Video‐assisted thoracoscopic lobectomy versus open thoracotomy conventional lobectomy for stage I non‐small cell lung cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of video‐assisted thorascopic lobectomy versus open thoracotomy for people with surgically‐viable stage I non‐small cell lung cancer.
Background
Lung cancer is the leading cause of cancer deaths worldwide (Ferlay 2010; Hashim 2016; Marshall 2016; Torre 2016). The latest USA Surveillance, Epidemiology, and End Results (SEER) data estimates that more than 220,000 new cases were diagnosed in 2016 which represents at least 13% of all new cases of cancers (National Cancer Institute 2016). In 2016, 158,080 deaths were attributed to lung cancer, representing 26.5% of all cancer deaths. Overall, SEER five‐year survival for bronchogenic carcinoma is estimated at 17.7% (National Cancer Institute 2016). In France and Australia, lung cancer incidence data follow the same trend with five‐year survival ranging from 14% to 15% (Cancer Australia 2016; French National Cancer Institute). However, when diagnosed at an early stage, five‐year survival may increase to 55.2% (National Cancer Institute 2016). The national UK lung cancer audit estimated that 20% to 25% of people with lung cancer are diagnosed at an early stage (I or II) (Royal College of Physicians 2015). Anatomical surgical resection (usually lobectomy) is considered to be the treatment of choice for people with stage I non‐small cell lung cancer (NSCLC) (Carr 2012; Padilla 2002; Pearson 1994; Varlotto 2011). The evidence increasingly supports the beneficial effects of thoracoscopic lobectomy compared to lobectomy performed via open thoracotomy. However, ongoing debate about the relative superiority of the techniques continues (Beckers 2016; Migliore 2000; Park 2011; Sandri 2015; Yan 2014).
Description of the condition
In observational studies of patients with NSCLC who are fit for surgery, it has been suggested that lobectomy may provide a five‐year survival rate of up to 90% in people with stage IA NSCLC and up to 80% survival for people with stage IB NSCLC (Carr 2012).
Manser 2005 reported that the evidence surrounding whether surgery was the best treatment for people with early stage lung cancer was inconclusive. In a systematic literature review, Manser 2005 found no studies that compared surgery to no intervention, and inconclusive results when compared to radiotherapy. However, it is ethically unacceptable to propose a study based on surgery compared to no treatment for people with lung cancer. According to more recent studies, lobectomy provides better overall survival and recurrence‐free survival compared with limited resection (Whitson 2011). Moreover, studies have not reported evidence of any survival differences between surgery and radiotherapy for people with early stage lung cancer (Aragón 2015; Cao 2015; Meyers 2015; Nieder 2015).
Evidence has been reported to support lobectomy as the option of choice for people with early stage lung cancer (Carr 2012; Padilla 2002; Pearson 1994; Varlotto 2011).
Description of the intervention
Open thoracotomy has been the historical surgical approach for performing lobectomy. Studies establishing lobectomy as the treatment of choice for people with early‐stage lung cancer have been conducted by studying lobectomies performed via open thoracotomy (Padilla 2002; Pearson 1994). The posterolateral thoracotomy was the first described technique; it required the latissimus dorsi muscle to be dissected and separated to enable access to the rib cage before opening the intercostal space. To enlarge the opening to view the pleural space, a rib had to be cut to enable a wide dissection; the posterior aspect of the intercostal space is naturally narrower. A later development was lateral muscle‐sparing thoracotomy which did not require dissection of the latissimus dorsi; instead, a split was made in the anterior serratus muscle. Over time, rib sections were abandoned. Studies comparing both techniques report equal effectiveness in providing visualisation of the thoracic space, but muscle‐sparing thoracotomy requires less narcotic or analgesia consumption, and offers the advantage of resecting muscles that could be needed to create a muscle flap. Both techniques are widely used for lobectomy (Akçali 2003; Athanassiadi 2007; Hazelrigg 1991; Nosotti 2010).
However, evolving technologies, miniaturisation of surgical tools and development of imaging and video technologies have led to introduction of video‐assisted thoracic surgery (VATS). VATS has the theoretical advantage of a restricted surgical approach using three or four port access, and a limited mini thoracotomy or both (Giudicelli 1994; McKenna 1994). When the technique was first developed studies reported various techniques, all of which were called 'video surgery'. Some studies classified lobectomy performed through a limited incision without dissection, but with stapling and incising the hilum of a lobe ‘en‐bloc’, as video surgery (Lewis 1995). Rocco 2008 highlighted the need for a comprehensive overview of different techniques described in the literature and proposed a universal definition (Migliore 2000). VATS has since been defined according to the following criteria:
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use of dedicated minimal thoracic incisions with no intercostal distraction;
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visualising the pleural space via indirect monitor imaging;
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structures of the hilum are dissected individually (as opposed to en‐bloc stapling of a lobe or lung pedicle); and
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use of specialised, dedicated instruments that differ from those used for open thoracotomy (Rocco 2008).
How the intervention might work
VATS has been reported to be a safe and effective technique for anatomical lung resections such as lobectomies and segmentectomies (McKenna 1994; Thomas 2002; Yamamoto 2010). VATS has the theoretical advantage of being a minimally invasive surgical approach with no intercostal distraction (Rocco 2008). VATS has been associated with limited postoperative intercostal pain and rapid recovery of respiratory mechanics. People who undergo VATS procedures recover faster than those who undergo open surgeries, leading to faster commencement of post‐surgical adjuvant therapies if required. Lobectomies have been safely and effectively performed using VATS for people with early stage lung cancer. Lymph node dissection may be conducted as an extended surgical procedure as for open thoracotomy (Kamiyoshihara 2013; Lee 2016).
In comparison to open thoracotomy, VATS may prove as effective with faster recovery and less postoperative pain. Consequently, as more patients may benefit from adjuvant therapies, survival may be at least equivalent or better following VATS procedures, with fewer adverse events related to the surgical procedure. On the other hand, VATS lobectomy may encounter obstacles such as dense pleural adhesions or bleeding from vascular injury, resulting in the need for conversion to open thoracotomy (Hanna 2013; Sandri 2015; Smith 2015). It remains difficult to determine whether these elements are sporadic events or if they impair overall survival of people undergoing the procedure.
Faster recovery following VATS may also lead to shorter stays in hospital and earlier return to active life. VATS could be cost‐effective, although with increased training and technical requirements (DeCamp 1995; Divisi 2016; Fang 2014; Kuritzky 2015; Spartalis 2015).
Why it is important to do this review
Lobectomy via open thoracotomy remains a gold standard procedure for people with early stage lung cancer, but VATS may offer survival advantages, albeit with a longer and more intensive learning curve for thoracic surgical teams (Cao 2014; Okyere 2015; Petersen 2010; Petersen 2012).
The review will aim to assess the evidence to inform thoracic surgeons' choices and patients' survival advantages associated with the use of VATS lobectomy as a standard surgical procedure for people with stage I resectable NSCLC.
Objectives
To assess the effects of video‐assisted thorascopic lobectomy versus open thoracotomy for people with surgically‐viable stage I non‐small cell lung cancer.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled studies (RCTs) comparing video‐assisted thoracoscopic lobectomy surgery to open thoracotomy lobectomy in people with confirmed, surgically‐amenable stage I non‐small cell lung cancer (NSCLC).
Types of participants
People of any age or gender who were fit for surgery (i.e. anatomical lung resection lobectomy and lymph node dissection) presenting with histologically‐ or cytologically‐confirmed stage I NSCLC at the time of trial entry.
Types of interventions
We will include studies of video‐assisted thoracoscopic lobectomy surgery as defined by Rocco 2008 compared with open thoracotomy lobectomy surgery.
Only lobectomies will be included, sub lobar resections will not be considered. Complete lymph node dissection should be associated with lobectomy to perform adequate carcinogenic resection.
Types of outcome measures
Primary outcomes
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‐Overall survival (all‐cause death will be included and measured from the date of participant randomisation to the date of death or study end date if the participant was alive).
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30 day mortality (all‐cause death).
Secondary outcomes
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Disease‐free survival (to be assessed from the date of participant randomisation to the date of pathologically‐confirmed disease recurrence or the study end date if the participant had no confirmed recurrence at that time point).
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Lung cancer‐specific survival (assessed from the date of participant randomisation to the date of NSCLC‐related death or other cause of death; participants who died of other causes will be censored; the end of study considered for patients still alive) at two, three, four or five years.
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Treatment (surgery)‐related deaths (death while anaesthetised, death related to an immediate complication during surgery, death related to specific postoperative complications).
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Locoregional recurrence (confirmed recurrence of initial NSCLC at the site of the pulmonary resection and lymph node dissection) rates at two, three, four or five years.
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Respiratory function, including forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), and maximum voluntary ventilation (MVV) at one and two years, and at any other time points described in the primary studies beyond three or six months. Measures will be performed during plethysmography.
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Quality of life and performance status will be measured based on validated assessment tools.
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Acute and chronic pain (i.e. post‐thoracotomy neuralgia) based on validated pain scales or questionnaires.
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Adverse events such as switch from video‐assisted to open thoracotomy, massive bleeding from surgical complications and transfusion needs, re‐operation rate, prolonged air leak (> 7 days) following surgery, atelectasis, empyema, lung infections following surgery (pneumonia), bronchopleural fistula, postoperative acute respiratory failure, bronchopleural fistula, cardiac arrhythmia, and pulmonary thromboembolism.
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Length of hospital stay.
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Time to administration to adjuvant therapy.
Search methods for identification of studies
Electronic searches
We will search the following databases:
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The Cochrane Central Register of Controlled Trials (CENTRAL, to the latest issue) (Appendix 1);
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MEDLINE accessed via PubMed (from 1946 to present) (Appendix 2); and
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Embase (from 1980 to present) (Appendix 3).
We will perform the MEDLINE search using the Cochrane highly sensitive search strategy, sensitivity and precision‐maximising version (2008 version) as described in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 6.4.11.1 and detailed in box 6.4.b) (Higgins 2011).
We will also search:
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Clinical trials registry platform (www.clinicaltrials.gov); and
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the World Health Organization (WHO) International Clinical Trials Registry Platform (www.who.int/ictrp).
There will be no limitation on publication language. We will conduct both MEDLINE and Embase searches on the same day to ensure chronological adequacy between the search results.
Searching other resources
We will also search for lung cancer and video‐assisted surgery reports from proceedings of the:
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European Society for Thoracic Surgery (ESTS) from 2013 to present;
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European Respiratory Society (ERS) from 2013 to present;
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European Association for Cardio‐Thoracic Surgery (EACTS) from 2013 to present;
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Society of Thoracic Surgery (STS) from 2013 to present;
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American Association of Thoracic Surgery (AATS) from 2013 to present;
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American Thoracic Society (ATS) from 2013 to present;
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American Society of Clinical Oncology (ASCO) from 1990 to present; and
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International Association for the Study of Lung Cancer (IASLC) from 2013 to present.
We will also contact authors identified in the search for further published or unpublished data.
We will search the reference lists of included studies for references that may have been missed from electronic and handsearching other resources.
We also plan to contact representatives of imaging and surgical companies that produce VATS instruments and technologies for information about any ongoing trials.
We will look for reviews submitted to the Federal Drug Adminitration (USA) on surgical devices.
From these resources, we will gather any information about RCTs published as abstracts. We plan to contact authors of RCTs published only as abstracts for further information or to clarify reported data.
Data collection and analysis
We will summarise data using standard Cochrane methods as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Selection of studies
Two review authors (AO, JR) will independently screen titles and abstracts for inclusion of all the potential studies we identify as a result of the search.
We will retrieve the full‐text study reports and two review authors (AO, JR) will independently screen the full‐text and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third review author (PE or GM). 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 record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009), and 'Characteristics of excluded studies' table. We will not impose any language restrictions.
The study selection process will be performed using Covidence systematic review software (Covidence 2017; Higgins 2011).
Data extraction and management
We will use a data collection form for study characteristics and outcome data which has been piloted on at least one study in the review. Three review authors (AO, PEF, JR) will extract study characteristics from included studies. We will extract the following study characteristics.
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Methods: study design, total duration of study, details of any run in period, number of study centres and locations, study setting, withdrawals, date of study and dates of first and last included participants.
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Participants: N, mean age, age range, gender, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria. Medical history prior to diagnosis of NSCLC, pathological confirmation of NSCLC, staging of the tumour according to the IASLC TNM classification for lung cancer.
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Interventions: intervention, comparison, duration, same or different surgeons, bleeding, transfusion, need for thoracotomy conversion.
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Outcomes: primary and secondary outcomes specified and collected, and time points reported.
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Results: number of inclusions in each arm, flow chart, sample size, intention to treat and missing participants, summary data for each group, estimates of effect with confidence interval and P value and subgroup analysis.
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Notes: funding for trial, and notable conflicts of interest of trial authors.
Three review authors (AO, PEF, JR) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data are not reported in a usable way. We will resolve disagreements by consensus or by involving a fourth review author (CF or GM). One review author (AO) will transfer data into the Review Manager file (RevMan 2014). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (PEF or JR) will spot‐check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Three review authors (AO, JR, PEF) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another review author (CF or GM). We will assess the risk of bias according to the following domains.
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Random sequence generation.
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Allocation concealment.
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Blinding of participants and personnel.
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Blinding of outcome assessment.
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Incomplete outcome data.
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Selective outcome reporting.
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Other bias.
We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes, where necessary. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
We will search for potential threats to internal validity of the studies such as the training and experience of the surgeons, the surgical volume in each centre, and baseline imbalances between the intervention and control groups. We will assess whether the recommendations of Farrokhyar 2010 have been applied in surgical randomised studies.
Assessment of bias in conducting the systematic review
We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will calculate summary estimates of treatment effect with 95% confidence intervals (CI) for each comparison and outcome. For time‐to‐event endpoints (overall survival, disease‐free survival, lung cancer‐specific survival) we will report hazard ratios (HRs). If trial reports do not provide adequate data to inform calculations, we will extract data according to methods proposed by Guyot 2012, Parmar 1998 and Tierney 2007.
For dichotomous variables (overall survival at 2, 3 and 5 years, treatment‐related deaths, adverse events from surgery, recurrence rates, 30 day mortality), results will be presented as odds ratios (ORs). For continuous outcomes (plethysmography results, quality of life and performance status) results will be reported as mean differences (MDs) for measures using the same scale, and standardised mean differences (SMDs) for measures that used different scales.
Unit of analysis issues
The participants will be the primary unit of analysis. In comparisons of different surgical techniques, neither cross‐over studies nor studies with multiple intervention groups are expected. Nevertheless, in the case of multiple intervention studies, we will perform pair‐wise comparisons (A versus control, B versus control, A versus B) and each compatison will be meta‐analysed. The same group will not be included twice in the same meta‐analysis.
Dealing with missing data
We will contact investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
If numerical outcome data are missing, such as standard deviations or correlation coefficients and they cannot be obtained from the authors, we will calculate them from other available statistics such as P values according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of heterogeneity
To determine what part of variability in the effect estimates is due to heterogeneity rather to sampling error, we will use the I² statistic (Higgins 2002). The I² value will give the heterogeneity assessment: 0% to 25% heterogeneity might not be important, 26% to 50% moderate heterogeneity; 51% to 75% substantial heterogeneity; 76% to 100% considerable heterogeneity. To pool trials we will first assess heterogeneity on one side, and clinical and methodological diversity on the other side. If sufficient trials are identified following this method, we will assess heterogeneity in subgroup analysis.
Assessment of reporting biases
If we are able to pool more than 10 trials (with no significant heterogeneity, and ratio of maximal to minimal variance effects across studies > 4), we will use asymmetry tests (Ioannidis 2007; Rücker 2008). . If evidence of small study effect is observed, we will perform sensitivity analyses according to regression‐based adjustment methods.
Data synthesis
We will pool data from studies we judge to be clinically homogeneous using Review Manager 5 software (RevMan 2014). If more than one study provides usable data in any single comparison, we will perform a meta‐analysis. We will combine treatment effect estimates of individual trials using fixed‐effect and random‐effect models. Choice to use of the random‐effects model will be made according to the clinical and methodological diversity across trials as well as their distribution and effect sizes. Differences in median survival will be given using the HR with 95% CI. If data from one study cannot be integrated, results will be presented narratively and tabulated.
Odds ratio will be re‐expressed as risk factors with the derivation of number needed to treat for an additional beneficial outcome (NNTB).
GRADE and 'Summary of findings' table
We will create a 'Summary of findings' table using the following outcomes: overall survival, 30 day mortality, disease‐free survival, switch from video‐assisted to open thoracotomy, major bleeding from surgical complications and transfusion needs, re‐operation rate, surgery‐related deaths in a summary of findings table. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEproGDT software (GRADEpro GDT 2015). We will justify all decisions to down‐ or up‐grade the quality of studies using footnotes, and we will make comments to aid the reader's understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
Although no subgroup analyses are planned, these will be conducted If sufficient trials are identified following testing for heterogeneity to identify sources of heterogeneity.
Sensitivity analysis
To test whether decisions made during the review process are robust, we will perform a sensitivity analysis. If possible we will restrict analysis to trials assessed at low risk of bias.
