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Cochrane Database of Systematic Reviews Protocol - Intervention

Limited resections versus lobectomy for stage I non‐small cell lung cancer

Authors' declarations of interest

Version published: 18 September 2020 Version history

https://doi.org/10.1002/14651858.CD013728
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Abstract

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the comparative effectiveness and safety of limited resections, either segmentectomy or wedge resection surgical techniques, and the standard surgical procedure of lobectomy in the management of people with operable stage I NSCLC.

Background

Description of the condition

Lung cancer was the leading cause of cancer death in the world in 2018, contributing to 18.4% of all cancer‐related mortality (Bray 2018). US Surveillance, Epidemiology, and End Results (SEER) data estimate there will be 228,820 new cases of lung cancer in 2020, accounting for 12.7% of all new cancer cases (National Cancer Institute 2020).

There are two main types of lung cancer: small cell lung cancer (SCLC) and non‐small cell lung cancer (NSCLC). About 15% to 20% of lung cancer are SCLC, and between 80% to 85% are NSCLC (American Cancer Society 2020).

Staging at diagnosis is a key predictor of lung cancer outcome. The 8th edition of the Tumor, Node, Metastasis (TNM) classification is the currently agreed‐upon staging guide (Goldstraw 2016); the staging groups are presented in Appendix 1 and Appendix 2. The majority of lung cancers are still diagnosed at a late stage. In the UK, only around 15% of NSCLC cases are diagnosed at an early stage (McPhail 2015).

Data from 16 countries around the world show that the overall five‐year survival rate ranges from 85% for pathological stage IA NSCLC to 73% for pathological stage IB NSCLC (Goldstraw 2016). For people with stage I NSCLC who are sufficiently fit, surgical resection is considered to be the best treatment option (Howington 2013; NICE 2019). For people with stage I NSCLC who are not fit enough for or who decline surgery, stereotactic radiotherapy is the recommended treatment (NICE 2019). Surgical resection rates are increasing in the UK, NLCA 2018, with the inclusion of more people aged 70 years and over (Beattie 2010; Jones 2018). However, age is associated with a slight increase in the likelihood of undergoing limited surgical resections such as wedge resection (Riaz 2012).

Description of the intervention

Conventionally, the standard surgical management of stage I NSCLC is lobectomy either by open, conventional thoracotomy or by video‐assisted thoracoscopic surgery (VATS) (NICE 2019). The excision of a smaller part of the lobe was introduced to lung cancer surgery in the 1970s (Kutschera 1984). These limited resections (also called sublobar resections) with sparing of the lung parenchyma include segmentectomy and wedge resections techniques (Stahel 2012).

Segmentectomy

Anatomical segmentectomy was introduced for stage 1A lung cancer in order to preserve better pulmonary function than lobectomy (Charloux 2017). Although that procedure was initially devised to treat bronchiectasis (Hurt 1996), it quickly became routine based on the assumption that reducing the volume of lung that was resected would allow the possibility of further resections in the case of a second primary lung cancer (Charloux 2017). Segmentectomy is now widely accepted as a reliable and safe procedure to allow complete tumour resection in the American College of Chest Physicians (ACCP) guidelines (Howington 2013), and is recommended in preference to non‐surgical treatments, especially stereotactic radiotherapy. However, it is recommended only when resection is possible with minimum resection margins of 2 cm. Segmentectomy allows for systematic pulmonary resection and intrapulmonary lymph node dissection and has been reported to provide better postoperative lung function than lobectomy (Villamizar 2014).

Wedge resection

Wedge resection was also introduced for stage I NSCLC in order to spare the lung parenchyma. It is defined as a non‐anatomical lesser excision of the lung parenchyma regardless of the bronchovascular anatomy (Aokage 2017). In clinical practice, wedge resection is usually performed in patients with multiple comorbidities or poor lung function who may not tolerate a more extensive operation (Little 2005). On the other hand, wedge resection does not allow for lymph node dissection and is known to increase the risk of local recurrence (Bille 2016).

The wedge resection or non‐anatomical resection is a much simpler procedure than segmentectomy, which involves careful anatomical dissection and assessment of intraparenchymal and hilar lymph nodes (Sato 2019).

Why it is important to do this review

Despite changes in NSCLC management, surgery is still widely accepted as standard care for people with early‐stage, operable NSCLC. In the UK, surgery rates in NSCLC have increased from 9% to 17% in the last 10 years (Jones 2018). However, there is conflicting evidence about the relative effectiveness of different surgical techniques for stage I NSCLC. For instance, long‐term survival rates were similar for limited resection and lobectomy surgical techniques across several recent retrospective cohort studies in patients with early‐stage NSCLC (Cao 2018; Fiorelli 2017). However, a cohort study using the SEER database suggested that lobectomy may be superior to resection in patients with tumours 1 cm in diameter or smaller, and that it may prolong survival in patients with tumours between 1 and 2 cm. Yet in the same study, when comparing the two techniques of limited resections, lower survival rates were seen for tumours between 1 and 2 cm in diameter after wedge resection compared with segmentectomy, whereas similar survival rates were observed for tumours 1 cm in diameter or smaller (Dai 2016). Another cohort study also looked at the three surgical procedures according to tumour size (Cao 2018), concluding that lobectomy, segmentectomy, and wedge resection are comparable oncologic procedures for stage IA tumours 1.0 cm or smaller in diameter. For tumours between 1.1 and 2.0 cm in diameter, they reported equivalent overall survival rates for lobectomy and segmentectomy, both being better than wedge resection. Nonetheless, similar survival rates were seen for segmentectomy and wedge resection with tumours between 2.1 and 3.0 cm in diameter, but these rates were lower than those seen after lobectomy (Cao 2018). For patients who are unsuitable for lobectomy with tumours between 2.1 and 3.0 cm, the Cao 2018 study suggested that wedge resection and segmentectomy can achieve similar survival rates.

Several reviews and meta‐analyses have been published in this area. The Shapiro 2009 review compared segmentectomy to lobectomy for stage IA patients of size 2 cm tumour or smaller, finding that the two techniques are similar with no increase in local recurrence (Shapiro 2009). However, another meta‐analysis showed that segmentectomy was inferior to lobectomy for overall survival or cause‐specific survival, or both, even for smaller tumours (size 2 cm or less) (Zhang 2015). Dziedzic 2017 found that wedge resection was associated with significantly lower three‐year and five‐year survival rates than lobectomy, but found no significant difference between segmentectomy and lobectomy for survival (Dziedzic 2017).

Consequently, an up‐to‐date systematic review and meta‐analysis comparing these surgical techniques is needed to determine the optimal surgical management of patients with stage I NSCLC.

Objectives

To assess the comparative effectiveness and safety of limited resections, either segmentectomy or wedge resection surgical techniques, and the standard surgical procedure of lobectomy in the management of people with operable stage I NSCLC.

Methods

Criteria for considering studies for this review

Types of studies

We will only include randomised controlled trials (RCTs).

We will apply no language or publication status restrictions.

Types of participants

People aged 18 years or over of any gender diagnosed with stage I NSCLC who are able to undergo surgical treatment.

Types of interventions

We will include the following comparisons.

  • Segmentectomy compared with lobectomy.

  • Wedge resection compared with lobectomy .

  • Segmentectomy compared with wedge resection.

Types of outcome measures

Primary outcomes

  • Overall survival (OS), defined as time from randomisation to death from any cause.

  • Rate of perioperative and postoperative adverse events (AE).

  • 90‐day mortality rate, defined as the number of deaths from any cause within 90 days of the date of surgery over the total number of participants.

Secondary outcomes

  • Local recurrence at one and two years.

  • Recurrence‐free survival (RFS), defined as time from randomisation to the date of pathologically confirmed disease recurrence.

  • Health‐related quality of life (HRQoL), measured by validated generic or disease‐specific questionnaires, or validated items, such as the Functional Assessment of Cancer Therapy‐Anemia (FACT‐An) scale plus lung subscales (Cella 1997).

  • Length of perioperative hospital stay.

  • Postoperative pulmonary function.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases from inception:

  • Cochrane Lung Cancer Group Trial Register;

  • Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library, current issue);

  • MEDLINE, accessed via PubMed;

  • Embase.

The search strategies for CENTRAL, MEDLINE, and Embase are shown in Appendix 3, Appendix 4, and Appendix 5.

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 (Section 6.4.11.1 and detailed in Box 6.4.b) (Higgins 2011).

We will also conduct searches in the following clinical trials registries to identify unpublished and ongoing trials:

We will apply no restriction on language of publication.

Searching other resources

We will handsearch the references of eligible studies to identify additional studies for inclusion.

We will search the meeting abstracts of conferences at the following sources from 2018 onwards.

  • World Conference on Lung Cancer (WCLC)

  • American Society of Clinical Oncology (ASCO)

  • American Thoracic Society (ATS)

  • American Association of Thoracic Surgery (AATS)

  • European Association for Cardio‐Thoracic Surgery (EACTS)

  • Society of Thoracic Surgery (STS)

Data collection and analysis

Selection of studies

We will select studies for inclusion according to the methods described in Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

Two review authors (RM, CM) will independently screen all titles and abstracts retrieved by the electronic searches using Covidence (Covidence). The same review authors will obtain the full texts for all relevant studies and will independently check each study against the review eligibility criteria. Any disagreements will be resolved by discussion or by involving a third review author (AB) when necessary. We will report the results of the study selection process using a PRISMA flow diagram (Moher 2009). We will record the reasons for exclusion of studies after full‐text assessment and report this information in the 'Characteristics of excluded studies' table.

Data extraction and management

We will develop a data extraction form using Covidence (Covidence). Two review authors (RM, CM) will independently extract relevant data and perform a cross‐check. We will involve a third review author to reach consensus when necessary (SPB). We will not be blinded to the names of study authors nor to the institutions where studies were conducted and funded. When we encounter multiple publications for the same study, we will choose the first publication dealing with the primary endpoint in this review as a study identifier (study ID).

We will extract the following details from each included study.

  • Methods: study design, total duration of study, number of study centres and locations, study setting, date of study and dates of first and last included participants.

  • Participants: N, mean age, age range, gender, pathological T and N, pathological postoperative N.

  • Interventions: intervention, duration, bleeding, transfusion, need for thoracotomy conversion, technical approach (VATS versus thoracotomy).

  • Outcomes: primary and secondary outcomes specified and collected, and time points reported.

  • Results: number of inclusions in each arm, estimates of effect with confidence interval and P value and subgroup analysis.

  • Notes: notable conflicts of interest of trial authors.

  • Miscellaneous: funding source.

Assessment of risk of bias in included studies

Two review authors (RM, CM) will independently apply the Cochrane 'Risk of bias' tool per Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions, in order to assess quality and potential biases across included studies (Higgins 2011). We will rate each domain of the tool as having 'low', 'high', or 'unclear' risk of bias at study level and for each outcome if possible, and we will support the rating of each domain with a brief description. We will summarise risk of bias for each outcome within a study by considering all domains relevant to the outcome (i.e. both study‐level entries, such as allocation sequence concealment, and outcome‐specific entries, such as blinding). We will provide a figure to summarise the risk of bias similar to Figure 8.6.C in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

If the two review authors cannot reach consensus, a third review author (SPB) will be consulted.

Using the Cochrane 'Risk of bias' tool, we will consider the following domains.

  • Selection bias: random sequence generation.

  • Selection bias: allocation concealment.

  • Performance bias: blinding of participants and personnel.

  • Detection bias: blinding of outcome assessment.

  • Attrition bias: incomplete outcome data for outcomes related to efficacy and safety.

  • Reporting bias: selective reporting of outcomes.

  • Other bias, such as inclusion of participants discordant to prespecified number of participants needed for calculation, unplanned interim analyses, and unbalanced baseline characteristics across study arms.

Measures of treatment effect

For time‐to‐event outcomes (OS and RFS), we will use hazard ratios (HRs) to measure treatment effects. We will report each HR along with the 95% confidence interval (CI). We will extract the HR from the included studies when this information is available.

For dichotomous outcomes (rate of perioperative and postoperative adverse events, 90‐day mortality, local recurrence at one and two years), we will use risk ratios (RRs) and 95% CIs if possible.

For continuous outcomes (HRQoL, length of perioperative hospital stay), we will use mean differences (MDs) between treatment arms when a similar scale is implemented to measure outcomes, and standardised mean differences (SMDs) when different scales are used to measure the same outcome. We will confirm that higher scores for continuous outcomes have the same meaning for the particular outcome, explain the direction, and report if directions were reversed.

Unit of analysis issues

The primary unit of analysis is the participant.

For studies with multiple comparison groups that compare two or more intervention groups with the same control group, we will first try to combine groups to create a single pair‐wise comparison. We will calculate within‐study correlation as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

In the case of missing or unclear individual data, we will contact the study authors directly. If we are unable to obtain the missing data from the study authors, we will perform analysis using the available data.

Assessment of heterogeneity

We will follow Cochrane recommendations for assessment of heterogeneity (Deeks 2011). We will visually investigate heterogeneity by using forest plots generated via Review Manager 5 (Review Manager 2020). We will assess statistical heterogeneity of treatment effects between pooled trials for each considered outcome using the I² statistic to quantify heterogeneity (Higgins 2002), considering I² > 30% as moderate heterogeneity, and I² > 75% as significant heterogeneity.

Assessment of reporting biases

We plan to generate funnel plots and to perform Egger's linear regression tests to investigate reporting biases for considered outcomes when a sufficient number of trials is included in a single meta‐analysis (at least 10 trials). We will follow the recommendations in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011).

Data synthesis

We will perform meta‐analyses if sufficient clinically similar studies are available, according to recommendations in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will enter data into Review Manager 5 (Review Manager 2020). One review author (RM) will enter the data, and a second review author (SPB) will double‐check the data for accuracy.

We will apply the generic inverse‐variance method and random‐effects model for all types of outcomes. For dichotomous outcomes, we will apply the DerSimonian and Laird method (DerSimonian 1986). We will consider rates of AE separately for each type, and AE combined according to their grades.

We will apply the GRADE approach when creating a ’Summary of findings’ table, as suggested in Chapters 11 and 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

'Summary of findings' table

We plan to present a 'Summary of findings' table reporting the following outcomes listed in order of priority (Appendix 6).

  • Overall survival (OS)

  • Rate of perioperative and postoperative AE

  • 90‐day mortality rate

  • Local recurrence at one year

  • Recurrence‐free survival (RFS)

  • Health‐related quality of life (HRQoL)

  • Length of perioperative hospital stay

Subgroup analysis and investigation of heterogeneity

We plan that if sufficient data are available, we will conduct subgroup analysis according to the following variables.

  • Approach (VATS versus thoracotomy).

  • Preoperative tumour size (≤ 2 cm versus > 2 cm, ≤ 1 cm versus > 1 cm).

  • Age (< 70 years old versus > 70 years old).

Sensitivity analysis

We will investigate the robustness of review findings by excluding results from studies with incomplete data.