Cochrane Database of Systematic Reviews

Chemo-radiotherapy versus surgery-based treatment for

Stage IIIA non-small cell lung cancer: a systematic review and
network meta-analysis (Protocol)

Soon YY, Zheng Q, Shi L, Chan ESY, Leong CN, Koh WY, Tham IWK

Soon YY, Zheng Q, Shi L, Chan ESY, Leong CN, Koh WY, Tham IWK.
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-anal-
ysis.
Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD012999.
DOI: 10.1002/14651858.CD012999.

www.cochranelibrary.com

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- i
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Chemo-radiotherapy versus surgery-based treatment for

Stage IIIA non-small cell lung cancer: a systematic review and
network meta-analysis

Yu Yang Soon1 , Qishi Zheng2 , Luming Shi2 , Edwin SY Chan2 , Cheng Nang Leong1 , Wee Yao Koh1 , Ivan Weng Keong Tham1

1
Department of Radiation Oncology, National University Cancer Institute, Singapore, Singapore. 2 Department of Epidemiology,
Singapore Clinical Research Institute, Singapore, Singapore

Contact address: Yu Yang Soon, Department of Radiation Oncology, National University Cancer Institute, 1E Kent Ridge Road,
NUHS Tower Block, Level 7, Singapore, 119228, Singapore. yysoon01@gmail.com.

Editorial group: Cochrane Lung Cancer Group.

Publication status and date: New, published in Issue 4, 2018.

Citation: Soon YY, Zheng Q, Shi L, Chan ESY, Leong CN, Koh WY, Tham IWK. Chemo-radiotherapy versus surgery-based treatment
for Stage IIIA non-small cell lung cancer: a systematic review and network meta-analysis. Cochrane Database of Systematic Reviews 2018,
Issue 4. Art. No.: CD012999. DOI: 10.1002/14651858.CD012999.

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

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

To assess the effectiveness and safety of chemo-radiotherapy with surgery for people with Stage IIIA non-small cell lung cancer (NSCLC).

BACKGROUND
Description of the condition
In 2012, there were 1.8 million new cases of lung cancer and
1.59 million deaths from the disease worldwide (International
Agency for Research on Cancer 2012). Lung cancer is the most
common cancer among men (1.2 million new cases), with the
highest incidence rates in Central and Eastern Europe and Eastern
Asia in 2012 (International Agency for Research on Cancer 2012).
Among women, the incidence rates of lung cancer are lower (0.6
million new cases), and the highest incidence rates are in Northern
America and Northern Europe in 2012 (International Agency for
Research on Cancer 2012).
The World Health Organization classifies lung cancers into two
major groups: non-small cell lung cancer (NSCLC) and small cell
lung cancer (Travis 2015). More than 80% of all lung cancer cases
are NSCLC. There are two major types of NSCLC: non-squa-
mous carcinoma (e.g. adenocarcinoma, large cell carcinoma) and
squamous cell carcinoma. Adenocarcinoma is the most common
type of lung cancer.
Twenty per cent of all lung and bronchial cancers are diagnosed
when the cancer has spread to regional lymph nodes or beyond
the primary site (Howlader 2017). The majority of the lung can-
cer cases (57%) are diagnosed when the disease has metastasised
(spread) to distant sites. The Tumor, Node, Metastasis (TNM)
staging system, proposed by the American Joint Committee on
Cancer (AJCC), is a widely accepted system to characterize the
extent of NSCLC.The TNM staging staging system is based on
the extent of tumour (T), extent of spread to the lymph nodes (N)
and the presence of metastases (M).The numbers after each letter
give more details about the cancer. For example, a higher number
after the T indicates a larger tumor while a higher number after

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 1
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the N suggests more lymph nodes are involved by the cancer.The
TNM system has undergone several changes over the last 40 years.
1. The first edition of the AJCC TNM system, published in
1977, defined Stage III disease as T3 with any N or M, N2 with
any T or M and M1 with any T or N (Beahrs 1977).
2. The second edition, published in 1983, broadened the
Stage III disease definition by including N1 disease with any T
or M (Beahrs 1983).
3. The third edition, published in 1988, first introduced the
category of Stage IIIA disease which is defined by T1 N2, T2
N2, T3 N0-2 (Beahrs 1988).
4. There was no difference in the definition of Stage IIIA
disease between the fourth edition (published in 1992) (Beahrs
1992) and third edition (Beahrs 1988).
5. The fifth edition, published in 1997, modified the category
of Stage IIIA disease slightly by removing T3N0 disease
(Fleming 1997).
6. The definition of Stage IIIA disease remained the same
between the sixth edition (published in 2002) (Greene 2002)
and fifth edition (Fleming 1997).
7. The seventh edition, published in 2010, broadened the
definition of Stage IIIA disease slightly by including T4N0-1
disease (Edge 2010).
8. The eighth edition, published in 2017, modified the Stage
IIIA disease category even further to include only T1-2N2,
T3N1, T4N0-1 (Amin 2017).
The prognostic significance of multi-station N2 disease was high-
lighted in the eighth edition of the AJCC TNM staging system,
in which an exploratory subclassification of pathologic N2 disease
was introduced. Presence of multi-station N2 disease is classified
as pN2b disease whereas single N2 disease can be categorized as
pN2a1 or N2a2 depending on the presence of concurrent N1 in-
volvement. The overall survival rate for people with pN2b dis-
ease is significantly lower than for those with pN2a disease,and
five-year overall survival rate of 38% (pN2b) versus 49% (pN2a)
(Amin 2017).
Pearson and colleagues reported a series of 141 N2 patients who
had undergone mediastinal lymph node examination and subse-
quent thoracotomy (an operation to allow the surgeon to access
the chest cavity). They demonstrated that for patients who had a
negative mediastinal lymph node evaluation, but had N2 disease
identified at subsequent thoracotomy, there were higher rates of
five-year overall survival compared with patients who had N2 dis-
ease at both mediastinal lymph node evaluation and subsequent
thoracotomy (24% versus 9%) (Pearson 1982).
The location and definition of thoracic lymph nodes has changed
over the years. Naruke and colleagues first proposed the thoracic
lymph node map in the 1960s and it was widely adopted in the
North America, Europe and Japan (Naruke 1967; Naruke 1978).
The map was further refined by the American Thoracic Soci-
ety (Tisi 1983), and by Mountain et al (Mountain 1997), and
was subsequently adopted in the fourth to sixth editions of the
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TNM staging system. There were important differences between
the maps by Naruke (Naruke 1967; Naruke 1978), and by Moun-
tain (Mountain 1997). The level 7 subcarinal lymph nodes in the
Mountain map corresponded to the levels 7 and 10 in the Naruke
map. This resulted in some tumours being staged as N2 disease
according to the Mountain map but as N1 disease according to
Naruke map.
To reconcile the differences between the maps by Naruke (Naruke
1967; Naruke 1978), and Mountain (Mountain 1997), the mem-
bers of the International Association for the Study of Lung Cancer
(IASLC) developed a revised lymph node map which was adopted
in the seventh (Edge 2010), and eighth (Amin 2017), editions of
the TNM staging system. It is important to note that the defini-
tion of lymph node stations was changed in the seventh edition
of the TNM staging system (Edge 2010). For example, the lymph
node station 4R below the azygos vein - considered as N2 disease
in the sixth edition of the TNM staging system (Greene 2002) -
is now N1 disease (station 10) based on the seventh edition of the
TNM staging system (Edge 2010).
Complete resection is a major prognostic factor for patients un-
dergoing lung cancer surgery (Osarogiagbon 2012; Osarogiagbon
2013). Rami-Porta and colleagues have proposed clear definitions
of what is considered a complete resection, incomplete resection
or uncertain resection (Rami-Porta 2005). These definitions are
consistent with the residual tumor classification , i.e. R0 for no
identifiable tumour remaining, negative surgical margins; R1 for
microscopic residual disease; and R2 for gross residual disease.
Initially there was a subdivision named Run, indicating that a
complete resection was probably achieved but not all criteria were
fulfilled, which was proposed but not adopted. Examples of Run
include incomplete nodal dissection when less than the required
three hilar/intrapulmonary nodal stations, or less than three me-
diastinal nodal stations, were removed. Recently, the eighth edi-
tion of the TNM staging system has formally adopted the Run
category (Amin 2017) (Appendix 1).
Description of the intervention
Surgery-based treatment approaches for Stage IIIA disease involve
surgery with other treatment modalities such as chemotherapy and
radiotherapy (National Comprehensive Cancer Network 2018).
Surgical intervention entails anatomic pulmonary resection, such
as lobectomy (excision of a lobe) or pneumonectomy (complete
removal of a lung), as well as N1 and N2 lymph node resec-
tion and mapping with a minimum of three N2 stations sam-
pled or complete lymph node dissection. In anatomically appro-
priate situations where margin-negative resection can be achieved,
lung sparing anatomic resection (sleeve lobectomy) is preferred to
pneumonectomy. Video assisted thoracic surgery (VATS) should
be considered in patients with no anatomic contraindications as
it has been shown to be associated with fewer complications and
shorter time in hospital compared with lobectomy by thoracotomy
2
(Cao 2013). The addition of chemotherapy, either preoperatively
or postoperatively, has been shown to improve overall survival in
patients with Stage IB to Stage IIIA NSCLC. An individual pa-
tient data meta-analysis, including 2385 patients, demonstrated
that adding preoperative chemotherapy improved overall survival
by five per cent at five years, from 40% to 45% in Stage IB-IIIA
NSCLC (NSCLC Collaborative Group 2014). A Cochrane indi-
vidual patient data meta-analysis, including 11,107 patients, re-
ported that there was a clear absolute survival benefit of four per
cent at five years from the addition of adjuvant chemotherapy, re-
gardless of whether chemotherapy was given in addition to surgery
or surgery plus radiotherapy for Stage IB to IIIA NSCLC (Burdett
2015).The role of adding radiotherapy to surgery for Stage IIIA
NSCLC is unclear. A Cochrane individual patient data meta-anal-
ysis, including 2343 patients, showed that postoperative radio-
therapy is detrimental to those with completely resected NSCLC
and should not be used in the routine treatment of such patients
(Burdett 2016). However, these trials employed now outdated ra-
diotherapy techniques. Randomized trials are awaited to deter-
mine the effects of modern post-operative radiotherapy in patients
with N2 disease. The role of adding radiotherapy to preoperative
chemotherapy for NSCLC is unclear. A randomized trial compar-
ing sequential neoadjuvant chemo-radiotherapy with neoadjuvant
chemotherapy in Stage IIIA/N2 NSCLC showed that radiother-
apy did not add any benefit to induction chemotherapy followed
by surgery (Pless 2015). As this trial only compared preoperative
sequential chemo-radiotherapy with preoperative chemotherapy,
it is unclear if there will be a benefit with preoperative concurrent
chemo-radiotherapy over chemotherapy alone for this group of
patients.
Non-surgical treatment includes combined chemo-radiotherapy
treatment. A randomized trial from 1968 involving 800 patients
with locally advanced NSCLC, which compared radiotherapy
alone and placebo, showed that the use of radiotherapy was asso-
ciated with a small improvement in survival (18% at one year ver-
sus 14% in the control group) (Roswit 1968). A Cochrane review
using individual patient data from 22 trials comparing radical ra-
diotherapy with radical radiotherapy plus chemotherapy showed
that there was a 10% reduction in the risk of death (correspond-
ing to absolute benefits of 3% at two years and 2% at five years)
with the use of radical radiotherapy plus chemotherapy (NSCLC
Collaborative Group 2000). An individual patient data meta-anal-
ysis of six trials (1205 patients) showed that concurrent chemo-
radiotherapy improved overall survival (4.5% absolute benefit at
five years) compared with sequential chemo-radiotherapy in un-
resectable NSCLC (Auperin 2010).
How the intervention might work
Surgery, radiotherapy and chemotherapy are the three modalities
used to treat patients with NSCLC according to the National
Comprehensive Cancer Network (NCCN) guidelines (National
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comprehensive Cancer Network 2018). They can be used alone
or in combination depending on the stage of the disease, patients’
performance status, comorbidities and pulmonary function. A pa-
tient can have resectable lung cancer by virtue of having a surgi-
cally removable NSCLC, but may not be operable due to poor
pulmonary function or multiple comorbities.
For resectable and operable Stage I or II NSCLC, surgical resection
should be used whenever possible. Postoperative chemotherapy
can be given in pathologic Stage II NSCLC to reduce disease recur-
rence and improve survival. Patients with Stage I or II NSCLC who
are inoperable or who refuse surgery may be candidates for defini-
tive radiotherapy treatment, delivered using stereotactic or con-
ventional techniques (National Comprehensive Cancer Network
2018).
For Stage III disease, a combined modality approach is used.
When surgical resection is clearly feasible, surgery followed by
postoperative chemotherapy with or without radiotherapy de-
pending on the findings at surgery is an option. For N2 disease,
options include preoperative chemotherapy or chemo-radiother-
apy, possibly followed by surgery. When surgical resection is not
feasible, the options include combinations of radiotherapy with
sequential or preferentially concurrent chemotherapy (National
Comprehensive Cancer Network 2018).
Why it is important to do this review
The optimal management of patients with resectable Stage IIIA
NSCLC is unclear. The NCCN guidelines recommend a surgery-
based approach for patients with resectable T1-3, N0-1 disease,
and definitive concurrent chemo-radiotherapy for N2 disease
(National Comprehensive Cancer Network 2018). The European
Society for Medical Oncology (ESMO) guidelines also recom-
mend surgery-based treatment for patients with N0-1 disease.
However, for patients with potentially resectable N2 disease, the
ESMO guidelines recognise that both surgery- and non-surgery-
based treatment approaches are reasonable options (Eberhardt
2015).
OBJECTIVES
To assess the effectiveness and safety of chemo-radiotherapy with
surgery for people with Stage IIIA non-small cell lung cancer
(NSCLC).
METHODS
Criteria for considering studies for this review
3
Types of studies
We will include randomized controlled trials that meet the eligi-
bility criteria. The included trials must be published as full text.
We will consider randomized trials regardless of language status.
As these trials include surgical interventions, the blinding of par-
ticipants or use of sham surgical procedure (i.e. placebo control)
can be difficult and so they will not be mandatory requirements.
Types of participants
We will include adults (aged 18 years or older) with histologically
diagnosed non-small cell lung cancer (NSCLC), staged by the 3rd
to 8th editions of American Joint Committee on Cancer (AJCC)
Tumor, Node, Metastasis (TNM) system.
Types of interventions
Intervention arm: chemo-radiotherapy. This arm will include rad-
ical chemo-radiotherapy treatment which can be given concur-
rently or sequentially. The minimum acceptable radiation dose in
terms of equivalent dose in 2 Gray (Gy) per fraction (EQD2) as-
suming tumour alpha/beta ratio of 10 is 60 Gy. The use of targeted
therapy or immunotherapy in this arm is allowed.
1. Chemo-radiotherapy (can be concurrent or sequential)
2. Chemo-radiotherapy + targeted therapy
3. Chemo-radiotherapy + immunotherapy
Comparison arm: surgery-based treatment. This arm must include
surgery with curative intent. Lung surgery will include lobectomy
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
or pneumonectomy. Video assisted thoracic surgery is allowed.
Adequate thoracic lymph node management should include N1
and N2 lymph node resection and mapping with a minimum of
three N2 stations sampled or complete lymph node dissection.
The use of chemotherapy, radiotherapy, targeted therapy and im-
munotherapy in this arm will be allowed.
Therefore, all the possible combinations of treatment are as fol-
lows.
1. Surgery alone
2. Surgery + chemotherapy (can be preoperative or
postoperative, or both)
3. Surgery + chemo-radiotherapy (can be preoperative or
postoperative, or both)
4. Surgery + targeted therapy +/- chemotherapy or chemo-
radiotherapy
5. Surgery + immunotherapy +/- chemotherapy or chemo-
radiotherapy
We plan to conduct both traditional meta-analysis and network
meta-analysis (NMA). In the meta-analysis, we will focus on broad
intervention and comparison arms (i.e. group all the possible com-
binations into surgery arm and chemo-radiotherapy arm), while
in NMA all the possible combinations will be considered as sepa-
rate arms. All interventions will be compared to each other using a
network meta-analysis (Figure 1). We assume that any participant
that meets the inclusion criteria is, in principle, equally likely to
be randomized to any of the eligible interventions.
4
 Figure 1. Network geometry of all interventions

4. Locoregional recurrence-free survival (LRFS): survival until lo-

Types of outcome measures
Primary outcomes
1. Overall survival (OS): survival until death from all causes. We
will assess survival from the time of randomization. This will be
reported as hazard ratio.
2. Adverse events (AEs): we will define the nature, timing and
management of these events according toindividual trial protocols.
We will examine the included trials for the incidence of Grade 5
adverse events, i.e. treatment related deaths. We will also look at
incidence of Grade 3 or 4 pulmonary, cardiac and hematological
adverse events (National Cancer Institute 2018). This will be re-
ported as risk ratio.
Secondary outcomes
3. Disease-free survival (DFS): survival until recurrence of disease
or death from all causes. We will assess disease-free survival from
the time of randomization. This will be reported as hazard ratio.
coregional disease recurrence or death from all causes. We will de-
fine locoregional disease recurrence according to individual trial
protocols. We will assess locoregional recurrence-free survival from
the time of randomization. This will be reported as hazard ratio.
5. Distant recurrence-free survival (DRFS): survival until distant
disease recurrence or death from all causes. We will define distant
disease recurrence according to individual trial protocols. We will
assess distant recurrence-free survival from the time of random-
ization. This will be reported as hazard ratio.
6. Health-related quality of life (HRQL): the measurement of
health-related quality of life outcomes, assessed using a scale that
has been validated through reporting of norms in a peer-reviewed
publication. An example of such a scale is the European Organi-
zation for Research and Treatment of Cancer (EORTC) quality of
life questionnaire (Aaronson 1993). This will be reported as mean
difference between treatment arms.
Search methods for identification of studies
We will adopt the search strategies recommended by the Cochrane

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 5
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lung Cancer Group. The search strategies are based on the use
of free-text terms and controlled vocabulary and are linked with
the Cochrane highly sensitive search strategy for identifying ran-
domized trials in MEDLINE, as referenced in Chapter 6.4.11.1
and detailed in box 6.4c of the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2011).
Electronic searches
We will search the following electronic databases for eligible stud-
ies. We will not apply any language restrictions. If necessary, we
will translate the non-English papers and assess them for potential
inclusion in the review.
1. Databases of medical literature
i) Cochrane Central Register of Controlled Trials
(CENTRAL; latest issue) (Appendix 2)
ii) MEDLINE, accessed via PubMed (1946 to present)
(Appendix 3)
iii) Embase (1980 to present) (Appendix 4)
2. Databases of ongoing trials
i) the ISRCTN register of controlled trials:
www.controlled-trials.com
ii) EU Clinical Trials Register:
www.clinicaltrialsregister.eu/ctr-search/search
iii) US National Institutes of Health Ongoing Trials
Register ClinicalTrials.gov:www.clinicaltrials.gov
iv) WHO international trials registry platform: http://
apps.who.int/trialsearch
Searching other resources
We will handsearch reference lists of included studies, relevant
chapters of books, and review articles for eligible trials. We will
also search the following, from 2015 onwards.
1. The proceedings of the annual meetings of the American
Society of Clinical Oncology (ASCO) and the American Society
for Radiation Oncology (ASTRO)
2. Lung cancer sections of the proceedings of the European
Society of Medical Oncology (ESMO) Congress
3. Lung cancer sections of the proceedings of the European
Conference of Clinical Oncology (ECCO) Congress
4. Proceedings of the World Conference on Lung Cancer
Data collection and analysis
We will summarize the evidence using the methods described in
the Cochrane Handbook for Systematic Reviews of Interventions (
Higgins 2011).
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Selection of studies
Two review authors (YYS, WYK) will independently screen titles
and abstracts of all identified studies, and exclude those which
do not meet the inclusion criteria. We will retrieve the full-text
copies of potentially relevant studies. Two review authors (YYS,
WYK) will independently assess the eligibility of retrieved papers.
We will identify and exclude duplicates and use the trial report
with the most up-to-date results. We will contact the investigators
when appropriate to clarify study eligibility. Disagreements will
be resolved by discussion between the two review authors and if
necessary by the third review author (IWKT). We will document
the reasons for exclusions.
Data extraction and management
For included studies, two review authors (YYS, WYK) will inde-
pendently extract the following study characteristics using a stan-
dardized data extraction form.
1. Study methodology: study design, randomization, total
duration of study, duration of follow-up period, numbers of
centres and location and withdrawals
2. Particpants: total sample size, numbers enrolled in each
arm, mean age, age range, gender, pathological confirmation of
NSCLC, NSCLC histological subtype, staging of NSCLC,
staging system used, smoking history, inclusion and exclusion
criteria.
3. Interventions
i) Chemo-radiotherapy arm: radiation dose fractionation
schedule, types of radiation technique, types of chemotherapy
use, timing of chemotherapy in relation to radiation, total
number of cycles of chemotherapy, use of targeted therapy and
immunotherapy in relation to radiotherapy
ii) Surgery-based treatment: types of lung surgery, types
of thoracic lymph node resection, use of chemotherapy,
radiotherapy, targeted therapy and immunotherapy in relation to
surgery
4. Outcomes
i) For time-to-event data (survival and disease
recurrence), 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 estimate the log (HR) and its standard error using
published methods (Parmar 1998; Tierney 2007).
ii) For dichotomous data (adverse events), we will extract
the number of patients in each treatment arm who experienced
the outcome of interest and the number of patients assessed at
the endpoint to estimate a risk ratio.
iii) For continuous data (health-related quality of life), we
will extract the final value and standard deviation of the outcome
of interest and the number of participants assessed in each
treatment arm at the endpoint at the end of follow-up to
estimate the mean difference between treatment arms and its
standard error.
6
We will extract both adjusted and unadjusted statistics if reported.
We will extract data that are relevant to an intention-to-
treat analysis in which participants were analysed in the groups
to which they were assigned. We will also note the time points at
which outcomes were collected.
Assessment of risk of bias in included studies
Two review authors (YYS, QZ) will evaluate the risk of bias for
each study independently using the criteria recommended in the
Cochrane ’Risk of bias’ tool (Higgins 2011). Disagreements will
be resolved by discussion between the two review authors and if
necessary by the third review author (IWKT). We will assess the
risk of bias according to the following domains.
1. Random sequence generation (per study)
2. Allocation concealment (per study)
3. Blinding of participants and personnel (per study)
4. Blinding of outcome assessment (per outcome)
5. Incomplete outcome data (per outcome)
6. Selective outcome reporting (per outcome)
7. Other bias.
We will classify each domain as high, low or uncertain risk of
bias and provide a quote from the study report together with a
justification for our judgement in the ’Risk of bias’ table. We will
summarize the ’Risk of bias’ judgements across different studies
for each listed domain.
Measures of treatment effect
We will analyse time-to-event data (survival, disease recurrence)
using hazard ratios if possible. We will analyse dichotomous out-
comes (adverse events) using risk ratios if possible. We will analyse
continuous outcomes (health-related quality of life) using mean
differences between treatment arms if possible.
We will undertake meta-analyses only when the treatments, par-
ticipants and the underlying clinical question are similar enough
for pooling to be appropriate. When multiple trial arms are re-
ported in a unique study, we will include only the relevant arms. If
two comparisons for continuous or dichotomous outcomes must
be included into the same meta-analysis, we will halve the control
group to avoid double counting.
Unit of analysis issues
We will analyse each eligible trial for potential unit of analysis
errors, such as using non-standard trial design or reporting mul-
tiple observations for the same outcomes. We believe that these
errors will be uncommon in this systematic review. If a trial reports
multiple observations for the same outcomes, we will choose the
observation with the most frequently reported time point across
the trials, and conduct sensitivity analyses based on which time
point is chosen.
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dealing with missing data
We will contact the trial investigators to obtain missing numerical
outcome data where possible. We will not impute missing outcome
data for the primary outcome.
Assessment of heterogeneity
We will use the I2 statistic to assess heterogeneity among the trials
in each pairwise comparison, for both standard meta-analysis and
direct comparisons within network meta-analysis (Higgins 2011).
If there is evidence of substantial heterogeneity (I2 greater than
50%) in the standard meta-analysis, we will explore and report the
possible causes using prespecified subgroup analysis.
We will assess heterogeneity of both meta-analysis and direct com-
parisons within the network meta-analysis, as network meta-anal-
ysis needs to fulfil three assumptions, i.e. heterogeneity (for direct
comparisons), similarity (for indirect comparisons) and consis-
tency (for combining direct and indirect comparisons) (Donegan
2013).
Assessment of similarity (transitivity)
We will assess the assumption of transitivity by comparing the pop-
ulation, intervention, comparison, and outcomes across different
comparisons to identify potential sources of effect modifiers.
Assessment of loop inconsistency
We will adopt the side-splitting method to evaluate the poten-
tial loop inconsistency within each comparison between estimates
from direct and indirect evidence. This method evaluates the con-
sistency assumption in each closed loop of the network separately
as the difference between direct and indirect estimates for a spe-
cific comparison in the loop (Dias 2010). Then, the magnitude of
the inconsistency factors and their 95% confidence intervals (CIs)
can be used to infer about the presence of inconsistency in each
loop.
Assessment of design inconsistency
To check the potential design inconsistency, we will use the “de-
sign-by-treatment” model (Higgins 2012; White 2012). This
method accounts for different sources of inconsistency that can
occur when studies with different designs (two-arm trials versus
three-arm trials) give different results, as well as disagreement be-
tween direct and indirect evidence (i.e. loop inconsistency). Using
this approach, we will infer about the presence of inconsistency
from any source in the entire network based on a global Wald test.
7
Assessment of reporting biases
We will assess selective reporting within each trial by comparing the
methods reported in the protocol (if available) and final published
study. We will try to contact the trial investigators if reporting bias
is suspected. If 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 conducting a
sensitivity analysis.
If there are ten or more trials available for pooling, we will inves-
tigate publication bias using a funnel plot.
Data synthesis
We will first perform the standard meta-analysis comparing
chemo-radiotherapy arm with surgery based treatment arm using
a random-effects model (Deeks 2011). For time-to-event data (i.e.
overall survival, disease-free survival, locoregional recurrence-free
survival and distant recurrence-free survival), we will use the in-
verse variance method. We will use the Mantel-Haenszel method
for handling binary outcomes (adverse events).
We will perform network meta-analysis using a random-effects
model in STATA with the mvmeta command within the network
suite of commands for network meta-analysis (White 2015), and
other STATA commands for visualising and reporting results in
network meta-analysis (Chaimani 2015). If meta-analysis is not
possible, we will undertake a narrative review of the findings.
We will present a ’Summary of findings’ table to identify the key
results of the review (Higgins 2011). We will include the follow-
ing outcomes: overall survival, adverse events, disease-free survival,
locoregional disease-free survival, distant disease-free survival and
health-related quality of life. We will also demonstrate the illus-
trative risk of these outcomes and define the absolute and relative
magnitude of effect.
We will use the five GRADE criteria (study limitations, consis-
tency of effect, imprecision, indirectness and publication bias) to
evaluate the quality of a body of evidence as it relates to the studies
which contribute data to the meta-analysis for each prespecified
outcome. We will use GRADEpro software (GRADEpro GDT
2015). We will justify all decisions to downgrade or upgrade the
REFERENCES
Additional references
Aaronson 1993
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M,
Cull A, Duez NJ, et al. The European Organization for
Research and Treatment of Cancer QLQ-C30: A quality-
of-life instrument for use in international clinical trials in
oncology. Journal of the National Cancer Institute 1993;85
(5):365–76.
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
quality of evidence using footnotes and we will make comments
to facilitate the readers’ comprehension.
Subgroup analysis and investigation of heterogeneity
We will consider the following subgroup analyses where possible.
1. Types of staging system: AJCC third/fourth edition versus
fifth/sixth edition versus seventh edition versus eighth edition
2. Types of Stage IIIA: N2 versus N1
3. Types of lung surgery: pneumonectomy versus lobectomy
4. Adequacy of lymph node dissection: adequate versus
inadequate or uncertain adequacy
5. Resection status: complete resection only versus incomplete
resection or uncertain resection status
6. Types of radiation technique: intensity modulated radiation
therapy versus non-intensity modulated radiation therapy
7. Timing of chemotherapy in relation to radiation:
concurrent versus sequential
8. Definition of survival time point: before versus after
induction therapy
Sensitivity analysis
We will perform sensitivity analyses by excluding studies with a
high risk of bias. Adequate random sequence generation and allo-
cation concealment are important for ensuring the study quality.
Hence, we will categorize those studies which are at high risk of
bias for either of these domains as having high risk of bias overall,
and will exclude them for this sensitivity analysis.
ACKNOWLEDGEMENTS
We acknowledge the help and support of the Cochrane Lung Can-
cer Group and particularly Paul Van Schil, Mia Schmidt-Hansen,
John Ruckdeschel, Fergus Macbeth, Corynne Marchal and Vir-
ginie Westeel, as well as the Information Specialists Francois Calais
and Giorgio Maria Agazzi for designing our search strategies.
Amin 2017
Amin MB, Edge SB, Greene FL, Byrd DR, Brookland
RK, Washington MK, et al. Cancer Staging Manual. 8th
Edition. New York: Springer, 2017.
Auperin 2010
Auperin A, Le Pechoux C, Rolland E, Curran W, Furuse
K, Fournel P, et al. Meta-analysis of concomitant versus
sequential radiochemotherapy in locally advanced non-
small cell lung cancer. Journal of Clinical Oncology 2010;28
(13):2181–90.
8
Beahrs 1977
Beahrs OH, Carr DT, Rubin P. Manual for staging of cancer.
1st Edition. Chicago: American Joint Committee, 1977.
Beahrs 1983
Beahrs OH, Myers MH. Manual for staging of cancer. 2nd
Edition. Philadelphia: JB Lippincott Company, 1983.
Beahrs 1988
Beahrs OH, Henson DE, Hutter RVP, Myers MH. Manual
for staging of cancer. 3rd Edition. Philadelphia: JB
Lippincott Company, 1988.
Beahrs 1992
Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ.
Manual for staging of cancer. 4th Edition. Philadelphia: JB
Lippincott Company, 1992.
Burdett 2015
Burdett S, Pignon JP, Tierney J, Tribodetn H, Stewart
L, Le Pechoux C, et al. Non-Small Cell Lung Cancer
Collaborative Group. Adjuvant chemotherapy for resected
early-stage non-small cell lung cancer. Cochrane Database
of Systematic Reviews 2015, Issue 3. DOI: 10.1002/
14651858.CD011430
Burdett 2016
Burdett S, Rydzewska L, Tierney J, Fisher D, Parmar MKB,
Arriagada R, et al for the PORT Meta-analysis Trialists
Group. Postoperative radiotherapy for non-small cell lung
cancer. Cochrane Database of Systematic Reviews 2016, Issue
10. DOI: 10.1002/14651858.CD002142.pub4
Cao 2013
Cao C, Manganas C, Ang SC, Peeceeven S, Yan TD. Video-
assisted thoracic surgery versus open thoractomy for non-
small cell lung cancer: a meta-analysis of propensity score
matched patients. Interactive cardiovascular and thoracic
surgery 2013;16(3):244–9.
Chaimani 2015
Chaimani A, Salanti G. Visualizing assumptions and results
in network meta-analysis: the network graphs package.
Stata Journal 2015 Jan 1;15(4):905–50.
Deeks 2011
Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing
data and undertaking meta-analyses. In: Cochrane
Handbook for Systematic Reviews of Interventions Version
5.1.0 (updated March 2011). The Cochrane Collaboration,
2011. Available from handbook.cochrane.org (accessed
15th March 2018).
Dias 2010
Dias S, Welton NJ, Caldwell DM, Ades AE. Checking
consistency in mixed treatment comparison meta-analysis.
Statistics in medicine 2010;29(7-8):932–44.
Donegan 2013
Donegan S, Williamson P, D’Alessandro U, Tudur Smith
C. Assessing key assumptions of network meta-analysis: a
review of methods. Research Synthesis Methods 2013;4(4):
291–323.
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Eberhardt 2015
Eberhardt W, De Ruysscher D, Weder W, Le Pechoux C,
De Lyn P, Hoffmann H, et al. 2nd ESMO Consensus
Conference in Lung Cancer: Locally advanced stage III
non-small lung cancer. Annals of Oncology 2015;26(8):
1573–88.
Edge 2010
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL,
Trotti A. Cancer Staging Manual. 7th Edition. New York:
Springer, 2010.
Fleming 1997
Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy
BJ, Murphy GP, et al. Manual for staging of cancer. 5th
Edition. Philadelphia: Lippincott-Raven, 1997.
GRADEpro GDT 2015 [Computer program]
McMaster University (developed by Evidence Prime).
GRADEpro GDT. Version accessed 1 March 2018.
Hamilton (ON): McMaster University (developed by
Evidence Prime), 2015.
Greene 2002
Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM,
Haller DG, et al. Cancer Staging Manual. 6th Edition.
New York: Springer, 2002.
Higgins 2011
Higgins JP, Green S, editor(s). Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0
(updated March 2011). The Cochrane Collaboration,
2011. Available from handbook.cochrane.org. 5.1. The
Cochrane Collaboration, (accessed 15th March 2018).
Higgins 2012
Higgins JP, Jackson D, Barrett JK, Lu G, Ades AE, White
IR. Consistency and inconsistency in network meta-
analysis: concepts and models for multi-arm studies.
Research Synthesis Methods 2012 Jun 1;3(2):98–110.
Howlader 2017
Howlader N, Noone AM, Krapcho M. SEER Cancer
Statistics Review, 1975-2014. seer.cancer.gov/csr/
1975 2014 (accessed 15th March 2018).
International Agency for Research on Cancer 2012
International Agency for Research on Cancer. Globocan
2012: Estimated Cancer Incidence, Mortality, and
Prevalence Worldwide in 2012. globocan.iarc.fr/Pages/
fact sheets cancer.aspx (accessed 15 March 2018).
Mountain 1997
Mountain CF, Dresler CM. Regional lymph node
classification for lung cancer staging. Chest 1997;111(6):
1718–23.
Naruke 1967
Naruke T. The spread of lung cancer and its relevance
to surgery. Nippon Kyobu Geka Gakkai Zasshi 1967;68:
1607–21.
Naruke 1978
Naruke T, Suemasu K, Ishikawa S. Lymph node mapping
and curabilityat various levels of metastasis in resected lung
9
 cancer. The journal of thoracic and cardiovascular surgery
1978;76(6):833–9.
National Cancer Institute 2018
National Cancer Institute. Common Terminology
Criteria for Adverse Events (CTCAE). ctep.cancer.gov/
protocoldevelopment/electronic applications/ctc.htm
(accessed 15th March 2018).
National Comprehensive Cancer Network 2018
National Comprehensive Cancer Network. Non-small cell
lung cancer. www.nccn.org/professionals/physician gls/pdf/
nscl blocks.pdf (accessed 15th March 2018).
NSCLC Collaborative Group 2000
NSCLC Collaborative Group 2000. Chemotherapy
for non-small cell lung cancer. Cochrane Database
of Systematic Reviews 2000, Issue 2. DOI: 10.1002/
14651858.CD002139
NSCLC Collaborative Group 2014
NSCLC Collaborative Group. Preoperative chemotherapy
for non-small cell lung cancers: a systematic review and
meta-individual participant data. Lancet 2014;383(9928):
1561–71.
Osarogiagbon 2012
Osarogiagbon RU, Yu X. Mediastinal lymph
nodeexamination and survival in resected early-stage non-
small cell lung cancer in the surveillance, epidemiology, and
end results database. Journal of Thoracic Oncology 2012;7
(12):1798–806.
Osarogiagbon 2013
Osarogiagbon RU, Yu X. Nonexamination of lymph
nodesand survival after resection of non-small cell lung
cancer. Annals of Thoracic Surgery 2013;96(4):1178–89.
Parmar 1998
Parmar MK, Torri V, Stewart L. Extracting summary
statistics to perform meta-analyses of the published literature
for survival endpoints. Statistics in Medicine 1998;17(24):
2815–34.
Pearson 1982
Pearson FG, DeLarue NC, Ilves R, Todd TR, Cooper
JD. Significance of positive superior mediastinal nodes
identified at mediastinoscopy in patients with resectable
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta-
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
cancer of the lung. The journal of thoracic and cardiovascular
surgery 1982;83(1):1–11.
Pless 2015
Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein
S, et al. Induction chemoradiation in stage IIIA/N2 non-
small cell lung cancer: a phase 3 randomized trial. Lancet
2015;386(9998):1049–56.
Rami-Porta 2005
Rami-Porta R, Wittekind C, Goldstraw P, International
Association for the Study of Lung Cancer (IASLC) Staging
Committee.Author information. Complete resection in
lung cancer surgery: proposed definition. Lung Cancer
2005;49(1):25–33.
Roswit 1968
Roswit B, Patno ME, Rapp R, Veinbergs A, Feder B,
Stuhlbarg J, et al. The survival of patients with inoperable
lung cancer: a large scale randomized study of radiation
therapy versus placebo. Radiology 1968;90(4):688–97.
Tierney 2007
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR.
Practical methods for incorporating summary time to event
data into meta-analysis. Trials 2007;8:16.
Tisi 1983
Tisi GM, Friedman PJ, Peters RM. Clinical staging of
primary lung cancer. American Review of Respiratory Diseases
1983;127:659–64.
Travis 2015
Travis WD, Brambilla EW, Burke AP. WHO CLassification
of Tumours of the Lung, Pleura, Thymus and Heart. Lyon:
IARC Press, 2015.
White 2012
White IR, Barrett JK, Jackson D, Higgins J. Consistency
and inconsistency in network meta-analysis: model
estimation using multivariate meta-regression. Research
Synthesis Methods 2012 Jun 1;3(2):111–25.
White 2015
White IR. Network meta-analysis. Stata Journal 2015 Jan
1;15(4):951–85.
∗
Indicates the major publication for the study
10
APPENDICES

Appendix 1. T,N,M descriptors for the eighth edition of TNM classification for lung cancer

T: Primary tumour

TX Primary tumour cannot be assessed or tumor proven by presence of malignant cells in sputum or bronchial
washings but not visualized by imaging or bronchoscopy

T0 No evidence of primary tumour

Tis Carcinoma in situ

T1 Tumour <=3cm in greatest dimension surrounded by lung or visceral pleura without bronchoscopic evidence
of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)

T1a(mi) Minimally invasive adenocarcinoma

T1a Tumour <= 1cm in greatest dimension

T1b Tumour > 1cm but <= 2cm in greatest dimension

T1c Tumour > 2cm but <= 3cm in greatest dimension

T2 Tumour > 3cm but <= 5cm or tumour with any of the following features:
-involves main bronchus regardless of distance from the carina but without involvement of the carina
-invades visceral pleura
-associated with atelectasis or obstructive pneumonitis that extends to the hilar regionm involving part or all
of the lung

T2a Tumour < 3cm but <= 4cm in greatest dimension

T2b Tumour > 4cm but <= 5cm in greatest dimension

T3 Tumour > 5cm but <= 7cm in greatest dimension or associated with separate tumour nodule(s) in the same
lobe as the primary tunour or directly invades any of the following structures: chest wall (including parietal
pleural and superior sulcus tumours), phrenic nerve, parietal pericardium

T4 Tumour > 7cm in greatest dimension or associated with separate tunour nodule(s) in a different ipsilateral
lobe than that of the primary tumour or invades any of the following structures: diaphragm, mediastinum,
heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina

N: Regional lymph node involvement

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 11
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

N1‘ Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, in-
cluding involvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymoh node(s)

N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavic-

ular lymph node(s)

M: Distant metastasis

M0 No distant metastasis

M1 Distant metastasis present

M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or pericardial nodule(s) or malignant
pleural or pericardial effusion

M1b Single extrathoracic metastases

M1c Multiple extrathoracic metastases in one or more organs

Stage groupings

Occult carcinoma TXN0M0

Stage 0 TisN0M0

Stage IA1 T1a(mi)N0M0

T1aN0M0

Stage IA2 T1bN0M0

Stage IA3 T1cN0M0

Stage IB T2aN0M0

Stage IIA T2bN0M0

Stage IIB T1a-2bN1M0

T3N0M0

Stage IIIA T1a-2bN2M0

T3N1M0
T4N0-1M0

Stage IIIB T1a-2bN3M0

T3-4N2M0

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 12
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Stage IIIC T3-4N3M0

Stage IVA Any T, Any N, M1a-b

Stage IVB Any T, Any N, M1c

Appendix 2. CENTRAL search strategy

#1MeSH descriptor: [Carcinoma, Non-Small-Cell Lung] explode all trees
#2nsclc
#3lung cancer*
#4lung carcinom*
#5lung neoplasm*
#6lung tumor*
#7lung tumour*
#8non small cell*
#9nonsmall cell*
#10(#3 or #4 or #5 or #6 or #7) and (#8 or #9)
#11#1 or #2 or #10
#12MeSH descriptor: [Thoracic Surgical Procedures] explode all trees
#13surger*
#14surgic*
#15resect*
#16MeSH descriptor: [Pneumonectomy] explode all trees
#17pneumonectom*
#18MeSH descriptor: [Thoracotomy] explode all trees
#19thoracotom*
#20preoperat*
#21postoperat*
#22lobectom*
#23#12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22
#24MeSH descriptor: [Radiotherapy] explode all trees
#25MeSH descriptor: [Chemoradiotherapy] explode all trees
#26radiother*
#27chemorad*
#28chemo-radiother*
#29chemother*
#30radiation therap*
#31MeSH descriptor: [Drug Therapy] explode all trees
#32antineoplas*
#33MeSH descriptor: [Antineoplastic Agents] explode all trees
#34#24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33
#35advanced
#36IIIa
#373a
#38#35 or #36 or #37
#39#23 and #34 and #38
#40#11 and #39
Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 13
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 3. MEDLINE search strategy
“#54,”“Search #42 AND #53”“
”#53,“”Search #51 NOT #52“”
“#52,”“Search animals [MeSH Terms] NOT humans [MeSH Terms]”“
”#51,“”Search #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50“”
“#50,”“Search groups[Title/Abstract]”“
”#49,“”Search trial[Title/Abstract]“”
“#48,”“Search randomly”“
”#47,“”Search drug therapy[MeSH Subheading]“”
“#46,”“Search placebo[Title/Abstract]”“
”#45,“”Search randomized[Title/Abstract]“
”#44,“”Search controlled clinical trial[Publication Type]“”
“#43,”“Search randomized controlled trial[Publication Type]”“
”#42,“”Search #11 AND #41“”
“#41,”“Search #23 AND #36 AND #40”“
”#40,“”Search #37 OR #38 OR #39“”
“#39,”“Search 3a”“
”#38,“”Search IIIa“”
“#37,”“Search advanced”“
”#36,“”Search #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35“”
“#35,”“Search antineoplastic agents[MeSH Terms]”“
”#34,“”Search antineoplas*“”
“#33,”“Search drug therapy[MeSH Terms]”“
”#32,“”Search radiation therap*“”
“#31,”“Search chemother*”“
”#30,“”Search chemo-radiother*“”
“#29,”“Search chemorad*”“
”#28,“”Search radiother*“”
“#27,”“Search chemoradiotherapy[MeSH Terms]”“
”#26,“”Search Radiotherapy[MeSH Terms]“”
“#23,”“Search #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22”“
”#22,“”Search lobectom*“”
“#21,”“Search postoperat*”“
”#20,“”Search preoperat*“”
“#19,”“Search Thoracotom*”“
”#18,“”Search thoracotomy[MeSH Terms]“”
“#17,”“Search Pneumonectom*”“
”#16,“”Search pneumonectomy[MeSH Terms]“”
“#15,”“Search resect*”“
”#14,“”Search surgic*“”
“#13,”“Search surger*”“
”#12,“”Search thoracic surgical procedures[MeSH Terms]“”
“#11,”“Search #1 OR #2 OR #10”“
”#10,“”Search (#3 OR #4 OR #5 OR #6 OR #7) AND (#8 OR #9)“”
“#9,”“Search nonsmall cell*[Title/Abstract]”“
”#8,“”Search non small cell*[Title/Abstract]“”
“#7,”“Search lung tumour*[Title/Abstract]”“
”#6,“”Search lung tumor*[Title/Abstract]“”
“#5,”“Search lung neoplasm*[Title/Abstract]”“
”#4,“”Search lung carcinom*[Title/Abstract]“”
“#3,”“Search lung cancer*[Title/Abstract]”“
”#2,“”Search nsclc[Title/Abstract]“”

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 14
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
“#1,”“Search Carcinoma, Non-Small-Cell Lung[MeSH Terms]”“

Appendix 4. Embase search strategy

#42 #11 AND #23 AND #36 AND #40 AND #41
#41 ’crossover procedure’/exp OR ’double-blind procedure’/exp OR ’randomized controlled trial’/exp OR ’single-blind procedure’/exp
OR random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR doubl* NEAR/1 blind* OR singl* NEAR/1
blind* OR assign* OR allocat* OR volunteer*
#40 #37 OR #38 OR #39
#39 3a:ti,ab
#38 iiia:ti,ab
#37 advanced:ti,ab
#36 #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35
#35 ’molecularly targeted therapy’/exp
#34 ’immunotherapy’/exp
#33 ’antineoplastic agent’/exp
#32 antineoplas*:ti,ab
#31 ’drug therapy’/exp
#30 ’radiation therap*’:ti,ab
#29 ’chemother*’:ti,ab
#28 ’chemo rad*’:ti,ab
#27 chemorad*:ti,ab
#26 radiother*:ti,ab
#25 ’chemoradiotherapy’/exp
#24 ’radiotherapy’/exp
#23 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22
#22 lobectom*:ti,ab
#21 postoperat*:ti,ab
#20 preoperat*:ti,ab
#19 thoracotom*:ti,ab
#18 ’thoracotomy’/exp
#17 pneumonectom*:ti,ab
#16 ’lung resection’/exp
#15 resect*:ti,ab
#14 surgic*:ti,ab
#13 surger*:ti,ab
#12 ’thorax surgery’/exp
#11 #1 OR #2 OR #10
#10 #3 OR #4 OR #5 OR #6 OR #7 AND (#8 OR #9)
#9 ’nonsmall cell*’:ti,ab
#8 ’non small cell*’:ti,ab
#7 ’lung tumour*’:ti,ab
#6 ’lung tumor*’:ti,ab
#5 ’lung neoplasm*’:ti,ab
#4 ’lung carcinom*’:ti,ab
#3 ’lung cancer*’:ti,ab
#2 ’nsclc’:ti,ab
#1 ’non small cell lung cancer’/exp

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 15
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CONTRIBUTIONS OF AUTHORS
Protocol development: YYS, QZ WYK, CNL, LS, EC, IWKT
Selection of trials for inclusion: YYS, QZ WYK, CNL IWKT
Methodological assessment and data extraction: YYS, QZ, WYK, CNL, LS, EC IWKT
Data entry and management: YYS, QZ
Data analysis: YYS, QZ, LM, EC
Preparation of manuscript: YYS, QZ, WYK, CNL, LS, EC IWKT

DECLARATIONS OF INTEREST
Yu Yang Soon: none known
Qishi Zheng: none known
Luming Shi: none known
Edwin SY Chan: none known
Cheng Nang Leong: none known
Wee Yao Koh: none known
Ivan Weng Keong Tham received sponsorship-in-kind from Elekta KK, honorarium from Celgene Pte Ltd for speaking services in
2016 and honorarium for ESMO Preceptorship Programme for Lung Cancer in 2017

Chemo-radiotherapy versus surgery-based treatment for Stage IIIA non-small cell lung cancer: a systematic review and network meta- 16
analysis (Protocol)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.