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Concurrent chemoradiotherapy in non-small cell lung cancer

(Review)
ORourke N, Roqu i Figuls M, Farr Bernad N, Macbeth F

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 6
http://www.thecochranelibrary.com

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 1 Overall survival. . .
Analysis 1.2. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 2 Overall survival 2-years.
Analysis 1.3. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 3 Progression-free survival.
Analysis 1.4. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 4 Progression-free survival 2years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.5. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 5 Locoregional progressionfree survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.6. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 6 Locoregional progressionfree survival 2-years.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.7. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 7 Toxicity. . . . .
Analysis 2.1. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 1 Overall survival. . . . . .
Analysis 2.2. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 2 Overall survival 2-years. . .
Analysis 2.3. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 3 Progression-free survival. . .
Analysis 2.4. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 4 Progression-free survival 2-years.
Analysis 2.5. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 5 Locoregional PFS 2-years.
.
Analysis 2.6. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 6 Toxicity. . . . . . . . .
Analysis 3.1. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 1 Chemotherapy regime.
Analysis 3.2. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 2 Frequency of chemotherapy
administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.3. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 3 Platinum dose. . .
Analysis 3.4. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 4 Radiotherapy
fractionation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.5. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 5 Dose of radiotherapy.
Analysis 3.6. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 6 Duration of follow-up.
Analysis 4.1. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 1 Dose of radiotherapy.
. . .
Analysis 4.2. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 2 Duration of follow-up. . . .
Analysis 5.1. Comparison 5 More frequent versus less frequent chemotherapy, Outcome 1 Frequency of chemotherapy.
Analysis 6.1. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 1 Overall survival. . . . . .
Analysis 6.2. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 2 Overall survival 2-years. . .
Analysis 6.3. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 3 Progression-free survival. . .
Analysis 6.4. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 4 Progression-free survival 2-years.
Analysis 6.5. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 5 Locoregional progression-free
survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 6.6. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 6 Locoregional progression-free
survival 2-years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 6.7. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 7 Toxicity. . . . . . . . .
Concurrent chemoradiotherapy in non-small cell lung cancer (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 7.1. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 1 Overall survival. . . . . . .
Analysis 7.2. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 2 Overall survival 2-years. . . .
Analysis 7.3. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 3 Progression-free survival. . . .
Analysis 7.4. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 4 Progression-free survival 2-years.
Analysis 7.5. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 5 Locoregional progression-free survival
2-years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 7.6. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 6 Toxicity. . . . . . . . . .
Analysis 8.1. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 1 Overall survival 2-years. . .
Analysis 8.2. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 2 Progression-free survival 2-years.
Analysis 8.3. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 3 Locoregional progression-free
survival 2-years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 9.1. Comparison 9 Sensitivity ITT: Concurrent vs Sequential, Outcome 1 Overall survival 2-years. . . .
Analysis 9.2. Comparison 9 Sensitivity ITT: Concurrent vs Sequential, Outcome 2 Progression-free survival 2-years.
Analysis 10.1. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 1 Overall survival. .
Analysis 10.2. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 2 Overall survival 2-years.
Analysis 10.3. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 3 Toxicity. . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Concurrent chemoradiotherapy in non-small cell lung cancer


Noelle ORourke1 , Marta Roqu i Figuls2 , Nuria Farr Bernad3 , Fergus Macbeth4
1 Beatson

Oncology Centre, Glasgow, UK. 2 Iberoamerican Cochrane Centre. CIBER Epidemiologa y Salud Pblica (CIBERESP)
Spain, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 3 Radiation Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona,
Spain. 4 Centre for Clinical Practice, National Institute for Health and Clinical Excellence, London, UK
Contact address: Noelle ORourke, Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, G12 0YN, UK.
noelle.orourke@talktalk.net. Noelle.ORourke@ggc.scot.nhs.uk.
Editorial group: Cochrane Lung Cancer Group.
Publication status and date: Edited (conclusions changed), published in Issue 6, 2010.
Review content assessed as up-to-date: 1 January 2010.
Citation: ORourke N, Roqu i Figuls M, Farr Bernad N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer.
Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD002140. DOI: 10.1002/14651858.CD002140.pub3.
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
This is an updated version of the original review published in Issue 4, 2004. The use of concurrent chemotherapy and radiotherapy in
non-small cell lung cancer (NSCLC) might be seen as a way of increasing the effectiveness of radical radiotherapy at the same time as
reducing the risks of metastatic disease.
Objectives
To determine the effectiveness of concurrent chemoradiotherapy as compared to radiotherapy alone with regard to overall survival,
tumour control and treatment-related morbidity. To determine the effectiveness of concurrent versus sequential chemoradiotherapy.
Search methods
For this update we ran a new search in October 2009, using a search strategy adapted from the design in the original review. We
searched: CENTRAL (accessed through The Cochrane Library, 2009, Issue 4), MEDLINE (accessed through PubMed), and EMBASE
(accessed through Ovid).
Selection criteria
Randomised trials of patients with stage I-III NSCLC undergoing radical radiotherapy and randomised to receive concurrent chemoradiotherapy versus radiotherapy alone, or concurrent versus sequential chemoradiotherapy.
Data collection and analysis
Study selection, data extraction and assessment of risk of bias was performed independently by two authors. Pooled hazard ratios and
relative risks were calculated according to a random-effects model.
Main results
Nineteen randomised studies (2728 participants) of concurrent chemoradiotherapy versus radiotherapy alone were included. Chemoradiotherapy significantly reduced overall risk of death (HR 0.71, 95% CI 0.64 to 0.80; I2 0%; 1607 participants) and overall progressionfree survival at any site (HR 0.69, 95% CI 0.58 to 0.81; I2 45%; 1145 participants). Incidence of acute oesophagitis, neutropenia and
anaemia were significantly increased with concurrent chemoradiation.
Concurrent chemoradiotherapy in non-small cell lung cancer (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Six trials (1024 patients) of concurrent versus sequential chemoradiation were included. A significant benefit of concurrent treatment
was shown in overall survival (HR 0.74, 95% CI 0.62 to 0.89; I2 0%; 702 participants). This represented a 10% absolute survival
benefit at 2 years. More treatment-related deaths (4% vs 2%) were reported in the concurrent arm without statistical significance (RR
2.02, 95% CI 0.90 to 4.52; I2 0%; 950 participants). There was increased severe oesophagitis with concurrent treatment (RR 4.96,
95%CI 2.17 to 11.37; I2 66%; 947 participants).
Authors conclusions
This update of the review published in 2004 incorporates additional trials and more mature data. It demonstrates the benefit of
concurrent chemoradiation over radiotherapy alone or sequential chemoradiotherapy. Patient selection is an important consideration
in view of the added toxicity of concurrent treatment. Uncertainty remains as to how far this is purely due to a radiosensitising effect
and whether similar benefits could be achieved by using modern radiotherapy techniques and more dose intensive accelerated and/ or
hyperfractionated radiotherapy regimens.

PLAIN LANGUAGE SUMMARY


Concurrent chemoradiotherapy reduces risk of death at two years compared to sequential chemoradiotherapy or radiotherapy
alone in patients with stage III non small cell lung cancer
The use of chemotherapy concurrent with radiotherapy in locally advanced non-small cell lung cancer may enhance the benefits of
radiotherapy in terms of local and regional control and thus improve survival. A total of twenty-five randomised studies (including
3752 patients) were included in this updated review: nineteen trials (2728 patients) comparing concurrent chemoradiotherapy with
radiotherapy alone and six trials (1024 patients) comparing concurrent with sequential chemoradiotherapy. Both comparisons demonstrated significant reduction in risk of death with use of concurrent chemoradiation, with an associated increase in incidence of acute
oesophagitis.

BACKGROUND
This review is an update of a previously published review in The
Cochrane Database of Systematic Reviews Issue 4, 2004 (Rowell
2004).
For patients of good performance status with locally advanced
NSCLC (i.e. stage IIIA and selected cases with stage IIIB) whose
disease can be encompassed within an appropriate treatment volume, radical (as opposed to palliative) radiotherapy is regarded as
the treatment of choice. Higher doses of conventionally fractionated radiotherapy (60 Gy in 30 daily fractions compared to 40 Gy
to 50 Gy in 20 to 25 fractions) have been found to be more effective
in terms of local control but not survival (Perez 1987). The use of
twice daily fractionation to a total dose of 69.6 Gy, in 58 fractions,
resulted in improved local control and survival compared to 60 Gy
conventionally fractionated (Cox 1990). Furthermore, a trial of
continuous hyperfractionated accelerated radiotherapy (CHART:
54 Gy in 36 fractions, over 12 days) in stages I-III NSCLC showed
an improvement in two-year survival from 20% to 29% when
compared to 60 Gy conventionally fractionated (Saunders 1999).
These studies provide compelling evidence of improved survival
and local control with more intensive regimens of radiotherapy.

In a meta-analysis of adjuvant chemotherapy in NSCLC (


NSCLCCG 1995; NSCLCCG 2000), there was a 13% reduction
in the risk of death with an absolute benefit in two-year survival
of 4% (95% CI 1% to 7%) in patients receiving radical radiotherapy; that review specifically excluded trials in which chemotherapy and radiotherapy were given concurrently (NSCLCCG
1995; NSCLCCG 2000). On this evidence sequential chemotherapy and radiotherapy was generally seen as the standard of care
for locally advanced NSCLC at the time this review was originally
published in 2004. The optimal timing of chemotherapy relative
to radiation was not established and although many of the trials
in the original meta-analysis examined the addition of chemotherapy after radiation (described variously as consolidation or
adjuvant), the most common practice in 2004 and indeed the
updated trials have used sequential chemotherapy meaning induction chemotherapy followed by radiation.
The rationale for combining chemotherapy and radiotherapy is
to combine the benefits of radiotherapy in terms of local regional
control with the benefits of chemotherapy in terms of reducing
the risks of metastatic disease. With concurrent chemoradiation

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

there is the potential for chemotherapy, given during a course of


radiotherapy, to enhance the effectiveness of radiotherapy (i.e. radiosensitisation).. This is now a standard approach in other tumour types (e.g. head and neck, cervical, anal and oesophageal
cancer). A number of randomised trials have compared concurrent chemoradiotherapy to radiotherapy alone in NSCLC but the
majority have failed to show a significant benefit. In recent years
there have in addition been trials of concurrent chemoradiotherapy versus sequential treatment but individual trials have been underpowered or closed early or not reported in full.
The purpose of this review was to determine whether the effectiveness of radical radiotherapy may be improved by the use of
concurrent chemoradiotherapy and whether any benefit is at the
expense of increased treatment-related morbidity. At the outset it
was anticipated that few, if any, trials would include data on quality of life.

Radical radiotherapy was defined as a minimum dose of 50 Gy in


25 daily fractions, or its radiobiological equivalent (Jones 2001),
and had to be the same in both arms of the study.
Concurrent chemotherapy was defined as chemotherapy given on
radiotherapy treatment days (whether before or after each fraction
of radiotherapy). Sequential chemoradiotherapy involved chemotherapy given before or after a course of radiotherapy but not during. Chemotherapy agents and doses had to be equivalent in both
arms of the study.
Trials were eligible for inclusion if additional chemotherapy had
been given prior to radiotherapy, following radiotherapy, or both,
provided this was the same in both treatment arms.
Types of outcome measures

Primary outcomes

Overall survival (OS).

OBJECTIVES
To determine the effectiveness in patients with NSCLC of
concurrent chemoradiotherapy as compared to radiotherapy
alone, in terms of overall survival and progression-free survival,
treatment-related mortality and morbidity.
To determine the effectiveness in patients with NSCLC of
concurrent chemoradiotherapy as compared to sequential
chemoradiotherapy, in terms of overall survival and progressionfree survival, treatment-related mortality and morbidity.

METHODS

Secondary outcomes

Progression-free survival (progression at any site whether locoregional or distant; PFS).


Locoregional progression-free survival (local PFS).
Overall survival at two years.
Progression-free survival (progression at any site whether locoregional or distant) at two years.
Locoregional progression-free survival at two years.
Treatment morbidity - acute
The incidence in each treatment arm of:
(1) lung damage, acute (pneumonitis), grade 3 or worse;
(2) oesophagitis, grade 3 or worse ;
(3) neutropenia, grade 3 or worse;
(4) anaemia, any grade.

Criteria for considering studies for this review

Types of studies
Randomised controlled trials.

Treatment morbidity - late


The incidence in each treatment arm of:
(1) lung damage, late (fibrosis), grade 3 or worse;
(2) oesophageal damage, grade 3 or worse;
(3) radiation myelopathy;
(4) quality of life.

Types of participants
Patients of any age and any performance status with pathologically
confirmed NSCLC but without distant metastases (i.e. stage IIII).

Types of interventions
Patients undergoing radical radiotherapy either randomised to receive concurrent chemoradiotherapy or radical radiotherapy alone,
or randomised to concurrent or sequential chemoradiotherapy.

Search methods for identification of studies


We ran a search in October 2009 to update the original completed review. In this update we adapted the original searches to
search the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 4),
MEDLINE (accessed through PubMed), and EMBASE (accessed
through Ovid). We include in the Appendix 1 the search strategies
used and the results obtained. We also report in the Appendix 2

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the text published for this section in the original review, and the
search strategies designed.
We additionally checked the reference lists from relevant studies
to identify further eligible studies. On-going trials were searched
for on the metaRegister of Controlled Trials (Current Controlled
Trials) . Only one trial was identified which fulfilled the criteria for
this review - the NCRI SOCCAR study (NCRI SOCCAR)- which
was converted from a randomised phase III to a phase II study
after slow recruitment and is now closed with results pending.

Data collection and analysis

unclear.
(2) Allocation concealment (checking for possible selection
bias)
We described for each included study the method used to conceal
the allocation sequence in sufficient detail and determine whether
intervention allocation could have been foreseen in advance of, or
during recruitment, or changed after assignment. We assessed the
methods as:
adequate (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes);
inadequate (open random allocation; unsealed or nonopaque envelopes, alternation; date of birth);
unclear.

Selection of studies
References identified by the search strategy were screened independently by two authors (NOR, MR) to assess eligibility for inclusion in the review and a list of trials eligible for inclusion was
agreed. In case of discrepancy, consensus was reached by discussion and the input of a third reviewer was sought if necessary.
Data extraction and management
For each of the included trials, details of treatment given and
outcomes were recorded independently by two authors (NOR,
NF or MR) and any disparity resolved by discussion.

(3) Incomplete outcome data (checking for possible attrition


bias through withdrawals, dropouts, protocol deviations)
We described for each included study and for each outcome or
class of outcomes the completeness of data including attrition and
exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at
each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.
We assessed whether each study was free of attrition bias:
yes;
no;
unclear.

Assessment of risk of bias in included studies


Two review authors (NOR or NF, and MR) independently assessed risk of bias for each study using the criteria outlined in
the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2009). Any disagreement was resolved by discussion or
involving a third assessor. From the risk of bias domains listed on
the handbook, the authors assessed three (sequence generation,
allocation concealment and incomplete outcome data). A fourth
domain wasnt assessed (blinding of participants, personnel and
outcome assessors) due to the practical difficulties or impossibility
to blind participants and health providers given the differences in
schedule of the interventions. Although outcome assessors could
have been blinded in the studies, it was not deemed necessary
given the objectivity of outcomes and the generalized use of standardized outcome assessment methods.
(1) Sequence generation (checking for possible selection bias)
We described for each included study the methods used to generate
the allocation sequence in sufficient detail to allow an assessment
of whether it should produce comparable groups. We assessed the
methods as:
adequate (any truly random process e.g. random number
table; computer random number generator),
inadequate (any non random process e.g. odd or even date
of birth; hospital or clinic record number) or

Measures of treatment effect


The effect of treatment was estimated by hazard ratios (HR) and
risks ratios (RR), with their corresponding confidence intervals
(CI). HR were computed for time-to-event variables (overall survival, progression-free survival at any site, locoregional progression-free survival). When the papers did not report HR, they were
computed following the formulae of Parmar (Parmar 1998) implemented in a freely-available spreadsheet (Tierney 2007).
Risk ratios were computed for dichotomous variables (time-toevent variables assessed at 2 years and treatment morbidity) in
preference to odds ratio as being less open to misinterpretation.
Percentages of OS, PFS and local PFS at 2 years were estimated
from Kaplan Meier graphics when they were not presented in the
text. Two trials (Bonner 1998; Trovo 1992) had minimum followup <24 months and thus the estimations from survival curves are
slightly unreliable. Absolute survival differences at 2 years were
computed as risk differences for overall survival at 2 years. These
estimations of absolute survival benefit approximate estimations
obtained with methods based on hazard ratios, with the advantage
to fully use the data provided by the included trials, since 2 years
survival data was available for all or them but not hazard ratios.

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Assessment of heterogeneity
Global estimates for each variable effect were computed by conducting a meta-analysis of single effect measures of the study (HR
for time-to-event variables and RR for dichotomous variables) applying a random-effects model (DerSimonian 1986). Prior to calculating estimates of effect, the presence and degree of heterogeneity was assessed by means of I2 .
Data synthesis
The reviews main analysis was an available data analysis, where
data for each included trial was analyzed as provided by the study
authors, either per protocol or by intention-to-treat.
Subgroup analysis and investigation of heterogeneity
Two planned subgroup analyses were performed:
- According to chemotherapy with platinum-based regimens
- According to frequency of chemotherapy administration
Other non-planned subgroup analysis were also performed:
- According to total dose of cisplatin or carboplatin. In the analysis
by platinum dose, trials were arbitrarily divided into those in which
the planned total dose of cisplatin was above or below 150 mg/m
2
; or the total dose of carboplatin was 700 mg/m2 and greater, or
less than 700 mg/m2 . Carboplatin was prescribed on mg/m2 basis
except in two trials where it had been prescribed as a total dose
(Jeremic 1995; Jeremic 1996); for the purposes of this analysis
total dose was converted to mg/m2 by assuming a typical body
surface area of 1.7m2 .
- Comparing once or twice daily radiotherapy fractionation
- According to radiotherapy dose. In the analysis by radiotherapy
dose, trials were divided into those who received a low dose (5060 Gy total dose) or a high dose (more than 60 Gy).
- According to duration of follow-up.
There were two three-arm trials (Jeremic 1995; Schaake-Koning
1992) which contained a single control arm and two treatment
arms with different frequency of chemotherapy. For most analyses, the data from the two treatment arms were combined and
treated as a single treatment group. In the subgroup analysis of frequency of chemotherapy administration (which differed between
the treatment arms), the control arm was included with the relevant treatment arm in each subgroup but data from the subgroups
were not combined to give an overall relative risk.
Statistical comparison of subgroups was performed with the
method implemented in RevMan for fixed-effect analyses based
on the inverse-variance method. The procedure is based on the
test for heterogeneity chi-squared statistics (see section 9.6.3.1 in
Higgins 2009).
Sensitivity analysis
Several sensitivity analyses were performed to assess how robust
the estimate of the global effect was regarding the:

missing data (performing an intention-to-treat analysis with


all randomised patients under a worst case scenario, where data
was imputed for all withdrawn participants assuming they did
not respond or presented an adverse outcome. When it was not
known the distribution of withdrawn participants among
treatment arms, they were divided equally among arms;
trials not fully assessed (excluding from the analysis trials
published only as abstracts);
statistical model (performing a meta-analysis with a fixedeffect model).
Dichotomous variables related to adverse effects were not considered in the ITT imputation sensitivity analysis, since the authors
considered it wrong to attribute unintended (adverse) effects to a
treatment that somebody did not receive (Higgins 2009b). Whenever number of lost patients was known but it was not known its
distribution by treatment arm, the losses were attributed to the
chemoradiotherapy arm in the comparison against radiotherapy
alone, and equally distributed in the comparison of concurrent
vs sequential. The only trial where no information about losses
was available was excluded from this sensitivity analysis (Curran
2003).

RESULTS

Description of studies
See: Characteristics of included studies; Characteristics of
excluded studies; Characteristics of studies awaiting classification;
Characteristics of ongoing studies.
In the first publication of the review, twenty-nine apparently randomised trials of concurrent chemoradiotherapy versus radiotherapy alone were identified. Twelve trials were excluded (Ball 1997;
Chan 1976; Furuse 1999; Guschall 2000; Isakovic-Vidovic2002;
Japan ACNU 1989; Johnson 1990; Koca 1996; Komaki 2002;
LePar 1967; Sarihan 2002; Ulutin 2000) and seventeen trials were
included (Ball 1999; Blanke 1995; Bonner 1998; Cakir 2004;
Clamon 1999; Curran 2003; Fournel 2001; Groen 1999; Huber
2003; Jeremic 1995; Jeremic 1996; Landgren 1974; Manegold
2003; Schaake-Koning 1992; Soresi 1988; Trovo 1992; Zatloukal
2003), of which three were then published only in abstract form.
In this update, a four-arm included trial (Ball 1999) was considered as two separate trials of once daily and twice daily radiotherapy each with and without chemotherapy (Ball 1999 once daily;
Ball 1999 twice daily), inflating the number of trials by one in the
text and analyses.
The update of the bibliographic search identified 501 unique references. Of those, nine new trials were included (Atagi 2005; Gouda
2006; Li 2008; Lu 2005; Rao 2007; Reinfuss 2005; Wu 2006;
Yadav 2005; Zhang 2006), five trials previously included had a

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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more complete publication (Fournel 2001; Groen 1999; Huber


2003; Manegold 2003; Zatloukal 2003) and three trials were excluded (Belderbos 2007; DasGupta 2006; Misirlioglu 2006). One
of the included trials was later labelled as awaiting assessment and
excluded from the review because it was not possible to retrieve a
paper copy of it (Zhang 2006).
A total of 25 studies (3752 participants) were included in this updated review (Table 1): 19 trials (2728 participants, Table 2) comparing concurrent chemoradiotherapy versus radiotherapy alone
and six trials (1024 participants, Table 3) comparing concurrent
versus sequential chemoradiotherapy. Duration of follow-up is
shown in Table 1.
Of the 19 randomised studies of concurrent chemoradiotherapy
versus radiotherapy alone, sixteen used platinum-based chemotherapy, in combination with etoposide in three; three used concurrent docetaxel or paclitaxel; one used hydroxyurea and one hydroxycomptothecin. Chemotherapy was administered on each radiotherapy treatment day in seven studies (by continuous infusion
in one of these); once-weekly in six; and two- to four-weekly in
eight (a total of 21 different intervention groups). The radiotherapy dose was most commonly 60 Gy given in 30 fractions over six
weeks (seven studies). There were four studies using accelerated or
hyperfractionated regimes and four employing a split course.
Two three-arm trials had their two intervention arms combined
for most analyses (Jeremic 1995; Schaake-Koning 1992). In timeto-event analyses, Jeremic 1995 appears twice because it presented
separated HR for each of its two-intervention arms compared to

its control arm. As a consequence, in these time-to-event analyses


the number of trials is artificially inflated by one. A sensitivity
analysis excluding one or the other HR for this trial didnt cause
relevant changes in metanalysis results.

Risk of bias in included studies


Overall, risk of bias in the 19 trials of concurrent chemoradiotherapy vs radiotherapy alone was moderate. Selection bias was not
adequately addressed since most trials were unclear on whether the
sequence generation was adequate or not, and whether there was
allocation concealment or not. On the other hand, attrition bias
was mostly adequately addressed, with all but two trials providing
data on the losses and exclusions or participants as well as the reasons for exclusion. The level of missing data is low with regard to
the total number of randomised participants, limiting the extent
to which attrition bias limits our confidence in the results.
Overall, risk of bias in the six trials of concurrent vs sequential
choradiotherapy was moderate. Selection bias was not adequately
addressed (allocation concealment unclear or inadequate for all
but one trials). Attrition bias was moderate since incomplete data
was addressed adequately in half of the trials and the overall level
of missing data was low with regard to the number of randomised
patients. Nevertheless, one of the included trials was only published as an abstract and this limits the confidence on their results.
See individual and summarized results of risk of bias assessment
in Figure 1 and Figure 2.

Figure 1. Methodological quality graph: review authors judgements about each methodological quality
item presented as percentages across all included studies.

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Figure 2. Methodological quality summary: review authors judgements about each methodological quality
item for each included study.

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Allocation
Sequence generation
Of the 19 trials of concurrent chemoradiotherapy vs radiotherapy
alone, the sequence generation was adequately generated in 8 trials
(Atagi 2005; Ball 1999 once daily; Ball 1999 twice daily; Blanke
1995; Bonner 1998; Groen 1999; Huber 2003; Yadav 2005), and
unclear in 11 trials.
Of the 5 fully published trials of concurrent vs sequential chemoradiotherapy, the sequence generation was adequately generated in
3 trials (Rao 2007; Reinfuss 2005; Wu 2006) and unclear in 2.
Allocation concealment
Of the 19 trials of concurrent chemoradiotherapy vs radiotherapy
alone, allocation was adequately concealed in 5 trials (Ball 1999
once daily; Ball 1999 twice daily; Bonner 1998; Groen 1999;
Huber 2003; Schaake-Koning 1992), inadequately concealed in 1
trial and unclear in 13 trials.
Of the 5 fully published trials of concurrent vs sequential
chemoradiotherapy, allocation was adequately concealed in 1 trial
(Zatloukal 2003), inadequate in 3 trials and unclear in 1.

Incomplete outcome data


Of the 19 trials of chemoradiotherapy versus radiotherapy alone,
risk of bias from incomplete outcome data was low on seventeen
trials and unclear in 2 (Li 2008; Lu 2005).
Of the 5 fully published trials of concurrent vs sequential chemoradiotherapy, risk of bias from incomplete outcome data was low on
3 trials (Fournel 2001; Reinfuss 2005; Zatloukal 2003), high in
one trial, unclear in 2.
Eight trials of chemoradiotherapy versus radiotherapy alone (Cakir
2004; Gouda 2006; Groen 1999; Landgren 1974; Manegold
2003; Schaake-Koning 1992;Yadav 2005), and two trials of
concurrent vs sequential chemoradiotherapy (Reinfuss 2005;
Zatloukal 2003) analyzed all randomized patients, either because
they had no losses or because they did an intention-to-treat analysis. Three trials stated an intention-to-treat analysis of the eligible
patients, but not of the randomised patients (Ball 1999 once daily;
Ball 1999 twice daily; Blanke 1995). On the 24 fully published
trials, 125 patients (3.3%) were excluded from analysis due to ineligibility, loss to follow-up and other reasons.

Other potential sources of bias


Other potential biases identified were the early stop of recruitment
in two trials (Groen 1999; Zatloukal 2003), and the lack of full
publication in one trial published as abstract (Curran 2003), which
stated neither details of the randomisation procedure nor data
analysis.

Effects of interventions
NOTE: In all time-to-event analyses, Jeremic 1995 appears twice,
corresponding the two comparisons defined by its three arms.
Across the whole review, Ball 1999 is considered as two separate
RCT, thus inflating the number of trials by one.
Concurrent chemoradiotherapy versus radiotherapy
alone
Overall survival (comparisons 1.1 and 1.2)
Meta-analysis of nine trials (based on 1607 evaluable participants)
showed that the addition of concurrent chemotherapy to radical
radiotherapy reduced the overall risk of death with no evidence
of heterogeneity (HR 0.71; 95% CI 0.64 to 0.80, I2 0%). The
analysis of risk of death at two years also showed a significant
benefit of chemoradiotherapy with moderate heterogeneity (RR
0.91; 95% CI 0.86 to 0.97, 20 trials, 2587 evaluable participants;
I2 38%). Absolute survival benefit at 2 years is 8% (RD -0.08;
95% CI -0.12 to -0.03; I2 39%).
Subgroup analyses of 2-year survival rates
- According to chemotherapy with platinum-based regimens
(comparison 3.1):
Sixteen trials administering platinum-based regimens (2173 participants) showed a benefit of concurrent chemoradiotherapy in
two-year survival with moderate heterogeneity (RR 0.92; 95% CI
0.86 to 0.98; I2 41%). Two trials administering taxane-containing regimens (301 participants) showed a benefit of concurrent
chemoradiotherapy in two-year survival (RR 0.82; 95% CI 0.71
to 0.94; I2 0%). Two trials (113 participants) administering other
regimens failed to show differences in two-year survival (RR 0.88;
95% CI 0.56 to 1.36; I2 70%). A test for differences between
subgroups was not significant (P = 0.25).
- According to frequency of chemotherapy administration (comparison 3.2):
Analysis by chemotherapy frequency showed that the benefit of
addition of two- to four-weekly chemotherapy was similar to that
achieved by weekly chemotherapy. The results in the group of 7
trials of daily chemotherapy (840 participants) were not significant
and contained relevant statistical heterogeneity (RR 0.94; 95%
CI 0.84 to 1.05; I2 55%). Seven trials with weekly chemotherapy
(1013 participants) showed a benefit of chemoradiotherapy in
two-year survival, with homogeneous results (RR 0.90; 95% CI
0.84 to 0.96; I2 0%). Eight trials with 2- to 4-weekly chemotherapy
(909 participants) showed a benefit of chemoradiotherapy in twoyear survival, with moderate heterogeneity (RR 0.90; 95% CI 0.81
to 0.99; I2 41%). A test for differences between subgroups was
not significant (P = 0.36).
To explore further the relationship between frequency of chemotherapy and outcome, a meta-analysis was undertaken using data

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from the two treatment arms in each of the two three-arm trials
(325 patients) that directly compared frequency of administration
to the same total dose (Jeremic 1995; Schaake-Koning 1992). No
differences were observed in survival at 2 years (RR 0.91; 95% CI
0.80 to 1.03; I2 0%).
- According to total dose of cisplatin or carboplatin (comparison
3.3):
Analysis by total platinum dose resulted in increased heterogeneity
and loss of power in the two subgroups of trials (high dose and
low dose). No differences were apparent in the results obtained by
the two subgroups. Nine trials with 1145 participants in the high
dose subgroup reached results on the verge of significance (RR
0.91; 95% CI 0.84 to 1.00; I2 40%), while seven trials with 1028
participants in the low dose subgroup failed to show significant
differences (RR 0.93; 95% CI 0.84 to 1.03; 48%). A test for
differences between subgroups was not significant (P = 0.45).
- Comparing once or twice daily radiotherapy fractionation (comparison 3.4):
In the subgroup analysis by radiotherapy fractionation, the benefit
of chemoradiotherapy persisted in the subgroup with once daily
fractionation (RR 0.91; 95% CI 0.85 to 0.97; I2 41%; 15 trials,
2065 participants) but not in the twice daily (RR 0.92; 95% CI
0.79 to 1.08; I2 40%; 5 trials, 522 participants). A test for differences between subgroups was not significant (P = 0.81).
- According to radiotherapy dose (comparison 3.5):
A subgroup analysis was performed to investigate the possibility
that effectiveness of concurrent chemotherapy was related to radiotherapy dose (up to or more than 60 Gy). Thirteen trials used
low doses of radiotherapy from 50 Gy to 60 Gy on 1691 participants (RR 0.93; 95% CI 0.86 to 1.01; I2 44%), while seven trials
used high doses of radiotherapy from 60 Gy to 69.6 Gy on 896
participants (RR 0.88; 95% CI 0.81 to 0.95; I2 21%). Although a
moderate level of heterogeneity can be observed among subgroups
(I2 46.7), a test for differences between subgroups was not significant (P = 0.17).
- According to duration of follow-up (comparison 3.6):
A sensitivity analysis was performed by dividing trials into three
subgroups: where the minimum follow-up duration was 22
months or more, less than 22 months, or where the duration of
follow-up was uncertain (Table 1). The hypothesis was that data
from trials with longer follow-up might be considered more reliable. The treatment effect estimates were similar for the subgroups
with long (RR 0.90; 95% CI 0.83 to 0.97; I2 39%; 7 trials, 1191
participants) or uncertain follow-up (RR 0.89; 95% CI 0.79 to
0.99; I2 40%; 9 trials, 1037 participants), but that of the subgroup
with short follow-up was higher (RR 0.99; 95% CI 0.85 to 1.15;
I2 24%;4 trials, 359 participants), suggesting that any bias due to
short follow-up was, if anything, reducing rather than increasing
the magnitude of the treatment effect. A test for differences between subgroups was not significant (P = 0.14).
Progression-free survival (comparisons 1.3, 1.4, 1.5 and 1.6)
A minority of trials reported progression-free survival for recur-

rence at any site (9 trials, 1405 participants), or locoregional


progression-free survival (5 trials, 872 participants). Concurrent
chemoradiotherapy resulted in significant improvements in overall
progression-free survival at any site (i.e. distant or locoregional),
(HR 0.69; 95% CI 0.58 to 0.81; I2 45%) as well as in overall
locoregional progression-free survival (HR 0.67; 95% CI 0.54 to
0.82; I2 60%). Results at two years corroborate these results both
for PFS (RR 0.91; 95% CI 0.86 to 0.97; I2 43%) and locorregional PFS (RR 0.84; 95% CI 0.72 to 0.98; I2 59%).
Treatment-related mortality and morbidity (comparison 1.7)
All trials reported treatment-related deaths and some aspect of
acute treatment-related morbidity. There were 6 treatment-related
deaths in the radiotherapy alone group (966 participants) and 11
in the chemoradiotherapy group (1109 participants) (RR 1.38;
95% CI 0.51 to 3.72; I2 0%; 14 trials, 2075 participants). The
incidence of acute pneumonitis (grade 3 or worse) ranged from
0% to12% in those receiving radiotherapy alone to 1% to 16% in
those receiving concurrent treatment (RR 1.06; 95% CI 0.58 to
1.93; I2 0%; 9 trials, 1179 participants). The incidence of grade
3 or worse acute oesophagitis ranged from 0% to 33% in those
receiving radiotherapy alone to 0% to 48% in those receiving concurrent treatment (RR 1.76; 95% CI 1.34 to 2.31; I2 0%; 17 trials, 2227 participants). Fewer trials reported pulmonary fibrosis (4
trials, 596 participants; RR 1.27; 95% CI 0.34 to 4.64; I2 50%) or
late oesophageal damage (2 trials, 300 participants; RR 1.72; 95%
CI 0.32 to 9.33; I2 23%); neither appeared statistically significantly increased and confidence intervals were wide. A single case
of radiation myelopathy was reported in a patient receiving radiotherapy alone (Landgren 1974). Neutropenia (grade 3 or worse)
was reported in 7 trials (837 participants), 3 of which used induction chemotherapy. Neutropenia was significantly more common
with combined treatment (RR 3.53; 95% CI 1.84 to 6.77; I2 0%)
but this result owed much to the greater incidence of neutropenia in two trials (Atagi 2005; Clamon 1999). Similarly, anaemia
(grade 3 or worse) was much more frequently reported in one trial
(Clamon 1999). Although considering all trials in this subgroup
(5 trials, 822 patients) severe anaemia was more frequent with concurrent chemotherapy (RR 4.17; 95% CI 1.13 to 15.35; I2 15%),
significance disappears when the effect measure is risk differences
and the analysis then takes into account the study by Ball with zero
events. In contrast, anaemia of any grade appeared more frequent
with concurrent chemoradiotherapy (RR 1.99; 95% CI 1.49 to
2.64; I2 0%; 9 trials, 887 patients).

Concurrent versus sequential chemoradiotherapy


Overall survival (comparison 2.1 and 2.2)
Meta-analysis is based on a total of 5 trials of concurrent versus
sequential treatment in 937 participants. Results indicated a significant benefit of concurrent over sequential treatment with respect to overall survival (HR 0.74; 95% CI 0.62 to 0.89; I2 0%; 3
trials, 702 participants) as well as survival at two years (RR 0.87;

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95% CI 0.78 to 0.97; I2 37%; 5 trials, 937 participants). Absolute


survival benefit at 2 years is 10% (RD -0.10; 95% CI -0.18 to 0.02; I2 41%). All the trials analyzed used cisplatin-based regimes
and once daily radiotherapy (Table 3).
Subgroup analyses of 2-year survival
The low number of trials included in this comparison precluded
deriving strong conclusions from the differences observed between
groups. Results in each subgroup lose power and differences in
significance cannot be reliably interpreted . Estimation of effect
was similar among all subgroups.
- According to radiotherapy dose (comparison 4.1):
The results in the single trial using low dose radiotherapy (RR
0.76; 95% CI 0.61 to 0.95; 102 participants) were similar to those
of the 4 trials (835 participants) using high dose radiotherapy (RR
0.89; 95% CI 0.79 to 1.01; I2 32%). A test for differences between
subgroups was not significant (P = 0.17).
- According to duration of follow-up (comparison 4.2):
Results in the 2 trials (607 participants) that had minimum followup of 22 or more months (RR 0.88; 95% CI 0.79 to 0.99; I2 0%)
were similar to those of the 3 trials (330 participants) that had a
minimum follow-up of 22 or less months (RR 0.84; 95% CI 0.66
to 1.06; I2 64%). A test for differences between subgroups was
not significant (P = 0.99).
Progression-free survival (comparison 2.3, 2.4 and 2.5)
Only two trials (378 participants) reported progression-free survival, which was not significantly different between the two groups.
Neither overall PFS (HR 0.67; 95% CI 0.30 to 1.50; I2 0%; 1
trial, 201 participants) nor results at 2 years were significant (RR
0.92; 95% CI 0.78 to 1.09; I2 69%; 2 trials, 378 participants).
Only one trial (402 participants) has thus far reported locoregional
progression-free survival at two years, which was not significantly
different between the two groups (RR 0.84; 95% CI 0.64 to 1.10).
Treatment-related mortality and morbidity (comparison 2.6)
More deaths (4% vs 2%) were reported in the concurrent arm
but this did not reach statistical significance (RR 2.02; 95% CI
0.90 to 4.52; I2 0%; 5 trials, 950 participants). There were no
significant differences in acute pneumonitis (grade 3 or worse) with
concurrent treatment compared to sequential treatment (RR 0.99;
95% CI 0.51 to 1.91; I2 41%; 5 trials, 947 participants). There
were more acute oesophagitis (grade 3 or worse) with concurrent
treatment (range 8% to 47%) compared to sequential treatment
(range 0% to 25%; RR 4.96; 95% CI 2.17 to 11.37; I2 66%; 5
trials, 947 participants). The incidence of neutropenia (grade 3 or
worse) was similar, overall, in both arms but there was significant
heterogeneity between trials (RR 1.18; 95% CI 0.90 to 1.55; I2
77%; 5 trials, 947 participants). The incidence of anaemia (grade
3 or worse) was reported in 2 trials (292 participants) without
differences among treatment arms (RR 0.95; 95% CI 0.41 to 2.21;
I2 42%). No data was presented on late morbidity in any study.
Sensitivity analyses
- Fixed-effect meta-analysis
Results changed minimally when a fixed-effect analysis was per-

formed, and no change in significance was observed in any outcome.


- ITT analysis of dichotomous efficacy variables
Data was imputed for the 125 ineligible patients excluded from
the main analysis, assuming all of them presented the outcome of
interest (death or local/distant progression).
Results changed minimally when an ITT analysis with data imputed was performed, and no change in significance related to the
random effect models was observed in any outcome .
- Restriction to trials fully published
This analysis was limited to the concurrent vs sequential comparison, where there was the only study published as abstract (Curran
2003). Results changed minimally when the study published as
abstract was excluded, and no change in significance was observed
in any outcome.

DISCUSSION

Summary of main results


In 2004 as a result of the meta-analysis of chemotherapy in
NSCLC (NSCLCCG 1995), the combination of (sequential) chemotherapy and radical radiotherapy had become the standard of
care for patients of good performance status with stage III NSCLC
whose disease could be encompassed within a radical radiotherapy
volume. The original version of this review concluded that with
concurrent chemoradiotherapy there was a 14% reduction in risk
of death at two years compared to sequential chemoradiotherapy
but only a 7% reduction compared to radiotherapy alone. With
only short follow-up, particularly in the concurrent versus sequential comparison, the review concluded that sequential treatment
should remain the standard of care while mature data and further
trials were awaited. This update of the review has identified additional trials but benefits also from full publication of the previous concurrent versus sequential comparisons and this has consolidated the evidence for concurrent chemoradiation. Of the 25
trials in both comparisons, only four included patients with stage
I/II disease, accounting for only a very small number of patients,
so conclusions should be regarded as relating only to patients with
stage III disease.
The differences in risk of death at two years are similar to the original review: an 8% reduction in risk for concurrent chemoradiation
compared to radiotherapy alone and a 13% reduction in risk with
the use of concurrent rather than sequential chemoradiation . This
update also describes overall survival benefit in terms of hazard
ratios for concurrent treatment compared to radiotherapy alone
(HR 0.71, 95%CI 0.64 to 0.80) and for concurrent compared to
sequential chemoradiation (HR 0.74, 95%CI 0.62 to 0.89). In
absolute survival terms the difference at 2 years is 10% benefit

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(RD -0.10; 95% CI -0.18 to -0.02) for concurrent compared to


sequential treatment.
With sequential chemoradiation the added survival benefit from
use of chemotherapy is presumed to be due to reduction in distant
metastases whereas for concurrent chemoradiation there should
additionally be improved local control by sensitising the tumour
to radiation. Only five trials reported locoregional progression-free
survival in the comparison of concurrent treatment against radiation alone. There was a significant benefit from concurrent therapy, which also held for the analysis at two years but there was substantial between-study heterogeneity in this analysis. In contrast
only one trial reported locoregional progression-free survival for
the concurrent versus sequential comparison and this was not different between the two treatment groups. The assumption remains
that the added value of concurrent chemotherapy is achieved by
radiosensitisation leading to improved local control but the data
in this review are inadequate to prove this.

Overall completeness and applicability of


evidence
This review includes over 3700 patients treated within randomised
controlled trials. We have used strict inclusion criteria to limit
comparisons to the effect of adding concurrent chemotherapy to
radical radiotherapy in the treatment of NSCLC and in so doing
have excluded trials with different radiotherapy or different chemotherapy regimens between the two arms. This is not an individual patient data meta-analysis and therefore the comparison of
absolute survival at 2 years is based on the number of deaths at
2 years computed as pooled risk differences. The lack of individual patient data and short follow-up in some trials mean that it
is difficult to comment on effect of treatment beyond two years.
Nonetheless the hazard ratios and confidence intervals on survival
demonstrate a statistically significant survival benefit for the use
of concurrent chemoradiation.
The purpose in undertaking this review was to determine whether
addition of concurrent chemotherapy to radical radiation would
improve survival. The conclusions however are limited by the trial
data available and by the treatments given within those trials. Although we have limited inclusion to radiotherapy regimens delivering more than 50Gy, the trials date back to 1974 and there is no
detail on radiotherapy technique or formal radiotherapy quality
assurance. The delivery of radical radiotherapy has improved substantially in recent years with improved imaging, PET staging and
definition of treatment volumes and continually evolving techniques of conformal, 4D and intensity modulated radiotherapy.
It is not clear by how much these techniques alone may improve
survival and, if so, whether the added benefit of concurrent chemotherapy is less or not. It is interesting that the absolute survival
benefit of 10% at 2 years for concurrent chemoradiation compared
to sequential is of the same magnitude as the benefit at 2 years
for CHART radiotherapy over conventional fractionation. Both

approaches enhance the effectiveness of local regional control, but


at the expense of increased local toxicity.
An increased risk of acute oesophagitis was convincingly demonstrated in this review for both comparisons for the use of concurrent chemoradiation. In one study (Reinfuss 2005) 21% of patients in the concurrent arm had their treatment discontinued due
to severe oesophagitis and in that study there was no difference in
outcome between the concurrent and sequential arms. Across all
trials there was not found to be increased risk of acute pneumonitis with the concurrent schedule but in one study (Atagi 2005)
there were four treatment-related deaths from acute pneumonitis
in the first 46 patients entered, leading to early closure of the trial.
For both neutropenia and anaemia there was increased incidence
with concurrent chemoradiation compared to radiation alone but
no difference in the comparison of concurrent versus sequential
therapy consistent with the expectation that these toxicities arise
from the use of chemotherapy, regardless of scheduling. In both
comparisons there were more treatment-related deaths (approximately twice as many) in the concurrent group but the difference
did not achieve statistical significance.
Subgroup analyses were used to investigate other factors which
might influence the results, but no significant differences were
found. The sensitivity analysis indicated that in the group with
short follow-up (i.e. where there is the greatest potential for bias)
there appeared to be no benefit from the concurrent treatment over
radiotherapy alone. Therefore, any bias resulting from including
trials with short follow-up would tend to have underestimated the
benefits of concurrent chemoradiotherapy rather than the reverse.
The majority of trials in this systematic review used platinumbased chemotherapy although there was considerable clinical heterogeneity in terms of frequency of administration and total dose.
Some trials used cisplatin, others carboplatin. Total doses ranged
from 90 to 210 mg/m2 cisplatin and 350 to 850mg/m2 carboplatin. In comparison with doses of cisplatin used in concurrent
regimes for head and neck cancer (up to 300 mg/m2 over a 7 week
course of radiotherapy), these doses appear relatively modest. The
optimal frequency of chemotherapy administration remains uncertain with the combined analysis of data from the two threearmed trials (Jeremic 1995; Schaake-Koning 1992). The principle underlying concurrent chemotherapy is that local control
can be improved by radiosensitisation and that in reducing micrometastatic disease the risk of systemic relapse is also reduced.
Low dose chemotherapy might be adequate to achieve radiosensitisation without the increase in toxicity seen with full dose combination chemotherapy but there is too little data for comparison
of full dose with radiosensitising doses of chemotherapy.
The other possible approach to enhancing the effectiveness of radiotherapy is to optimise the schedule of radiation in terms of
dose, fractionation and overall treatment time. One trial excluded
from this review was EORTC 08972 (Belderbos 2007) using hypofractionated accelerated radiotherapy with concurrent low dose
cisplatin which produced favourable survival figures but the study

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closed early and was underpowered. The CHART trial of hyperfractionated accelerated radiotherapy gave a 9% increase in 2-year
survival from altered fractionation alone, raising the possiblity of
further enhanced results if this were combined with chemotherapy.

Quality of the evidence


Since the original publication of this review the new format for
Cochrane reviews has incorporated risk of bias tables. This has
enabled a more structured assessment of the methodological quality of the studies included in the review. The trials included in
this update show overall moderate risk of selection and attrition
bias and these biases could cause the interventions tested to appear more beneficial and clinically relevant than they really are.
Nonetheless, the number of trials and participants included and
the consistency of their results with regard to overall survival supports the confidence on the review conclusions.

Agreements and disagreements with other


studies or reviews
Individual patient data meta-analyses can estimate treatment effects with greater precision. Two such analyses were conducted by
Rolland et al (Rolland 2007) and Auperin et al (Auperin 2003,
Auperin 2007, Auperin 2010). Rolland reported on 16 trials comparing concurrent chemoradiation with radiation alone, demonstrating significant improvement with concurrent treatment in
overall survival (HR = 0.88) and in progression-free survival (HR
= 0.81). Auperin undertook comparison of concurrent with sequential treatment, including 6 trials . The conclusion was that
concurrent improved overall survival (HR, 0.84; 95% CI, 0.74 to
0.95; P = 0.004), as well as locoregional progression-free survival
(HR, 0.77; 95% CI, 0.62 to 0.95; P = 0.01) but with no difference
in distant progression between the two arms. There are differences
between the inclusion criteria set for the present review and these
meta-analyses with only two overlapping trials in the concurrent
versus sequential comparison which may account in part for the
difference in results. Median follow-up in the Auperin meta-analysis is longer than in this review which may also contribute to the
lower absolute survival benefit seen..
The largest single trial listed in this review is the Curran report on
RTOG 9410 with 402 patients. Unfortunately this trial has only
ever been published as an abstract in 2003 and this was a limiting
factor in our analysis of these patients. However data from this
trial were included in the Auperin meta-analysis.
It is interesting that in both the IPD meta-analyses and in the
current review the magnitude of survival benefit observed with
concurrent chemoradiation is similar whether compared against
sequential chemoradiation or against radiation alone. There are
several factors which may contribute to the lack of efficacy of the

sequential schedule. Firstly there is a risk of disease progression


during induction chemotherapy such that patients do not complete the scheduled treatment. In the Zatloukal trial only 58% of
patients in the sequential group completed chemotherapy compared to 83% in the concurrent group (Zatloukal 2003). More importantly only 64% of the sequential group received radiotherapy
treatment against 94% of concurrent group. Similarly in the Fournel trial less than 60% of the sequential patients received more than
60 Gy radiotherapy compared to 88% in the concurrent group
(Fournel 2001). In these trials therefore the benefit achieved by
concurrent chemoradiation might be due less to radiosensitisation
than to the fact that in the sequential arm many patients did not
get radiotherapy at all.
A further consideration with sequential treatment is that if there is
a delay before starting radiotherapy, tumour regrowth has been observed following completion of neoadjuvant chemotherapy which
is at a rate more rapid than prior to treatment (El Sharouni 2003).
It is possible that this accelerated repopulation may render tumours more resistant to subsequent irradiation, further contributing to the difference in effectiveness of concurrent and sequential
chemoradiotherapy. It is possible that longer conventional fractionation schedules over 6 to 7 weeks (in contrast to accelerated
regimens of 4 weeks or less) may be particularly vulnerable to accelerated repopulation.
In summary, concurrent chemoradiotherapy appears more effective than radiotherapy alone or sequential chemoradiotherapy. The
optimal chemotherapy regimen remains unclear, in particular, it
is unknown whether platinum- or taxane-based chemotherapy is
more effective and whether dose and frequency of administration have a significant impact on outcome. Equally the optimal
radiotherapy schedule is unclear. The majority of trials in this
review used conventional fractionation over 6-7 weeks with the
presumed benefit of concurrent chemoradiation derived from radiosensitisation at this schedule. Severe oesophagitis is signficantly
increased with concurrent chemoradiation and there is an increase
in treatment related mortality. The focus for future practice and
research should be on appropriate selection of patients for concurrent chemoradiation regimes, addressing ways of reducing toxicity and evaluating the optimal chemotherapy combinations and
optimal radiotherapy schedules, using modern, quality assured radiotherapy techniques.

AUTHORS CONCLUSIONS
Implications for practice
The trials reported in this review demonstrate a survival benefit for
concurrent chemoradiation but with increased toxicity compared
to radiation alone or sequential chemoradiation. For patients of
good performance status with locally advanced NSCLC which can
be encompassed within a radical radiotherapy volume concurrent

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12

chemoradiotherapy should be considered. It is important to note


however that the effects of altered radiotherapy fractionation or
technique may similarly enhance local regional control and survival and the optimal radiotherapy schedule remains uncertain.

* compare platinum- and taxane-based chemotherapy;


* investigate the impact of anaemia on the benefits of chemoradiotherapy.

Implications for research


Further trials are required to address the optimal chemotherapy
regime to use in combination with radiotherapy. Trials should be
designed to:
* investigate the combination of chemotherapy with alternative
radiotherapy fractionation schedules such as 55 Gy in 20 fractions
over 4 weeks, or CHART;
*incorporate optimal radiotherapy techniques with formal quality
assurance of radiotherapy treatment
* investigate the impact of total dose of chemotherapy delivered
during radiotherapy;
* compare more frequent versus less frequent chemotherapy administration;

ACKNOWLEDGEMENTS
The authors acknowledge the key contribution to Dr Nick Rowell
in the design and conduct of the first published version of the
review.
The authors are grateful to Ms Juan and Dr Ali Sever for translations, to Dr David Ball and Dr Harry Groen for additional data
and to colleagues for support and comment. They also acknowledge the useful contributions of Gian Luca Di Tanna and Mia
Schmidt-Hansen, who peer-reviewed the manuscript. The original version of the review was possible with the support of Maidstone & Tunbridge Wells NHS Trust and Beatson Oncology Centre.

REFERENCES

References to studies included in this review


Atagi 2005 {published data only}
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Ball D, Bishop J, Smith J, OBrien P, Davis S, Ryan


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Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S.


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Landgren RC, Hussey DH, Barkley HT, Samuels ML.


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without weekly docetaxel (Taxotere) following induction
chemotherapy with cisplatin (DDP) and docetaxel in
unresectable stage IIIA/B non-small cell lung cancer.
Proceedings of the American Society of Clinical Oncology 2002;
21:320a (abstr 1279).

Scagliotti GV, Szczesna A, Ramlau R, Cardenal F, Mattson


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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

14

non-small-cell lung cancer. British Journal of Cancer 2006;


94:137582. [DOI: 10.1038/sj.bjc.6603115]
Rao 2007 {published data only}
Rao CZ. Study of concurrent versus sequential
chemoradiotherapy with vinorelbine and cisplatin is stage
III non-small cell lung cancer. Chinese Journal of Cancer
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Reinfuss 2005 {published data only}
Reinfuss M, Skolyszewski J, Kowalska T, Glinski B, Dymek
P, Walasek T, et al.Evaluation of efficacy of combined
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Nowotwory 2005;55(3):2006.
Schaake-Koning 1992 {published data only}

Schaake-Koning C, van den Bogert W, Dalesio O, Festen


J, Hoogenhout J, van Houtte P, et al.Effects of concomitant
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Soresi 1988 {published data only}

Soresi E, Clerici M, Grilli R, Borghini U, Zucali R, Leoni


M, et al.A randomized clinical trial comparing radiation
therapy v radiation therapy plus cis-dichlorodiammine
platinum (II) in the treatment of locally advanced nonsmall cell lung cancer. Seminars in Oncology 1988;15 Suppl
7(6):205.
Trovo 1992 {published data only}

Trovo MG, Minatel E, Franchin G, Boccieri MG,


Nascimben O, Bolzicco G, et al.Radiotherapy versus
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Wu 2006 {published data only}
Wu H, Zhou D, Wu Q, Cai Y, Liu Y, Jiang J. [Clinical
trial of concurrent low-dose chemotherapy plus radiation
vs sequential chemoradiotherapy for unresectable stage III
non-small cell lung cancer]. Chinese Journal of Lung Cancer
2006;9(3):2835.
Yadav 2005 {published data only}
Yadav B S, Ghoshal S, Sharma SC, Behera D, Kapoor V.
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advanced non-small cell lung cancer - a pilot study. Bulletin,
Postgraduate Institute of Medical Education & Research,
Chandigarh 2005;39(2):7580.
Zatloukal 2003 {published data only}

Zatloukal P, Petruzelka L, Zemanova M, Havel L,


Janku F, Judas L, et al.Concurrent versus sequential
chemoradiotherapy with cisplatin and vinorelbine in locally
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Zatloukal P, Petruzelka L, Zemanova M, Havel L, Pecen L,
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non-small cell lung cancer. A randomized phase II study -

long-term follow-up data. Lung Cancer 2003;41 Suppl(2):


76.
Zatloukal P, Petruzelka L, Zemanova M, Havel L,
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radiochemotherapy with vinorelbine plus cisplatin (V-P) in
locally advanced non-small cell lung cancer. A randomized
phase II study [abstract]. Proceedings of the American Society
of Clinical Oncology 2002;21:290.

References to studies excluded from this review


Ball 1997 {published data only}

Ball D, Smith J, Olver I, Davis S, OBrien P, Bernshaw


D, et al.A phase III study of radiotherapy with or without
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6907.
Belderbos 2007 {published data only}
Belderbos J, Uitterhoeve L, van Zandwijk N, Belderbos
H, Rodrigus P, van de Vaart P, et al.Randomised trial of
sequential versus concurrent chemo-radiotherapy in patients
with inoperable non-small cell lung cancer (EORTC 0897222973). European Journal of Cancer 2007;43(1):11421.
Chan 1976 {published data only}

Chan PYM, Byfield JE, Kagan AR, Aronstam EM.


Unresectable squamous cell carcinoma of the lung and its
management by combined bleomycin and radiotherapy.
Cancer 1976;37(6):26716.
DasGupta 2006 {published data only}
Dasgupta A, Dasgupta C, Basu S, Majumdar A. A
prospective and randomized study of radiotherapy,
sequential chemotherapy radiotherapy and concomitant
chemotherapy-radiotherapy in unresectable non small
cell carcinoma of the lung. Journal of cancer research and
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Furuse K, Fukuoka M, Kawahara M, Nishikawa H,


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cell lung cancer. Journal of Clinical Oncology 1999;17(9):
26929.
Guschall 2000 {published data only}

Gurschall W-R, Schneemann-Heinze S, Floegel R,


Liebetrau G, Dittrich I. The therapy of the inoperable non
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4751.
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Japan Radiation-ACNU Study Group. A randomized


prospective study of radiation versus radiation plus ACNU

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

15

in inoperable non-small cell carcinoma of the lung. Cancer


1989;63(2):24954.

References to ongoing studies

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Johnson DH, Einhorn LH, Bartolucci A, Birch R, Omura


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NCRI SOCCAR {published data only}


SOCCAR Trial Cisplatin and Vinorelbine for NSCLC

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Koca S, Oner-Dincbas F, Serdengecti S, Yaman M, Ongen


G, Dimirci S, et al.Inoperabl kucuk hucreli disi akciger
kanserinde hiperfraksiyone radyoterapi ile cisplatin+5FU
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Komaki R, Seiferheld W, Ettinger D, Lee JS, Mosvas


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LePar E, Faust DS, Brady LW, Beckloff GL. Clinical


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Sarihan S, Kayisogullari U, Sozer N, Ercan I, Ozkan L,


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(LUWOS-012/1). Ongoing study 01/12/2005.

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Auperin A, Le Pchoux C, Rolland E, Curran W, Furuse
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Ball 1999
Ball D, Bishop J, Smith J, OBrien P, Davis S, Ryan
G, et al.A randomised phase II study of accelerated or
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Cox 1990
Cox JD, Azarnia N, Byhardt RW, Shin KH, Emami B,
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possible survival benefit with greater than or equal to
69.6Gy in favorable patients with Radiation Therapy
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report of Radiation Therapy Oncology Group 83-11.
Journal of Clinical Oncology 1990;8:154355.
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Biomed Central. Current Controlled Trials.
www.controlled-trials.com (accessed 19 October 2009).

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Zhang 2006 {published data only}


Zhang Y, Gao X. [The clinical research on 10hydroxycamplothecin (HCPT) for radiosensitization on
local advanced non-small cell lung cancer]. Chinese Journal
of Clinical Oncology 2006;33(8):45861.

El Sharouni 2003
El Sharouni SY, Kal HB, Battermann JJ. Accelerated
regrowth of non-small cell lung tumours after induction
chemotherapy. British Journal of Cancer 2003;89(12):
218489.

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

16

Higgins 2009
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.0.2. [updated
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Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16:
Special topics in statistics. Higgins JPT, Green S (editors).
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Version 5.0.2 (updated September 2009). The Cochrane
Collaboration, 2009.
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Jones B, Dale RG, Deehan C, Hopkins KI, Morgan DA.
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Non-small Cell Lung Cancer Collaborative Group.
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randomised clinical trials. BMJ 1995;311:899909.
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Non-small Cell Lung Cancer Collaborative Group.
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Parmar MKB, Torri V, Stewart L. Extracting summary
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Perez CA, Pajak TF, Rubin P, Simpson JR, Mohiuddin M,
Brady LW, et al.Long-term observations of the patterns of

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Saunders M, Dische S, Barrett A, Harvey A, Griffiths G,
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References to other published versions of this review


Rowell 2004
Rowell NP, ORourke NArt. No.: CD002140. DOI:
10.1002/14651858.CD002140.pub2. Concurrent
chemoradiotherapy in non-small cell lung cancer. Cochrane
Database of Systematic Reviews 2004, Issue 4. [Art. No.:
CD002140. DOI: 10.1002/14651858.CD002140.pub2]

Indicates the major publication for the study

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

17

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]


Atagi 2005
Methods

Randomised

Participants

46 patients with stage III NSCLC

Interventions

RT to 60 Gy in 30 fractions alone vs
with daily carboplatin 30mg/m2 for first 20 fractions

Outcomes

Median survival 428 vs 554 days

Notes

Closed early after 4 treatment-related deaths

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

By minimization method balancing PS, stage and institution

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

All 46 randomised patients were analysed.

Ball 1999 once daily


Methods

Randomised

Participants

208 patients with stage I-IIIB

Interventions

RT to 60Gy in 30 fractions randomised between once and twice daily fractionation v


RT once or twice daily with weekly carboplatin

Outcomes

Overall 31% 2-year survival; no significant difference between arms

Notes

Subset treated with once daily irradiation

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Randomisation within each stratum was based on an adaptative


biased coin procedure weighted to achieve approximate balance
between the four treatment arms. However, because fo the large

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

18

Ball 1999 once daily

(Continued)

number of strata, the total numbers of patients in the four arms


were slightly imbalanced.
Allocation concealment?

Yes

Randomised by telephone to the central trial office.

Incomplete outcome data addressed?


All outcomes

Yes

208 patients were randomised. All patients were analysed


according to their randomised treatment arm (intention-totreat), except for the exclusion from the toxicity analysis of three
patients who received no treatment and one patient who received
only 6 Gy. Response rates were calculated as percentages of all
randomised patients.All patients were followed up to January
6, 1998 (close-out data) Four patients were deemed to be ineligible after review of their records revealed that two (one R3,
one R6C) had pleural effusions at the time of randomisation. A
third (R3) had a pleural effusion evident 1 day after randomisation and a fourth (R6C) was noted to have cervical lymph node
involvement 3 days after randomisation. this left 204 patients
available for analysis.

Ball 1999 twice daily


Methods

Randomised

Participants

208 patients with stage I-IIIB

Interventions

RT to 60Gy in 30 fractions randomised between once and twice daily fractionation v


RT once or twice daily with weekly carboplatin

Outcomes

Overall 31% 2-year survival; no significant difference between arms

Notes

Subset treated with twice daily irradiation

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Randomisation within each stratum was based on an adaptative


biased coin procedure weighted to achieve approximate balance
between the four treatment arms. However, because fo the large
number of strata, the total numbers of patients in the four arms
were slightly imbalanced.

Allocation concealment?

Yes

Randomised by telephone to the central trial office.

Incomplete outcome data addressed?


All outcomes

Yes

208 patients were randomised. All patients were analysed


according to their randomised treatment arm (intention-totreat), except for the exclusion from the toxicity analysis of three
patients who received no treatment and one patient who received

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

19

Ball 1999 twice daily

(Continued)

only 6 Gy. Response rates were calculated as percentages of


all randomised patients.All patients were followed up to January 6, 1998 (close-out data) 208 patients were randomised.
Four patients were deemed to be ineligible after review of their
records revealed that two (one R3, one R6C) had pleural effusions at the time of randomisation. A third (R3) had a pleural
effusion evident 1 day after randomisation and a fourth (R6C)
was noted to have cervical lymph node involvement 3 days after
randomisation. this left 204 patients available for analysis.

Blanke 1995
Methods

Randomised

Participants

240 patients with stage I-IIIB

Interventions

Daily RT to 60-65Gy v RT with three-weekly cisplatin

Outcomes

1-year survival 45% v 43%; 2-year survival 13% v 18%.

Notes

Improved progression-free survival for non-squamous cancers

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Patients were stratified. Permuted-blocks randomization was


used to assign patients within the strata

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

Although they claim an ITT analysis, only assessable patients are


included in the analysis. Description of the flow of patients and
reasons for ineligibility is providedn in the paper, although no
reasons are provided for non-assessable patients. the intent-totreat principle was adhered to throughout for eligible patients.
240 patients were enrolled. Thirteen patients (six on the
thoracic XRT arm and seven on the combination arm) were
ineligible and 12 additional patients (six on each arm) were not
assessable for reasons listen in Table 1

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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20

Bonner 1998
Methods

Randomised

Participants

110 patients with stage IIIA/B

Interventions

Twice daily RT to 60Gy v RT with cisplatin and etoposide

Outcomes

2 year survival 27% v 25%.

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Randomization to one of the three treatment arms was performed by a dynamic allocation procedure that balanced the
marginal distributions of the stratification factors among the
study arms.

Allocation concealment?

Yes

Patients were randomized at a centralized NCCTG randomization center.

Incomplete outcome data addressed?


All outcomes

Yes

110 patients entered the study. Eleven patients were declared


ineligible on the basis of the eligibility criteria listed above, leaving 99 patients with analyzable data.

Cakir 2004
Methods

Randomised

Participants

185 patients with stage IIIA/B

Interventions

Daily RT to 64Gy v RT with cisplatin days 1-5 in weeks 2 and 6

Outcomes

2-year survival 5% v 23%

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

A stratified randomisation procedure was performed; the stages


(III-A,III-B) were used as a stratifying factor. The patients having
these two stages allocated to treatment arms equally.

Allocation concealment?

Unclear

Not reported.

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

21

Cakir 2004

(Continued)

Incomplete outcome data addressed?


All outcomes

Yes

Of the 185 pt who underwent randomisation, 9 patients (4


assigned to radiotherapy plus cisplatin and 5 assigned to radiotherapy alone) were subsequently found to be ineligible and were
excluded. The reasons for exclusion were the patients admission in another protocol, and presence of other malignant conditions, or patients refusal to participate in the study. Of the
remaining 176 stage III patients, 88 were randomly assigned to
radiotherapy plus cisplatin and 88 to radiotherapy alone

Clamon 1999
Methods

Randomised

Participants

283 patients with stage IIIA/B

Interventions

Induction chemotherapy then daily RT to 60Gy v induction chemo and RT with weekly
carboplatin

Outcomes

1-year survival 54% v 56%;


2-year survival 26% v 29%.

Notes

In-field failure rate 69% v 59%

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Randomization was stratified by stage so that an equal proportion of clinical stage IIIA and IIIB patients would be assigned
to each treatment arm

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

Of the 283 patients registered onto the trial, 137 were randomized to receive induction chemotherapy and radiation therapy,
and 146 were randomized to receive the same therapy but with
the addition of weekly carboplatin during the radiation treatment. One patient in each treatment group left the study before
receiving any protocol therapy. 16 patients in the first group
and 15 in the carboplatin group were considered ineligible after
review, and reasons of inegibility are described

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22

Curran 2003
Methods

Randomised

Participants

402 patients with stage II-IIIB

Interventions

Chemotherapy with vinblastine and cisplatin plus daily RT to 60Gy commencing day
1 (concurrent) or day 50 (sequential)

Outcomes

1-year survival 63% v 57%; 2-year survival 37% v 31%

Notes

Third arm of study included hyperfractionated RT (total number of patients in study =


610). This study was published as an abstract

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Unclear

Numbers are presented, although causes of patients loss and


groups they belong to arent. 610 enrolled patients, 595 analyzable patients

Fournel 2001
Methods

Randomised

Participants

212 patients with stage IIIAN2/IIIB

Interventions

Chemotherapy with vinblastine and etoposide plus daily RT to 66Gy commencing day
1 followed by cisplatin and vinorelbine (concurrent) or chemotherapy with cisplatin and
vinorelbine followed by RT alone commencing approx week 13 (sequential)

Outcomes

1-year survival 56% v 56%; 2-year survival 35% v 23%

Notes

Although etoposide used concurrently with RT in place of vinorelbine; study designed


to deliver the same total dose of cisplatin in both arms

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Its not clear how patients were randomised. Patients were stratified by stage (IIIA-N2/IIIB) and were then randomly assigned
to receive sequential or concurrent therapy.

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

23

Fournel 2001

(Continued)

Allocation concealment?

Unclear

Its not clear whether randomisation was centralized. The central office stratified patients according to institute and stage (IIIAN2/IIIB).

Incomplete outcome data addressed?


All outcomes

Yes

212 patients were enrolled Seven patients were not eligible


after panel file revue (three in the sequential arm and four in
the concurrent arm); six patients had stage IV disease, and one
had pleural effusion. Thus, 205 patients (103 in the sequential
arm and 102 in the concurrent arm) were assessable for survival,
and 193, for toxicity. Four patients were lost to follow-up. 201
eligible patients

Gouda 2006
Methods

Randomised

Participants

40 patients with stage III NSCLC

Interventions

60Gy at conventional fractionation vs RT with 2 cycles concurrent carboplatin/taxol

Outcomes

2y survival 10% RT vs 45% concurrent chemoRT

Notes

Only two arms (n=40) are analyzed in this review.

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

All 60 randomised patients were analysed.

Groen 1999
Methods

Randomised

Participants

160 patients with stage IIIA/B

Interventions

Daily RT to 60Gy v RT with carboplatin continuous infusion

Outcomes

2-year survival 28% v 20%

Notes

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

24

Groen 1999

(Continued)

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Patients were stratified according to stage, performance status


and hospital. Block randomization was used

Allocation concealment?

Yes

treatment allocation was performed by telephone into either


carboplatin and radiation, or radiation alone.

Incomplete outcome data addressed?


All outcomes

Yes

After randomizing 160 patients, /../ the trial was closed. Five
patients were ineligible after data review because of pretreatment
distant metastases: three in the carboplatin arm and two in the
radiotherapy alone arm. This report is about these 160 patients.

Huber 2003
Methods

Randomised

Participants

219 patients with stage IIIA/IIIB

Interventions

Induction chemotherapy then daily RT to 60Gy v induction chemo and RT with weekly
paclitaxel

Outcomes

2-year survival 27% v 35%

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Random assignment after response evaluation allocated patients to radiotherapy alone or to chemoradiotherapy by stratification according to center and stage using computer-generated
random lists of permuted blocks of varying size.

Allocation concealment?

Yes

The study center in Munich, Germany, was responsible for


central random assignment based on patient details the centers
had submitted.

Incomplete outcome data addressed?


All outcomes

Yes

The analysis of time to progression and overall survival was


based on the intent-to-treat population. Two hundred nineteen patients were randomly assigned (115 patients to radiotherapy alone and 104 patients to simultaneous chemoradiotherapy). After careful review, five patients were excluded (three
patients were randomly assigned despite progressive disease, and

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

25

Huber 2003

(Continued)

two patients showed brain metastasis before the start of treatment), leading to 214 patients (radiotherapy alone: n = 113;
simultaneous chemoradiotherapy: n = 101). Two patients were
completely lost from follow-up. Survival analyses are limited to
212 patients (99 receiving chemoradiotherapy and 113 receiving radiotherapy alone; Fig 1).

Jeremic 1995
Methods

Randomised

Participants

178 patients with stage IIIA/IIIB

Interventions

Twice daily RT to 64.8Gy v RT with weekly carboplatin and etoposide v RT with


carboplatin and etoposide alternate weeks

Outcomes

1-year survival 39% v 73% v 50%;


2-year survival 25% v 35% v 27%;
3-year survival 6.6% v 23% v 16%.

Notes

More toxicity in alternate week chemotherapy arm resulting in more treatment interruptions

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

178 randomised patients, 169 patients assessable. Nine patients


(six in group Iand three in group III) were excluded. No
patient was lost for follow-up evaluation.

Jeremic 1996
Methods

Randomised

Participants

135 patients with stage IIIA/IIIB

Interventions

Twice daily RT to 69.6Gy v RT with daily carboplatin and etoposide

Outcomes

1-year survival 68% v 74%;


2-year survival 26% v 43%;
3-year survival 11% v 23%.

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

26

Jeremic 1996

(Continued)

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

Four patients (two in each group) were subsequently found to


have /.../ and data for them were excluded from further analysis.
All patients completed treatment as planned, and no patient
was lost for follow-up evaluation. 135 enrolled, 131 assessd

Landgren 1974
Methods

Randomised

Participants

54 patients with unresectable NSCLC

Interventions

RT to 60Gy in 20 fractions split over 8 weeks v RT with daily hydroxyurea

Outcomes

1-year survival 48% v 46%;


2-year survival 12% v 11%.

Notes

Only 64% completed RT as planned

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

54 patients were randomised All patients (except one from the


irradiation-alone group /.../ were considered evaluable.

Li 2008
Methods

Randomised

Participants

60 patients with stage IIIA-IIIB

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

27

Li 2008

(Continued)

Interventions

RT 62.4Gy treating bd over 6 weeks v same RT with daily hydroxycomptothecin on first


and last week of RT

Outcomes

2-year survival 54.4% in concurrent vs 33.9% radiotherapy

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Unclear

60 patients randomised. Two patients lost to follow-up, but they


dont specify the group they belong to

Lu 2005
Methods

Randomised

Participants

92 patients with stage III disease

Interventions

2 cycles induction cis/vin then 60-65Gy either alone follwed by 4 more cycles or with 2
concurrent cycles and 2 subsequent

Outcomes

2y survival 42.5% concurrent vs 33.3% RT alone

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Randomisation using envelopes . It does not specify whether


envelopes sealed or opaque

Incomplete outcome data addressed?


All outcomes

Unclear

92 patients randomised. 7 patients lost to follow-up, but they


dont specify the group they belong to

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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28

Manegold 2003
Methods

Randomised

Participants

89 patients with stage IIIA/IIIB

Interventions

Induction chemo followed by randomisation to daily RT to 60Gy v RT with weekly


docetaxel

Outcomes

Median survival 14.0m v 14.9m

Notes

Insufficient follow-up; 2-year survival not published

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not described although patients stratified according to centre


and disease stage.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

The primary objective was overall response rate (ORR) at study


end (i.e. 12 weeks from randomisation) for the intent-to-treat
(ITT) population. 108 patients were enrolled Eighty-nine
patients were subsequently randomised to local treatment (ITT
population). Reasons for treatment discontinuation among the
remaining 19 patients were: PD (n=10), protocol deviation (n=
1), adverse event (n=2), death (n=3) and other (n=3: investigator
decision, metastasis, massive decay of lesions (a contraindication for radiotherapy owing to the high risk of developing lifethreatening pulmonary haemorrhage) (one patient each)).

Rao 2007
Methods

Randomised

Participants

55 patients with stage III NSCLC

Interventions

2 cycles cis/vin induction then 62-70Gy alone followed by up to 4 more cycles or


induction and concurrent followed by up to 2 more cycles

Outcomes

2y survival 17.2% sequential vs 42.3% concurrent

Notes
Risk of bias
Item

Authors judgement

Description

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

29

Rao 2007

(Continued)

Adequate sequence generation?

Yes

Randomisation by number table.

Allocation concealment?

No

Randomisation by number table.

Incomplete outcome data addressed?


All outcomes

Unclear

55 patients randomised. Two patients who were lost in the


follow-up were deemed as dead. The follow-up rate ws 95.65%
Its not clear to which group did they pertain

Reinfuss 2005
Methods

Randomised

Participants

173 patients with stage III disease

Interventions

2 cycles cis/vin then 70.2Gy vs same RT concurr with 2 cis/vin

Outcomes

2y survival 26% sequential vs 25% concurrent

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Used randomisation tables.

Allocation concealment?

No

Used randomisation tables.

Incomplete outcome data addressed?


All outcomes

Yes

All 173 patients randomised were analysed.

Schaake-Koning 1992
Methods

Randomised

Participants

331 patients with stage I-IIIB NSCLC

Interventions

RT to 55Gy in 20 fractions split over 7 weeks versus RT with weekly cisplatin v RT with
daily cisplatin

Outcomes

1-year survival 46% v 44% v 54%;


2-year survival 13% v 19% v 26%;
3-year survival 2% v 13% v 16%.

Notes
Risk of bias
Concurrent chemoradiotherapy in non-small cell lung cancer (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

30

Schaake-Koning 1992

(Continued)

Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Yes

randomisation performed centrally

Incomplete outcome data addressed?


All outcomes

Yes

331 patients were enrolled. Twenty-two patients were later


found to be ineligible. All ineligible patients were included in
the survival analyses. Numbers for inegibility are listed with
the groups they belonged to, but causes are given aggregated by
trial. Sixty-three patients could not be evaluated for response
to treatment, and 45 could not be evaluated for toxic effects

Soresi 1988
Methods

Randomised

Participants

95 patients with stage IIIA/B NSCLC

Interventions

Daily RT to 50.4Gy v RT with weekly cisplatin

Outcomes

2-year survival 23% v 39%

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

95 randomised patients Two patients in the RT group were lost


too early to follow-up /.../ so they were excluded from analysis
of progression-free interval and survival.

Trovo 1992
Methods

Randomised

Participants

173 patients with stage IIIA/B NSCLC

Interventions

RT 45Gy in 15 fractions over 3 weeks v RT with daily cisplatin

Outcomes

2-year survival 14% v 15%.

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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31

Trovo 1992

(Continued)

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not reported.

Allocation concealment?

Unclear

Not reported.

Incomplete outcome data addressed?


All outcomes

Yes

173 randomised patients. four patients (three in the RT group


and one in the combined ttm group) were found to be ineligible.
Reasons are described, but only aggregated numbers per group
they belong to. Patients evaluable for response and toxicity: 73
per group (146). 167 patients ealuable for survival

Wu 2006
Methods

Randomised

Participants

80 unresectable stage III NSCLC

Interventions

RT60Gy /30-33 concurr with cis/vin followed by 3 more cycles or RT alone followed
by 4-5 cycles cis/vin

Outcomes

No survival data accrued yet - just toxicity data

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Randomisation table

Allocation concealment?

No

Randomisation table

Incomplete outcome data addressed?


All outcomes

No

Inadequate follow-up so far to report any outcome data

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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32

Yadav 2005
Methods

Randomised

Participants

30 patients with stage III NSCLC

Interventions

50Gy/25 alone vs with weekly cisplatin

Outcomes

2y survival 25% RT alone vs 19% concurrent chemoRT

Notes
Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Yes

Randomisation by table of Tippet (random numbers table).

Allocation concealment?

No

Randomisation by table of Tippet (random numbers table).

Incomplete outcome data addressed?


All outcomes

Yes

30 randomised patients. Response rate was quoted for all 30


patients in study suggesting complete follow-up at least to time
of response assessment. Response assessment on CXR alone and
immediately at end of treatment

Zatloukal 2003
Methods

Randomised

Participants

102 patients with stage IIIA/B

Interventions

4 cycles of cisplatin and vinorelbine with daily RT to 60Gy starting week 5 (concurrent)
or following completion of chemo approx week 17 (sequential)

Outcomes

1-year survival 69% v 53%; 2-year survival 34% v 14%

Notes

Due to the slow accrual and results of interim analysis, which demonstrated statistical
difference in survival in favor of concurrent arm, the study was prematurely terminated.

Risk of bias
Item

Authors judgement

Description

Adequate sequence generation?

Unclear

Not described, although randomisation was by envelope method

Allocation concealment?

Yes

Randomisation by envelope method was used

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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33

Zatloukal 2003

(Continued)

Incomplete outcome data addressed?


All outcomes

Yes

102 eligible patients were enrolled in the study All eligible


patients at study entry were included in the intent-to-treat (ITT)
population for efficacy Four patients were not enrolled for
the response analysis. Reasons were provided for the 4 patients
not enrolled. Of the 101 patients qualified for safety analysis,
99 were assessable. Reasons provided for the 2 non-assessable
patients

Patients with stage I/II disease were those considered medically inoperable.
Ball 1999 once daily and Ball 1999 twice daily refer both to the same study Ball 1999

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Ball 1997

Radiation dose less than 50Gy (20Gy in 5 fractions)

Belderbos 2007

Different chemotherapy in the two study arms ; sequential had gemcitabine/cisplatin combination and
concurrent had cisplatin alone. Also very variable radiation doses 49-94Gy

Chan 1976

Radiation dose less than 50Gy (20Gy in 5 fractions, 3-week gap then further 20Gy in 5 fractions)

DasGupta 2006

Different radiotherapy doses in the two arms 65Gy in sequential arm and 50 Gy in concurrent arm

Furuse 1999

Radiation fractionation different between arms (56Gy in 28 fractions in both arms but included 10 day gap
in concurrent arm, continuous in sequential arm)

Guschall 2000

Concurrent chemotherapy arm had total of 6 cycles of chemotherapy (2 concurrent, 4 sequential) versus
none in RT alone arm so comparison could not distinguish how much benefit was from concurrent treatment
and how much was due to additional sequential chemotherapy

Isakovic-Vidovic2002

Planned radiation dose differed between two arms (60Gy in 30 fractions in RT alone arm and 55Gy in 20
fractions split over 6 weeks in concurrent arm)

Japan ACNU 1989

25/73 patients had stage IV disease

Johnson 1990

Post-radiotherapy chemotherapy differed in 2 arms: 29/104 in RT alone arm crossed over to receive vindesine
while responders in concurrent arm continued vindesine for up to 6 months

Koca 1996

Post-radiotherapy chemotherapy differed in 2 arms; concurrent arm also received 6 cycles of chemotherapy
after radiotherapy

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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34

(Continued)

Komaki 2002

Both arms had concurrent chemotherapy, one with daily RT, the other twice-daily; the once-daily arm also
received induction chemotherapy (ie both sequential and concurrent)

LePar 1967

Trial may have included patients with stage IV disease; one patient (of 26) had small cell lung cancer

Misirlioglu 2006

The concurrent chemotherapy arm also has consolidation chemotherapy

Sarihan 2002

Planned radiation dose differed between two arms (63Gy in RT alone arm and 59.Gy in concurrent arm)

Ulutin 2000

Not randomised: accrual into treatment groups by consecutive registration

Characteristics of studies awaiting assessment [ordered by study ID]


Zhang 2006
Methods
Participants
Interventions
Outcomes
Notes

This study is pending translation.

Characteristics of ongoing studies [ordered by study ID]


NCRI SOCCAR
Trial name or title

SOCCAR Trial Cisplatin and Vinorelbine for NSCLC


(LUWOS-012/1)

Methods

Randomised phase III trial

Participants

Patients with inoperable stage III NSCLC and good performance status

Interventions

Sequential arm - patients receive 4 x 21 day cycle of vinorelbine and cisplatin, followed by radical radiotherapy.
Concurrent arm - patients receive vinorelbine concurrently with fractions 1, 6, 15 and 20 of radical radiotherapy and cisplatin with fractions 1-4 and 16-19. Four weeks after concurrent treatment is completed patients
receive 2 x 21 day cycle of vinorelbine and cisplatin

Outcomes

Overall survival; progression-free survival; local progression-free survival; hematological, pulmonary,


esophageal, and neurological toxicities; response; quality of life; cost-effectiveness

Starting date

01/12/2005

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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35

NCRI SOCCAR

(Continued)

Contact information

Dr Joseph Maguire
Clatterbridge Centre for Oncology
Bebington
Wirral
Liverpool
United Kingdom
CH63 4JY

Notes

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

36

DATA AND ANALYSES

Comparison 1. Concurrent chemoradiotherapy vs Radiotherapy alone

Outcome or subgroup title


1 Overall survival
2 Overall survival 2-years
3 Progression-free survival
4 Progression-free survival 2-years
5 Locoregional progression-free
survival
6 Locoregional progression-free
survival 2-years
7 Toxicity
7.1 Treatment-related deaths
7.2 Acute pneumonitis
7.3 Acute oesophagitis
7.4 Pulmonary fibrosis
7.5 Late oesophagitis
7.6 Neutropenia
7.7 Anaemia (grade 3 to 4)
7.8 Anaemia (grade 1 to 4)

No. of
studies

No. of
participants

9
20
7
9
2

1607
2587
1145
1405
345

Hazard Ratio (Random, 95% CI)


Risk Difference (M-H, Random, 95% CI)
Hazard Ratio (Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Hazard Ratio (Fixed, 95% CI)

0.71 [0.64, 0.80]


-0.08 [-0.12, -0.03]
0.69 [0.58, 0.81]
0.91 [0.86, 0.97]
0.67 [0.54, 0.82]

872

Risk Ratio (M-H, Random, 95% CI)

0.84 [0.72, 0.98]

19
14
9
17
4
2
7
5
9

2075
1179
2227
596
300
837
822
887

Risk Ratio (M-H, Random, 95% CI)


Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

Subtotals only
1.38 [0.51, 3.72]
1.06 [0.58, 1.93]
1.76 [1.34, 2.31]
1.27 [0.34, 4.64]
1.72 [0.32, 9.33]
3.53 [1.84, 6.77]
4.17 [1.13, 15.35]
1.99 [1.49, 2.64]

Statistical method

Effect size

Comparison 2. Concurrent vs Sequential chemoradiotherapy

Outcome or subgroup title


1 Overall survival
2 Overall survival 2-years
3 Progression-free survival
4 Progression-free survival 2-years
5 Locoregional PFS 2-years
6 Toxicity
6.1 Treatment-related deaths
6.2 Acute pneumonitis
6.3 Acute oesophagitis
6.4 Neutropenia
6.5 Anaemia

No. of
studies

No. of
participants

3
5
1
2
1
5
5
5
5
5
2

702
937
201
378
402
950
947
947
947
292

Statistical method
Hazard Ratio (Random, 95% CI)
Risk Difference (M-H, Random, 95% CI)
Hazard Ratio (Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size
0.74 [0.62, 0.89]
-0.10 [-0.18, -0.02]
0.67 [0.30, 1.50]
0.92 [0.78, 1.09]
0.84 [0.64, 1.10]
Subtotals only
2.02 [0.90, 4.52]
0.99 [0.51, 1.91]
4.96 [2.17, 11.37]
1.18 [0.90, 1.55]
0.95 [0.41, 2.21]

37

Comparison 3. Subgroup analysis Chemoradiotherapy vs Radiotherapy

Outcome or subgroup title


1 Chemotherapy regime
1.1 Platinum-containing
regimes
1.2 Taxane-containing
regimes
1.3 Other regimes
2 Frequency of chemotherapy
administration
2.1 Daily administration
2.2 Weekly administration
2.3 Two- to four-weekly
administration
3 Platinum dose
3.1 High dose
3.2 Low dose
4 Radiotherapy fractionation
4.1 Once daily fractionation
4.2 Twice daily fractionation
5 Dose of radiotherapy
5.1 Low dose
5.2 High dose
6 Duration of follow-up
6.1 Minimum follow-up 22
months or more
6.2 Minimum follow-up 18
months or less
6.3 Duration of follow-up
uncertain

No. of
studies

No. of
participants

20
16

2587
2173

Risk Ratio (M-H, Random, 95% CI)


Risk Ratio (M-H, Random, 95% CI)

0.91 [0.86, 0.97]


0.92 [0.86, 0.98]

301

Risk Ratio (M-H, Random, 95% CI)

0.82 [0.71, 0.94]

2
20

113

Risk Ratio (M-H, Random, 95% CI)


Risk Ratio (M-H, Random, 95% CI)

0.88 [0.56, 1.36]


Subtotals only

7
7
8

840
1013
909

Risk Ratio (M-H, Random, 95% CI)


Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

0.94 [0.84, 1.05]


0.90 [0.84, 0.96]
0.90 [0.81, 0.99]

16
9
7
20
15
5
20
13
7
20
7

2173
1145
1028
2587
2065
522
2587
1691
896
2587
1191

Risk Ratio (M-H, Random, 95% CI)


Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

0.92 [0.86, 0.98]


0.91 [0.84, 1.00]
0.93 [0.84, 1.03]
0.91 [0.86, 0.97]
0.91 [0.85, 0.97]
0.92 [0.79, 1.08]
0.91 [0.86, 0.97]
0.93 [0.86, 1.01]
0.88 [0.81, 0.95]
0.91 [0.86, 0.97]
0.90 [0.83, 0.97]

359

Risk Ratio (M-H, Random, 95% CI)

0.99 [0.85, 1.15]

1037

Risk Ratio (M-H, Random, 95% CI)

0.89 [0.79, 0.99]

Statistical method

Effect size

Comparison 4. Subgroup analysis Concurrent vs Sequential

Outcome or subgroup title


1 Dose of radiotherapy
1.1 Low dose
1.2 High dose
2 Duration of follow-up
2.1 Minimum follow-up 22
months or more
2.2 Minimum follow-up 18
months or less

No. of
studies

No. of
participants

5
1
4
5
2

937
102
835
937
607

Risk Ratio (M-H, Random, 95% CI)


Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

0.87 [0.78, 0.97]


0.76 [0.61, 0.95]
0.89 [0.79, 1.01]
0.87 [0.78, 0.97]
0.88 [0.79, 0.99]

330

Risk Ratio (M-H, Random, 95% CI)

0.84 [0.66, 1.06]

Statistical method

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size

38

2.3 Duration of follow-up


uncertain

Risk Ratio (M-H, Random, 95% CI)

Not estimable

Comparison 5. More frequent versus less frequent chemotherapy

Outcome or subgroup title

No. of
studies

No. of
participants

1 Frequency of chemotherapy

325

Statistical method
Risk Ratio (M-H, Random, 95% CI)

Effect size
0.91 [0.80, 1.03]

Comparison 6. Sensitivity fixed: Concurrent vs Radiotherapy

Outcome or subgroup title


1 Overall survival
2 Overall survival 2-years
3 Progression-free survival
4 Progression-free survival 2-years
5 Locoregional progression-free
survival
6 Locoregional progression-free
survival 2-years
7 Toxicity
7.1 Treatment-related deaths
7.2 Acute pneumonitis
7.3 Acute oesophagitis
7.4 Pulmonary fibrosis
7.5 Late oesophagitis
7.6 Neutropenia
7.7 Anaemia (grade 3 to 4)
7.8 Anaemia (grade 1 to 4)

No. of
studies
9
20
7
9
2

No. of
participants

2587
1405

Statistical method

Effect size

Hazard Ratio (Fixed, 95% CI)


Risk Ratio (M-H, Fixed, 95% CI)
Hazard Ratio (Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Hazard Ratio (Fixed, 95% CI)

0.71 [0.64, 0.80]


0.90 [0.86, 0.94]
0.70 [0.62, 0.79]
0.91 [0.87, 0.95]
0.67 [0.54, 0.82]

872

Risk Ratio (M-H, Fixed, 95% CI)

0.84 [0.76, 0.91]

19
14
9
17
4
2
7
5
9

2075
1179
2227
596
300
837
822
887

Risk Ratio (M-H, Fixed, 95% CI)


Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only
1.51 [0.60, 3.79]
1.00 [0.57, 1.74]
1.96 [1.50, 2.57]
1.21 [0.56, 2.60]
1.94 [0.53, 7.14]
4.29 [2.28, 8.07]
4.96 [1.82, 13.51]
1.95 [1.46, 2.61]

Comparison 7. Sensitivity fixed: Concurrent vs Sequential

Outcome or subgroup title


1 Overall survival
2 Overall survival 2-years
3 Progression-free survival
4 Progression-free survival 2-years
5 Locoregional progression-free
survival 2-years
6 Toxicity

No. of
studies
3
5
1
2
1
5

No. of
participants

937
378
402

Statistical method

Effect size

Hazard Ratio (Fixed, 95% CI)


Risk Ratio (M-H, Fixed, 95% CI)
Hazard Ratio (Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)

0.74 [0.62, 0.89]


0.88 [0.81, 0.96]
0.67 [0.30, 1.50]
0.91 [0.83, 1.00]
0.84 [0.64, 1.10]

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

39

6.1 Treatment-related deaths


6.2 Acute pneumonitis
6.3 Acute oesophagitis
6.4 Neutropenia

5
5
5
5

950
947
947
947

Risk Ratio (M-H, Fixed, 95% CI)


Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)
Risk Ratio (M-H, Fixed, 95% CI)

2.09 [0.95, 4.57]


0.94 [0.60, 1.46]
4.97 [3.28, 7.53]
1.08 [0.97, 1.20]

Comparison 8. Sensitivity ITT: Concurrent vs Radiotherapy

Outcome or subgroup title


1 Overall survival 2-years
2 Progression-free survival 2-years
3 Locoregional progression-free
survival 2-years

No. of
studies

No. of
participants

20
9
5

2691
1458
902

Statistical method
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

Effect size
0.92 [0.87, 0.97]
0.92 [0.86, 0.98]
0.85 [0.74, 0.99]

Comparison 9. Sensitivity ITT: Concurrent vs Sequential

Outcome or subgroup title


1 Overall survival 2-years
2 Progression-free survival 2-years

No. of
studies

No. of
participants

5
2

944
385

Statistical method
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

Effect size
0.87 [0.78, 0.97]
0.93 [0.79, 1.08]

Comparison 10. Sensitivity fully published: Concurrent vs Sequential

Outcome or subgroup title


1 Overall survival
2 Overall survival 2-years
3 Toxicity
3.1 Treatment-related deaths
3.2 Acute pneumonitis
3.3 Acute oesophagitis
3.4 Neutropenia

No. of
studies
2
4
4
4
4
4
4

No. of
participants

535
548
545
545
545

Statistical method
Hazard Ratio (Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)
Risk Ratio (M-H, Random, 95% CI)

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size
0.63 [0.44, 0.90]
0.84 [0.72, 0.99]
Subtotals only
2.45 [0.81, 7.43]
1.22 [0.57, 2.65]
4.85 [1.52, 15.45]
1.35 [0.79, 2.32]

40

Analysis 1.1. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 1 Overall


survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone


Outcome: 1 Overall survival

Concurrent
chemoRT

Radiotherapy

log [Hazard Ratio]

Hazard Ratio

(SE)

IV,Random,95% CI

Blanke 1995

104

111

-0.13 (0.14)

17.1 %

0.88 [ 0.67, 1.16 ]

Cakir 2004

88

88

-0.61 (0.16)

13.1 %

0.54 [ 0.40, 0.74 ]

Clamon 1999

130

120

-0.12 (0.37)

2.4 %

0.89 [ 0.43, 1.83 ]

Huber 2003

99

113

-0.27 (0.16)

13.1 %

0.76 [ 0.56, 1.04 ]

Jeremic 1995

52

61

-0.61 (0.2)

8.4 %

0.54 [ 0.37, 0.80 ]

Jeremic 1995

56

-0.28 (0.21)

7.6 %

0.76 [ 0.50, 1.14 ]

Jeremic 1996

65

66

-0.44 (0.19)

9.3 %

0.64 [ 0.44, 0.93 ]

217

114

-0.25 (0.12)

23.2 %

0.78 [ 0.62, 0.99 ]

Soresi 1988

45

48

-0.39 (0.29)

4.0 %

0.68 [ 0.38, 1.20 ]

Yadav 2005

15

15

-0.59 (0.42)

1.9 %

0.55 [ 0.24, 1.26 ]

100.0 %

0.71 [ 0.64, 0.80 ]

Study or subgroup

Schaake-Koning 1992

Weight

Hazard Ratio
IV,Random,95% CI

Total (95% CI)


Heterogeneity: Tau2 = 0.0; Chi2 = 8.77, df = 9 (P = 0.46); I2 =0.0%
Test for overall effect: Z = 5.84 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours chemoRT

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

Favours RT

41

Analysis 1.2. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 2 Overall


survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone


Outcome: 2 Overall survival 2-years

Study or subgroup

RT + chemo

Risk
Difference
MH,Random,95%
CI

RT alone

Weight

Risk
Difference
MH,Random,95%
CI

n/N

n/N

Atagi 2005

15/23

17/23

2.2 %

-0.09 [ -0.35, 0.18 ]

Ball 1999 once daily

32/54

39/53

4.2 %

-0.14 [ -0.32, 0.03 ]

Ball 1999 twice daily

39/51

31/46

4.1 %

0.09 [ -0.09, 0.27 ]

Blanke 1995

85/104

97/111

8.3 %

-0.06 [ -0.15, 0.04 ]

Bonner 1998

24/32

24/33

3.2 %

0.02 [ -0.19, 0.24 ]

Cakir 2004

68/88

84/88

8.2 %

-0.18 [ -0.28, -0.08 ]

Clamon 1999

92/130

89/120

7.3 %

-0.03 [ -0.14, 0.08 ]

Gouda 2006

11/20

18/20

2.4 %

-0.35 [ -0.60, -0.10 ]

Groen 1999

66/82

56/78

6.1 %

0.09 [ -0.04, 0.22 ]

Huber 2003

63/99

88/113

6.6 %

-0.14 [ -0.26, -0.02 ]

Jeremic 1995

75/108

46/61

5.7 %

-0.06 [ -0.20, 0.08 ]

Jeremic 1996

37/65

49/66

4.8 %

-0.17 [ -0.33, -0.01 ]

Landgren 1974

25/28

22/25

4.4 %

0.01 [ -0.16, 0.18 ]

Li 2008

14/30

20/30

2.5 %

-0.20 [ -0.45, 0.05 ]

Lu 2005

27/47

30/45

3.6 %

-0.09 [ -0.29, 0.11 ]

Manegold 2003

29/43

38/46

4.1 %

-0.15 [ -0.33, 0.03 ]

168/217

99/114

9.3 %

-0.09 [ -0.18, -0.01 ]

Soresi 1988

18/45

29/50

3.5 %

-0.18 [ -0.38, 0.02 ]

Trovo 1992

73/84

72/85

7.7 %

0.02 [ -0.08, 0.13 ]

Yadav 2005

12/15

11/15

1.8 %

0.07 [ -0.24, 0.37 ]

1365

1222

100.0 %

-0.08 [ -0.12, -0.03 ]

Schaake-Koning 1992

Total (95% CI)

Total events: 973 (RT + chemo), 959 (RT alone)


Heterogeneity: Tau2 = 0.00; Chi2 = 31.07, df = 19 (P = 0.04); I2 =39%
Test for overall effect: Z = 3.46 (P = 0.00053)

-2

-1

favours chemoRT

favours RT alone

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

42

Analysis 1.3. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 3


Progression-free survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone


Outcome: 3 Progression-free survival

Concurrent
chemoRT

Radiotherapy

log [Hazard Ratio]

Hazard Ratio

(SE)

IV,Random,95% CI

Blanke 1995

104

111

-0.27 (0.14)

16.6 %

0.76 [ 0.58, 1.00 ]

Cakir 2004

88

88

-0.6 (0.15)

15.6 %

0.55 [ 0.41, 0.74 ]

Clamon 1999

130

120

-0.04 (0.13)

17.7 %

0.96 [ 0.74, 1.24 ]

Huber 2003

99

113

-0.56 (0.16)

14.7 %

0.57 [ 0.42, 0.78 ]

Jeremic 1995

56

-0.29 (0.2)

11.4 %

0.75 [ 0.51, 1.11 ]

Jeremic 1995

52

61

-0.62 (0.2)

11.4 %

0.54 [ 0.36, 0.80 ]

Soresi 1988

45

48

-0.27 (0.25)

8.5 %

0.76 [ 0.47, 1.25 ]

Yadav 2005

15

15

-0.51 (0.4)

4.0 %

0.60 [ 0.27, 1.32 ]

100.0 %

0.69 [ 0.58, 0.81 ]

Study or subgroup

Weight

Hazard Ratio
IV,Random,95% CI

Total (95% CI)


Heterogeneity: Tau2 = 0.03; Chi2 = 12.68, df = 7 (P = 0.08); I2 =45%
Test for overall effect: Z = 4.34 (P = 0.000014)
Test for subgroup differences: Not applicable

0.01

0.1

Favours experimental

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours control

43

Analysis 1.4. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 4


Progression-free survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone


Outcome: 4 Progression-free survival 2-years

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Blanke 1995

93/104

106/111

20.2 %

0.94 [ 0.87, 1.01 ]

Cakir 2004

72/88

84/88

15.7 %

0.86 [ 0.77, 0.96 ]

111/130

103/120

16.6 %

0.99 [ 0.90, 1.10 ]

Huber 2003

65/99

93/113

9.7 %

0.80 [ 0.68, 0.94 ]

Jeremic 1995

82/108

52/61

11.2 %

0.89 [ 0.77, 1.03 ]

Manegold 2003

34/43

41/46

8.5 %

0.89 [ 0.74, 1.07 ]

Soresi 1988

25/45

39/50

3.9 %

0.71 [ 0.53, 0.96 ]

Trovo 1992

68/84

66/85

10.7 %

1.04 [ 0.89, 1.22 ]

Yadav 2005

13/15

12/15

3.5 %

1.08 [ 0.79, 1.49 ]

716

689

100.0 %

0.91 [ 0.86, 0.97 ]

Study or subgroup

Clamon 1999

Total (95% CI)

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

Total events: 563 (Concurrent chemoRT), 596 (Radiotherapy)


Heterogeneity: Tau2 = 0.00; Chi2 = 14.00, df = 8 (P = 0.08); I2 =43%
Test for overall effect: Z = 2.75 (P = 0.0059)

0.5

0.7

Favours experimental

1.5

Favours control

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

44

Analysis 1.5. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 5


Locoregional progression-free survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone


Outcome: 5 Locoregional progression-free survival

Concurrent
chemoRT

Radiotherapy

log [Hazard Ratio]

(SE)

Cakir 2004

88

88

-0.63 (0.16)

45.0 %

0.53 [ 0.39, 0.73 ]

Jeremic 1995

56

-0.06 (0.2)

28.8 %

0.94 [ 0.64, 1.39 ]

Jeremic 1995

52

61

-0.4 (0.21)

26.1 %

0.67 [ 0.44, 1.01 ]

100.0 %

0.67 [ 0.54, 0.82 ]

Study or subgroup

Hazard Ratio

Weight

IV,Fixed,95% CI

Hazard Ratio
IV,Fixed,95% CI

Total (95% CI)


Heterogeneity: Chi2 = 4.95, df = 2 (P = 0.08); I2 =60%
Test for overall effect: Z = 3.78 (P = 0.00016)
Test for subgroup differences: Not applicable

0.01

0.1

Favours experimental

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours control

45

Analysis 1.6. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 6


Locoregional progression-free survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone


Outcome: 6 Locoregional progression-free survival 2-years

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Bonner 1998

21/32

19/33

11.0 %

1.14 [ 0.78, 1.68 ]

Cakir 2004

58/88

83/88

26.5 %

0.70 [ 0.60, 0.82 ]

Jeremic 1995

69/108

40/61

20.1 %

0.97 [ 0.77, 1.23 ]

Jeremic 1996

28/65

39/66

12.9 %

0.73 [ 0.52, 1.03 ]

150/217

92/114

29.6 %

0.86 [ 0.75, 0.97 ]

510

362

100.0 %

0.84 [ 0.72, 0.98 ]

Study or subgroup

Schaake-Koning 1992

Total (95% CI)

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

Total events: 326 (Concurrent chemoRT), 273 (Radiotherapy)


Heterogeneity: Tau2 = 0.02; Chi2 = 9.81, df = 4 (P = 0.04); I2 =59%
Test for overall effect: Z = 2.21 (P = 0.027)

0.1 0.2

0.5

Favours experimental

10

Favours control

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

46

Analysis 1.7. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 7 Toxicity.


Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone


Outcome: 7 Toxicity

Study or subgroup

Favours experimental

Radiotherapy

Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Atagi 2005

3/23

1/23

3.00 [ 0.34, 26.76 ]

Ball 1999 once daily

0/54

0/53

0.0 [ 0.0, 0.0 ]

Ball 1999 twice daily

2/51

3/46

0.60 [ 0.11, 3.44 ]

Blanke 1995

2/104

0/111

5.33 [ 0.26, 109.80 ]

Bonner 1998

0/32

0/33

0.0 [ 0.0, 0.0 ]

Clamon 1999

2/130

2/120

0.92 [ 0.13, 6.45 ]

Groen 1999

0/82

0/78

0.0 [ 0.0, 0.0 ]

Huber 2003

0/99

0/113

0.0 [ 0.0, 0.0 ]

Jeremic 1995

0/108

0/61

0.0 [ 0.0, 0.0 ]

Jeremic 1996

0/65

0/66

0.0 [ 0.0, 0.0 ]

Landgren 1974

0/26

0/25

0.0 [ 0.0, 0.0 ]

2/217

0/114

2.64 [ 0.13, 54.48 ]

Soresi 1988

0/45

0/50

0.0 [ 0.0, 0.0 ]

Trovo 1992

0/73

0/73

0.0 [ 0.0, 0.0 ]

1109

966

1.38 [ 0.51, 3.72 ]

1 Treatment-related deaths

Schaake-Koning 1992

Subtotal (95% CI)

Total events: 11 (Favours experimental), 6 (Radiotherapy)


Heterogeneity: Tau2 = 0.0; Chi2 = 2.49, df = 4 (P = 0.65); I2 =0.0%
Test for overall effect: Z = 0.64 (P = 0.52)
2 Acute pneumonitis
Atagi 2005

1/23

1/23

1.00 [ 0.07, 15.04 ]

Bonner 1998

5/32

4/33

1.29 [ 0.38, 4.37 ]

Clamon 1999

1/130

5/120

0.18 [ 0.02, 1.56 ]

Groen 1999

2/82

5/78

0.38 [ 0.08, 1.90 ]

Huber 2003

1/99

0/113

3.42 [ 0.14, 83.01 ]

Jeremic 1995

8/108

3/61

1.51 [ 0.41, 5.47 ]

Jeremic 1996

4/65

3/66

1.35 [ 0.32, 5.81 ]


0.01

0.1

Favours experimental

10

100

Favours control

(Continued . . . )

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

47

(. . .
Study or subgroup

Favours experimental

Radiotherapy

Continued)
Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Landgren 1974

1/26

0/25

2.89 [ 0.12, 67.75 ]

Soresi 1988

1/45

0/50

3.33 [ 0.14, 79.64 ]

610

569

1.06 [ 0.58, 1.93 ]

0/23

0/23

0.0 [ 0.0, 0.0 ]

Ball 1999 once daily

11/53

6/51

1.76 [ 0.70, 4.42 ]

Ball 1999 twice daily

24/50

15/46

1.47 [ 0.89, 2.44 ]

Blanke 1995

3/104

3/111

1.07 [ 0.22, 5.17 ]

Bonner 1998

4/32

3/33

1.38 [ 0.33, 5.66 ]

Clamon 1999

13/130

4/120

3.00 [ 1.01, 8.95 ]

Gouda 2006

5/20

1/20

5.00 [ 0.64, 39.06 ]

Groen 1999

8/82

2/78

3.80 [ 0.83, 17.36 ]

Huber 2003

13/99

6/113

2.47 [ 0.98, 6.26 ]

Jeremic 1995

4/108

3/61

0.75 [ 0.17, 3.25 ]

Jeremic 1996

5/65

4/66

1.27 [ 0.36, 4.52 ]

Landgren 1974

10/26

8/25

1.20 [ 0.57, 2.55 ]

Lu 2005

10/47

2/45

4.79 [ 1.11, 20.66 ]

7/43

0/46

16.02 [ 0.94, 272.34 ]

Schaake-Koning 1992

5/217

0/114

5.80 [ 0.32, 104.02 ]

Trovo 1992

12/73

6/73

2.00 [ 0.79, 5.04 ]

Yadav 2005

0/15

1/15

0.33 [ 0.01, 7.58 ]

1187

1040

1.76 [ 1.34, 2.31 ]

4/23

2/23

2.00 [ 0.41, 9.87 ]

Clamon 1999

2/130

7/120

0.26 [ 0.06, 1.24 ]

Jeremic 1995

7/108

0/61

8.53 [ 0.50, 146.87 ]

Jeremic 1996

3/65

2/66

1.52 [ 0.26, 8.82 ]

326

270

1.27 [ 0.34, 4.64 ]

Subtotal (95% CI)

Total events: 24 (Favours experimental), 21 (Radiotherapy)


Heterogeneity: Tau2 = 0.0; Chi2 = 6.07, df = 8 (P = 0.64); I2 =0.0%
Test for overall effect: Z = 0.19 (P = 0.85)
3 Acute oesophagitis
Atagi 2005

Manegold 2003

Subtotal (95% CI)

Total events: 134 (Favours experimental), 64 (Radiotherapy)


Heterogeneity: Tau2 = 0.0; Chi2 = 13.51, df = 15 (P = 0.56); I2 =0.0%
Test for overall effect: Z = 4.07 (P = 0.000047)
4 Pulmonary fibrosis
Atagi 2005

Subtotal (95% CI)

0.01

0.1

Favours experimental

10

100

Favours control

(Continued . . . )
Concurrent chemoradiotherapy in non-small cell lung cancer (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

48

(. . .
Study or subgroup

Favours experimental

Radiotherapy

n/N

n/N

Continued)
Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

Total events: 16 (Favours experimental), 11 (Radiotherapy)


Heterogeneity: Tau2 = 0.86; Chi2 = 5.96, df = 3 (P = 0.11); I2 =50%
Test for overall effect: Z = 0.35 (P = 0.72)
5 Late oesophagitis
Jeremic 1995

5/108

0/61

6.26 [ 0.35, 111.26 ]

Jeremic 1996

3/65

3/66

1.02 [ 0.21, 4.85 ]

173

127

1.72 [ 0.32, 9.33 ]

10/23

0/23

21.00 [ 1.30, 338.51 ]

Ball 1999 once daily

7/53

0/51

14.44 [ 0.85, 246.55 ]

Ball 1999 twice daily

1/50

0/46

2.76 [ 0.12, 66.22 ]

20/130

7/120

2.64 [ 1.16, 6.01 ]

Gouda 2006

5/20

1/20

5.00 [ 0.64, 39.06 ]

Huber 2003

2/99

0/113

5.70 [ 0.28, 117.32 ]

Manegold 2003

2/43

1/46

2.14 [ 0.20, 22.75 ]

418

419

3.53 [ 1.84, 6.77 ]

Subtotal (95% CI)

Total events: 8 (Favours experimental), 3 (Radiotherapy)


Heterogeneity: Tau2 = 0.41; Chi2 = 1.29, df = 1 (P = 0.26); I2 =23%
Test for overall effect: Z = 0.63 (P = 0.53)
6 Neutropenia
Atagi 2005

Clamon 1999

Subtotal (95% CI)

Total events: 47 (Favours experimental), 9 (Radiotherapy)


Heterogeneity: Tau2 = 0.0; Chi2 = 3.76, df = 6 (P = 0.71); I2 =0.0%
Test for overall effect: Z = 3.79 (P = 0.00015)
7 Anaemia (grade 3 to 4)
Ball 1999 once daily

0/53

1/51

0.32 [ 0.01, 7.70 ]

Ball 1999 twice daily

0/50

0/46

0.0 [ 0.0, 0.0 ]

19/130

2/120

8.77 [ 2.09, 36.85 ]

Groen 1999

2/82

0/78

4.76 [ 0.23, 97.59 ]

Huber 2003

1/99

0/113

3.42 [ 0.14, 83.01 ]

414

408

4.17 [ 1.13, 15.35 ]

Clamon 1999

Subtotal (95% CI)

Total events: 22 (Favours experimental), 3 (Radiotherapy)


Heterogeneity: Tau2 = 0.29; Chi2 = 3.51, df = 3 (P = 0.32); I2 =15%
Test for overall effect: Z = 2.15 (P = 0.032)
8 Anaemia (grade 1 to 4)
Atagi 2005

16/23

8/23

2.00 [ 1.07, 3.72 ]

Ball 1999 once daily

20/53

6/51

3.21 [ 1.40, 7.34 ]

Ball 1999 twice daily

15/50

8/46

1.73 [ 0.81, 3.68 ]

8/88

7/88

1.14 [ 0.43, 3.02 ]

Cakir 2004

0.01

0.1

Favours experimental

10

100

Favours control

(Continued . . . )
Concurrent chemoradiotherapy in non-small cell lung cancer (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

49

(. . .
Study or subgroup

Favours experimental

Radiotherapy

Continued)
Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Gouda 2006

18/20

7/20

2.57 [ 1.39, 4.76 ]

Groen 1999

19/82

11/78

1.64 [ 0.84, 3.23 ]

Manegold 2003

0/43

0/46

0.0 [ 0.0, 0.0 ]

Trovo 1992

4/73

3/73

1.33 [ 0.31, 5.75 ]

Yadav 2005

1/15

0/15

3.00 [ 0.13, 68.26 ]

447

440

1.99 [ 1.49, 2.64 ]

Subtotal (95% CI)

Total events: 101 (Favours experimental), 50 (Radiotherapy)


Heterogeneity: Tau2 = 0.0; Chi2 = 4.02, df = 7 (P = 0.78); I2 =0.0%
Test for overall effect: Z = 4.71 (P < 0.00001)

0.01

0.1

Favours experimental

10

100

Favours control

Analysis 2.1. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 1 Overall survival.


Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 2 Concurrent vs Sequential chemoradiotherapy


Outcome: 1 Overall survival

Concurrent
chemoRT

Sequential chemoRT

log [Hazard Ratio]

Hazard Ratio

(SE)

IV,Random,95% CI

Curran 2003

200

199

-0.24 (0.11)

73.8 %

0.79 [ 0.63, 0.98 ]

Fournel 2001

100

101

-0.4 (0.34)

7.7 %

0.67 [ 0.34, 1.31 ]

52

50

-0.49 (0.22)

18.5 %

0.61 [ 0.40, 0.94 ]

100.0 %

0.74 [ 0.62, 0.89 ]

Study or subgroup

Zatloukal 2003

Weight

Hazard Ratio
IV,Random,95% CI

Total (95% CI)


Heterogeneity: Tau2 = 0.0; Chi2 = 1.13, df = 2 (P = 0.57); I2 =0.0%
Test for overall effect: Z = 3.16 (P = 0.0016)
Test for subgroup differences: Not applicable

0.01

0.1

Favours concurrent

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours sequential

50

Analysis 2.2. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 2 Overall survival 2years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 2 Concurrent vs Sequential chemoradiotherapy


Outcome: 2 Overall survival 2-years

Study or subgroup

Risk
Difference
MH,Random,95%
CI

Risk
Difference
MH,Random,95%
CI

Concurrent

Sequential

Weight

n/N

n/N

Curran 2003

127/201

139/201

30.1 %

-0.06 [ -0.15, 0.03 ]

Fournel 2001

62/102

76/103

22.2 %

-0.13 [ -0.26, 0.00 ]

Rao 2007

15/26

24/29

9.5 %

-0.25 [ -0.49, -0.02 ]

Reinfuss 2005

63/84

66/89

21.7 %

0.01 [ -0.12, 0.14 ]

Zatloukal 2003

34/52

43/50

16.6 %

-0.21 [ -0.37, -0.05 ]

Total (95% CI)

465

472

100.0 %

-0.10 [ -0.18, -0.02 ]

Total events: 301 (Concurrent), 348 (Sequential)


Heterogeneity: Tau2 = 0.00; Chi2 = 6.80, df = 4 (P = 0.15); I2 =41%
Test for overall effect: Z = 2.51 (P = 0.012)

-2

-1

favours concurrent

favours sequential

Analysis 2.3. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 3 Progression-free


survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 2 Concurrent vs Sequential chemoradiotherapy


Outcome: 3 Progression-free survival

Study or subgroup

Concurrent
chemoRT

Sequential chemoRT

log [Hazard Ratio]

Hazard Ratio

(SE)

IV,Random,95% CI

100

101

-0.4 (0.41)

Fournel 2001

Weight

Hazard Ratio
IV,Random,95% CI

Total (95% CI)

100.0 %

0.67 [ 0.30, 1.50 ]

100.0 %

0.67 [ 0.30, 1.50 ]

Heterogeneity: not applicable


Test for overall effect: Z = 0.98 (P = 0.33)
Test for subgroup differences: Not applicable

0.01

0.1

Favours concurrent

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours sequential

51

Analysis 2.4. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 4 Progression-free


survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 2 Concurrent vs Sequential chemoradiotherapy


Outcome: 4 Progression-free survival 2-years

Study or subgroup

Concurrent

Sequential

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Fournel 2001

72/102

86/103

44.9 %

0.85 [ 0.73, 0.98 ]

Reinfuss 2005

74/84

79/89

55.1 %

0.99 [ 0.89, 1.11 ]

Total (95% CI)

186

192

100.0 %

0.92 [ 0.78, 1.09 ]

Total events: 146 (Concurrent), 165 (Sequential)


Heterogeneity: Tau2 = 0.01; Chi2 = 3.22, df = 1 (P = 0.07); I2 =69%
Test for overall effect: Z = 0.94 (P = 0.35)
Test for subgroup differences: Not applicable

0.5

0.7

Favours concurrent

1.5

Favours sequential

Analysis 2.5. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 5 Locoregional PFS 2years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 2 Concurrent vs Sequential chemoradiotherapy


Outcome: 5 Locoregional PFS 2-years

Study or subgroup

Curran 2003

Total (95% CI)

Concurrent

Sequential

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

64/201

76/201

100.0 %

0.84 [ 0.64, 1.10 ]

201

201

100.0 %

0.84 [ 0.64, 1.10 ]

Total events: 64 (Concurrent), 76 (Sequential)


Heterogeneity: not applicable
Test for overall effect: Z = 1.25 (P = 0.21)

0.2

0.5

favours concurrent

favours sequential

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

52

Analysis 2.6. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 6 Toxicity.


Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 2 Concurrent vs Sequential chemoradiotherapy


Outcome: 6 Toxicity

Study or subgroup

Concurrent

Sequential

Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Curran 2003

6/201

4/201

1.50 [ 0.43, 5.24 ]

Fournel 2001

10/93

3/100

3.58 [ 1.02, 12.62 ]

Reinfuss 2005

2/84

2/89

1.06 [ 0.15, 7.35 ]

Wu 2006

0/40

0/40

0.0 [ 0.0, 0.0 ]

Zatloukal 2003

0/52

0/50

0.0 [ 0.0, 0.0 ]

470

480

2.02 [ 0.90, 4.52 ]

1 Treatment-related deaths

Subtotal (95% CI)


Total events: 18 (Concurrent), 9 (Sequential)

Heterogeneity: Tau2 = 0.0; Chi2 = 1.45, df = 2 (P = 0.48); I2 =0.0%


Test for overall effect: Z = 1.71 (P = 0.088)
2 Acute pneumonitis
Curran 2003

8/201

14/201

0.57 [ 0.25, 1.33 ]

Fournel 2001

5/93

11/100

0.49 [ 0.18, 1.35 ]

Reinfuss 2005

5/84

2/89

2.65 [ 0.53, 13.28 ]

13/40

8/40

1.63 [ 0.76, 3.49 ]

2/51

1/48

1.88 [ 0.18, 20.09 ]

469

478

0.99 [ 0.51, 1.91 ]

Wu 2006
Zatloukal 2003

Subtotal (95% CI)


Total events: 33 (Concurrent), 36 (Sequential)

Heterogeneity: Tau2 = 0.22; Chi2 = 6.81, df = 4 (P = 0.15); I2 =41%


Test for overall effect: Z = 0.02 (P = 0.98)
3 Acute oesophagitis
Curran 2003

50/201

8/201

6.25 [ 3.04, 12.84 ]

Fournel 2001

30/93

3/100

10.75 [ 3.40, 34.05 ]

Reinfuss 2005

7/84

0/89

15.88 [ 0.92, 273.84 ]

19/40

10/40

1.90 [ 1.01, 3.56 ]

Wu 2006

0.02

0.1

Favours concurrent

10

50

Favours sequential

(Continued . . . )

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

53

(. . .
Study or subgroup

Concurrent

Continued)
Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

n/N

n/N

9/51

2/48

4.24 [ 0.96, 18.62 ]

469

478

4.96 [ 2.17, 11.37 ]

Zatloukal 2003

Subtotal (95% CI)

Sequential

Total events: 115 (Concurrent), 23 (Sequential)


Heterogeneity: Tau2 = 0.52; Chi2 = 11.81, df = 4 (P = 0.02); I2 =66%
Test for overall effect: Z = 3.79 (P = 0.00015)
4 Neutropenia
Curran 2003

117/201

113/201

1.04 [ 0.87, 1.23 ]

Fournel 2001

72/93

88/100

0.88 [ 0.77, 1.00 ]

Reinfuss 2005

4/84

1/89

4.24 [ 0.48, 37.15 ]

Wu 2006

26/40

17/40

1.53 [ 1.00, 2.34 ]

Zatloukal 2003

33/51

19/48

1.63 [ 1.09, 2.45 ]

469

478

1.18 [ 0.90, 1.55 ]

19/93

28/100

0.73 [ 0.44, 1.21 ]

6/51

3/48

1.88 [ 0.50, 7.11 ]

144

148

0.95 [ 0.41, 2.21 ]

Subtotal (95% CI)

Total events: 252 (Concurrent), 238 (Sequential)


Heterogeneity: Tau2 = 0.06; Chi2 = 17.59, df = 4 (P = 0.001); I2 =77%
Test for overall effect: Z = 1.19 (P = 0.23)
5 Anaemia
Fournel 2001
Zatloukal 2003

Subtotal (95% CI)


Total events: 25 (Concurrent), 31 (Sequential)

Heterogeneity: Tau2 = 0.19; Chi2 = 1.72, df = 1 (P = 0.19); I2 =42%


Test for overall effect: Z = 0.11 (P = 0.91)

0.02

0.1

Favours concurrent

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

50

Favours sequential

54

Analysis 3.1. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 1


Chemotherapy regime.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy


Outcome: 1 Chemotherapy regime

Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Atagi 2005

15/23

17/23

2.0 %

0.88 [ 0.60, 1.30 ]

Ball 1999 once daily

32/54

39/53

3.5 %

0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily

39/51

31/46

4.0 %

1.13 [ 0.88, 1.46 ]

Blanke 1995

85/104

97/111

9.6 %

0.94 [ 0.83, 1.05 ]

Bonner 1998

24/32

24/33

3.2 %

1.03 [ 0.77, 1.38 ]

Cakir 2004

68/88

84/88

9.2 %

0.81 [ 0.72, 0.91 ]

Clamon 1999

92/130

89/120

7.5 %

0.95 [ 0.82, 1.11 ]

Gouda 2006

11/20

18/20

1.7 %

0.61 [ 0.40, 0.93 ]

Groen 1999

66/82

56/78

6.4 %

1.12 [ 0.94, 1.34 ]

Jeremic 1995

75/108

46/61

5.8 %

0.92 [ 0.76, 1.11 ]

Jeremic 1996

37/65

49/66

3.9 %

0.77 [ 0.59, 0.99 ]

Lu 2005

27/47

30/45

2.7 %

0.86 [ 0.62, 1.19 ]

168/217

99/114

10.5 %

0.89 [ 0.81, 0.99 ]

Soresi 1988

18/45

29/50

1.6 %

0.69 [ 0.45, 1.06 ]

Trovo 1992

73/84

72/85

9.1 %

1.03 [ 0.91, 1.16 ]

Yadav 2005

12/15

11/15

1.9 %

1.09 [ 0.73, 1.62 ]

1165

1008

82.5 %

0.92 [ 0.86, 0.98 ]

1 Platinum-containing regimes

Schaake-Koning 1992

Subtotal (95% CI)

Total events: 842 (favours chemoRT), 791 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 25.29, df = 15 (P = 0.05); I2 =41%
Test for overall effect: Z = 2.48 (P = 0.013)
2 Taxane-containing regimes
Huber 2003

63/99

88/113

6.3 %

0.82 [ 0.68, 0.98 ]

Manegold 2003

29/43

38/46

4.1 %

0.82 [ 0.64, 1.04 ]

142

159

10.4 %

0.82 [ 0.71, 0.94 ]

Subtotal (95% CI)

Total events: 92 (favours chemoRT), 126 (RT alone)


Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 1.00); I2 =0.0%

0.5

0.7

favours chemoRT

1.5

favours RT alone

(Continued . . . )

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

55

(. . .
Study or subgroup

Risk Ratio
MH,Random,95%
CI

Weight

Continued)
Risk Ratio
MH,Random,95%
CI

favours chemoRT

RT alone

n/N

n/N

Landgren 1974

25/28

22/25

5.7 %

1.01 [ 0.84, 1.23 ]

Li 2008

14/30

20/30

1.5 %

0.70 [ 0.44, 1.11 ]

58

55

7.1 %

0.88 [ 0.56, 1.36 ]

100.0 %

0.91 [ 0.86, 0.97 ]

Test for overall effect: Z = 2.74 (P = 0.0061)


3 Other regimes

Subtotal (95% CI)

Total events: 39 (favours chemoRT), 42 (RT alone)


Heterogeneity: Tau2 = 0.07; Chi2 = 3.31, df = 1 (P = 0.07); I2 =70%
Test for overall effect: Z = 0.58 (P = 0.56)

Total (95% CI)

1365

1222

Total events: 973 (favours chemoRT), 959 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 30.56, df = 19 (P = 0.05); I2 =38%
Test for overall effect: Z = 3.13 (P = 0.0017)

0.5

0.7

favours chemoRT

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1.5

favours RT alone

56

Analysis 3.2. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 2 Frequency


of chemotherapy administration.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy


Outcome: 2 Frequency of chemotherapy administration

Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Atagi 2005

15/23

17/23

6.8 %

0.88 [ 0.60, 1.30 ]

Groen 1999

66/82

56/78

17.4 %

1.12 [ 0.94, 1.34 ]

Jeremic 1996

37/65

49/66

11.9 %

0.77 [ 0.59, 0.99 ]

Landgren 1974

25/28

22/25

15.9 %

1.01 [ 0.84, 1.23 ]

Li 2008

14/30

20/30

5.1 %

0.70 [ 0.44, 1.11 ]

79/107

99/114

20.9 %

0.85 [ 0.74, 0.97 ]

73/84

72/85

21.9 %

1.03 [ 0.91, 1.16 ]

419

421

100.0 %

0.94 [ 0.84, 1.05 ]

1 Daily administration

Schaake-Koning 1992
Trovo 1992

Subtotal (95% CI)

Total events: 309 (favours chemoRT), 335 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 13.26, df = 6 (P = 0.04); I2 =55%
Test for overall effect: Z = 1.11 (P = 0.27)
2 Weekly administration
Clamon 1999

92/130

89/120

22.0 %

0.95 [ 0.82, 1.11 ]

Huber 2003

63/99

88/113

16.2 %

0.82 [ 0.68, 0.98 ]

Jeremic 1995

34/52

46/61

8.6 %

0.87 [ 0.68, 1.11 ]

Manegold 2003

29/43

38/46

8.5 %

0.82 [ 0.64, 1.04 ]

89/110

99/114

38.6 %

0.93 [ 0.83, 1.05 ]

Soresi 1988

18/45

29/50

2.8 %

0.69 [ 0.45, 1.06 ]

Yadav 2005

12/15

11/15

3.3 %

1.09 [ 0.73, 1.62 ]

494

519

100.0 %

0.90 [ 0.84, 0.96 ]

Schaake-Koning 1992

Subtotal (95% CI)

Total events: 337 (favours chemoRT), 400 (RT alone)


Heterogeneity: Tau2 = 0.0; Chi2 = 5.34, df = 6 (P = 0.50); I2 =0.0%
Test for overall effect: Z = 2.93 (P = 0.0034)
3 Two- to four-weekly administration
Ball 1999 once daily

32/54

39/53

9.4 %

0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily

39/51

31/46

10.6 %

1.13 [ 0.88, 1.46 ]

0.5

0.7

favours chemoRT

1.5

favours RT alone

(Continued . . . )

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57

(. . .
Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Continued)
Risk Ratio
MH,Random,95%
CI

n/N

n/N

Blanke 1995

85/104

97/111

23.4 %

0.94 [ 0.83, 1.05 ]

Bonner 1998

24/32

24/33

8.7 %

1.03 [ 0.77, 1.38 ]

Cakir 2004

68/88

84/88

22.5 %

0.81 [ 0.72, 0.91 ]

Gouda 2006

11/20

18/20

4.7 %

0.61 [ 0.40, 0.93 ]

Jeremic 1995

41/56

46/61

13.2 %

0.97 [ 0.78, 1.20 ]

Lu 2005

27/47

30/45

7.4 %

0.86 [ 0.62, 1.19 ]

452

457

100.0 %

0.90 [ 0.81, 0.99 ]

Subtotal (95% CI)

Total events: 327 (favours chemoRT), 369 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 11.81, df = 7 (P = 0.11); I2 =41%
Test for overall effect: Z = 2.10 (P = 0.036)

0.5

0.7

favours chemoRT

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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1.5

favours RT alone

58

Analysis 3.3. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 3 Platinum


dose.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy


Outcome: 3 Platinum dose

Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

32/54

39/53

4.3 %

0.81 [ 0.61, 1.06 ]

Blanke 1995

85/104

97/111

11.5 %

0.94 [ 0.83, 1.05 ]

Bonner 1998

24/32

24/33

3.9 %

1.03 [ 0.77, 1.38 ]

Cakir 2004

68/88

84/88

11.0 %

0.81 [ 0.72, 0.91 ]

Groen 1999

66/82

56/78

7.8 %

1.12 [ 0.94, 1.34 ]

Jeremic 1995

75/108

46/61

7.1 %

0.92 [ 0.76, 1.11 ]

Jeremic 1996

37/65

49/66

4.8 %

0.77 [ 0.59, 0.99 ]

Lu 2005

27/47

30/45

3.3 %

0.86 [ 0.62, 1.19 ]

Yadav 2005

12/15

11/15

2.3 %

1.09 [ 0.73, 1.62 ]

595

550

56.0 %

0.91 [ 0.84, 1.00 ]

1 High dose
Ball 1999 once daily

Subtotal (95% CI)

Total events: 426 (favours chemoRT), 436 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 13.33, df = 8 (P = 0.10); I2 =40%
Test for overall effect: Z = 2.04 (P = 0.041)
2 Low dose
Atagi 2005

15/23

17/23

2.5 %

0.88 [ 0.60, 1.30 ]

Ball 1999 twice daily

39/51

31/46

4.8 %

1.13 [ 0.88, 1.46 ]

Clamon 1999

92/130

89/120

9.0 %

0.95 [ 0.82, 1.11 ]

Gouda 2006

11/20

18/20

2.1 %

0.61 [ 0.40, 0.93 ]

168/217

99/114

12.5 %

0.89 [ 0.81, 0.99 ]

Soresi 1988

18/45

29/50

2.0 %

0.69 [ 0.45, 1.06 ]

Trovo 1992

73/84

72/85

11.0 %

1.03 [ 0.91, 1.16 ]

570

458

44.0 %

0.93 [ 0.84, 1.03 ]

100.0 %

0.92 [ 0.86, 0.98 ]

Schaake-Koning 1992

Subtotal (95% CI)

Total events: 416 (favours chemoRT), 355 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 11.52, df = 6 (P = 0.07); I2 =48%
Test for overall effect: Z = 1.35 (P = 0.18)

Total (95% CI)

1165

1008

Total events: 842 (favours chemoRT), 791 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 25.29, df = 15 (P = 0.05); I2 =41%
Test for overall effect: Z = 2.48 (P = 0.013)

0.5

0.7

favours chemoRT

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1.5

favours RT alone

59

Analysis 3.4. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 4


Radiotherapy fractionation.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy


Outcome: 4 Radiotherapy fractionation

Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Atagi 2005

15/23

17/23

2.0 %

0.88 [ 0.60, 1.30 ]

Ball 1999 once daily

32/54

39/53

3.5 %

0.81 [ 0.61, 1.06 ]

Blanke 1995

85/104

97/111

9.6 %

0.94 [ 0.83, 1.05 ]

Cakir 2004

68/88

84/88

9.2 %

0.81 [ 0.72, 0.91 ]

Clamon 1999

92/130

89/120

7.5 %

0.95 [ 0.82, 1.11 ]

Gouda 2006

11/20

18/20

1.7 %

0.61 [ 0.40, 0.93 ]

Groen 1999

66/82

56/78

6.4 %

1.12 [ 0.94, 1.34 ]

Huber 2003

63/99

88/113

6.3 %

0.82 [ 0.68, 0.98 ]

Landgren 1974

25/28

22/25

5.7 %

1.01 [ 0.84, 1.23 ]

Lu 2005

27/47

30/45

2.7 %

0.86 [ 0.62, 1.19 ]

Manegold 2003

29/43

38/46

4.1 %

0.82 [ 0.64, 1.04 ]

168/217

99/114

10.5 %

0.89 [ 0.81, 0.99 ]

Soresi 1988

18/45

29/50

1.6 %

0.69 [ 0.45, 1.06 ]

Trovo 1992

73/84

72/85

9.1 %

1.03 [ 0.91, 1.16 ]

Yadav 2005

12/15

11/15

1.9 %

1.09 [ 0.73, 1.62 ]

1079

986

81.7 %

0.91 [ 0.85, 0.97 ]

1 Once daily fractionation

Schaake-Koning 1992

Subtotal (95% CI)

Total events: 784 (favours chemoRT), 789 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 23.86, df = 14 (P = 0.05); I2 =41%
Test for overall effect: Z = 2.93 (P = 0.0034)
2 Twice daily fractionation
Ball 1999 twice daily

39/51

31/46

4.0 %

1.13 [ 0.88, 1.46 ]

Bonner 1998

24/32

24/33

3.2 %

1.03 [ 0.77, 1.38 ]

Jeremic 1995

75/108

46/61

5.8 %

0.92 [ 0.76, 1.11 ]

Jeremic 1996

37/65

49/66

3.9 %

0.77 [ 0.59, 0.99 ]

0.5

0.7

favours chemoRT

1.5

favours RT alone

(Continued . . . )

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

60

(. . .
Study or subgroup

favours chemoRT

Li 2008

Subtotal (95% CI)

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Continued)
Risk Ratio
MH,Random,95%
CI

n/N

n/N

14/30

20/30

1.5 %

0.70 [ 0.44, 1.11 ]

286

236

18.3 %

0.92 [ 0.79, 1.08 ]

100.0 %

0.91 [ 0.86, 0.97 ]

Total events: 189 (favours chemoRT), 170 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 6.69, df = 4 (P = 0.15); I2 =40%
Test for overall effect: Z = 1.02 (P = 0.31)

Total (95% CI)

1365

1222

Total events: 973 (favours chemoRT), 959 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 30.56, df = 19 (P = 0.05); I2 =38%
Test for overall effect: Z = 3.13 (P = 0.0017)

0.5

0.7

1.5

favours chemoRT

favours RT alone

Analysis 3.5. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 5 Dose of


radiotherapy.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy


Outcome: 5 Dose of radiotherapy

Study or subgroup

Favours experimental

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Atagi 2005

15/23

17/23

2.0 %

0.88 [ 0.60, 1.30 ]

Ball 1999 once daily

32/54

39/53

3.5 %

0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily

39/51

31/46

4.0 %

1.13 [ 0.88, 1.46 ]

Bonner 1998

24/32

24/33

3.2 %

1.03 [ 0.77, 1.38 ]

Clamon 1999

92/130

89/120

7.5 %

0.95 [ 0.82, 1.11 ]

Gouda 2006

11/20

18/20

1.7 %

0.61 [ 0.40, 0.93 ]

Groen 1999

66/82

56/78

6.4 %

1.12 [ 0.94, 1.34 ]

Huber 2003

63/99

88/113

6.3 %

0.82 [ 0.68, 0.98 ]

1 Low dose

0.5

0.7

Favours experimental

1.5

Favours control

(Continued . . . )

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61

(. . .
Study or subgroup

Favours experimental

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Continued)
Risk Ratio
MH,Random,95%
CI

n/N

n/N

29/43

38/46

4.1 %

0.82 [ 0.64, 1.04 ]

168/217

99/114

10.5 %

0.89 [ 0.81, 0.99 ]

Soresi 1988

18/45

29/50

1.6 %

0.69 [ 0.45, 1.06 ]

Trovo 1992

73/84

72/85

9.1 %

1.03 [ 0.91, 1.16 ]

Yadav 2005

12/15

11/15

1.9 %

1.09 [ 0.73, 1.62 ]

895

796

61.7 %

0.93 [ 0.86, 1.01 ]

Manegold 2003
Schaake-Koning 1992

Subtotal (95% CI)

Total events: 642 (Favours experimental), 611 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 21.31, df = 12 (P = 0.05); I2 =44%
Test for overall effect: Z = 1.79 (P = 0.074)
2 High dose
Blanke 1995

85/104

97/111

9.6 %

0.94 [ 0.83, 1.05 ]

Cakir 2004

68/88

84/88

9.2 %

0.81 [ 0.72, 0.91 ]

Jeremic 1995

75/108

46/61

5.8 %

0.92 [ 0.76, 1.11 ]

Jeremic 1996

37/65

49/66

3.9 %

0.77 [ 0.59, 0.99 ]

Landgren 1974

25/28

22/25

5.7 %

1.01 [ 0.84, 1.23 ]

Li 2008

14/30

20/30

1.5 %

0.70 [ 0.44, 1.11 ]

Lu 2005

27/47

30/45

2.7 %

0.86 [ 0.62, 1.19 ]

470

426

38.3 %

0.88 [ 0.81, 0.95 ]

100.0 %

0.91 [ 0.86, 0.97 ]

Subtotal (95% CI)

Total events: 331 (Favours experimental), 348 (RT alone)


Heterogeneity: Tau2 = 0.00; Chi2 = 7.55, df = 6 (P = 0.27); I2 =21%
Test for overall effect: Z = 3.11 (P = 0.0019)

Total (95% CI)

1365

1222

Total events: 973 (Favours experimental), 959 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 30.56, df = 19 (P = 0.05); I2 =38%
Test for overall effect: Z = 3.13 (P = 0.0017)

0.5

0.7

Favours experimental

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Favours control

62

Analysis 3.6. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 6 Duration


of follow-up.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy


Outcome: 6 Duration of follow-up

Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Ball 1999 once daily

32/54

39/53

3.5 %

0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily

39/51

31/46

4.0 %

1.13 [ 0.88, 1.46 ]

Blanke 1995

85/104

97/111

9.6 %

0.94 [ 0.83, 1.05 ]

Cakir 2004

68/88

84/88

9.2 %

0.81 [ 0.72, 0.91 ]

Huber 2003

63/99

88/113

6.3 %

0.82 [ 0.68, 0.98 ]

Landgren 1974

25/28

22/25

5.7 %

1.01 [ 0.84, 1.23 ]

Schaake-Koning 1992

168/217

99/114

10.5 %

0.89 [ 0.81, 0.99 ]

Subtotal (95% CI)

641

550

48.6 %

0.90 [ 0.83, 0.97 ]

1 Minimum follow-up 22 months or more

Total events: 480 (favours chemoRT), 460 (RT alone)


Heterogeneity: Tau2 = 0.00; Chi2 = 9.76, df = 6 (P = 0.13); I2 =39%
Test for overall effect: Z = 2.83 (P = 0.0046)
2 Minimum follow-up 18 months or less
Bonner 1998

24/32

24/33

3.2 %

1.03 [ 0.77, 1.38 ]

Soresi 1988

18/45

29/50

1.6 %

0.69 [ 0.45, 1.06 ]

Trovo 1992

73/84

72/85

9.1 %

1.03 [ 0.91, 1.16 ]

Yadav 2005

12/15

11/15

1.9 %

1.09 [ 0.73, 1.62 ]

176

183

15.9 %

0.99 [ 0.85, 1.15 ]

Subtotal (95% CI)

Total events: 127 (favours chemoRT), 136 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 3.95, df = 3 (P = 0.27); I2 =24%
Test for overall effect: Z = 0.11 (P = 0.91)
3 Duration of follow-up uncertain
Atagi 2005

15/23

17/23

2.0 %

0.88 [ 0.60, 1.30 ]

Clamon 1999

92/130

89/120

7.5 %

0.95 [ 0.82, 1.11 ]

Gouda 2006

11/20

18/20

1.7 %

0.61 [ 0.40, 0.93 ]

Groen 1999

66/82

56/78

6.4 %

1.12 [ 0.94, 1.34 ]

Jeremic 1995

75/108

46/61

5.8 %

0.92 [ 0.76, 1.11 ]

0.5

0.7

favours chemoRT

1.5

favours RT alone

(Continued . . . )

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

63

(. . .
Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Continued)
Risk Ratio
MH,Random,95%
CI

n/N

n/N

Jeremic 1996

37/65

49/66

3.9 %

0.77 [ 0.59, 0.99 ]

Li 2008

14/30

20/30

1.5 %

0.70 [ 0.44, 1.11 ]

Lu 2005

27/47

30/45

2.7 %

0.86 [ 0.62, 1.19 ]

Manegold 2003

29/43

38/46

4.1 %

0.82 [ 0.64, 1.04 ]

548

489

35.5 %

0.89 [ 0.79, 0.99 ]

100.0 %

0.91 [ 0.86, 0.97 ]

Subtotal (95% CI)

Total events: 366 (favours chemoRT), 363 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 13.31, df = 8 (P = 0.10); I2 =40%
Test for overall effect: Z = 2.18 (P = 0.029)

Total (95% CI)

1365

1222

Total events: 973 (favours chemoRT), 959 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 30.56, df = 19 (P = 0.05); I2 =38%
Test for overall effect: Z = 3.13 (P = 0.0017)

0.5

0.7

favours chemoRT

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1.5

favours RT alone

64

Analysis 4.1. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 1 Dose of radiotherapy.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 4 Subgroup analysis Concurrent vs Sequential


Outcome: 1 Dose of radiotherapy

Study or subgroup

Favours experimental

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

34/52

43/50

17.1 %

0.76 [ 0.61, 0.95 ]

52

50

17.1 %

0.76 [ 0.61, 0.95 ]

1 Low dose
Zatloukal 2003

Subtotal (95% CI)

Total events: 34 (Favours experimental), 43 (RT alone)


Heterogeneity: not applicable
Test for overall effect: Z = 2.36 (P = 0.018)
2 High dose
Curran 2003

127/201

139/201

30.0 %

0.91 [ 0.79, 1.05 ]

Fournel 2001

62/102

76/103

21.1 %

0.82 [ 0.68, 1.00 ]

Rao 2007

15/26

24/29

8.0 %

0.70 [ 0.48, 1.01 ]

Reinfuss 2005

63/84

66/89

23.9 %

1.01 [ 0.85, 1.20 ]

413

422

82.9 %

0.89 [ 0.79, 1.01 ]

100.0 %

0.87 [ 0.78, 0.97 ]

Subtotal (95% CI)

Total events: 267 (Favours experimental), 305 (RT alone)


Heterogeneity: Tau2 = 0.00; Chi2 = 4.44, df = 3 (P = 0.22); I2 =32%
Test for overall effect: Z = 1.85 (P = 0.064)

Total (95% CI)

465

472

Total events: 301 (Favours experimental), 348 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 6.31, df = 4 (P = 0.18); I2 =37%
Test for overall effect: Z = 2.45 (P = 0.014)
Test for subgroup differences: Chi2 = 0.0, df = 1 (P = 0.0), I2 =0.0%

0.5

0.7

Favours experimental

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Favours control

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Analysis 4.2. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 2 Duration of follow-up.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 4 Subgroup analysis Concurrent vs Sequential


Outcome: 2 Duration of follow-up

Study or subgroup

favours chemoRT

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Curran 2003

127/201

139/201

30.0 %

0.91 [ 0.79, 1.05 ]

Fournel 2001

62/102

76/103

21.1 %

0.82 [ 0.68, 1.00 ]

303

304

51.0 %

0.88 [ 0.79, 0.99 ]

1 Minimum follow-up 22 months or more

Subtotal (95% CI)

Total events: 189 (favours chemoRT), 215 (RT alone)


Heterogeneity: Tau2 = 0.0; Chi2 = 0.72, df = 1 (P = 0.40); I2 =0.0%
Test for overall effect: Z = 2.17 (P = 0.030)
2 Minimum follow-up 18 months or less
Rao 2007

15/26

24/29

8.0 %

0.70 [ 0.48, 1.01 ]

Reinfuss 2005

63/84

66/89

23.9 %

1.01 [ 0.85, 1.20 ]

Zatloukal 2003

34/52

43/50

17.1 %

0.76 [ 0.61, 0.95 ]

162

168

49.0 %

0.84 [ 0.66, 1.06 ]

Subtotal (95% CI)

Total events: 112 (favours chemoRT), 133 (RT alone)


Heterogeneity: Tau2 = 0.03; Chi2 = 5.60, df = 2 (P = 0.06); I2 =64%
Test for overall effect: Z = 1.46 (P = 0.14)
3 Duration of follow-up uncertain

Subtotal (95% CI)

0.0 %

0.0 [ 0.0, 0.0 ]

465

472

100.0 %

0.87 [ 0.78, 0.97 ]

Total events: 0 (favours chemoRT), 0 (RT alone)


Heterogeneity: not applicable
Test for overall effect: not applicable

Total (95% CI)

Total events: 301 (favours chemoRT), 348 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 6.31, df = 4 (P = 0.18); I2 =37%
Test for overall effect: Z = 2.45 (P = 0.014)

0.5

0.7

favours chemoRT

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favours RT alone

66

Analysis 5.1. Comparison 5 More frequent versus less frequent chemotherapy, Outcome 1 Frequency of
chemotherapy.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 5 More frequent versus less frequent chemotherapy


Outcome: 1 Frequency of chemotherapy

Study or subgroup

Jeremic 1995
Schaake-Koning 1992

Total (95% CI)

more
frequent
chemo

less frequent chemo

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

34/52

41/56

24.6 %

0.89 [ 0.69, 1.15 ]

79/107

89/110

75.4 %

0.91 [ 0.79, 1.05 ]

159

166

100.0 %

0.91 [ 0.80, 1.03 ]

Total events: 113 (more frequent chemo), 130 (less frequent chemo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%
Test for overall effect: Z = 1.51 (P = 0.13)

0.5

0.7

more frequent chemo

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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1.5

less frequent chemo

67

Analysis 6.1. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 1 Overall survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Outcome: 1 Overall survival
Study or subgroup

log [Hazard Ratio]

Hazard Ratio

(SE)

Weight

IV,Fixed,95% CI

Hazard Ratio
IV,Fixed,95% CI

Blanke 1995

-0.13 (0.14)

17.1 %

0.88 [ 0.67, 1.16 ]

Cakir 2004

-0.61 (0.16)

13.1 %

0.54 [ 0.40, 0.74 ]

Clamon 1999

-0.12 (0.37)

2.4 %

0.89 [ 0.43, 1.83 ]

Huber 2003

-0.27 (0.16)

13.1 %

0.76 [ 0.56, 1.04 ]

Jeremic 1995

-0.28 (0.21)

7.6 %

0.76 [ 0.50, 1.14 ]

Jeremic 1995

-0.61 (0.2)

8.4 %

0.54 [ 0.37, 0.80 ]

Jeremic 1996

-0.44 (0.19)

9.3 %

0.64 [ 0.44, 0.93 ]

Schaake-Koning 1992

-0.25 (0.12)

23.2 %

0.78 [ 0.62, 0.99 ]

Soresi 1988

-0.39 (0.29)

4.0 %

0.68 [ 0.38, 1.20 ]

Yadav 2005

-0.59 (0.42)

1.9 %

0.55 [ 0.24, 1.26 ]

100.0 %

0.71 [ 0.64, 0.80 ]

Total (95% CI)


Heterogeneity: Chi2 = 8.77, df = 9 (P = 0.46); I2 =0.0%
Test for overall effect: Z = 5.84 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours chemoRT

10

Favours RT

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

68

Analysis 6.2. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 2 Overall survival 2years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Outcome: 2 Overall survival 2-years

Study or subgroup

RT + chemo

RT alone

n/N

n/N

Atagi 2005

15/23

17/23

1.7 %

0.88 [ 0.60, 1.30 ]

Ball 1999 once daily

32/54

39/53

3.9 %

0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily

39/51

31/46

3.3 %

1.13 [ 0.88, 1.46 ]

Blanke 1995

85/104

97/111

9.4 %

0.94 [ 0.83, 1.05 ]

Bonner 1998

24/32

24/33

2.4 %

1.03 [ 0.77, 1.38 ]

Cakir 2004

68/88

84/88

8.4 %

0.81 [ 0.72, 0.91 ]

Clamon 1999

92/130

89/120

9.3 %

0.95 [ 0.82, 1.11 ]

Gouda 2006

11/20

18/20

1.8 %

0.61 [ 0.40, 0.93 ]

Groen 1999

66/82

56/78

5.7 %

1.12 [ 0.94, 1.34 ]

Huber 2003

63/99

88/113

8.2 %

0.82 [ 0.68, 0.98 ]

Jeremic 1995

75/108

46/61

5.9 %

0.92 [ 0.76, 1.11 ]

Jeremic 1996

37/65

49/66

4.9 %

0.77 [ 0.59, 0.99 ]

Landgren 1974

25/28

22/25

2.3 %

1.01 [ 0.84, 1.23 ]

Li 2008

14/30

20/30

2.0 %

0.70 [ 0.44, 1.11 ]

Lu 2005

27/47

30/45

3.1 %

0.86 [ 0.62, 1.19 ]

Manegold 2003

29/43

38/46

3.7 %

0.82 [ 0.64, 1.04 ]

168/217

99/114

13.0 %

0.89 [ 0.81, 0.99 ]

Soresi 1988

18/45

29/50

2.8 %

0.69 [ 0.45, 1.06 ]

Trovo 1992

73/84

72/85

7.2 %

1.03 [ 0.91, 1.16 ]

Yadav 2005

12/15

11/15

1.1 %

1.09 [ 0.73, 1.62 ]

1365

1222

100.0 %

0.90 [ 0.86, 0.94 ]

Schaake-Koning 1992

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 973 (RT + chemo), 959 (RT alone)


Heterogeneity: Chi2 = 30.56, df = 19 (P = 0.05); I2 =38%
Test for overall effect: Z = 4.57 (P < 0.00001)

0.5

0.7

favours chemoRT

1.5

favours RT alone

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

69

Analysis 6.3. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 3 Progression-free


survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Outcome: 3 Progression-free survival

Study or subgroup

log [Hazard Ratio]

Hazard Ratio

(SE)

Weight

IV,Fixed,95% CI

Hazard Ratio
IV,Fixed,95% CI

Blanke 1995

-0.27 (0.14)

19.2 %

0.76 [ 0.58, 1.00 ]

Cakir 2004

-0.6 (0.15)

16.7 %

0.55 [ 0.41, 0.74 ]

Clamon 1999

-0.04 (0.13)

22.2 %

0.96 [ 0.74, 1.24 ]

Huber 2003

-0.56 (0.16)

14.7 %

0.57 [ 0.42, 0.78 ]

Jeremic 1995

-0.62 (0.2)

9.4 %

0.54 [ 0.36, 0.80 ]

Jeremic 1995

-0.29 (0.2)

9.4 %

0.75 [ 0.51, 1.11 ]

Soresi 1988

-0.27 (0.25)

6.0 %

0.76 [ 0.47, 1.25 ]

Yadav 2005

-0.51 (0.4)

2.4 %

0.60 [ 0.27, 1.32 ]

100.0 %

0.70 [ 0.62, 0.79 ]

Total (95% CI)


Heterogeneity: Chi2 = 12.68, df = 7 (P = 0.08); I2 =45%
Test for overall effect: Z = 5.82 (P < 0.00001)
Test for subgroup differences: Not applicable

0.01

0.1

Favours experimental

10

100

Favours control

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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70

Analysis 6.4. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 4 Progression-free


survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Outcome: 4 Progression-free survival 2-years

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Blanke 1995

93/104

106/111

17.1 %

0.94 [ 0.87, 1.01 ]

Cakir 2004

72/88

84/88

14.0 %

0.86 [ 0.77, 0.96 ]

111/130

103/120

17.8 %

0.99 [ 0.90, 1.10 ]

Huber 2003

65/99

93/113

14.4 %

0.80 [ 0.68, 0.94 ]

Jeremic 1995

82/108

52/61

11.1 %

0.89 [ 0.77, 1.03 ]

Manegold 2003

34/43

41/46

6.6 %

0.89 [ 0.74, 1.07 ]

Soresi 1988

25/45

39/50

6.1 %

0.71 [ 0.53, 0.96 ]

Trovo 1992

68/84

66/85

10.9 %

1.04 [ 0.89, 1.22 ]

Yadav 2005

13/15

12/15

2.0 %

1.08 [ 0.79, 1.49 ]

716

689

100.0 %

0.91 [ 0.87, 0.95 ]

Study or subgroup

Clamon 1999

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 563 (Concurrent chemoRT), 596 (Radiotherapy)


Heterogeneity: Chi2 = 14.00, df = 8 (P = 0.08); I2 =43%
Test for overall effect: Z = 3.93 (P = 0.000086)
Test for subgroup differences: Not applicable

0.01

0.1

Favours experimental

10

100

Favours control

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71

Analysis 6.5. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 5 Locoregional


progression-free survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Outcome: 5 Locoregional progression-free survival

Study or subgroup

log [Hazard Ratio]

Hazard Ratio

(SE)
Cakir 2004

Weight

IV,Fixed,95% CI

Hazard Ratio
IV,Fixed,95% CI

-0.63 (0.16)

45.0 %

0.53 [ 0.39, 0.73 ]

Jeremic 1995

-0.4 (0.21)

26.1 %

0.67 [ 0.44, 1.01 ]

Jeremic 1995

-0.06 (0.2)

28.8 %

0.94 [ 0.64, 1.39 ]

100.0 %

0.67 [ 0.54, 0.82 ]

Total (95% CI)


Heterogeneity: Chi2 = 4.95, df = 2 (P = 0.08); I2 =60%
Test for overall effect: Z = 3.78 (P = 0.00016)
Test for subgroup differences: Not applicable

0.01

0.1

Favours experimental

10

100

Favours control

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

72

Analysis 6.6. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 6 Locoregional


progression-free survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Outcome: 6 Locoregional progression-free survival 2-years

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Bonner 1998

21/32

19/33

6.0 %

1.14 [ 0.78, 1.68 ]

Cakir 2004

58/88

83/88

26.6 %

0.70 [ 0.60, 0.82 ]

Jeremic 1995

69/108

40/61

16.4 %

0.97 [ 0.77, 1.23 ]

Jeremic 1996

28/65

39/66

12.4 %

0.73 [ 0.52, 1.03 ]

150/217

92/114

38.6 %

0.86 [ 0.75, 0.97 ]

510

362

100.0 %

0.84 [ 0.76, 0.91 ]

Study or subgroup

Schaake-Koning 1992

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 326 (Concurrent chemoRT), 273 (Radiotherapy)


Heterogeneity: Chi2 = 9.81, df = 4 (P = 0.04); I2 =59%
Test for overall effect: Z = 3.97 (P = 0.000072)
Test for subgroup differences: Not applicable

0.01

0.1

Favours experimental

10

100

Favours control

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

73

Analysis 6.7. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 7 Toxicity.


Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Outcome: 7 Toxicity

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Atagi 2005

3/23

1/23

3.00 [ 0.34, 26.76 ]

Ball 1999 once daily

0/54

0/53

0.0 [ 0.0, 0.0 ]

Ball 1999 twice daily

2/51

3/46

0.60 [ 0.11, 3.44 ]

Blanke 1995

2/104

0/111

5.33 [ 0.26, 109.80 ]

Bonner 1998

0/32

0/33

0.0 [ 0.0, 0.0 ]

Clamon 1999

2/130

2/120

0.92 [ 0.13, 6.45 ]

Groen 1999

0/82

0/78

0.0 [ 0.0, 0.0 ]

Huber 2003

0/99

0/113

0.0 [ 0.0, 0.0 ]

Jeremic 1995

0/108

0/61

0.0 [ 0.0, 0.0 ]

Jeremic 1996

0/65

0/66

0.0 [ 0.0, 0.0 ]

Landgren 1974

0/26

0/25

0.0 [ 0.0, 0.0 ]

2/217

0/114

2.64 [ 0.13, 54.48 ]

Soresi 1988

0/45

0/50

0.0 [ 0.0, 0.0 ]

Trovo 1992

0/73

0/73

0.0 [ 0.0, 0.0 ]

1109

966

1.51 [ 0.60, 3.79 ]

Study or subgroup

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI

1 Treatment-related deaths

Schaake-Koning 1992

Subtotal (95% CI)

Total events: 11 (Concurrent chemoRT), 6 (Radiotherapy)


Heterogeneity: Chi2 = 2.49, df = 4 (P = 0.65); I2 =0.0%
Test for overall effect: Z = 0.88 (P = 0.38)
2 Acute pneumonitis
Atagi 2005

1/23

1/23

1.00 [ 0.07, 15.04 ]

Bonner 1998

5/32

4/33

1.29 [ 0.38, 4.37 ]

Clamon 1999

1/130

5/120

0.18 [ 0.02, 1.56 ]

Groen 1999

2/82

5/78

0.38 [ 0.08, 1.90 ]

Huber 2003

1/99

0/113

3.42 [ 0.14, 83.01 ]

Jeremic 1995

8/108

3/61

1.51 [ 0.41, 5.47 ]

Jeremic 1996

4/65

3/66

1.35 [ 0.32, 5.81 ]


0.01

0.1

Favours experimental

10

100

Favours control

(Continued . . . )

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

74

(. . .

Continued)

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Landgren 1974

1/26

0/25

2.89 [ 0.12, 67.75 ]

Soresi 1988

1/45

0/50

3.33 [ 0.14, 79.64 ]

610

569

1.00 [ 0.57, 1.74 ]

0/23

0/23

0.0 [ 0.0, 0.0 ]

Ball 1999 once daily

11/53

6/51

1.76 [ 0.70, 4.42 ]

Ball 1999 twice daily

24/50

15/46

1.47 [ 0.89, 2.44 ]

Blanke 1995

3/104

3/111

1.07 [ 0.22, 5.17 ]

Bonner 1998

4/32

3/33

1.38 [ 0.33, 5.66 ]

Clamon 1999

13/130

4/120

3.00 [ 1.01, 8.95 ]

Gouda 2006

5/20

1/20

5.00 [ 0.64, 39.06 ]

Groen 1999

8/82

2/78

3.80 [ 0.83, 17.36 ]

Huber 2003

13/99

6/113

2.47 [ 0.98, 6.26 ]

Jeremic 1995

4/108

3/61

0.75 [ 0.17, 3.25 ]

Jeremic 1996

5/65

4/66

1.27 [ 0.36, 4.52 ]

Landgren 1974

10/26

8/25

1.20 [ 0.57, 2.55 ]

Lu 2005

10/47

2/45

4.79 [ 1.11, 20.66 ]

7/43

0/46

16.02 [ 0.94, 272.34 ]

Schaake-Koning 1992

5/217

0/114

5.80 [ 0.32, 104.02 ]

Trovo 1992

12/73

6/73

2.00 [ 0.79, 5.04 ]

Yadav 2005

0/15

1/15

0.33 [ 0.01, 7.58 ]

1187

1040

1.96 [ 1.50, 2.57 ]

4/23

2/23

2.00 [ 0.41, 9.87 ]

Clamon 1999

2/130

7/120

0.26 [ 0.06, 1.24 ]

Jeremic 1995

7/108

0/61

8.53 [ 0.50, 146.87 ]

Jeremic 1996

3/65

2/66

1.52 [ 0.26, 8.82 ]

326

270

1.21 [ 0.56, 2.60 ]

Study or subgroup

Subtotal (95% CI)

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI

Total events: 24 (Concurrent chemoRT), 21 (Radiotherapy)


Heterogeneity: Chi2 = 6.07, df = 8 (P = 0.64); I2 =0.0%
Test for overall effect: Z = 0.01 (P = 0.99)
3 Acute oesophagitis
Atagi 2005

Manegold 2003

Subtotal (95% CI)

Total events: 134 (Concurrent chemoRT), 64 (Radiotherapy)


Heterogeneity: Chi2 = 13.51, df = 15 (P = 0.56); I2 =0.0%
Test for overall effect: Z = 4.89 (P < 0.00001)
4 Pulmonary fibrosis
Atagi 2005

Subtotal (95% CI)

0.01

0.1

Favours experimental

10

100

Favours control

(Continued . . . )
Concurrent chemoradiotherapy in non-small cell lung cancer (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

75

(. . .
Study or subgroup

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Risk Ratio

Continued)
Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI

Total events: 16 (Concurrent chemoRT), 11 (Radiotherapy)


Heterogeneity: Chi2 = 5.96, df = 3 (P = 0.11); I2 =50%
Test for overall effect: Z = 0.48 (P = 0.63)
5 Late oesophagitis
Jeremic 1995

5/108

0/61

6.26 [ 0.35, 111.26 ]

Jeremic 1996

3/65

3/66

1.02 [ 0.21, 4.85 ]

173

127

1.94 [ 0.53, 7.14 ]

10/23

0/23

21.00 [ 1.30, 338.51 ]

Ball 1999 once daily

7/53

0/51

14.44 [ 0.85, 246.55 ]

Ball 1999 twice daily

1/50

0/46

2.76 [ 0.12, 66.22 ]

20/130

7/120

2.64 [ 1.16, 6.01 ]

Gouda 2006

5/20

1/20

5.00 [ 0.64, 39.06 ]

Huber 2003

2/99

0/113

5.70 [ 0.28, 117.32 ]

Manegold 2003

2/43

1/46

2.14 [ 0.20, 22.75 ]

418

419

4.29 [ 2.28, 8.07 ]

Subtotal (95% CI)

Total events: 8 (Concurrent chemoRT), 3 (Radiotherapy)


Heterogeneity: Chi2 = 1.29, df = 1 (P = 0.26); I2 =23%
Test for overall effect: Z = 1.00 (P = 0.32)
6 Neutropenia
Atagi 2005

Clamon 1999

Subtotal (95% CI)

Total events: 47 (Concurrent chemoRT), 9 (Radiotherapy)


Heterogeneity: Chi2 = 3.76, df = 6 (P = 0.71); I2 =0.0%
Test for overall effect: Z = 4.51 (P < 0.00001)
7 Anaemia (grade 3 to 4)
Ball 1999 once daily

0/53

1/51

0.32 [ 0.01, 7.70 ]

Ball 1999 twice daily

0/50

0/46

0.0 [ 0.0, 0.0 ]

19/130

2/120

8.77 [ 2.09, 36.85 ]

Groen 1999

2/82

0/78

4.76 [ 0.23, 97.59 ]

Huber 2003

1/99

0/113

3.42 [ 0.14, 83.01 ]

414

408

4.96 [ 1.82, 13.51 ]

Clamon 1999

Subtotal (95% CI)

Total events: 22 (Concurrent chemoRT), 3 (Radiotherapy)


Heterogeneity: Chi2 = 3.51, df = 3 (P = 0.32); I2 =15%
Test for overall effect: Z = 3.13 (P = 0.0017)
8 Anaemia (grade 1 to 4)
Atagi 2005

16/23

8/23

2.00 [ 1.07, 3.72 ]

Ball 1999 once daily

20/53

6/51

3.21 [ 1.40, 7.34 ]

Ball 1999 twice daily

15/50

8/46

1.73 [ 0.81, 3.68 ]

8/88

7/88

1.14 [ 0.43, 3.02 ]

Cakir 2004

0.01

0.1

Favours experimental

10

100

Favours control

(Continued . . . )
Concurrent chemoradiotherapy in non-small cell lung cancer (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

76

(. . .

Continued)

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Gouda 2006

18/20

7/20

2.57 [ 1.39, 4.76 ]

Groen 1999

19/82

11/78

1.64 [ 0.84, 3.23 ]

Manegold 2003

0/43

0/46

0.0 [ 0.0, 0.0 ]

Trovo 1992

4/73

3/73

1.33 [ 0.31, 5.75 ]

Yadav 2005

1/15

0/15

3.00 [ 0.13, 68.26 ]

447

440

1.95 [ 1.46, 2.61 ]

Study or subgroup

Subtotal (95% CI)

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI

Total events: 101 (Concurrent chemoRT), 50 (Radiotherapy)


Heterogeneity: Chi2 = 4.02, df = 7 (P = 0.78); I2 =0.0%
Test for overall effect: Z = 4.53 (P < 0.00001)

0.01

0.1

Favours experimental

10

100

Favours control

Analysis 7.1. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 1 Overall survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 7 Sensitivity fixed: Concurrent vs Sequential


Outcome: 1 Overall survival

Study or subgroup

log [Hazard Ratio]

Hazard Ratio

(SE)

Weight

IV,Fixed,95% CI

Hazard Ratio
IV,Fixed,95% CI

Curran 2003

-0.24 (0.11)

73.8 %

0.79 [ 0.63, 0.98 ]

Fournel 2001

-0.4 (0.34)

7.7 %

0.67 [ 0.34, 1.31 ]

-0.49 (0.22)

18.5 %

0.61 [ 0.40, 0.94 ]

100.0 %

0.74 [ 0.62, 0.89 ]

Zatloukal 2003

Total (95% CI)


Heterogeneity: Chi2 = 1.13, df = 2 (P = 0.57); I2 =0.0%
Test for overall effect: Z = 3.16 (P = 0.0016)
Test for subgroup differences: Not applicable

0.01

0.1

Favours concurrent

10

100

Favours sequential

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

77

Analysis 7.2. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 2 Overall survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 7 Sensitivity fixed: Concurrent vs Sequential


Outcome: 2 Overall survival 2-years

Study or subgroup

Concurrent

Sequential

n/N

n/N

Risk Ratio

Weight

Curran 2003

127/201

139/201

40.3 %

0.91 [ 0.79, 1.05 ]

Fournel 2001

62/102

76/103

21.9 %

0.82 [ 0.68, 1.00 ]

Rao 2007

15/26

24/29

6.6 %

0.70 [ 0.48, 1.01 ]

Reinfuss 2005

63/84

66/89

18.6 %

1.01 [ 0.85, 1.20 ]

Zatloukal 2003

34/52

43/50

12.7 %

0.76 [ 0.61, 0.95 ]

Total (95% CI)

465

472

100.0 %

0.88 [ 0.81, 0.96 ]

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 301 (Concurrent), 348 (Sequential)


Heterogeneity: Chi2 = 6.31, df = 4 (P = 0.18); I2 =37%
Test for overall effect: Z = 2.96 (P = 0.0031)

0.5

0.7

favours concurrent

1.5

favours sequential

Analysis 7.3. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 3 Progression-free


survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 7 Sensitivity fixed: Concurrent vs Sequential


Outcome: 3 Progression-free survival

Study or subgroup

log [Hazard Ratio]

Hazard Ratio

(SE)
Fournel 2001

Weight

IV,Fixed,95% CI

Hazard Ratio
IV,Fixed,95% CI

-0.4 (0.41)

Total (95% CI)

100.0 %

0.67 [ 0.30, 1.50 ]

100.0 %

0.67 [ 0.30, 1.50 ]

Heterogeneity: not applicable


Test for overall effect: Z = 0.98 (P = 0.33)
Test for subgroup differences: Not applicable

0.01

0.1

Favours concurrent

10

100

Favours sequential

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78

Analysis 7.4. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 4 Progression-free


survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 7 Sensitivity fixed: Concurrent vs Sequential


Outcome: 4 Progression-free survival 2-years

Study or subgroup

Concurrent

Sequential

n/N

n/N

Risk Ratio

Weight

Fournel 2001

72/102

86/103

52.7 %

0.85 [ 0.73, 0.98 ]

Reinfuss 2005

74/84

79/89

47.3 %

0.99 [ 0.89, 1.11 ]

Total (95% CI)

186

192

100.0 %

0.91 [ 0.83, 1.00 ]

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 146 (Concurrent), 165 (Sequential)


Heterogeneity: Chi2 = 3.22, df = 1 (P = 0.07); I2 =69%
Test for overall effect: Z = 1.86 (P = 0.062)

0.01

0.1

Favours concurrent

10

100

Favours sequential

Analysis 7.5. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 5 Locoregional


progression-free survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 7 Sensitivity fixed: Concurrent vs Sequential


Outcome: 5 Locoregional progression-free survival 2-years

Study or subgroup

Curran 2003

Total (95% CI)

Concurrent

Sequential

n/N

n/N

Risk Ratio

Weight

64/201

76/201

100.0 %

0.84 [ 0.64, 1.10 ]

201

201

100.0 %

0.84 [ 0.64, 1.10 ]

M-H,Fixed,95% CI

Risk Ratio
M-H,Fixed,95% CI

Total events: 64 (Concurrent), 76 (Sequential)


Heterogeneity: not applicable
Test for overall effect: Z = 1.25 (P = 0.21)

0.2

0.5

favours concurrent

favours sequential

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

79

Analysis 7.6. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 6 Toxicity.


Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 7 Sensitivity fixed: Concurrent vs Sequential


Outcome: 6 Toxicity

Study or subgroup

Concurrent

Sequential

n/N

n/N

Risk Ratio

Risk Ratio

Curran 2003

6/201

4/201

1.50 [ 0.43, 5.24 ]

Fournel 2001

10/93

3/100

3.58 [ 1.02, 12.62 ]

Reinfuss 2005

2/84

2/89

1.06 [ 0.15, 7.35 ]

Wu 2006

0/40

0/40

0.0 [ 0.0, 0.0 ]

Zatloukal 2003

0/52

0/50

0.0 [ 0.0, 0.0 ]

470

480

2.09 [ 0.95, 4.57 ]

M-H,Fixed,95% CI

M-H,Fixed,95% CI

1 Treatment-related deaths

Subtotal (95% CI)


Total events: 18 (Concurrent), 9 (Sequential)

Heterogeneity: Chi2 = 1.45, df = 2 (P = 0.48); I2 =0.0%


Test for overall effect: Z = 1.84 (P = 0.066)
2 Acute pneumonitis
Curran 2003

8/201

14/201

0.57 [ 0.25, 1.33 ]

Fournel 2001

5/93

11/100

0.49 [ 0.18, 1.35 ]

Reinfuss 2005

5/84

2/89

2.65 [ 0.53, 13.28 ]

13/40

8/40

1.63 [ 0.76, 3.49 ]

2/51

1/48

1.88 [ 0.18, 20.09 ]

469

478

0.94 [ 0.60, 1.46 ]

Wu 2006
Zatloukal 2003

Subtotal (95% CI)


Total events: 33 (Concurrent), 36 (Sequential)

Heterogeneity: Chi2 = 6.81, df = 4 (P = 0.15); I2 =41%


Test for overall effect: Z = 0.29 (P = 0.77)
3 Acute oesophagitis
Curran 2003

50/201

8/201

6.25 [ 3.04, 12.84 ]

Fournel 2001

30/93

3/100

10.75 [ 3.40, 34.05 ]

Reinfuss 2005

7/84

0/89

15.88 [ 0.92, 273.84 ]

19/40

10/40

1.90 [ 1.01, 3.56 ]

9/51

2/48

4.24 [ 0.96, 18.62 ]

469

478

4.97 [ 3.28, 7.53 ]

Wu 2006
Zatloukal 2003

Subtotal (95% CI)

Total events: 115 (Concurrent), 23 (Sequential)


Heterogeneity: Chi2 = 11.81, df = 4 (P = 0.02); I2 =66%
Test for overall effect: Z = 7.56 (P < 0.00001)

0.01

0.1

Favours concurrent

10

100

Favours sequential

(Continued . . . )

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

80

(. . .
Study or subgroup

Risk Ratio

Continued)
Risk Ratio

Concurrent

Sequential

n/N

n/N

Curran 2003

117/201

113/201

1.04 [ 0.87, 1.23 ]

Fournel 2001

72/93

88/100

0.88 [ 0.77, 1.00 ]

Reinfuss 2005

4/84

1/89

4.24 [ 0.48, 37.15 ]

Wu 2006

26/40

17/40

1.53 [ 1.00, 2.34 ]

Zatloukal 2003

33/51

19/48

1.63 [ 1.09, 2.45 ]

469

478

1.08 [ 0.97, 1.20 ]

M-H,Fixed,95% CI

M-H,Fixed,95% CI

4 Neutropenia

Subtotal (95% CI)

Total events: 252 (Concurrent), 238 (Sequential)


Heterogeneity: Chi2 = 17.59, df = 4 (P = 0.001); I2 =77%
Test for overall effect: Z = 1.37 (P = 0.17)

0.01

0.1

Favours concurrent

10

100

Favours sequential

Analysis 8.1. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 1 Overall survival 2years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 8 Sensitivity ITT: Concurrent vs Radiotherapy


Outcome: 1 Overall survival 2-years

Study or subgroup

RT + chemo

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Atagi 2005

15/23

17/23

1.8 %

0.88 [ 0.60, 1.30 ]

Ball 1999 once daily

34/56

39/53

3.4 %

0.83 [ 0.63, 1.08 ]

Ball 1999 twice daily

41/53

31/46

3.8 %

1.15 [ 0.90, 1.47 ]

Blanke 1995

98/117

109/123

10.3 %

0.95 [ 0.85, 1.05 ]

Bonner 1998

28/36

28/37

3.7 %

1.03 [ 0.80, 1.32 ]

Cakir 2004

72/92

89/93

9.3 %

0.82 [ 0.73, 0.92 ]

108/146

106/137

8.3 %

0.96 [ 0.84, 1.09 ]

11/20

18/20

1.5 %

0.61 [ 0.40, 0.93 ]

Clamon 1999
Gouda 2006

0.5

0.7

favours chemoRT

1.5

favours RT alone

(Continued . . . )

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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81

(. . .
Study or subgroup

RT + chemo

RT alone

Risk Ratio
MH,Random,95%
CI

Weight

Continued)
Risk Ratio
MH,Random,95%
CI

n/N

n/N

Groen 1999

66/82

56/78

6.1 %

1.12 [ 0.94, 1.34 ]

Huber 2003

68/104

90/115

6.3 %

0.84 [ 0.70, 0.99 ]

Jeremic 1995

81/114

49/64

5.9 %

0.93 [ 0.78, 1.11 ]

Jeremic 1996

39/67

51/68

3.8 %

0.78 [ 0.61, 0.99 ]

Landgren 1974

25/28

23/26

5.5 %

1.01 [ 0.84, 1.22 ]

Li 2008

14/30

20/30

1.3 %

0.70 [ 0.44, 1.11 ]

Lu 2005

27/47

30/45

2.5 %

0.86 [ 0.62, 1.19 ]

Manegold 2003

29/43

38/46

3.8 %

0.82 [ 0.64, 1.04 ]

168/217

99/114

10.3 %

0.89 [ 0.81, 0.99 ]

Soresi 1988

18/45

29/50

1.5 %

0.69 [ 0.45, 1.06 ]

Trovo 1992

74/85

75/88

9.1 %

1.02 [ 0.91, 1.15 ]

Yadav 2005

12/15

11/15

1.7 %

1.09 [ 0.73, 1.62 ]

1420

1271

100.0 %

0.92 [ 0.87, 0.97 ]

Schaake-Koning 1992

Total (95% CI)

Total events: 1028 (RT + chemo), 1008 (RT alone)


Heterogeneity: Tau2 = 0.01; Chi2 = 30.21, df = 19 (P = 0.05); I2 =37%
Test for overall effect: Z = 3.08 (P = 0.0021)

0.5

0.7

favours chemoRT

1.5

favours RT alone

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82

Analysis 8.2. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 2 Progression-free


survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 8 Sensitivity ITT: Concurrent vs Radiotherapy


Outcome: 2 Progression-free survival 2-years

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Blanke 1995

93/104

106/111

20.0 %

0.94 [ 0.87, 1.01 ]

Cakir 2004

72/88

84/88

15.2 %

0.86 [ 0.77, 0.96 ]

Clamon 1999

127/146

120/137

18.1 %

0.99 [ 0.91, 1.09 ]

Huber 2003

70/104

95/115

9.9 %

0.81 [ 0.70, 0.95 ]

Jeremic 1995

88/114

55/64

11.5 %

0.90 [ 0.78, 1.03 ]

Manegold 2003

34/43

41/46

8.0 %

0.89 [ 0.74, 1.07 ]

Soresi 1988

25/45

39/50

3.6 %

0.71 [ 0.53, 0.96 ]

Trovo 1992

69/85

69/88

10.6 %

1.04 [ 0.89, 1.20 ]

Yadav 2005

13/15

12/15

3.2 %

1.08 [ 0.79, 1.49 ]

744

714

100.0 %

0.92 [ 0.86, 0.98 ]

Study or subgroup

Total (95% CI)

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

Total events: 591 (Concurrent chemoRT), 621 (Radiotherapy)


Heterogeneity: Tau2 = 0.00; Chi2 = 13.74, df = 8 (P = 0.09); I2 =42%
Test for overall effect: Z = 2.77 (P = 0.0056)

0.01

0.1

Favours experimental

10

100

Favours control

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83

Analysis 8.3. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 3 Locoregional


progression-free survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 8 Sensitivity ITT: Concurrent vs Radiotherapy


Outcome: 3 Locoregional progression-free survival 2-years

Concurrent
chemoRT

Radiotherapy

n/N

n/N

Bonner 1998

25/36

23/37

12.6 %

1.12 [ 0.80, 1.56 ]

Cakir 2004

62/92

88/93

26.1 %

0.71 [ 0.61, 0.83 ]

Jeremic 1995

75/114

43/64

20.1 %

0.98 [ 0.79, 1.22 ]

Jeremic 1996

30/67

41/68

12.8 %

0.74 [ 0.53, 1.03 ]

150/217

92/114

28.4 %

0.86 [ 0.75, 0.97 ]

526

376

100.0 %

0.85 [ 0.74, 0.99 ]

Study or subgroup

Schaake-Koning 1992

Total (95% CI)

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

Total events: 342 (Concurrent chemoRT), 287 (Radiotherapy)


Heterogeneity: Tau2 = 0.02; Chi2 = 10.07, df = 4 (P = 0.04); I2 =60%
Test for overall effect: Z = 2.16 (P = 0.031)

0.01

0.1

Favours experimental

10

100

Favours control

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

84

Analysis 9.1. Comparison 9 Sensitivity ITT: Concurrent vs Sequential, Outcome 1 Overall survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 9 Sensitivity ITT: Concurrent vs Sequential


Outcome: 1 Overall survival 2-years

Study or subgroup

Concurrent

Sequential

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Curran 2003

127/201

139/201

29.9 %

0.91 [ 0.79, 1.05 ]

Fournel 2001

66/106

79/106

21.9 %

0.84 [ 0.69, 1.01 ]

Rao 2007

15/26

24/29

7.7 %

0.70 [ 0.48, 1.01 ]

Reinfuss 2005

63/84

66/89

23.7 %

1.01 [ 0.85, 1.20 ]

Zatloukal 2003

34/52

43/50

16.7 %

0.76 [ 0.61, 0.95 ]

Total (95% CI)

469

475

100.0 %

0.87 [ 0.78, 0.97 ]

Total events: 305 (Concurrent), 351 (Sequential)


Heterogeneity: Tau2 = 0.01; Chi2 = 6.16, df = 4 (P = 0.19); I2 =35%
Test for overall effect: Z = 2.45 (P = 0.014)

0.5

0.7

favours concurrent

1.5

favours sequential

Analysis 9.2. Comparison 9 Sensitivity ITT: Concurrent vs Sequential, Outcome 2 Progression-free survival
2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 9 Sensitivity ITT: Concurrent vs Sequential


Outcome: 2 Progression-free survival 2-years

Study or subgroup

Concurrent

Sequential

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Fournel 2001

76/106

89/106

45.1 %

0.85 [ 0.74, 0.99 ]

Reinfuss 2005

74/84

79/89

54.9 %

0.99 [ 0.89, 1.11 ]

Total (95% CI)

190

195

100.0 %

0.93 [ 0.79, 1.08 ]

Total events: 150 (Concurrent), 168 (Sequential)


Heterogeneity: Tau2 = 0.01; Chi2 = 2.95, df = 1 (P = 0.09); I2 =66%
Test for overall effect: Z = 0.95 (P = 0.34)
Test for subgroup differences: Not applicable

0.01

0.1

Favours concurrent

10

100

Favours sequential

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

85

Analysis 10.1. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 1 Overall
survival.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 10 Sensitivity fully published: Concurrent vs Sequential


Outcome: 1 Overall survival

Study or subgroup

log [Hazard Ratio]

Hazard Ratio

(SE)

IV,Random,95% CI

Fournel 2001
Zatloukal 2003

Weight

Hazard Ratio
IV,Random,95% CI

-0.4 (0.34)

29.5 %

0.67 [ 0.34, 1.31 ]

-0.49 (0.22)

70.5 %

0.61 [ 0.40, 0.94 ]

100.0 %

0.63 [ 0.44, 0.90 ]

Total (95% CI)


Heterogeneity: Tau2 = 0.0; Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0%
Test for overall effect: Z = 2.51 (P = 0.012)
Test for subgroup differences: Not applicable

0.01

0.1

Favours concurrent

10

100

Favours sequential

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

86

Analysis 10.2. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 2 Overall
survival 2-years.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 10 Sensitivity fully published: Concurrent vs Sequential


Outcome: 2 Overall survival 2-years

Study or subgroup

Concurrent

Sequential

Risk Ratio
MH,Random,95%
CI

Weight

Risk Ratio
MH,Random,95%
CI

n/N

n/N

62/102

76/103

29.3 %

0.82 [ 0.68, 1.00 ]

Rao 2007

15/26

24/29

13.6 %

0.70 [ 0.48, 1.01 ]

Reinfuss 2005

63/84

66/89

32.0 %

1.01 [ 0.85, 1.20 ]

Zatloukal 2003

34/52

43/50

25.1 %

0.76 [ 0.61, 0.95 ]

Total (95% CI)

264

271

100.0 %

0.84 [ 0.72, 0.99 ]

Fournel 2001

Total events: 174 (Concurrent), 209 (Sequential)


Heterogeneity: Tau2 = 0.01; Chi2 = 5.93, df = 3 (P = 0.12); I2 =49%
Test for overall effect: Z = 2.12 (P = 0.034)

0.5

0.7

favours concurrent

1.5

favours sequential

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87

Analysis 10.3. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 3 Toxicity.
Review:

Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 10 Sensitivity fully published: Concurrent vs Sequential


Outcome: 3 Toxicity

Study or subgroup

Concurrent

Sequential

Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Fournel 2001

10/93

3/100

3.58 [ 1.02, 12.62 ]

Reinfuss 2005

2/84

2/89

1.06 [ 0.15, 7.35 ]

Wu 2006

0/40

0/40

0.0 [ 0.0, 0.0 ]

Zatloukal 2003

0/52

0/50

0.0 [ 0.0, 0.0 ]

269

279

2.45 [ 0.81, 7.43 ]

1 Treatment-related deaths

Subtotal (95% CI)


Total events: 12 (Concurrent), 5 (Sequential)

Heterogeneity: Tau2 = 0.05; Chi2 = 1.07, df = 1 (P = 0.30); I2 =7%


Test for overall effect: Z = 1.59 (P = 0.11)
2 Acute pneumonitis
Fournel 2001

5/93

11/100

0.49 [ 0.18, 1.35 ]

Reinfuss 2005

5/84

2/89

2.65 [ 0.53, 13.28 ]

13/40

8/40

1.63 [ 0.76, 3.49 ]

2/51

1/48

1.88 [ 0.18, 20.09 ]

268

277

1.22 [ 0.57, 2.65 ]

Wu 2006
Zatloukal 2003

Subtotal (95% CI)


Total events: 25 (Concurrent), 22 (Sequential)

Heterogeneity: Tau2 = 0.22; Chi2 = 4.67, df = 3 (P = 0.20); I2 =36%


Test for overall effect: Z = 0.52 (P = 0.61)
3 Acute oesophagitis
Fournel 2001

30/93

3/100

10.75 [ 3.40, 34.05 ]

Reinfuss 2005

7/84

0/89

15.88 [ 0.92, 273.84 ]

19/40

10/40

1.90 [ 1.01, 3.56 ]

9/51

2/48

4.24 [ 0.96, 18.62 ]

268

277

4.85 [ 1.52, 15.45 ]

Wu 2006
Zatloukal 2003

Subtotal (95% CI)


Total events: 65 (Concurrent), 15 (Sequential)

Heterogeneity: Tau2 = 0.88; Chi2 = 9.76, df = 3 (P = 0.02); I2 =69%


Test for overall effect: Z = 2.67 (P = 0.0076)
4 Neutropenia
Fournel 2001

72/93

88/100

0.88 [ 0.77, 1.00 ]

Reinfuss 2005

4/84

1/89

4.24 [ 0.48, 37.15 ]


0.01

0.1

Favours concurrent

10

100

Favours sequential

(Continued . . . )

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

88

(. . .
Study or subgroup

Concurrent

Sequential

Continued)
Risk Ratio
MH,Random,95%
CI

Risk Ratio
MH,Random,95%
CI

n/N

n/N

Wu 2006

26/40

17/40

1.53 [ 1.00, 2.34 ]

Zatloukal 2003

33/51

19/48

1.63 [ 1.09, 2.45 ]

268

277

1.35 [ 0.79, 2.32 ]

Subtotal (95% CI)

Total events: 135 (Concurrent), 125 (Sequential)


Heterogeneity: Tau2 = 0.21; Chi2 = 19.65, df = 3 (P = 0.00020); I2 =85%
Test for overall effect: Z = 1.10 (P = 0.27)

0.01

0.1

Favours concurrent

10

100

Favours sequential

ADDITIONAL TABLES
Table 1. Recruitment and duration of follow-up for individual trials

author

study name

N analized / ran- date accrued


domized

minimum follow-up

comparators

Atagi 2005

JCOG9812

46/46

1999-2001

unclear

concurrent v RT alone

Ball 1999

Australian
multicentre

204/208

1989-1995

32 months

concurrent v RT alone

Blanke 1995

Hoosier Oncology 215/240


Group

1986-1992

26 months

concurrent v RT alone

Bonner 1998

North Central Can- 99/110


cer
Treatment
Group

1992-1993

18 months

concurrent v RT alone

Cakir 2004

Turkey
(Samsun 176/185
and Ankara)

1997-1999

36 months

concurrent v RT alone

Clamon 1999

CALGB/ECOG

250/283

>1991

uncertain

concurrent v RT alone

Gouda 2006

Egypt

60/60

1998-2000

uncertain

concurrent v RT alone

Groen 1999

Netherlands

160/160

1994-1998

uncertain

concurrent v RT alone

Huber 2003

BROCAT

212/219

not stated

3 years (except for


2 patients lost)

concurrent v RT alone

Jeremic 1995

Kragujevac (single 169/178


centre)

1988-1989

uncertain

concurrent v RT alone

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

89

Table 1. Recruitment and duration of follow-up for individual trials

(Continued)

Jeremic 1996

Kragujevac (single 131/165


centre)

1990-1991

uncertain

concurrent v RT alone

Landgren 1974

MDAnderson

53/54

1970-1971

24 months

concurrent v RT alone

Li 2008

China

58/60

not stated

(median 24 months)

concurrent v RT alone

Lu 2005

China

85/92

2001-2003

uncertain

concurrent v RT alone

Manegold 2003

European multicen- 98/98


tre (8 centres)

1999-2001

uncertain

concurrent v RT alone

Schaake-Koning
1992

EORTC

331/331

1984-1989

22 months

concurrent v RT alone

Soresi 1988

Milan

93/95

1986-1987

uncertain
(median 12 months)

concurrent v RT alone

Trovo 1992

GOCCNE

167/173

1987-1991

6 months

concurrent v RT alone

Yadav 2005

India

30/30

2002-2003

uncertain
(median 10 months)

concurrent v RT alone

Curran 2003

RTOG 94-10

402/402

1994-1998

48 months

concurrent v sequential

Fournel 2001

GLOT-GFPC
NPC 95-01

201/212

1996-2000

(median 4.8 years)

concurrent v sequential

Rao 2007

China

53/55

not stated

4 months

concurrent v sequential

Reinfuss 2005

Poland

173/173

2001-2004

12 months

concurrent v sequential

Wu 2006

China

--/80

not stated

uncertain

concurrent v sequential

Zatloukal 2003

Czech Lung Cancer 102/102


Group

not stated

18 months

concurrent v sequential

Table 2. Concurrent chemoradiotherapy versus radiotherapy alone: treatment details

trial

induction
chemo

RT dose & frac- chemo


tions
frequency

chemo details

no

60Gy in 30 frac- daily


tions in 6 weeks

Daily
carbo- 600mg/m2 car- no
platin 30mg/m2 boplatin in CRT
for first 20 frac- arm

Atagi 2005

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

total platinum chemo post RT


dose

90

Table 2. Concurrent chemoradiotherapy versus radiotherapy alone: treatment details

(Continued)

tions
Ball 1999 - once no
daily

60Gy in 30 daily 4-weekly


fractions over 6
weeks

carbo700mg/m2
platin 70mg/m2
days 1-5 weeks 1
&5

no

Ball 1999 - twice no


daily

60Gy in 30 frac- 3-weekly


tions
(twice daily) over
3 weeks

carbo350mg/m2
platin 70mg/m2
days 1-5 week 1

no

Blanke 1995

no

60-65Gy in daily 3-weekly


fractions of 1.82Gy (6-7 weeks)

cisplatin 70mg/ 210mg/m2


m2 weeks 1,4 &
7

no

Bonner 1998

no

60Gy in 40 frac- 4-weekly


tions of 1.5Gy
(twice daily) split
over 6 weeks

cisplatin 30mg/ 180mg/m2


m2 + etoposide
100mg/m2 days
1-3, weeks 1 & 5

no

Cakir 2004

no

64Gy in 32 frac- 3-weekly


tions over 6.5
weeks

cis200mg/m2
platin 20mg/m2
days 1-5 weeks 2
&6

no

Clamon 1999

cisplatin 100mg/ 60Gy in 30 daily weekly


m2 days 1 & 29 + fractions over 6
vinblastine 5mg/ weeks
m2 days 1,8,15,
22,29

car600mg/m2
boplatin 100mg/
m2 weekly

no

Gouda 2006
No

60
Gy 2 to 4-weekly
at conventional
fractionation
in 30 fractions

Groen 1999

no

Huber 2003

carboplatin
60Gy in 30 daily weekly
AUC6 + pacli- fractions over 6
taxel
200mg/ weeks
m2; 3-weekly, 2
cycles

PacliCarbo AUC6 x2 No
taxel175mg/m2 in group B
Carbo
AUC6 D1 and
D28 concur with
RT

60Gy in 30 daily continuous infu- carboplatin


840mg/m2
fractions over 6 sion
840mg/m2 conweeks
tinuous infusion
over 6 weeks
paclitaxel 60mg/ m2 weekly

Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


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no

no

91

Table 2. Concurrent chemoradiotherapy versus radiotherapy alone: treatment details

(Continued)

Jeremic 1995

no

64.8Gy in 54 weekly OR alterfractions of 1. nate weeks


2Gy (twice daily)
over 5.5 weeks

car1200mg
total no
boplatin 100mg (approx 700mg/
total dose days m2)
1,2 + etoposide
100mg total dose
days 1-3 each
week OR carboplatin 200mg
total dose days
1,2 + etopside
100mg total dose
days 1-5 weeks 1,
3, & 5

Jeremic 1996

no

69.6Gy in 58 daily
fractions of 1.
2Gy (twice daily)
over 6 weeks

carbo1450mg
total no
platin 50mg to- (approx 850mg/
tal dose + etopo- m2)
side 50mg total
dose daily

Landgren 1974

no

60Gy in 20 daily daily


fractions
split
over 8 weeks

hydroxyurea
30mg/kg daily

no

Li 2008

no

1.
Daily
2 Gy bd. AP/PA
to 38.4 Gy then
changed field angles to continue
to total RT dose.
62.4-67.2 GY

Hydroxycomphothecin
10 mg/d for 1st
and last week of
radiotherapy

no

Lu 2005

40 Gy/20 AP/ 2 to 4-weekly


2 cycles both PA with subsequent boost to
arms
tumour avoiding
cord to total dose
60-65Gy

Vinorelbine 15- 4-6 cycles


18 mg/m2 D1 240-360mg/m2
and D8
Cisplatin 60mg/
m2 D1
q 3w

2-4 cycles chemo

Manegold 2003

cisplatin 40mg/ 60Gy in 30 daily weekly


m2 days 1,2 + fractions over 6
docetaxel 85mg/ weeks
m2 day 1; 3weekly, 2 cycles

docetaxel 20mg/ m2 weekly

no

Schaake-Koning
1992

no

55Gy in 20 daily weekly OR daily cisplatin 30mg/ 120mg/m2


fractions
split
m2 weekly OR
over 7 weeks
cisplatin 6mg/
m2 daily

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no

92

Table 2. Concurrent chemoradiotherapy versus radiotherapy alone: treatment details

(Continued)

Soresi 1988

no

50.4Gy in 28 weekly
fractions over 5.
5 weeks

cisplatin 15mg/ 90mg/m2


m2 weekly

no

Trovo 1992

no

45Gy in 15 daily daily


fractions over 3
weeks

cisplatin
m2 daily

no

50 Gy in 25 #
weekly
AP/PA with cord
shielding last five
fractions ? same
treatment both
arms

cisplatin 30mg/ 150mg/m2


m2 IV weekly

Yadav 2005
No

6mg/ 90mg/m2

no

Table 3. Concurrent versus sequential chemoradiotherapy : treatment details

trial

chemotherapy

RT dose & frac- concurrent RT


tions

Curran 2003

cisplatin 100mg/ 63 Gy once daily RT starting day 1


m2 days 1,29 + fractions
vinblastine 5mg/m2
days1,8,15,22,29

RT starting day 50

Fournel 2001

sequential: cisplatin 66 Gy in 33 daily RT starting day 1


120mg/m2 days 1, fractions over 6.5
29,57 + vinorelbine weeks
30mg/m2
weekly; concurrent:
cisplatin 20mg/m2
+ etoposide days 15 & 29-33 followed
by cisplatin 80mg/
m2 days 78 & 106 +
vinorelbine weekly
days 78-127

RT starting day 85

Rao 2007

vinorel 25mg/m2
D1, D8
cisplatin 25mg/m2
D1-3 q 3w

36 Gy/18 AP/PA
RT starting day 1
with tumour boost
26-34Gy avoiding
cord

RT starting after 2
cycles chemo approx D42

Reinfuss 2005

cisplatin
100mg/m2 D1, vinorel 20mg/m2 D1,
D8 q4wks 2 cycles

50.4 Gy/28# with RT starting day 1


boost 19.8 Gy/11#
same schedule both
arms

RT starting day 8 cisplatin 200mg/


second course
m2 both arms

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sequential RT

notes

total cisplatin dose


same in both arms

93

Table 3. Concurrent versus sequential chemoradiotherapy : treatment details

Wu 2006

Zatloukal
2003

vinorelbine 12.5mg/
m2 and cisplatin
40mg/m2 D1, 8, 29
and 36 during RT

40 Gy/20-22 AP/ RT starting day 1


PA then avoiding
cord to total dose of
60Gy/30-33

(Continued)

RT starting D1 with
chemo given subsequent to RT

2002, cisplatin 80mg/m2 60


Gy RT starting day 4 RT starting day 113
day 1 + vinorelbine in 30 daily fractions cycle 2
(approx)
25mg/m2 days 1,8, over 6 weeks
15 (12.5mg/m2 in
cycles 2 & 3) 4weekly cycles x4

APPENDICES
Appendix 1. Updated search strategy

CENTRAL (The Cochrane Library 2009, Issue 4)


#1 MeSH descriptor Antineoplastic Agents explode all trees 28644
#2 MeSH descriptor Antineoplastic Protocols explode all trees 8440
#3 MeSH descriptor Chemotherapy, Adjuvant explode all trees 2443
#4 chemotherap* 27875
#5 adjuvant:ti AND therapy:ti 1328
#6 (#1 OR #2 OR #3 OR #4 OR #5) 45628
#7 cisplatin* 5852
#8 etoposide 2148
#9 vinblastine 1150
#10 mitomycin* 1820
#11 vindesine 545
#12 gemcitabine 926
#13 paclitaxel 1919
#14 docetaxel 1037
#15 carboplatin 1861
#16 cyclophosphamide 6123
#17 ifos*amide 810
#18 fluorouracil 5248
#19 pemetrexed 85
#20 (#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19) 50158
#21 MeSH descriptor Carcinoma, Non-Small-Cell Lung explode all trees 1570
#22 non small cell lung 3733
#23 nsclc 1850
#24 (#21 OR #22 OR #23) 3876
#25 MeSH descriptor Radiotherapy explode all trees 3989
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94

#26
#27
#28
#29
#30

radiotherap* 11360
irradiat* 4696
(#25 OR #26 OR #27) 13583
(#20 AND #24 AND #28) 677
(#20 AND #24 AND #28), from 2004 to 2009 206 (117 in Clinical Trials)

MEDLINE (PubMed 15. October. 2009)


#5
Search Carcinoma, Non-Small-Cell Lung[Mesh] 19937
#6
Search non small cell lung[tw] 24487
#7
Search nsclc[tw]
10435
#8
Search ((#5) OR (#6)) OR (#7)
24808
#9
Search Radiotherapy[Mesh]
109762
#10
Search radiotherap*[tw] 199013
#11
Search irradiat*[tw]
159619
#12
Search ((#9) OR (#10)) OR (#11)
321865
#13
Search Chemotherapy, Adjuvant[Mesh]
20902
#14
Search Antineoplastic Agents[Mesh] 201197
#15
Search chemotherap*[tw] 241706
#16
Search adjuvant[ti] AND therapy[ti] 3830
#17
Search Antineoplastic Protocols[Mesh]
78967
#18
Search ((((#13) OR (#14)) OR (#15)) OR (#16)) OR (#17) 384400
#19
Search ((#8) AND (#12)) AND (#18) 2833
#20
Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR clinical
trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals[mh] NOT (humans[mh] AND animals[mh])) 619556
#21
Search (#19) AND (#20) 932 (310)

EMBASE (Ovid 15. October. 2009)


1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22

exp lung non small cell cancer/ (23516)


(non small cell adj3 lung).mp. (26227)
nsclc.mp. (9972)
1 or 2 or 3 (26470)
exp radiotherapy/ (162634)
radiotherap*.mp. (130110)
irradiat*.mp. (120294)
(radiation adj2 therapy).mp. (34853)
8 or 6 or 7 or 5 (266901)
exp chemotherapy/ (196505)
exp antineoplastic agent/ (764918)
chemotherap*.mp. (265018)
(adjuvant adj3 therapy).mp. (41008)
11 or 13 or 10 or 12 (857609)
4 and 9 and 14 (4547)
Clinical trial/ (558947)
Randomized controlled trials/ (174578)
Random Allocation/ (27087)
Single-Blind Method/ (8587)
Double-Blind Method/ (74328)
Cross-Over Studies/ (21843)
Placebos/ (132301)

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95

23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48

Randomi?ed controlled trial$.tw. (35268)


RCT.tw. (2950)
Random allocation.tw. (647)
Randomly allocated.tw. (10529)
Allocated randomly.tw. (1372)
(allocated adj2 random).tw. (565)
Single blind$.tw. (7704)
Double blind$.tw. (86977)
((treble or triple) adj blind$).tw. (142)
Placebo$.tw. (113396)
Prospective Studies/ (86261)
33 or 32 or 21 or 26 or 17 or 22 or 18 or 30 or 16 or 23 or 29 or 25 or 27 or 28 or 20 or 24 or 19 or 31 (733789)
Case study/ (6429)
Case report.tw. (123578)
Abstract report/ or letter/ (513341)
35 or 36 or 37 (640898)
34 not 38 (708199)
animal/ not human/ (14494)
39 not 40 (708103)
synchronous.ti,ab. (13207)
concurrent.ti,ab. (43027)
concomitant.ti,ab. (82547)
sequential.ti,ab. (61371)
45 or 44 or 42 or 43 (196219)
46 and 15 (990)
41 and 47 (604)

Appendix 2. Old Search strategy


The databases and search strategies used were the same than in the previous version of this review. We include here the text published
in Rowell 2004: Trials were identified by electronic searching of the Cochrane Central Register of Controlled Trials (CENTRAL) using
a search strategy, and by electronic searching of MEDLINE 1966 to 2004 (OVID version 4.1.1). We also searched EMBASE and
CINAHL (1980 to 2004) (See Appendix 1). Titles, abstracts and, where necessary, full papers were examined to determine whether
chemotherapy had been given sequentially or concurrently with radiotherapy. Further studies were sought from references cited in
the initial list. Handsearching of published abstracts of major meetings (ASCO, ESTRO and WCLC) published since 1998 was also
carried out.
MEDLINE
1. exp carcinoma, bronchogenic/
2. exp carcinoma, small cell/
3. 1 not 2
4. carcinoma, non-small-cell lung/
5. 3 or 4
6. exp radiotherapy/
7. radiotherapy.ti,ab
8. irradiation.ti,ab
9. 6 or 7 or 8
10. exp antineoplastic agents/
11. chemotherapy adjuvant/
12. chemotherapy.ti,ab
13. 10 or 11 or 12
14. 5 and 9 and 13
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15. synchronous.ti,ab
16. concurrent.ti,ab
17. concomitant.ti,ab
18. 15 or 16 or 17
19. 14 and 18
20. exp randomized controlled trials/
21. exp random allocation/
22. 20 or 21
23. 19 and 22
24. postoperative.ti,ab
25. preoperative.ti,ab
26. palliative.ti,ab
27. (phase 1 or phase I).ti,ab
28. 24 or 25 or 26 or 27
29. 23 not 28
30. sequential.ti,ab
31. 29 and 30
EMBASE
1. CHEMOTHERAPY
2. CHEMOTHERAPY-ADJUVANT*:ME
3. DRUG-THERAPY*:ME
4. ANTINEOPLASTIC-AGENTS*:ME
5. CISPLATIN*
6. ETOPOSIDE
7. VINBLASTINE
8. MITOMYCIN*
9. VINDESINE
10. GEMCITABINE
11. PACLITAXEL
12. DOCETAXEL
13. CARBOPLATIN
14. CYCLOPHOSPHAMIDE
15. IFOS*AMIDE
16. FLUOROURACIL
17. or/1-16
18. LUNG and CANCER
19. NON-SMALL and CELL
20. #18 and #19
21. CARCINOMA-NON-SMALL-CELL-LUNG*:ME
22. BRONCHOGENIC and CARCINOMA
23. CARCINOMA-BRONCHOGENIC*:ME
24. or/20-23
25. CARCINOMA-SMALL-CELL*:ME
26. #24 not #25
27. RADIOTHERAPY*:ME
28. RADIOTHERAPY
29. #27 or #28
30. #17 and #26 and #29

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WHATS NEW
Last assessed as up-to-date: 1 January 2010.

Date

Event

Description

13 January 2010

New citation required and conclusions have changed

A search was run and nine new studies were identified


with updated publications on five studies included in
original review. Conclusions changed
Contact author changed.

HISTORY
Protocol first published: Issue 1, 2000
Review first published: Issue 4, 2004

Date

Event

Description

18 September 2008

Amended

Converted to new review format.

2 July 2004

New citation required and conclusions have changed

Substantive amendment

CONTRIBUTIONS OF AUTHORS
NOR screened the search results, extracted data for all new and updated trials, and drafted the manuscript.
MR screened the search results, assessed risk of bias data for trials included in the original version of the review, extracted data for
updated trials, extracted time-to-event data for all trials, performed the statistical analysis.
NF extracted data for all new trials included in the update.
FM helped with interpretation of the results and in drafting the manuscript.
All authors commented on the manuscript. NOR and Nick Rowell developed the original version of the review.

DECLARATIONS OF INTEREST
None known.

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SOURCES OF SUPPORT
Internal sources
Beatson Oncology Centre, UK.

External sources
National Institute for Health Research, UK.
2009 CochraneReview Incentive Scheme. Funding awarded to the completion of the update of this review

INDEX TERMS
Medical Subject Headings (MeSH)
Antineoplastic Combined Chemotherapy Protocols [therapeutic use]; Carcinoma, Non-Small-Cell Lung [ drug therapy;
radiotherapy]; Combined Modality Therapy [adverse effects; methods; mortality]; Lung Neoplasms [ drug therapy; radiotherapy];
Radiation-Sensitizing Agents [therapeutic use]; Randomized Controlled Trials as Topic

MeSH check words


Humans

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