Impact of Anesthesia Maintenance Methods on Long-term Survival
Condition: Aged; Neoplasms; Surgical Procedure, Operative; Anesthesia, Inhalation; Anesthesia, Intravenous; Survival
MeSH terms: Neoplasms; Respiratory Aspiration
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): Sevoflurane; Propofol
Intervention type(s): Drug; Drug
Intervention description(s): 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 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.
Other intervention name(s): Sevoflurane for inhalation; Propofol for injection
Intervention MeSH terms: Propofol; Sevoflurane
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Sevoflurane; Propofol; Aged; Neoplasm; Surgical Procedure, Operative; Long-term survival