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Impact of Anesthesia Maintenance Methods on Long-term Survival Rate

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02660411
Recruitment Status : Active, not recruiting
First Posted : January 21, 2016
Last Update Posted : December 11, 2019
Sponsor:
Collaborators:
Hebei Medical University Fourth Hospital
The People's Hospital of Ningxia
Peking University Hospital of Stomatology
Beijing Cancer Hospital
Beijing Shijitan Hospital
Guizhou Provincial People's Hospital
Affiliated Hospital of Qinghai University
The Third Xiangya Hospital of Central South University
Cancer Hospital of Guangxi Medical University
Shaanxi Provincial People's Hospital
Zhongda Hospital
The First Affiliated Hospital of Zhengzhou University
Tang-Du Hospital
Shanxi Province Cancer Hospital
Tianjin Nankai Hospital
Shenzhen Second People's Hospital
Information provided by (Responsible Party):
Dong-Xin Wang, Peking University First Hospital

Tracking Information
First Submitted Date  ICMJE January 7, 2016
First Posted Date  ICMJE January 21, 2016
Last Update Posted Date December 11, 2019
Actual Study Start Date  ICMJE April 2015
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2017)
3-year survival after surgery [ Time Frame: Until the end of the 3rd year after surgery ]
Duration of survival within 3 years after surgery
Original Primary Outcome Measures  ICMJE
 (submitted: January 17, 2016)
Survival rate at 3rd year after surgery [ Time Frame: The 3rd year after surgery ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2017)
  • Survival rates at different timepoints after surgery [ Time Frame: At the 1st, 2nd, and 3rd year after surgery ]
    Survival rates at different timepoints after surgery
  • 3-year recurrence-free survival after surgery [ Time Frame: Until the end of the 3rd year after surgery ]
    Duration of recurrence-free survival within 3 years after surgery
  • Recurrence-free survival rates at different timepoints after surgery [ Time Frame: At the 1st, 2nd, and 3rd year after surgery ]
    Recurrence-free survival rates at different timepoints after surgery
  • Quality of life of survivors at 3 years after surgery [ Time Frame: Assessed at the end of the 3rd year after surgery ]
    Quality of life is assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
  • Cognitive function of survivors at 3 years after surgery [ Time Frame: Assessed at the 3rd year after surgery ]
    Cognitive function is assessed with the Telephone Interview for Cognitive Status-Modified (TICS-m)
Original Secondary Outcome Measures  ICMJE
 (submitted: January 17, 2016)
  • Duration of survival after surgery [ Time Frame: Up to 3 years after surgery ]
  • Survival rate at different time after surgery [ Time Frame: At the 1st, 2nd, and 3rd year after surgery ]
  • Duration of recurrence-free survival after surgery [ Time Frame: Up to 3 years after surgery ]
  • Recurrence-free survival rate at different time after surgery [ Time Frame: At the 1st, 2nd, and 3rd year after surgery ]
  • Quality of life of survivors as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at 3 years after surgery [ Time Frame: Assessed at the 3rd year after surgery ]
  • Cognitive function of survivors as assessed by the Modified Telephone Interview for Cognitive Status (TICS-m) at 3 years after surgery [ Time Frame: Assessed at the 3rd year after surgery ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact of Anesthesia Maintenance Methods on Long-term Survival Rate
Official Title  ICMJE Impact of Inhalational Versus Intravenous Anesthesia Maintenance Methods on Long-term Survival Rate in Elderly Patients After Cancer Surgery: an Open-label, Randomized Controlled Trial
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Long-term Effects Secondary to Cancer Therapy in Adults
Intervention  ICMJE
  • 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, with or without 50% nitrous oxide. Sevoflurane inhalational concentration will be decreased towards the end of surgery. Sevoflurane inhalation will be stopped at the end of surgery.
    Other Name: Sevoflurane for inhalation
  • Drug: 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, with or without 50% nitrous oxide. Propofol infusion rate will be decreased towards the end of surgery. Propofol infusion will be stopped at the end of surgery.
    Other Name: Propofol for injection
Study Arms  ICMJE
  • Active Comparator: Sevoflurane group

    Anesthesia will be induced intravenously with midazolam (0.015-0.03 mg/kg), sufentanil, propofol and rocuronium.

    Sevoflurane will be administered by inhalation for anesthesia maintenance. The concentration of inhaled sevoflurane will be adjusted to maintain the bispectral index (BIS) value between 40 and 60, with or without 50% nitrous oxide. Analgesia will be supplemented with remifentanil (administered by continuous infusion), sufentanil (administered by intermittent injection/continuous infusion), or fentanyl (administered by intermittent injection).

    Towards the end of surgery, sevoflurane inhalational concentration will be decreased and fentanyl/sufentanil will be administered when necessary. Sevoflurane inhalation will be stopped at the end of surgery.

    Intervention: Drug: Sevoflurane
  • Experimental: Propofol group

    Anesthesia will be induced intravenously with midazolam (0.015-0.03 mg/kg), sufentanil, propofol and rocuronium.

    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, with or without 50% nitrous oxide. Analgesia will be supplemented with remifentanil (administered by continuous infusion), sufentanil (administered by intermittent injection/continuous infusion), or fentanyl (administered by intermittent injection).

    Towards the end of surgery, propofol infusion rate will be decreased and fentanyl/sufentanil will be administered when necessary. Propofol infusion will be stopped at the end of surgery.

    Intervention: Drug: Propofol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 15, 2017)
1200
Original Estimated Enrollment  ICMJE
 (submitted: January 17, 2016)
1000
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years to 90 Years   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02660411
Other Study ID Numbers  ICMJE 2015[869]-2
ChiCTR-IPR-15006209 ( Registry Identifier: Chinese Clinical Trial Registry (www.chictr.org.cn) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Dong-Xin Wang, Peking University First Hospital
Study Sponsor  ICMJE Peking University First Hospital
Collaborators  ICMJE
  • Hebei Medical University Fourth Hospital
  • The People's Hospital of Ningxia
  • Peking University Hospital of Stomatology
  • Beijing Cancer Hospital
  • Beijing Shijitan Hospital
  • Guizhou Provincial People's Hospital
  • Affiliated Hospital of Qinghai University
  • The Third Xiangya Hospital of Central South University
  • Cancer Hospital of Guangxi Medical University
  • Shaanxi Provincial People's Hospital
  • Zhongda Hospital
  • The First Affiliated Hospital of Zhengzhou University
  • Tang-Du Hospital
  • Shanxi Province Cancer Hospital
  • Tianjin Nankai Hospital
  • Shenzhen Second People's Hospital
Investigators  ICMJE
Principal Investigator: Dong-Xin Wang, MD, PhD Peking University First Hospital
PRS Account Peking University First Hospital
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP