Anaesthetic techniques for risk of malignant tumour recurrence
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To establish whether anaesthetic technique (general anaesthesia versus regional anaesthesia or a combination of both techniques) influences the long‐term prognosis of malignant tumours.
Background
Cancer is the second most common cause of death in the United States and Europe (Centers for Disease Control and Prevention 2009; European Public Health Alliance 2009). Cancer might be tumour forming (malignant tumour) or not (such as leukaemia). The most common cancers contributing to mortality are malignant tumours of lung, prostate, and breast and colorectal malignant tumours (Jemal 2010). For these malignant tumours surgery remains the mainstay of treatment. Surgery may be curative in the early stages and it may at least prolong life in late stages.
Description of the condition
Metastatic disease is the most important cause of cancer related death in patients after malignant tumour surgery (Snyder 2010). Surgical manipulation leads to a significant systemic release of tumour cells (Eschwege 1995; Wang 2006; Yamaguchi 2000; Yamashita 2000). Whether these lead to metastases is largely dependent on the balance between the aggressiveness of the tumour cells and the resilience of the body. At least three perioperative factors shift the balance toward progression of minimal residual disease.
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Surgery per se induces a stress response that can decrease host defences and promote tumour growth. The innate immunity and especially natural killer (NK) cells are known to play a major role in elimination of circulating tumour cells (Shakhar 2003; Whiteside 1995). Several studies have demonstrated a decreased postoperative NK cell activity and an inverse correlation of NK cell activity on tumour stage and metastatic growth (Konjevic 1993; Lennard 1985; Mafune 2000; Pollock 1991; Tarle 1993). Additionally, increased postoperative concentrations of pro‐angiogenic factors such as vascular endothelia growth factor (VEGF) were found in humans (Ikeda 2002; Maniwa 1998). Moreover, in animal models the surgical removal of the primary tumour significantly reduces concentrations of tumour‐related anti‐angiogenic factors (for example angiostatin and endostatin) and promotes tumour growth (Holmgren 1995).
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Anaesthetic agents might impair numerous immune functions, including those of neutrophils, macrophages, dendritic cells, T cells, and natural killer cells. Numerous in vitro and animal studies were able to show the immunosuppressive effect of anaesthetic agents such as halothane, isoflurane, ketamine, and thiopental (Kurosawa 2008; Melamed 2003; Moudgil 1997). More recently, the immunosuppressive effect of the volatile anaesthetic isoflurane was confirmed in humans undergoing non‐cancer surgery (Inada 2004; Schneemilch 2005).
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Opioid analgesics inhibit both cellular and humoral immune function in humans (Beilin 1996; Sacerdote 2000; Vallejo 2004; Yardeni 2008; Yeager 1995). Moreover, in a human cell culture model, morphine increased angiogenesis and promoted breast tumour growth in a mice model (Gupta 2002).
Other perioperative interventions or medications may influence the patient's immune response as well. In recent years perioperative intravenous lidocaine infusion was introduced into clinical practice to improve pain management after major surgery. Randomized controlled trials in humans suggest that the continuous administration of perioperative low dose lidocaine reduces postoperative opioid consumption, attenuates postoperative pain scores, and reduces surgery induced alterations of immunity (Koppert 2004; Yardeni 2009).
Description of the intervention
Regional anaesthetic techniques include neuraxial techniques, such as spinal anaesthesia and epidural anaesthesia; nerve block techniques, such as intercostal or paravertebral nerve blocks; and an intravenous regional anaesthesia technique. Local anaesthetic techniques, such as wound infiltration as a single shot or continuously via a catheter, might also be considered as a type of regional anaesthesia. All these techniques provide pain relief during, as well as after, surgical procedures; they therefore reduce the amount of systemic opioids needed perioperatively. Additionally, regional anaesthesia techniques are known to prevent or attenuate the surgical stress response by blocking afferent neuronal transmission, which prevents noxious afferent input from reaching the central nervous system (Deegan 2009; O'Riain 2005).
How the intervention might work
Regional anaesthetic techniques provide excellent pain relief during and after surgical interventions. A working regional anaesthesia technique implies that:
1. in many cases general anaesthesia can be replaced by regional anaesthetic techniques, and the potential immunosuppressive effects of anaesthetic agents such as volatile anaesthetics can be avoided;
2. the amount of intra‐ and postoperative opioids needed for intra‐ and postoperative pain management can at least be significantly reduced without compromising adequate pain relief;
3. the surgical stress response is at least attenuated by regional anaesthetic techniques and therefore the immunosuppressive effect of surgical stress might be attenuated as well.
Why it is important to do this review
Based on the available basic research data outlined above, the hypothesis was stated that perioperative immunosuppression caused by surgical stress, anaesthetics, and opioids might promote the progress of minimal residual disease in patients undergoing surgical resection of malignant tumours. Clinical researchers started to investigate the long‐term outcome of cancer patients after tumour surgery dependent on the anaesthetic technique used both intra‐ and postoperatively. However, these data seem to be inconsistent until today. Therefore, the aim of this Cochrane review is to provide the clinician with an up to date and comprehensive summary of the best available evidence on whether anaesthetic techniques may reduce malignant tumour recurrence.
Objectives
To establish whether anaesthetic technique (general anaesthesia versus regional anaesthesia or a combination of both techniques) influences the long‐term prognosis of malignant tumours.
Methods
Criteria for considering studies for this review
Types of studies
We will consider any randomized controlled trials (RCTs) or controlled clinical trials (CCTs) that investigate the effect of the anaesthetic technique on the risk of malignant tumour recurrence in patients undergoing resection of primary malignant tumours. We will not include non‐randomized studies in the meta‐analysis but we will provide a narrative summary of non‐randomized studies in the discussion. In order to obtain the widest range of studies we will not set date of publication or language limits.
Types of participants
We will consider all studies that include patients having surgery for primary malignant tumour resection. We will include both adult and paediatric patient populations. We define paediatric patients as children aged less than 18 years.
Types of interventions
Interventions of interest are the different anaesthetic techniques used during the surgical procedure for primary malignant tumour resection. General anaesthesia will include inhalational and intravenous techniques of drug administration. Regional anaesthesia will include peripheral regional anaesthesia; neuraxial regional anaesthesia, that is spinal anaesthesia and epidural anaesthesia; and local anaesthesia including continuous wound infiltration techniques.
The comparisons of interventions are:
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general anaesthesia alone versus general anaesthesia combined with one or more regional anaesthetic techniques;
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general anaesthesia combined with one or more regional anaesthetic techniques versus one, or a combination, of any regional anaesthetic techniques;
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general anaesthesia alone versus one or more regional anaesthetic techniques.
Types of outcome measures
Primary outcomes
1. Overall survival (OS): the time elapsed between surgery and death from any cause, with censoring of patients who were lost to follow up.
2. Progression‐free survival (PFS): the time elapsed between surgery and tumour progression or death from any cause, with censoring of patients who were lost to follow up.
3. Time to tumour progression (TTP): the time elapsed between surgery and tumour progression with censoring of patients who died or were lost to follow up.
Secondary outcomes
1. Postoperative adverse events including postoperative nausea and vomiting (PONV), postoperative respiratory complications, and postoperative cardiac complications.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue); PubMed (1950 to present); EMBASE (1974 to present); Scopus (from inception to present); BIOSIS (1926 to present); and Web of Science (1965 to present). We will develop a specific search strategy for each database based on that developed for PubMed (Appendix 1). We will combine the PubMed search strategy with the Cochrane highly sensitive search strategy for identifying randomized controlled trials (Higgins 2008a).
Searching other resources
We will identify trials by manually searching abstracts of relevant conference proceedings, such as the American Society of Anesthesiologists Annual Meetings, European Society of Anaesthesiologists Annual Meetings, National Cancer Research Institute (NCRI) cancer conference.
We will check the reference lists of relevant articles. We will contact relevant trial authors to identify any additional or ongoing studies. We will also search for relevant trials on specific sites:
http://controlled‐trials.com/,
http://www.nyam.org/library/pages/grey_literature_report,
http://www.science.gov/index.html.
We will not apply language or publication date restrictions.
Data collection and analysis
Selection of studies
We will merge the results identified by the described variety of search strategies using literature manager software (Reference Manager). Two authors (OSC, KK) will independently scan the titles and abstracts of identified reports. We will retrieve and evaluate potentially relevant studies chosen by at least one author in the full‐text version. We will identify multiple reports of the same study. Two authors (OSC and KK) will independently assess the congruence of the remaining trials with the review's inclusion criteria using a checklist that has been designed in advance (study eligibility screening form) (Appendix 2). A third author (CCA) will settle any disagreements.
Data extraction and management
Two authors (OSC, KK) will independently extract data using a data abstracting form (Appendix 3) based on the CARG data extraction form (CARG 2007; Jűni 2001). For each of the outcome variables, three authors (OS, PFS, TTP) will use the data abstraction tables suggested by Tierney 2007. If the individual trial report provides summary statistics with odds ratios (OR), relative risks (RR) or Kaplan Meier curves, the extracted data will enable us to calculate the hazard ratio using the HR calculating spreadsheet (Tierney 2007). We will resolve any disagreement through consultation with a third author (NLP).
Assessment of risk of bias in included studies
We will judge the study quality using the Cochrane Collaboration’s tool for assessing risk of bias, a two‐part tool that addresses the six specific domains of: sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias (Higgins 2008b). The first part describes the risk of bias, the second part provides criteria for making judgements about the risk of bias from each of the six domains in the tool (Appendix 4). Based on this tool we will implement a 'Risk of bias' worksheet to be filled out for each study (Appendix 5). The risk of bias will be assessed by two authors (OSC, KK). We will resolve any disagreement through consultation with a third author (CCA). We will display the results by creating a 'Risk of bias' graph and a 'Risk of bias' summary figure using RevMan 5.0 software, if appropriate. We will present the risk of bias in the result section. We will provide summary assessments of the risk of bias for each outcome within and across studies.
Measures of treatment effect
All primary outcome variables are time‐to‐event data. The treatment effect will be the log hazard ratio for general anaesthesia versus regional anaesthesia or a combination of both for overall survival (OS), progression‐free survival (PFS), and time‐to‐tumour progression (TTP). The treatment effect for the dichotomous secondary outcomes (adverse events) will be expressed as the risk ratio (RR).
Unit of analysis issues
We do not expect to find crossover studies.
Dealing with missing data
Where necessary, we will contact authors of included studies regarding missing data. Where data are found to be missing and the authors can not be contacted we will, if possible, calculate missing statistics from other quoted statistics. If missing data remain then we will perform an available case analysis, excluding data where outcome information is unavailable. An intention‐to‐treat analysis will be conducted to address missing data due to patients dropping out.
Assessment of heterogeneity
We will assess statistical heterogeneity using the Chi2 test. We will consider a P value ≤ 0.05 as statistically significant. If we include a small number of studies or studies with small sample sizes, we will increase the significance level to 0.10. We will assess the level of inconsistency across the studies using the I2 statistic, where I2 > 50 % indicates significant inconsistency. If present, we will explore and discuss possible reasons for heterogeneity and inconsistency (Higgins 2008a). If heterogeneity can not be readily explained, we will use a random‐effects model to analyse the data.
Assessment of reporting biases
We will assess reporting biases through careful attention to quality assessment, particular of study methodology. A thorough search for unpublished studies through contact with known experts in the field will also assist in reducing the risk of publication bias. We will use funnel plot analysis to examine publication bias if a minimum number of 10 studies are included in the review.
Data synthesis
The effect measure for comparing the interventions for survival outcomes will be the log hazard ratio (HR) and standard error (SEHR). We will report hazard ratios with 95 % confidence intervals (CI) on a non‐log scale. If individual patient data (IPD) are available for a trial, the data will be analysed to obtain HR and SEHR. For trials providing the HR but not providing IPD and not reporting the SEHR, we will use the methods of Parmar 1998 to estimate the variance from the reported CI (Parmar 1998). For trials that do not report the HR, we will use the approximation methods of Parmar 1998 and Williamson 2002 to estimate HR and variance from the cumulative survival rates (Kaplan‐Meir plots), observed and expected event tallies, the logrank statistics, or the Mantel‐Haenszel test (Parmar 1998; Williamson 2002). If clinical heterogeneity of trials is not excessive, estimation of the summary HR across trials will use the generic inverse variance (GIV) method with a fixed‐effect model, using the statistical software Review Manager. We will create funnel plots from the GIV tables.
The pooled treatment effect for RR will be performed in Review Manager using an inverse variance approach. If adverse events are rare, the treatment effect measure will be changed to the odds ratio (OR) to allow use of the Peto OR approach.
Subgroup analysis and investigation of heterogeneity
We will conduct subgroup analysis where data are available. We will analyse separately and compare the following.
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Adults and children.
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Types of cancer.
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Tumour stages at the time of surgical resection of the primary tumour.
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Use of perioperative continuous intravenous lidocaine.
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Administration of any opioids either intrathecally, epidurally, or peripherally.
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Type of general anaesthesia (total intravenous anaesthesia (TIVA); balanced anaesthesia, i.e. a combination of intravenous and volatile anaesthesia (BAL)).
Sensitivity analysis
We will perform sensitivity analysis to explore the consistency of effect size measures with the domains of the risk of bias. We will also perform sensitivity analysis with different definitions of progression‐free survival.
Summary of findings table
The outcomes overall survival, progression‐free survival, and time‐to‐tumour progression will be incorporated into a 'Summary of findings' table. The treatment effect of all these three primary outcomes is the hazard ratio of time‐to‐event data, incorporating both beneficial and adverse effects. No other adverse effects are expected in the included studies.
Using the content of the included studies and the 'Risk of bias' tables, the quality of evidence will be presented using the GRADE approach with particular attention to limitations of study design and heterogeneity of results.
