Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the benefits and harms of adjuvant chemotherapy for people with cholangiocarcinoma who have undergone curative‐intent resection.
Background
Description of the condition
Cholangiocarcinoma is a malignant epithelial tumour arising in the bile duct (intrahepatic and extrahepatic bile duct). Several conditions have been established as risk factors associated with cholangiocarcinoma including cirrhosis, hepatitis B, hepatitis C, chronic inflammation with liver injury secondary to the primary sclerosing cholangitis, and infection with Opisthorchis viverrini (O viverrini) (South Asian liver fluke) and Clonorchis sinensis (C sinensis) (Chinese liver fluke). The age‐standardised incidence rates of cholangiocarcinoma vary widely between the different geographical regions, largely due to variations in regional environmental risk factors. Cholangiocarcinoma is relatively rare among Western countries with an age‐standardised incidence rate between 0.3 and 2 per 100,000 person‐years. The age‐standardised incidence rate of cholangiocarcinoma in Asian countries ranges from 1 to 85 per 100,000 person‐years. The highest age‐standardised incidence rate of cholangiocarcinoma is found in the northeast provinces of Thailand where the liver fluke O viverrini is endemic (up to 113 per 100,000 person‐years in men and 50 per 100,000 person‐years in women) (Parkin 2002; Sripa 2008; Bergquist 2015; Khuntikeo 2016).
Cholangiocarcinoma is commonly classified based on anatomical location. The intrahepatic type is defined as a cholangiocarcinoma that arises in a bile duct proximal to a second‐degree bile duct. Perihilar type is located in the bile duct between a second‐degree bile duct and a junction of cystic duct and a common bile duct. Distal type is localised in the area between the insertion of a cystic duct and the ampulla of Vater (Nakeeb 1996). Appendix 1 displays the American Joint Committee staging for Cancer (AJCC) tumour‐nodes metastasis (TNM) staging system for cholangiocarcinoma (NCCN 2016).
Complete resection remains the gold standard of treatment for cholangiocarcinoma. Malignancy positive surgical margins and regional lymph node metastasis negatively impact on the survival of people with cholangiocarcinoma who undergo curative intent resection (Isa 2001; Weber 2001; Pattanathien 2013; Titapun 2015). Median survivals of people who have negative resection margins range from 25 to 61 months compared to 12 to 20 months in people with positive resection margins (Isa 2001; Pattanathien 2013; Titapun 2015). Median survivals are 10 to 12 months in people with negative resection margins and 27 to 63 months in people with positive resection margins, for people who have a lymph node metastasis and those without a lymph node metastasis (Isa 2001; Pattanathien 2013; Titapun 2015).
Description of the intervention
Chemotherapy is the use of drugs to treat cancer, principally by inhibiting the growth and division of cancer cells and promoting cell death. Adjuvant (supplementary treatment after initial treatment) chemotherapy can be defined as an additional chemotherapy given immediately after primary surgery or primary radiotherapy in an attempt to lessen the risk of the cancer returning by eradicating residual diseases, particularly micrometastatic lesions that are supposed to be outside the field of the primary treatment covered (Carter 1986; Powell 1987). Chemotherapy agents can be administered locally (e.g. topical application or intracavitary injection) or systemically (e.g. oral, intramuscular injection, or intravenous injection) administered. The choice of chemotherapy agents for each patient mainly depends on the type and stage of cancer, patient's performance status, and details of previous treatment received (Carter 1986; Powell 1987). Although the best chemotherapy for cholangiocarcinoma remains to be determined, 5‐fluorouracil and gemcitabine, as a single chemotherapeutic agent or in combination with other drugs, have been proposed as active and well‐tolerated regimens (Thongprasert 2005).
How the intervention might work
The mainstay of treatment of cholangiocarcinoma is surgical resection (Razumilava 2014; Luvira 2016). The operation for intrahepatic cholangiocarcinoma is resection of the involved hemi‐liver. For perihilar cholangiocarcinoma, additional bile duct resection, complete caudate lobe resection, and hepato‐duodenal lymph node dissection are required. Pancreaticoduodenectomy is the operation of choice for people with distal cholangiocarcinoma (Razumilava 2014). Although complete resection offers the best chance of cure for people with cholangiocarcinoma, recurrence can be high, ranging from 46% to 61% (Weber 2001; Yamamoto 2001; Hyder 2013). Cholangiocarcinoma can recur locally in the remaining liver or systemically in the distant organs. It is generally accepted that the recurrence of cancers arises not only because of inadequacy of surgical resection, but it is also secondary to pre‐existing microscopic tumour that spread systematically (Al Ustwani 2012). This concept motivates the attempt of postoperative adjuvant chemotherapy to supplement surgical resection in order to eradicate microscopic disease following resection of clinically detectable lesions of cholangiocarcinoma. Adjuvant chemotherapy given after surgical resection may reduce the risk of the cancer recurrence by eradicating residual diseases and micrometastatic lesions.
A number of Cochrane systematic reviews have addressed the benefits of adjuvant chemotherapy given after primary surgery in lengthening survival in a variety of cancers (Figueredo 2008; Petersen 2012; Burdett 2015; Lawrie 2015). In people with completely resected stage II colon cancer, adjuvant chemotherapy reduced the risk of cancer recurrence by approximately 17% compared with the control group who underwent surgery alone (risk ratio (RR) for disease‐free survival 0.83, 95% confidence interval (CI) 0.75 to 0.92; Figueredo 2008). In people with rectal cancer undergoing curative intent surgery, adjuvant chemotherapy reduced the risk of death by 17% (hazard ratio (HR) 0.83, 95% CI 0.76 to 0.91) and disease recurrence by 25% (HR 0.75, 95% CI 0.68 to 0.83) among people undergoing postoperative adjuvant chemotherapy compared with people undergoing observation (Petersen 2012). When compared with the control group, adjuvant postoperative chemotherapy given to women with early‐stage ovarian cancer reduced the 10‐year risk of death (RR 0.76, 95% CI 0.62 to 0.94), as did the risk of disease progression (RR 0.72, 95% CI 0.60 to 0.87; Lawrie 2015). Additionally, compared to surgery alone, adjuvant chemotherapy in people with resected early‐stage non‐small cell lung cancer reduced the risk of death by approximately 14% (HR 0.86, 95% CI 0.81 to 0.92; Burdett 2015).
Why it is important to do this review
Although various novel surgical techniques for treating cholangiocarcinoma have been developed, prognosis of patients after resection remains poor. Therefore, interventions for improving treatment outcomes among people with cholangiocarcinoma operated for cure are needed. The high tendency for cholangiocarcinomas to recur provides a rationale for adjuvant therapy after definitive surgery (Yang 2014). Postoperative adjuvant chemotherapy appears to be a promising adjuvant treatment for people with cholangiocarcinoma. However, to our knowledge, there has been no systematic review evaluating the effectiveness of adjuvant chemotherapy following surgical resection of cholangiocarcinoma. Therefore, we will conduct a Cochrane systematic review to evaluate the effectiveness and safety of adjuvant chemotherapy for people with cholangiocarcinoma undergoing curative‐intent surgery.
Objectives
To assess the benefits and harms of adjuvant chemotherapy for people with cholangiocarcinoma who have undergone curative‐intent resection.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised clinical trials irrespective of blinding, publication status, or language. We will exclude quasi‐randomised and observational studies from the analysis on benefits, but we will include non‐randomised studies identified with the search for RCTs for the assessment of adverse events. By focusing mainly on randomised clinical trials, we are aware that the review may be biased towards assessments of benefits. We will include unpublished trials only if trial data and methodological descriptions were provided in written form or obtained through direct contact with study authors.
Types of participants
Adults (aged 18 years or older) of both sexes who underwent curative‐intent resection for cholangiocarcinoma and received any type of postoperative adjuvant chemotherapy compared with people with the same condition but receiving no postoperative treatment, or receiving a different regimen of adjuvant chemotherapy. We will include only trials with participants whose diagnosis of cholangiocarcinoma was established by pathological examination of surgical specimens. According to the definition of cholangiocarcinoma, we will not include participants with cancer of gallbladder and ampulla of Vater. We will also include people receiving any type of neoadjuvant treatment prior to operation, who were subsequently randomised to postoperative adjuvant chemotherapy, if the cointerventions were equally applied in the trial groups.
Types of interventions
All regimens of postoperative chemotherapy (intravenous infusion, intravenous bolus, intraportal infusion, and oral administration of single or combination chemotherapy regimens) compared with control group (receiving no treatment, placebo, or different regimen of chemotherapy).
Types of outcome measures
Primary outcomes
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All‐cause mortality (death from any cause).
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Serious adverse events. We will use the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice's definition of a serious adverse event (ICH‐GCP 1997), that is, any untoward medical occurrence that results in death, is life threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. We will consider all other adverse events as non‐serious (see below).
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Health‐related quality of life (as reported by the participants and as assessed by standard grading systems measured on a valid scale (e.g. Functional Assessment of Cancer Therapy‐Hepatobiliary cancers (FACT‐Hep 2015)).
Secondary outcomes
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Cancer‐related mortality (death from cancer).
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Time to recurrence of the tumour.
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Non‐serious adverse events.
Search methods for identification of studies
Electronic searches
We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (latest issue), MEDLINE Ovid (1946 to present), Embase Ovid (1974 to present), LILACS (1982 to present; Bireme), and Science Citation Index Expanded (1900 to present; Web of Science) (Royle 2003). Appendix 2 provides the preliminary search strategies for identification of relevant studies for our review.
We will endeavour to identify randomised clinical trials referenced in non‐English databases, using our personal contacts or local access, or asking the Cochrane Hepato‐Biliary Group Information Specialist, Sarah Klingenberg, to contact Cochrane collaborators from around the world, with the same intent.
We will not restrict our searches by language.
Searching other resources
We will handsearch reference lists of articles retrieved by the search and contact trial authors to obtain addition data if necessary.
We will search online trial registries such as ClinicalTrial.gov (www.clinicaltrials.gov/), European Medicines Agency (EMA) (www.ema.europa.eu/ema/), World Health Organization (WHO) International Clinical Trial Registry Platform (www.who.int/ictrp), Google Scholar (scholar.google.com), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials.
We will contact the Cholangiocarcinoma Foundation (cholangiocarcinoma.org), the Alan Morement Memorial Fund (ammf.org.uk), and the Cholangiocarcinoma Foundation of Thailand (cloud.cascap.in.th) to ask for additional relevant data.
Data collection and analysis
We will perform the review following the recommendations of Cochrane (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2017). We will perform the analyses using Review Manager 5 (RevMan 2014) and Trial Sequential Analysis (Thorlund 2011; TSA 2011; Wetterslev 2017).
Selection of studies
We will download all titles and abstracts retrieved by electronic searching to a reference management database (Endnote). After duplicates are removed, we will transfer these data to Covidence (www.covidence.org). After excluding studies that clearly do not match the review criteria, we will obtain the full text of potentially relevant references for detailed reviewing. Two review authors (VL and ES) will independently assess the eligibility of the retrieved publications. We will resolve any disagreement through discussion or, if necessary, we will consult a third review author (AP or CK). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will use the details of the selection process in Covidence to create a PRISMA flow diagram (Liberati 2009).
Data extraction and management
Two review authors (VL and ES) will independently extract study characteristics and outcome data from included studies using Covidence. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third review author (AP or CK). One review author (PP) will transfer data into Review Manager 5 (RevMan 2014). A second review author (PL) will check study characteristics for accuracy against the trial report.
For included studies, we will extract the following data: author, year of publication, and journal citation (including language); country; setting; inclusion and exclusion criteria; study methodology; study population and characteristics; total number enrolled, participant characteristics, age, comorbidities, other baseline characteristics, stage of cholangiocarcinoma, tumour size in largest diameter, histopathological type, status of surgical margin and lymph nodes, volume of residual lesion; intervention details, regimens of adjuvant chemotherapy, dose of adjuvant chemotherapy; comparison details; risks of bias in study (see below); duration of follow‐up; outcomes; results; funding for trial, notable conflicts of interest of trial authors.
We plan the following.
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For time to event data (e.g. all‐cause mortality and cancer‐related mortality), we will extract the log of the hazard ratio (log(HR)) and its standard error from trial reports. If these are not reported, we will attempt to estimate the log (HR) and its standard error using the methods of Parmar 1998.
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For dichotomous outcomes (e.g. adverse events), we will extract the number of people in each treatment arm who experienced the outcome of interest and the number of people assessed at end of follow‐up, to estimate an RR.
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For continuous outcomes (e.g. health‐related quality of life measures), we will extract the final value and standard deviation of the outcome of interest and the number of people assessed at end of follow‐up in each treatment arm, to estimate the mean difference between the treatment arms.
We will calculate 95% CIs for each estimate.
Where possible, all data extracted will be those relevant to an intention‐to‐treat analysis, in which participants will be analysed in groups to which they were assigned.
Assessment of risk of bias in included studies
Two review authors (VL and ES) will independently assess the risk of bias of each included trial according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the Cochrane Hepato‐Biliary Group Module (Gluud 2017), and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Lundh 2017). We will use the following definitions in the assessment of risk of bias.
Allocation sequence generation
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Low risk of bias: the study performed sequence generation using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if an independent person not otherwise involved in the study performed them.
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Unclear risk of bias: the study authors did not specify the method of sequence generation.
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High risk of bias: the sequence generation method was not random. We will only include such studies for assessment of harms.
Allocation concealment
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Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. A central and independent randomisation unit controlled allocation. The investigators were unaware of the allocation sequence (e.g. if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
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Unclear risk of bias: the study authors did not describe the method used to conceal the allocation so the intervention allocations may have been foreseen before, or during, enrolment.
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High risk of bias: it is likely that the investigators who assigned the participants knew the allocation sequence. We will only include such studies for assessment of harms.
Blinding of participants and personnel
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Low risk of bias: any of the following: no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; or blinding of participants and key study personnel ensured, and it is unlikely that the blinding could have been broken.
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Unclear risk of bias: any of the following: insufficient information to permit judgement of 'low risk' or 'high risk;' or the trial did not address this outcome.
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High risk of bias: any of the following: no blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Blinded outcome assessment
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Low risk of bias: any of the following: no blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; or blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
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Unclear risk of bias: any of the following: insufficient information to permit judgement of 'low risk' or 'high risk;' or the trial did not address this outcome.
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High risk of bias: any of the following: no blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Incomplete outcome data
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Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. The study used sufficient methods, such as multiple imputation, to handle missing data.
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Unclear risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
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High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
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Low risk of bias: the trial reported the following predefined outcomes: all‐cause mortality, serious adverse events, and time to recurrence of the tumour. If the original trial protocol is available, the outcomes should be those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought should be those enumerated in the original protocol if the trial protocol was registered before or at the time that the trial was begun. If the trial protocol was registered after the trial was begun, we will not consider those outcomes to be reliable.
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Unclear risk of bias: the study authors do not report all predefined outcomes fully, or it is unclear whether the study authors recorded data on these outcomes or not.
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High risk of bias: the study authors do not report one or more predefined outcomes.
For‐profit bias
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Low risk of bias: the trial appears free of industry sponsorship or other type of for‐profit support that could manipulate the trial design, conductance, or trial results.
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Unclear risk of bias: the trial may or may not be free of for‐profit bias as the trial does not provide any information on clinical trial support or sponsorship.
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High risk of bias: the trial is sponsored by industry or received other type of for‐profit support.
Other bias
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Low risk of bias: the trial appears to be free of other factors that could put it at risk of bias.
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Unclear risk of bias: the trial may or may not be free of other factors that could put it at risk of bias.
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High risk of bias: there were other factors in the trial that could put it at risk of bias.
We will judge trials to be at a low risk of bias if they are assessed as having a low risk of bias in all the above domains. We will judge trials to be at a high risk of bias if they are assessed as having an unclear risk of bias or a high risk of bias in one or more of the above domains.
We will resolve any differences in opinion through discussion, and in the case of unsettled disagreements, a third review author will adjudicate.
Measures of treatment effect
We will use the following measures of the effect of treatment.
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For mortality, we will use the HR and 95% CI.
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For dichotomous outcomes, we will analyse data based on the number of events and the number of people assessed in the intervention and comparison groups. We will use these to calculate the RR and 95% CI and Trial Sequential Analysis‐adjusted CI.
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For continuous outcomes, we will analyse data based on the mean, standard deviation, and number of people assessed for both the intervention and comparison groups to calculate the mean difference between treatment arms with a 95% CI and Trial Sequential Analysis‐adjusted CI. If the mean difference is reported without individual group data, we will use this mean difference to report the study results. If more than one study measures the same outcome using different tools, we will calculate the standardised mean difference and 95% CI using the inverse variance method.
Unit of analysis issues
In a study with multiple intervention groups, we will combine all relevant experimental intervention groups into a single group to create a single pair‐wise comparison (Higgins 2011).
Dealing with missing data
If trialists used intention‐to‐treat analysis to deal with missing data, we will use these data in our primary analysis. Otherwise, we will attempt to contact study authors to obtain missing data or we will use the data that are available to us.
Dealing with missing data using sensitivity analysis
If trials report only per protocol analysis results, we will include missing data by considering participants as treatment failures or treatment successes by imputing them according to the following two scenarios:
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'extreme‐case' analysis favouring the experimental intervention ('best‐worse' case scenario): none of the participants who dropped out from the experimental group experienced the outcome, but all of the participants who dropped out from the control group experienced the outcome; including all randomised participants in the denominator;
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'extreme‐case' analysis favouring the control ('worst‐best' case scenario): all participants who dropped out from the experimental group, but none from the control group experienced the outcome; including all randomised participants in the denominator.
Assessment of heterogeneity
We will assess heterogeneity between the included studies using visual inspection of the forest plots. We will also assess statistical heterogeneity in each meta‐analysis using the I² statistic and Chi² test (Higgins 2003). We will regard heterogeneity as substantial if the I² statistic value is greater than 50%, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity (Deeks 2001; Higgins 2011). If there is substantial statistical heterogeneity, we will carry out subgroup analyses to assess differences between the included studies. However, if there are clinical, methodological, or remarkably high statistical heterogeneity (I² greater than 75%) across included studies, we will not report pooled results from meta‐analysis, but we will instead use a narrative approach to data synthesis.
Assessment of reporting biases
We will examine funnel plots corresponding to meta‐analysis of the primary outcome to assess the potential for small‐study effects such as publication bias if more than 10 trials are identified. We plan to assess funnel plot asymmetry visually, and if asymmetry of funnel plots is identified, we will perform exploratory analyses to investigate it (Sterne 2011).
Data synthesis
Meta‐analysis
We will perform the analysis using Review Manager 5 (RevMan 2014). We will perform meta‐analysis using random‐effects and fixed‐effect models, and we will report the most conservative finding, using a P value of 0.025 or less, two‐tailed, as statistically significant due to the three primary and three secondary outcomes (Jakobsen 2014). We will apply the eight‐step procedure proposed by Jakobsen 2014 when assessing the statistical and clinical significance of the results of the meta‐analyses.
Trial Sequential Analyses
We will apply Trial Sequential Analysis (Thorlund 2011) to minimise random errors in our meta‐analysis (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010; Wetterslev 2017). We will calculate the required information size (i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) which will also be accounted for the diversity observed in the meta‐analysis (Wetterslev 2008; Wetterslev 2009; Wetterslev 2017).
We will calculate the required information size for dichotomous outcomes based on the event proportion in the control group; assumption of an a priori risk ratio reduction of 10% observed in the included trials; and the risk ratio reduction observed in trials at low risks of bias; a risk of type I error of 2.5% for both primary and secondary outcomes; a risk of type II error of 90%; and the assumed diversity of the meta‐analysis. For continuous outcomes, we will estimate the required information size based on the standard deviation observed in the control group and a minimal relevant difference of 50% of this standard deviation, and the observed diversity in the trials in the meta‐analysis.
We will add the trials according to the year of publication, and, if more than one trial has been published in a year, we will add trials alphabetically according to the last name of the first author. On the basis of the required information size, we will construct trial sequential monitoring boundaries (Wetterslev 2008; Thorlund 2011). These boundaries will determine the statistical inference that one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may be superfluous. In contrast, if the boundary is not surpassed, it is most probably necessary to continue doing trials to detect or reject a certain intervention effect. That can be determined by assessing whether or not the cumulative Z‐curve crosses the trial sequential monitoring boundary for futility (Wetterslev 2008). We will conduct Trial Sequential Analysis using software from The Copenhagen Trial Unit (Thorlund 2011; TSA 2011).
For our meta‐analyses using HRs, we will conduct robustness analyses by changing them into relative risk reduction as described above or use software that can handle HRs (Miladinovic 2013).
Subgroup analysis and investigation of heterogeneity
We will carry out subgroup analysis for the following factors.
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Trials at low risk of bias compared to trials at high risk of bias.
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Surgical margin status (histologically negative compared to histologically positive, regarding rest of cancer).
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Status of regional lymph node (negative compared to positive regarding cancer metastasis).
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Location of tumour (intrahepatic, perihilar, distal).
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Type of adjuvant chemotherapy (i.e. gemcitabine‐based chemotherapy compared to similar chemotherapy without gemcitabine).
We will assess subgroup differences by interaction tests available within Review Manager 5 (RevMan 2014). We will report the results of subgroup analyses quoting the Chi² statistic and P value, the interaction test, and I² statistic value.
Sensitivity analysis
We will apply 'best‐worst case' and 'worst‐best case' scenarios, when possible, to sensitivity analyses based on the outcomes of mortality and serious adverse events.
'Summary of findings' tables
We will create 'Summary of findings' tables on all review outcomes obtained from the included trials using GRADEpro software. We will also provide the review outcomes based on trials with low risk of bias in the 'Summary of findings' table. The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed (GRADEpro). The quality of a body of evidence considers within‐study risk of bias, indirectness of the evidence, heterogeneity of the data, imprecision of effect estimates, and risk of publication bias (Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; Guyatt 2013a; Guyatt 2013b; Guyatt 2013c; Guyatt 2013d; Mustafa 2013; Guyatt 2017). We will evaluate imprecision using Trial Sequential Analysis as suggested by Jakobsen and colleagues (Jakobsen 2014).
