Concurrent ChemoRT in NSCLC

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
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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. . . . . . . . .
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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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[Intervention Review]

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.
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.
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

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

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.

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

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.

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

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

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;

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

10
(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

11
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

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}
Atagi S, Kawahara M, Tamura T, Noda K, Watanabe K,
Yokoyama A, et al.Standard thoracic radiotherapy with or
without concurrent daily low-dose carboplatin in elderly
patients with locally advanced non-small cell lung cancer:
A phase III trial of the Japan Clinical Oncology Group
(JCOG9812). Japanese Journal of Clinical Oncology 2005;
35(4):195201.
Ball 1999 once daily {published data only}
Ball D, Bishop J, Smith J, OBrien P, Davis S, Ryan

G, et al.A randomised phase II study of accelerated or
standard fraction radiotherapy with or without concurrent
carboplatin in inoperable non-small cell lung cancer: final
report of an Australian multi-centre trial. Radiotherapy and
Oncology 1999;52(2):12936.
Group Protocol. Proceedings of the American Society of

Clinical Oncology 1991;10:241.
Blanke C, Ansari R, Mantravadi R, Gonin R, Tokars R,

Fisher W, et al.Phase III trial of thoracic irradiation with or
without cisplatin for locally advanced unresectable nonsmall-cell lung cancer: a Hoosier Oncology Group Protocol.
Journal of Clinical Oncology 1995;13(6):14259.
Bonner 1998 {published data only}
Bonner JA, McGinnis WL, Stella PJ, Marschke FR,

Sloan JA, Shaw EG, et al.The possible advantage of
hyperfractionated thoracic radiotherapy in the treatment of
locally advanced non-small lung carcinoma. Cancer 1996;
82(6):103748.
Ball 1999 twice daily {published data only}

Oncology 1999;52(2):12936.
Cakir 2004 {published data only}
Cakir S, Egehan I. A randomised clinical trial of

radiotherapy plus cisplatin versus radiotherapy alone in
stage III non-small cell lung cancer. Lung Cancer 2004;43:
30916.
Clamon 1999 {published data only}
Clamon G, Herndon J, Cooper R, Chang AY, Rosenman

J, Green MR. Radiosensitization with carboplatin for
patients with unresectable stage III non-small-cell lung
cancer: a phase III trial of the Cancer and Leukaemia Group
B and the Eastern Cooperative Oncology Group. Journal of
Clinical Oncology 1999;17(1):411.
Blanke 1995 {published data only}

Ansari R, Tokars R, Fisher W, Pennington K, Mantravadi R,
OConnor T, et al.A phase III study of thoracic irradiation
with or without concomitant cisplatin in locoregional
unresectable non small cell lung cancer: a Hoosier Oncology
Curran 2003 {published and unpublished data}
Curran WJ, Scott CB, Langer CJ, Komaki R, Lee JS,

Hauser S, et al.Long-term benefit is observed in a phase III
comparison of sequential vs concurrent chemoradiation for
patients with unresected stage III NSCLC: RTOG 9410.

13
Proceedings of the American Society of Clinical Oncology 2003;

22:621.
Fournel 2001 {published data only}
Fournel P, Perol M, Robinet G, Thomas P, Souquet JP,
Lena H, et al.A randomized phase III trial of sequential
chemo-radiotherapy versus concurrent chemo-radiotherapy
in locally advanced non small cell lung cancer (NSCLC)
(GLOT-GFPC NPC 95-01 study) [abstract]. Proceedings of
the American Society of Clinical Oncology 2001;20:312.
Fournel P, Robinet G, Thomas P, Souquet PJ, Lena

H, Vergnenegre A, et al.Randomized phase III trial of
sequential chemoradiotherapy compared with concurrent
chemoradiotherapy in locally advanced non-small-cell
lung cancer: Groupe Lyon-Saint-Etienne dOncologie
Thoracique-Groupe Francais de Pneumo-Cancerologie
NPC 95-01 Study. Journal of Clinical Oncology 2005;23
(25):59107.
Vergnenegre A, Combescure C, Fournel P, Bayle S, Gimenez
C, Souquet PJ, et al.Cost-minimization analysis of a
phase III trial comparing concurrent versus sequential
radiochemotherapy for locally advanced non-small-cell lung
cancer (GFPC-GLOT 95-01). Annals of Oncology 2006;17
(8):126974.
Gouda 2006 {published data only}
Gouda YS, Kohail HM, Eldeeb NA, Omar AM, El-Geneidy
MM, Elkerm YM. Randomized study of concurrent
carboplatin, paclitaxel, and radiotherapy with or without
prior induction chemotherapy in patients with locally
advanced non-small cell lung cancer. Journal of the Egyptian
National Cancer Institute 2006;18(1):7381.
Groen 1999 {published and unpublished data}
Groen HJ, van der Leest AH, Fokkema E, Timmer

PR, Nossent GD, Smit WJ, et al.Continuously infused
carboplatin used as radiosensitizer in locally unresectable
non-small-cell lung cancer: a multicenter phase III study.
Annals of oncology : official journal of the European Society for
Medical Oncology / ESMO 2004;15(3):42732.
Groen HJM, van der Leest AHW, Snoek WJ, Nossent GD,
Oosterhuis B, Nabers H, et al.Phase III study of continuous
infusion carboplatin over 6 weeks with radiation versus
radiation alone in stage III non-small cell lung cancer
[abstract]. Proceedings of the American Society of Clinical
Oncology 1999;18:466.
Huber 2003 {published and unpublished data}
Huber RM, Flentje M, Schmidt M, Pllinger B, Gosse H,

Willner J, et al.Simultaneous chemoradiotherapy compared
with radiotherapy alone after induction chemotherapy in
inoperable stage IIIA or IIIB non-small-cell lung cancer:
study CTRT99/97 by the Bronchial Carcinoma Therapy
Group. Journal of clinical oncology : official journal of
the American Society of Clinical Oncology 2006;24(27):
4397404.
Huber RM, Schmidt M, Flentje M, Poellinger B,
Gosse H, Willner J, et al for the BROCAT group.
Induction chemotherapy and following simultaneous
radio/chemotherapy versus induction chemotherapy and
radiotherapy alone in inoperable NSCLC (stage IIIA/IIIB).

22:622.
Jeremic 1995 {published data only}
Jeremic B, Shibamoto Y, Acimovic L, Djuric L. Randomized
trial of hyperfractionated radiation therapy with or without
concurrent chemotherapy for stage III non-small-cell lung
cancer. Journal of Clinical Oncology 1995;13(2):4528.
Jeremic 1996 {published data only}
Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S.

Hyperfractionated radiation therapy with or without
concurrent low-dose daily carboplatin / etoposide for stage
III non-small-cell lung cancer: a randomized study. Journal
of Clinical Oncology 1996;14(4):106570.
Landgren 1974 {published data only}
Landgren RC, Hussey DH, Barkley HT, Samuels ML.

Split-course irradiation compared to split-course irradiation
plus hydroxyurea in inoperable bronchogenic carcinoma
- a randomized study of 53 patients. Cancer 1974;34:
15981601.
Li 2008 {published data only}
Li GZ, Zhang SH, Zhang Z, Song WG, Wang RL, Fu ZZ.
The clinical comparative study on hydroxycomptothecin
combined with cocurrent hyperfractionated radiotherapy
for unresectable stage III non-small cell lung cancer. Tumor
2008;28(2):1568.
Lu 2005 {published data only}
Lu C, Liu J, Wang J, Wang C, Guo J, Pan F, et al.Analysis
of concurrent chemoradiotherapy in patients with stage III
non-small cell lung cancer after two cycles of induction
chemotherapy. Chinese Journal of Lung Cancer 2005;8(1):
4850.
Manegold 2003 {published data only}
Manegold C, Debus J, Buchholz E, Scagliotti GV,
Ricardi U, Cardenal F, et al.A phase II randomized study
comparing docetaxel/cisplatin induction therapy followed
by thoracic radiotherapy with or without weekly docetaxel
in unresectable stage IIIA-IIIB non-small cell lung cancer.
European Journal of Cancer 2003;1 Suppl(5):2489.
Ramlau R, Scagliotti GV, Manegold C, Buchholz E,
Szczesna A, Cardenal F, et al.Radiotherapy and concurrent
weekly docetaxel following cisplatin-docetaxel induction
chemotherapy in unresectable stage IIIA-B non-small-cell
lung cancer: a randomized phase II trial. Annals of oncology
: official journal of the European Society for Medical Oncology
/ ESMO 2002;13(suppl 5):134.
Scagliotti GV, Manegold C, Bucholtz E, Zierhut D,
Szczesna A, Kaczmarek Z, et al.Randomized phase II study
evaluating the feasibility of thoracic radiotherapy with or
without weekly docetaxel (Taxotere) following induction
chemotherapy with cisplatin (DDP) and docetaxel in
unresectable stage IIIA/B non-small cell lung cancer.
21:320a (abstr 1279).
Scagliotti GV, Szczesna A, Ramlau R, Cardenal F, Mattson

K, Van Zandwijk N, et al.Docetaxel-based induction
therapy prior to radiotherapy with or without docetaxel for

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
Prevention and Treatment 2007;14(12):9423.
Reinfuss 2005 {published data only}
Reinfuss M, Skolyszewski J, Kowalska T, Glinski B, Dymek
P, Walasek T, et al.Evaluation of efficacy of combined
chemoradiotherapy in locoregional advanced, inoperable
Non-Small Cell Lung Cancer (clinical randomized trial).
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
cisplatin and radiotherapy on inoperable non-small-cell
lung cancer. The New England Journal of Medicine 1992;
326(8):52430.
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
radiotherapy enhanced by cisplatin in stage III non-small
cell lung cancer. International Journal of Radiation Oncology,
Biology, Physics 1992;24(1):115.
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.
Radiotherapy versus weekly concomitant cisplatin in locally
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
advanced non-small cell lung cancer: A randomized study.
Lung Cancer 2004;46(1):8798.
Zatloukal P, Petruzelka L, Zemanova M, Havel L, Pecen L,
Judas L. Concurrent versus sequential radiochemotherapy
with vinorelbine plus cisplatin (V-P) in locally advanced
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,
Pecen L, Krepela E, et al.Concurrent versus sequential
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
continuous-infusion fluorouracil as palliation for nonsmall-cell lung cancer. British Journal of Cancer 1997;75(5):
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
therapeutics 2006;2(2):4751.
Furuse 1999 {published data only}
Furuse K, Fukuoka M, Kawahara M, Nishikawa H,

Takada Y, Kudoh S, et al.Phase III study of concurrent versus
sequential radiotherapy in combination with mitomycin,
vindesine and cisplatin in unresectable stage III non-small
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
small cell lung cancer: radiotherapy vs radio-chemotherapy.
Lung Cancer 2000;29 Suppl(1):1156.
Isakovic-Vidovic2002 {published data only}
Isakovic-Vidovic S, Radosevic-Jelic L, Borojevic N.

Combined chemoradiotherapy in the treatment of locally
advanced non-small cell lung cancer. Journal of B.U.ON:
official journal of the Balkan Union of Oncology 2002;7(1):
4751.
Japan ACNU 1989 {published data only}
Japan Radiation-ACNU Study Group. A randomized

prospective study of radiation versus radiation plus ACNU

15
in inoperable non-small cell carcinoma of the lung. Cancer

1989;63(2):24954.
References to ongoing studies
Johnson 1990 {published data only}
Johnson DH, Einhorn LH, Bartolucci A, Birch R, Omura

G, Perez CA, et al.Thoracic radiotherapy does not prolong
survival in patients with locally advanced, unresectable nonsmall cell lung cancer. Annals of Internal Medicine 1990;113
(1):338.
NCRI SOCCAR {published data only}

SOCCAR Trial Cisplatin and Vinorelbine for NSCLC
Koca 1996 {published data only}
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
kombinasyonunun yeri: randomize prospektif klinik
calisma [Radiotherapy alone vs combined chemotherapy
and radiotherapy in nonresectable non-small cell lung
cancer: a phase III randomized clinical trial]. Cerrahpasa J
Med 1996;27:6369.
Auperin 2003
Auperin A, Le Pchoux C. Meta-analysis of randomized
trials evaluating cisplatin or carboplatin-based concomitant
chemoradiation versus radiotherapy alone in locally
advanced non-small cell lung cancer (NSCLC). Lung Cancer
2003;41 Suppl(2):70.
Komaki 2002 {published data only}
Komaki R, Seiferheld W, Ettinger D, Lee JS, Mosvas

B, Sause W. Randomized phase II chemotherapy and
radiotherapy trial for patients with locally advanced
inoperable non-small-cell lung cancer: long-term followup of RTOG 92-04. International Journal of Radiation
Oncology, Biology, Physics 2002;53(3):54857.
LePar 1967 {published data only}
LePar E, Faust DS, Brady LW, Beckloff GL. Clinical

evaluation of the adjunctive use of hydroxyurea (NSC32065) in radiation therapy of carcinoma of the lung.
Radiologia Clinica et Biologica 1967;36:3240.
Misirlioglu 2006 {published data only}
Misirlioglu CH, Erkal H, Elgin Y, Ugur I, Altundag K.
Effect of concomitant use of pentoxifylline and alphatocopherol with radiotherapy on the clinical outcome of
patients with stage IIIB non-small cell lung cancer: A
randomized prospective clinical trial. Medical Oncology
2006;23(2):1859.
Sarihan 2002 {published data only}
Sarihan S, Kayisogullari U, Sozer N, Ercan I, Ozkan L,

Engin K. A phase III study: results of radiotherapy alone
versus radiotherapy with paclitaxel concomitantly in nonsmall cell lung cancer. Radiotherapy and Oncology 2002;64
Suppl(1):258.
Ulutin 2000 {published data only}
Ulutin HC, Guden M, Oysul K, Surenkok S, Pak Y.

Split-course radiotherapy with or without concurrent or
sequential chemotherapy in non-small cell lung cancer.
Radiation Medicine 2000;18:936.
(LUWOS-012/1). Ongoing study 01/12/2005.
Additional references
Auperin 2007
Auperin A, Rolland E, Curran WJ, Furuse K, Fournel P,
Belderbos J, et al.Concomitant radio-chemotherapy (RTCT) versus sequential RT-CT in locally advanced non-small
cell lung cancer (NSCLC): a meta-analysis using individual
patient data (IPD) from randomised clinical trials (RCTs).
Journal of Thoracic Oncology 2007;2(8):suppl 4 S310.
Auperin 2010
Auperin A, Le Pchoux C, Rolland E, Curran W, Furuse
K, Fournel P, et al.Meta-Analysis of Concomitant Versus
Sequential Radiochemotherapy in Locally Advanced NonSmall-Cell Lung Cancer. Journal of Clinical Oncology
2010 Mar 29 [Epub ahead of print].
Ball 1999
Oncology 1999;52(2):12936.
Cox 1990
Cox JD, Azarnia N, Byhardt RW, Shin KH, Emami B,
Pajak TF. A randomized phase I/II trial of hyperfractionated
radiation therapy with total doses of 60.0Gy to 79.2Gy:
possible survival benefit with greater than or equal to
69.6Gy in favorable patients with Radiation Therapy
Oncology Group stage III non-small cell lung carcinoma:
report of Radiation Therapy Oncology Group 83-11.
Journal of Clinical Oncology 1990;8:154355.
Current Controlled Trials
Biomed Central. Current Controlled Trials.
www.controlled-trials.com (accessed 19 October 2009).
References to studies awaiting assessment
DerSimonian 1986
DerSimonian R. Laird N. Meta-analysis in clinical trials.
Controlled Clinical Trials 1986;7(3):17788.
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.

16
Higgins 2009
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.0.2. [updated
September 2009]. The Cochrane Collaboration, 2009.
Higgins 2009b
Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16:
Special topics in statistics. Higgins JPT, Green S (editors).
Cochrane Handbook for Systematic Reviews of Interventions
Version 5.0.2 (updated September 2009). The Cochrane
Collaboration, 2009.
Jones 2001
Jones B, Dale RG, Deehan C, Hopkins KI, Morgan DA.
The role of biologically effective dose (BED) in clinical
oncology. Clinical Oncology 2001;13(2):7181.
NSCLCCG 1995
Non-small Cell Lung Cancer Collaborative Group.
Chemotherapy in non-small cell lung cancer: a metaanalysis using updated data on individual patients from 52
randomised clinical trials. BMJ 1995;311:899909.
NSCLCCG 2000
Non-small Cell Lung Cancer Collaborative Group.
Chemotherapy for non-small cell lung cancer. Cochrane
Database of Systematic Reviews 2000, Issue 2. [DOI:
10.1002/14651858.CD002139]
Parmar 1998
Parmar MKB, Torri V, Stewart L. Extracting summary
statistics to perform meta-analyses of the published
literature for survival endpoints. Statistics in Medicine 1998;
17:281534.
Perez 1987
Perez CA, Pajak TF, Rubin P, Simpson JR, Mohiuddin M,
Brady LW, et al.Long-term observations of the patterns of
failure in patients with unresectable non-oat cell carcinoma

of the lung treated with definitive radiotherapy. Cancer
1987;59:187481.
Rolland 2007
Rolland E, Le Chevalier T, Auperin A, Burdett S, Pignon JP
on behalf of the NSCLC Collaborative Group. Sequential
radio-chemotherapy(RT-CT) versus radiotherapy alone
(RT) and concomitant RT-CT versus RTalone in locally
advanced non-small cell lung cancer (NSCLC): two
metaanalyses using individual patient data (IPD) from
randomised clinical trials(RCTs). Journal of Thoracic
Oncology 2007;2(8):Suppl 4 S309-10.
Saunders 1999
Saunders M, Dische S, Barrett A, Harvey A, Griffiths G,
Parmar M (on behalf of the CHART steering committee).
Continuous hyperfractionated accelerated radiotherapy
(CHART) versus conventional radiotherapy in nonsmall cell lung cancer: mature data from the randomised
multicentre trial. Radiotherapy and Oncology 1999;52:
13748.
Tierney 2007
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR.
Practical methods for incorporating summary time-to-event
data into meta-analysis. Trials 2007;8:116.
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

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
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

18
(Continued)
number of strata, the total numbers of patients in the four arms

were slightly imbalanced.
Yes
Randomised by telephone to the central trial office.

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
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
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.
Yes
Randomised by telephone to the central trial office.

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

19
(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
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
Yes
Patients were stratified. Permuted-blocks randomization was

used to assign patients within the strata
Unclear
Not reported.

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

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
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.
Yes
Patients were randomized at a centralized NCCTG randomization center.

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
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
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.
Unclear
Not reported.

21
Cakir 2004
(Continued)

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
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
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
Unclear
Not reported.

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

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
Unclear
Not reported.
Unclear
Not reported.

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
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
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.

23
Fournel 2001
(Continued)
Unclear
Its not clear whether randomisation was centralized. The central office stratified patients according to institute and stage (IIIAN2/IIIB).

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
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
Unclear
Not reported.
Unclear
Not reported.

All outcomes
Yes
All 60 randomised patients were analysed.
Groen 1999
Methods
Randomised
Participants
Interventions
Daily RT to 60Gy v RT with carboplatin continuous infusion
Outcomes
Notes

24
Groen 1999
(Continued)
Risk of bias
Item
Authors judgement
Description
Yes
Patients were stratified according to stage, performance status

and hospital. Block randomization was used
Yes
treatment allocation was performed by telephone into either

carboplatin and radiation, or radiation alone.

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
Notes
Risk of bias
Item
Authors judgement
Description
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.
Yes
The study center in Munich, Germany, was responsible for

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

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

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
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%;

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
Unclear
Not reported.
Unclear
Not reported.

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


26
Jeremic 1996
(Continued)
Notes
Risk of bias
Item
Authors judgement
Description
Unclear
Not reported.
Unclear
Not reported.

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

Notes
Only 64% completed RT as planned
Risk of bias
Item
Authors judgement
Description
Unclear
Not reported.
Unclear
Not reported.

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

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
Unclear
Not reported.
Unclear
Not reported.

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
Unclear
Not reported.
Unclear
Randomisation using envelopes . It does not specify whether

envelopes sealed or opaque

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

dont specify the group they belong to

28
Manegold 2003
Methods
Randomised
Participants
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
Unclear
Not described although patients stratified according to centre

and disease stage.
Unclear
Not reported.

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
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

29
Rao 2007
(Continued)
Yes
Randomisation by number table.
No
Randomisation by number table.

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
Yes
Used randomisation tables.
No
Used randomisation tables.

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

3-year survival 2% v 13% v 16%.
Notes
Risk of bias
30
Schaake-Koning 1992
(Continued)
Item
Authors judgement
Description
Unclear
Not reported.
Yes
randomisation performed centrally

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
Notes
Risk of bias
Item
Authors judgement
Description
Unclear
Not reported.
Unclear
Not reported.

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

31
Trovo 1992
(Continued)
Notes
Risk of bias
Item
Authors judgement
Description
Unclear
Not reported.
Unclear
Not reported.

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
Yes
Randomisation table
No
Randomisation table

All outcomes
No
Inadequate follow-up so far to report any outcome data

32
Yadav 2005
Methods
Randomised
Participants
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
Yes
Randomisation by table of Tippet (random numbers table).
No
Randomisation by table of Tippet (random numbers table).

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
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
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
Unclear
Not described, although randomisation was by envelope method
Yes
Randomisation by envelope method was used

33
Zatloukal 2003
(Continued)

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

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

35
NCRI SOCCAR
(Continued)
Contact information
Dr Joseph Maguire
Clatterbridge Centre for Oncology
Bebington
Wirral
Liverpool
United Kingdom
CH63 4JY
Notes

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
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)
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)
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
0.84 [0.72, 0.98]
19
14
9
17
4
2
7
5
9
2075
1179
2227
596
300
837
822
887

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

1 Overall survival
5 Locoregional PFS 2-years
6 Toxicity
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
Risk Difference (M-H, Random, 95% CI)

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

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
months or less
6.3 Duration of follow-up
uncertain
No. of
studies
No. of
participants
20
16
2587
2173

0.91 [0.86, 0.97]

0.92 [0.86, 0.98]
301
0.82 [0.71, 0.94]
2
20
113

0.88 [0.56, 1.36]

Subtotals only
7
7
8
840
1013
909

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

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
0.99 [0.85, 1.15]
1037
0.89 [0.79, 0.99]
Statistical method
Effect size
Comparison 4. Subgroup analysis Concurrent vs Sequential

1 Dose of radiotherapy
1.1 Low dose
1.2 High dose
2 Duration of follow-up
months or more
months or less
No. of
studies
No. of
participants
5
1
4
5
2
937
102
835
937
607

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
0.84 [0.66, 1.06]
Statistical method

Effect size
38
2.3 Duration of follow-up

uncertain
Not estimable
Comparison 5. More frequent versus less frequent chemotherapy
No. of
studies
No. of
participants
1 Frequency of chemotherapy
325
Statistical method
Effect size
0.91 [0.80, 1.03]
Comparison 6. Sensitivity fixed: Concurrent vs Radiotherapy

1 Overall survival
survival
survival 2-years
7 Toxicity
7.4 Pulmonary fibrosis
7.5 Late oesophagitis
7.6 Neutropenia
No. of
studies
9
20
7
9
2
No. of
participants
2587
1405
Statistical method
Effect size

Risk Ratio (M-H, 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
0.84 [0.76, 0.91]
19
14
9
17
4
2
7
5
9
2075
1179
2227
596
300
837
822
887

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

1 Overall survival
survival 2-years
6 Toxicity
No. of
studies
3
5
1
2
1
5
No. of
participants
937
378
402
Statistical method
Effect size

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]
Subtotals only

39

6.4 Neutropenia
5
5
5
5
950
947
947
947

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

survival 2-years
No. of
studies
No. of
participants
20
9
5
2691
1458
902
Statistical method
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

No. of
studies
No. of
participants
5
2
944
385
Statistical method
Effect size
0.87 [0.78, 0.97]
0.93 [0.79, 1.08]
Comparison 10. Sensitivity fully published: Concurrent vs Sequential

1 Overall survival
3 Toxicity
3.4 Neutropenia
No. of
studies
2
4
4
4
4
4
4
No. of
participants
535
548
545
545
545
Statistical method

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:
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

10
Favours RT
41
Analysis 1.2. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 2 Overall

survival 2-years.
Review:

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 ]
32/54
39/53
4.2 %
-0.14 [ -0.32, 0.03 ]
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

42
Analysis 1.3. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 3

Progression-free survival.
Review:

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)

0.01
0.1
Favours experimental

10
100
Favours control
43

Progression-free survival 2-years.
Review:

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)

0.5
0.7
1.5
Favours control

44

Locoregional progression-free survival.
Review:

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%
0.01
0.1

10
100
Favours control
45

Locoregional progression-free survival 2-years.
Review:

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

0.1 0.2
0.5
10
Favours control

46
Analysis 1.7. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 7 Toxicity.

Review:

Outcome: 7 Toxicity
Study or subgroup
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 ]
0/54
0/53
0.0 [ 0.0, 0.0 ]
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)

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
10
100
Favours control
(Continued . . . )

47
(. . .
Study or subgroup
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 ]
11/53
6/51
1.76 [ 0.70, 4.42 ]
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)

3 Acute oesophagitis
Atagi 2005
Manegold 2003
Subtotal (95% CI)

4 Pulmonary fibrosis
Atagi 2005
Subtotal (95% CI)
0.01
0.1
10
100
Favours control
(Continued . . . )
48
(. . .
Study or subgroup
Radiotherapy
n/N
n/N
Continued)
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI

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 ]
7/53
0/51
14.44 [ 0.85, 246.55 ]
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)

6 Neutropenia
Atagi 2005
Clamon 1999
Subtotal (95% CI)

7 Anaemia (grade 3 to 4)
0/53
1/51
0.32 [ 0.01, 7.70 ]
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)

Atagi 2005
16/23
8/23
2.00 [ 1.07, 3.72 ]
20/53
6/51
3.21 [ 1.40, 7.34 ]
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
10
100
Favours control
(Continued . . . )
49
(. . .
Study or subgroup
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)

0.01
0.1
10
100
Favours control
Analysis 2.1. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 1 Overall survival.

Review:
Comparison: 2 Concurrent vs Sequential chemoradiotherapy

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)

0.01
0.1
Favours concurrent

10
100
Favours sequential
50
Analysis 2.2. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 2 Overall survival 2years.
Review:

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)

-2
-1
favours concurrent
favours sequential
Analysis 2.3. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 3 Progression-free

survival.
Review:

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

0.01
0.1
Favours concurrent

10
100
Favours sequential
51
Analysis 2.4. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 4 Progression-free

survival 2-years.
Review:

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 ]

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:

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 ]

0.2
0.5
favours concurrent
favours sequential

52
Analysis 2.6. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 6 Toxicity.

Review:

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 ]
Subtotal (95% CI)


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)


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 . . . )

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

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)

5 Anaemia
Fournel 2001
Zatloukal 2003
Subtotal (95% CI)


0.02
0.1
Favours concurrent

10
50
Favours sequential
54
Analysis 3.1. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 1

Chemotherapy regime.
Review:
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 ]
32/54
39/53
3.5 %
0.81 [ 0.61, 1.06 ]
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)

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)

0.5
0.7
favours chemoRT
1.5
favours RT alone
(Continued . . . )

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 ]

3 Other regimes
Subtotal (95% CI)

Total (95% CI)
1365
1222

0.5
0.7
favours chemoRT

1.5
favours RT alone
56
Analysis 3.2. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 2 Frequency

of chemotherapy administration.
Review:

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)

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)

3 Two- to four-weekly administration
32/54
39/53
9.4 %
0.81 [ 0.61, 1.06 ]
39/51
31/46
10.6 %
1.13 [ 0.88, 1.46 ]
0.5
0.7
favours chemoRT
1.5
favours RT alone
(Continued . . . )

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)

0.5
0.7
favours chemoRT

1.5
favours RT alone
58
Analysis 3.3. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 3 Platinum

dose.
Review:

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
Subtotal (95% CI)

2 Low dose
Atagi 2005
15/23
17/23
2.5 %
0.88 [ 0.60, 1.30 ]
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 (95% CI)
1165
1008

0.5
0.7
favours chemoRT

1.5
favours RT alone
59
Analysis 3.4. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 4

Radiotherapy fractionation.
Review:

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 ]
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)

2 Twice daily fractionation
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 . . . )

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 (95% CI)
1365
1222

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:

Outcome: 5 Dose of radiotherapy
Study or subgroup
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 ]
32/54
39/53
3.5 %
0.81 [ 0.61, 1.06 ]
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
1.5
Favours control
(Continued . . . )

61
(. . .
Study or subgroup
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)

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 (95% CI)
1365
1222

0.5
0.7

1.5
Favours control
62
Analysis 3.6. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 6 Duration

of follow-up.
Review:

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
32/54
39/53
3.5 %
0.81 [ 0.61, 1.06 ]
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

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)

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 . . . )

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 (95% CI)
1365
1222

0.5
0.7
favours chemoRT

1.5
favours RT alone
64
Analysis 4.1. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 1 Dose of radiotherapy.
Review:
Comparison: 4 Subgroup analysis Concurrent vs Sequential

Outcome: 1 Dose of radiotherapy
Study or subgroup
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)

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 (95% CI)
465
472

Test for subgroup differences: Chi2 = 0.0, df = 1 (P = 0.0), I2 =0.0%
0.5
0.7

1.5
Favours control
65
Analysis 4.2. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 2 Duration of follow-up.
Review:
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)

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)

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 ]

Test for overall effect: not applicable
Total (95% CI)

0.5
0.7
favours chemoRT

1.5
favours RT alone
66
Analysis 5.1. Comparison 5 More frequent versus less frequent chemotherapy, Outcome 1 Frequency of
chemotherapy.
Review:
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)
0.5
0.7
more frequent chemo

1.5
less frequent chemo
67
Analysis 6.1. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 1 Overall survival.
Review:
Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy

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%
0.1 0.2
0.5
Favours chemoRT
10
Favours RT

68
Analysis 6.2. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 2 Overall survival 2years.
Review:

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 ]
32/54
39/53
3.9 %
0.81 [ 0.61, 1.06 ]
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

0.5
0.7
favours chemoRT
1.5
favours RT alone

69
Analysis 6.3. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 3 Progression-free

survival.
Review:

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)

0.01
0.1
10
100
Favours control

70
Analysis 6.4. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 4 Progression-free

survival 2-years.
Review:

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

0.01
0.1
10
100
Favours control

71
Analysis 6.5. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 5 Locoregional

progression-free survival.
Review:

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)

0.01
0.1
10
100
Favours control

72
Analysis 6.6. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 6 Locoregional

progression-free survival 2-years.
Review:

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

0.01
0.1
10
100
Favours control

73
Analysis 6.7. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 7 Toxicity.

Review:

Outcome: 7 Toxicity
Concurrent
chemoRT
Radiotherapy
n/N
n/N
Atagi 2005
3/23
1/23
3.00 [ 0.34, 26.76 ]
0/54
0/53
0.0 [ 0.0, 0.0 ]
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
Schaake-Koning 1992
Subtotal (95% CI)

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
10
100
Favours control
(Continued . . . )

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 ]
11/53
6/51
1.76 [ 0.70, 4.42 ]
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

Atagi 2005
Manegold 2003
Subtotal (95% CI)

4 Pulmonary fibrosis
Atagi 2005
Subtotal (95% CI)
0.01
0.1
10
100
Favours control
(Continued . . . )
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

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 ]
7/53
0/51
14.44 [ 0.85, 246.55 ]
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)

6 Neutropenia
Atagi 2005
Clamon 1999
Subtotal (95% CI)

0/53
1/51
0.32 [ 0.01, 7.70 ]
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)

Atagi 2005
16/23
8/23
2.00 [ 1.07, 3.72 ]
20/53
6/51
3.21 [ 1.40, 7.34 ]
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
10
100
Favours control
(Continued . . . )
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

0.01
0.1
10
100
Favours control
Analysis 7.1. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 1 Overall survival.
Review:
Comparison: 7 Sensitivity fixed: Concurrent vs Sequential

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)

0.01
0.1
Favours concurrent
10
100
Favours sequential

77
Analysis 7.2. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 2 Overall survival 2-years.
Review:

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

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:

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 ]

0.01
0.1
Favours concurrent
10
100
Favours sequential

78
Analysis 7.4. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 4 Progression-free

survival 2-years.
Review:

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

0.01
0.1
Favours concurrent
10
100
Favours sequential
Analysis 7.5. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 5 Locoregional

Review:

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

0.2
0.5
favours concurrent
favours sequential

79
Analysis 7.6. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 6 Toxicity.

Review:

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
Subtotal (95% CI)


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)


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)

0.01
0.1
Favours concurrent
10
100
Favours sequential
(Continued . . . )

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)

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:
Comparison: 8 Sensitivity ITT: Concurrent vs Radiotherapy

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 ]
34/56
39/53
3.4 %
0.83 [ 0.63, 1.08 ]
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 . . . )

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)

0.5
0.7
favours chemoRT
1.5
favours RT alone

82
Analysis 8.2. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 2 Progression-free

survival 2-years.
Review:

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

0.01
0.1
10
100
Favours control

83
Analysis 8.3. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 3 Locoregional

Review:

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

0.01
0.1
10
100
Favours control

84
Analysis 9.1. Comparison 9 Sensitivity ITT: Concurrent vs Sequential, Outcome 1 Overall survival 2-years.
Review:
Comparison: 9 Sensitivity ITT: Concurrent vs Sequential

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 ]

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:
Comparison: 9 Sensitivity ITT: Concurrent vs Sequential

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 ]

0.01
0.1
Favours concurrent
10
100
Favours sequential

85
Analysis 10.1. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 1 Overall
survival.
Review:
Comparison: 10 Sensitivity fully published: Concurrent vs Sequential

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)

0.01
0.1
Favours concurrent
10
100
Favours sequential

86
Analysis 10.2. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 2 Overall
survival 2-years.
Review:

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

0.5
0.7
favours concurrent
1.5
favours sequential

87
Analysis 10.3. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 3 Toxicity.
Review:

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 ]
Subtotal (95% CI)


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)


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)


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 . . . )

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)

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
Blanke 1995
Hoosier Oncology 215/240

Group
1986-1992
26 months
Bonner 1998
North Central Can- 99/110

cer
Treatment
Group
1992-1993
18 months
Cakir 2004
Turkey
(Samsun 176/185
and Ankara)
1997-1999
36 months
Clamon 1999
CALGB/ECOG
250/283
>1991
uncertain
Gouda 2006
Egypt
60/60
1998-2000
uncertain
Groen 1999
Netherlands
160/160
1994-1998
uncertain
Huber 2003
BROCAT
212/219
not stated
3 years (except for

2 patients lost)
Jeremic 1995
Kragujevac (single 169/178

centre)
1988-1989
uncertain

89
Table 1. Recruitment and duration of follow-up for individual trials
(Continued)
Jeremic 1996
Kragujevac (single 131/165

centre)
1990-1991
uncertain
Landgren 1974
MDAnderson
53/54
1970-1971
24 months
Li 2008
China
58/60
not stated
(median 24 months)
Lu 2005
China
85/92
2001-2003
uncertain
Manegold 2003
European multicen- 98/98

tre (8 centres)
1999-2001
uncertain
Schaake-Koning
1992
EORTC
331/331
1984-1989
22 months
Soresi 1988
Milan
93/95
1986-1987
uncertain
(median 12 months)
Trovo 1992
GOCCNE
167/173
1987-1991
6 months
Yadav 2005
India
30/30
2002-2003
uncertain
(median 10 months)
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)
Rao 2007
China
53/55
not stated
4 months
Reinfuss 2005
Poland
173/173
2001-2004
12 months
Wu 2006
China
--/80
not stated
uncertain
Zatloukal 2003
Czech Lung Cancer 102/102

Group
not stated
18 months
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

total platinum chemo post RT

dose
90
(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

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

m2 + etoposide
100mg/m2 days
1-3, weeks 1 & 5
no
Cakir 2004
no

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

no
no
91
(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

no
92
(Continued)
Soresi 1988
no
50.4Gy in 28 weekly
fractions over 5.
5 weeks

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

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

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
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)

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
96
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

97
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.

98
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

99

Concurrent ChemoRT in NSCLC

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Concurrent chemoradiotherapy in non-small cell lung cancer

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

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

Concurrent chemoradiotherapy in non-small cell lung cancer

PLAIN LANGUAGE SUMMARY

In a meta-analysis of adjuvant chemotherapy in NSCLC (

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

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

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

Overall survival (OS).

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

Criteria for considering studies for this review

Treatment morbidity - late

Search methods for identification of studies

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

Data collection and analysis

(3) Incomplete outcome data (checking for possible attrition

Assessment of risk of bias in included studies

Measures of treatment effect

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

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

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

more complete publication (Fournel 2001; Groen 1999; Huber

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

Risk of bias in included studies

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

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

Incomplete outcome data

Other potential sources of bias

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

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

Concurrent versus sequential chemoradiotherapy

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

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

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

Summary of main results

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

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

Overall completeness and applicability of

approaches enhance the effectiveness of local regional control, but

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

Quality of the evidence

Agreements and disagreements with other

sequential schedule. Firstly there is a risk of disease progression

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

chemoradiotherapy should be considered. It is important to note

* compare platinum- and taxane-based chemotherapy;

Implications for research

References to studies included in this review

Ball D, Bishop J, Smith J, OBrien P, Davis S, Ryan

Group Protocol. Proceedings of the American Society of

Blanke C, Ansari R, Mantravadi R, Gonin R, Tokars R,

Bonner JA, McGinnis WL, Stella PJ, Marschke FR,

Ball 1999 twice daily {published data only}

Ball D, Bishop J, Smith J, OBrien P, Davis S, Ryan

Cakir 2004 {published data only}

Cakir S, Egehan I. A randomised clinical trial of

Clamon G, Herndon J, Cooper R, Chang AY, Rosenman

Blanke 1995 {published data only}

Curran 2003 {published and unpublished data}

Curran WJ, Scott CB, Langer CJ, Komaki R, Lee JS,

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

Proceedings of the American Society of Clinical Oncology 2003;

Fournel P, Robinet G, Thomas P, Souquet PJ, Lena