of Qinghai University	Xining	Qinghai
China	Ningxia People's Hospital	Yinchuan	Ningxia
China	The First Affiliated Hospital of Zhengzhou University	Zhenzhou	Henan

Sponsors (14)

Lead Sponsor

Collaborator

Peking University First Hospital

Affiliated Hospital of Qinghai University, Beijing Shijitan Hospital, Capital Medical University, Cancer Hospital of Guangxi Medical University, Guizhou Provincial People's Hospital, Hebei Medical University Fourth Hospital, Shanxi Provincial People's Hospital, Shenzhen Second People's Hospital, Tang-Du Hospital, The First Affiliated Hospital of Zhengzhou University, The People's Hospital of Ningxia, The Third Xiangya Hospital of Central South University, Tianjin Nankai Hospital, Zhongda Hospital

Country where clinical trial is conducted

China, 

References & Publications (18)

Benzonana LL, Perry NJ, Watts HR, Yang B, Perry IA, Coombes C, Takata M, Ma D. Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro. Anesthesiology. 2013 Sep;119(3):593-605. doi: 10.1097/ALN.0b013e31829e47fd. — View Citation

Buckley A, McQuaid S, Johnson P, Buggy DJ. Effect of anaesthetic technique on the natural killer cell anti-tumour activity of serum from women undergoing breast cancer surgery: a pilot study. Br J Anaesth. 2014 Jul;113 Suppl 1:i56-62. doi: 10.1093/bja/aeu200. Epub 2014 Jul 9. — View Citation

Deegan CA, Murray D, Doran P, Moriarty DC, Sessler DI, Mascha E, Kavanagh BP, Buggy DJ. Anesthetic technique and the cytokine and matrix metalloproteinase response to primary breast cancer surgery. Reg Anesth Pain Med. 2010 Nov-Dec;35(6):490-5. doi: 10.1097/AAP.0b013e3181ef4d05. — View Citation

Desmond F, McCormack J, Mulligan N, Stokes M, Buggy DJ. Effect of anaesthetic technique on immune cell infiltration in breast cancer: a follow-up pilot analysis of a prospective, randomised, investigator-masked study. Anticancer Res. 2015 Mar;35(3):1311-9. — View Citation

Ecimovic P, Murray D, Doran P, Buggy DJ. Propofol and bupivacaine in breast cancer cell function in vitro - role of the NET1 gene. Anticancer Res. 2014 Mar;34(3):1321-31. — View Citation

Enlund M, Berglund A, Andreasson K, Cicek C, Enlund A, Bergkvist L. The choice of anaesthetic--sevoflurane or propofol--and outcome from cancer surgery: a retrospective analysis. Ups J Med Sci. 2014 Aug;119(3):251-61. doi: 10.3109/03009734.2014.922649. Epub 2014 May 26. — View Citation

Huang H, Benzonana LL, Zhao H, Watts HR, Perry NJ, Bevan C, Brown R, Ma D. Prostate cancer cell malignancy via modulation of HIF-1a pathway with isoflurane and propofol alone and in combination. Br J Cancer. 2014 Sep 23;111(7):1338-49. doi: 10.1038/bjc.2014.426. Epub 2014 Jul 29. — View Citation

Liang H, Gu M, Yang C, Wang H, Wen X, Zhou Q. Sevoflurane inhibits invasion and migration of lung cancer cells by inactivating the p38 MAPK signaling pathway. J Anesth. 2012 Jun;26(3):381-92. doi: 10.1007/s00540-011-1317-y. Epub 2012 Feb 17. — View Citation

Liang H, Yang CX, Zhang B, Wang HB, Liu HZ, Lai XH, Liao MJ, Zhang T. Sevoflurane suppresses hypoxia-induced growth and metastasis of lung cancer cells via inhibiting hypoxia-inducible factor-1a. J Anesth. 2015 Dec;29(6):821-30. doi: 10.1007/s00540-015-2035-7. Epub 2015 May 23. — View Citation

Margarit SC, Vasian HN, Balla E, Vesa S, Ionescu DC. The influence of total intravenous anaesthesia and isoflurane anaesthesia on plasma interleukin-6 and interleukin-10 concentrations after colorectal surgery for cancer: a randomised controlled trial. Eur J Anaesthesiol. 2014 Dec;31(12):678-84. doi: 10.1097/EJA.0000000000000057. — View Citation

Miao Y, Zhang Y, Wan H, Chen L, Wang F. GABA-receptor agonist, propofol inhibits invasion of colon carcinoma cells. Biomed Pharmacother. 2010 Nov;64(9):583-8. doi: 10.1016/j.biopha.2010.03.006. Epub 2010 May 4. — View Citation

Müller-Edenborn B, Roth-Z'graggen B, Bartnicka K, Borgeat A, Hoos A, Borsig L, Beck-Schimmer B. Volatile anesthetics reduce invasion of colorectal cancer cells through down-regulation of matrix metalloproteinase-9. Anesthesiology. 2012 Aug;117(2):293-301. doi: 10.1097/ALN.0b013e3182605df1. — View Citation

Ren XF, Li WZ, Meng FY, Lin CF. Differential effects of propofol and isoflurane on the activation of T-helper cells in lung cancer patients. Anaesthesia. 2010 May;65(5):478-82. doi: 10.1111/j.1365-2044.2010.06304.x. Epub 2010 Mar 19. — View Citation

Wang P, Chen J, Mu LH, Du QH, Niu XH, Zhang MY. Propofol inhibits invasion and enhances paclitaxel- induced apoptosis in ovarian cancer cells through the suppression of the transcription factor slug. Eur Rev Med Pharmacol Sci. 2013 Jul;17(13):1722-9. Erratum in: Eur Rev Med Pharmacol Sci. 2021 Nov;25(21):6446. — View Citation

Wei GH, Zhang J, Liao DQ, Li Z, Yang J, Luo NF, Gu Y. The common anesthetic, sevoflurane, induces apoptosis in A549 lung alveolar epithelial cells. Mol Med Rep. 2014 Jan;9(1):197-203. doi: 10.3892/mmr.2013.1806. Epub 2013 Nov 18. — View Citation

Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, Gawande AA. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet. 2008 Jul 12;372(9633):139-144. doi: 10.1016/S0140-6736(08)60878-8. Epub 2008 Jun 24. — View Citation

Wigmore TJ, Mohammed K, Jhanji S. Long-term Survival for Patients Undergoing Volatile versus IV Anesthesia for Cancer Surgery: A Retrospective Analysis. Anesthesiology. 2016 Jan;124(1):69-79. doi: 10.1097/ALN.0000000000000936. — View Citation

Zhang T, Fan Y, Liu K, Wang Y. Effects of different general anaesthetic techniques on immune responses in patients undergoing surgery for tongue cancer. Anaesth Intensive Care. 2014 Mar;42(2):220-7. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of life in 3-year survivors after surgery.	Quality of life is assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).	Assessed at the end of the 3rd year after surgery.
Other	Cognitive function in 3-year survivors after surgery.	Cognitive function is assessed with the Telephone Interview for Cognitive Status-Modified (TICS-m).	Assessed at the end of the 3rd year after surgery.
Primary	Over survival after surgery.	Time from surgery to the date of all-cause death.	Up to 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 occurs first.	Up to 5 years after surgery
Secondary	Event-free survival after surgery	Time from surgery to the date of cancer recurrence/metastasis, new cancer, new serious non-cancer disease, or all-cause death, whichever occurs first.	Up to 5 years after surgery