Concurrent ChemoRT in NSCLC

Concurrent chemoradiotherapy in non-small cell lung cancer

(Review)

O’Rourke N, Roqué i Figuls M, Farré Bernadó N, Macbeth F

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010, 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.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 1 Overall survival. . . 41

Analysis 1.2. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 2 Overall survival 2-years. 42

Analysis 1.3. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 3 Progression-free survival. 43

Analysis 1.4. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 4 Progression-free survival 2-

years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

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

free survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

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

free survival 2-years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Analysis 1.7. Comparison 1 Concurrent chemoradiotherapy vs Radiotherapy alone, Outcome 7 Toxicity. . . . . 47

Analysis 2.1. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 1 Overall survival. . . . . . 50

Analysis 2.2. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 2 Overall survival 2-years. . . 51

Analysis 2.3. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 3 Progression-free survival. . . 51

Analysis 2.4. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 4 Progression-free survival 2-years. 52

Analysis 2.5. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 5 Locoregional PFS 2-years. . 52

Analysis 2.6. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 6 Toxicity. . . . . . . . . 53

Analysis 3.1. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 1 Chemotherapy regime. 55

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

administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Analysis 3.3. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 3 Platinum dose. . . 59

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

fractionation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Analysis 3.5. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 5 Dose of radiotherapy. 61

Analysis 3.6. Comparison 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy, Outcome 6 Duration of follow-up. 63

Analysis 4.1. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 1 Dose of radiotherapy. . . . 65

Analysis 4.2. Comparison 4 Subgroup analysis Concurrent vs Sequential, Outcome 2 Duration of follow-up. . . . 66

Analysis 5.1. Comparison 5 More frequent versus less frequent chemotherapy, Outcome 1 Frequency of chemotherapy. 67

Analysis 6.1. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 1 Overall survival. . . . . . 68

Analysis 6.2. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 2 Overall survival 2-years. . . 69

Analysis 6.3. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 3 Progression-free survival. . . 70

Analysis 6.4. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 4 Progression-free survival 2-years. 71

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

survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

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

survival 2-years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Analysis 6.7. Comparison 6 Sensitivity fixed: Concurrent vs Radiotherapy, Outcome 7 Toxicity. . . . . . . . . 74

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


Analysis 7.1. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 1 Overall survival. . . . . . . 77

Analysis 7.2. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 2 Overall survival 2-years. . . . 78

Analysis 7.3. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 3 Progression-free survival. . . . 78

Analysis 7.4. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 4 Progression-free survival 2-years. 79

Analysis 7.5. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 5 Locoregional progression-free survival

2-years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Analysis 7.6. Comparison 7 Sensitivity fixed: Concurrent vs Sequential, Outcome 6 Toxicity. . . . . . . . . . 80

Analysis 8.1. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 1 Overall survival 2-years. . . 81

Analysis 8.2. Comparison 8 Sensitivity ITT: Concurrent vs Radiotherapy, Outcome 2 Progression-free survival 2-years. 83

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

survival 2-years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Analysis 9.1. Comparison 9 Sensitivity ITT: Concurrent vs Sequential, Outcome 1 Overall survival 2-years. . . . 85

Analysis 9.2. Comparison 9 Sensitivity ITT: Concurrent vs Sequential, Outcome 2 Progression-free survival 2-years. 85

Analysis 10.1. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 1 Overall survival. . 86

Analysis 10.2. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 2 Overall survival 2-years. 87

Analysis 10.3. Comparison 10 Sensitivity fully published: Concurrent vs Sequential, Outcome 3 Toxicity. . . . . 88

89ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

98HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

98CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

98DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

98SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

99INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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


[Intervention Review]

Concurrent chemoradiotherapy in non-small cell lung cancer

Noelle O’Rourke1, Marta Roqué i Figuls2 , Nuria Farré Bernadó3, Fergus Macbeth4

1Beatson Oncology Centre, Glasgow, UK. 2Iberoamerican Cochrane Centre. CIBER Epidemiología y Salud Pública (CIBERESP)

Spain, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 3Radiation Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona,

Spain. 4Centre for Clinical Practice, National Institute for Health and Clinical Excellence, London, UK

Contact address: Noelle O’Rourke, Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, G12 0YN, UK.

[email protected]. Noelle.O’[email protected].

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: O’Rourke N, Roqué i Figuls M, Farré Bernadó 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.


A B S T R A C T

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 chemora-

diotherapy 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. Chemora-

diotherapy significantly reduced overall risk of death (HR 0.71, 95% CI 0.64 to 0.80; I2 0%; 1607 participants) and overall progression-

free 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.

1Concurrent chemoradiotherapy in non-small cell lung cancer (Review)


mailto:[email protected]

mailto:Noelle.O'[email protected]

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.

P L A I N L A N G U A G E S U M M A R Y

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 demon-

strated significant reduction in risk of death with use of concurrent chemoradiation, with an associated increase in incidence of acute

oesophagitis.

B A C K G R O U N D

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 vol-

ume, radical (as opposed to palliative) radiotherapy is regarded as

the treatment of choice. Higher doses of conventionally fraction-

ated 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 radio-

therapy; that review specifically excluded trials in which chemo-

therapy and radiotherapy were given concurrently (NSCLCCG

1995; NSCLCCG 2000). On this evidence sequential chemother-

apy 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 chemo-

therapy after radiation (described variously as ’consolidation’ or

’adjuvant’), the most common practice in 2004 and indeed the

updated trials have used ’sequential’ chemotherapy meaning in-

duction 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. ra-

diosensitisation).. This is now a standard approach in other tu-

mour types (e.g. head and neck, cervical, anal and oesophageal

cancer). A number of randomised trials have compared concur-

rent 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 chemoradiother-

apy versus sequential treatment but individual trials have been un-

derpowered or closed early or not reported in full.

The purpose of this review was to determine whether the effec-

tiveness 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 qual-

ity of life.

O B J E C T I V E S

• 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 progression-

free survival, treatment-related mortality and morbidity.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials.

Types of participants

Patients of any age and any performance status with pathologically

confirmed NSCLC but without distant metastases (i.e. stage I-

III).

Types of interventions

Patients undergoing radical radiotherapy either randomised to re-

ceive concurrent chemoradiotherapy or radical radiotherapy alone,

or randomised to concurrent or sequential chemoradiotherapy.

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 chemo-

therapy given before or after a course of radiotherapy but not dur-

ing. 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).

Secondary outcomes

Progression-free survival (progression at any site whether locore-

gional or distant; PFS).

Locoregional progression-free survival (local PFS).

Overall survival at two years.

Progression-free survival (progression at any site whether locore-

gional 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.

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.

Search methods for identification of studies

We ran a search in October 2009 to update the original com-

pleted review. In this update we adapted the original searches to

search the following databases: Cochrane Central Register of Con-

trolled 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

Selection of studies

References identified by the search strategy were screened inde-

pendently by two authors (NOR, MR) to assess eligibility for in-

clusion in the review and a list of trials eligible for inclusion was

agreed. In case of discrepancy, consensus was reached by discus-

sion 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.

Assessment of risk of bias in included studies

Two review authors (NOR or NF, and MR) independently as-

sessed 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 wasn’t 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 stan-

dardized 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

• 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 non-

opaque envelopes, alternation; date of birth);

• unclear.

(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 ex-

clusions were reported, the numbers included in the analysis at

each stage (compared with the total randomised participants), rea-

sons for attrition or exclusion where reported, and whether miss-

ing data were balanced across groups or were related to outcomes.

We assessed whether each study was free of attrition bias:

• yes;

• no;

• unclear.

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 sur-

vival, progression-free survival at any site, locoregional progres-

sion-free survival). When the papers did not report HR, they were

computed following the formulae of Parmar (Parmar 1998) im-

plemented in a freely-available spreadsheet (Tierney 2007).

Risk ratios were computed for dichotomous variables (time-to-

event 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 follow-

up <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 con-

ducting a meta-analysis of single effect measures of the study (HR

for time-to-event variables and RR for dichotomous variables) ap-

plying a random-effects model (DerSimonian 1986). Prior to cal-

culating estimates of effect, the presence and degree of heterogene-

ity was assessed by means of I2.

Data synthesis

The review’s 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/m2; 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 (50-

60 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 anal-

yses, the data from the two treatment arms were combined and

treated as a single treatment group. In the subgroup analysis of fre-

quency of chemotherapy administration (which differed between

the treatment arms), the control arm was included with the rele-

vant 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 fixed-

effect model).

Dichotomous variables related to adverse effects were not consid-

ered 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). When-

ever 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).

R E S U L T S

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 ran-

domised trials of concurrent chemoradiotherapy versus radiother-

apy 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 consid-

ered as two separate trials of once daily and twice daily radiother-

apy 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 refer-

ences. 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 ex-

cluded (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 up-

dated review (Table 1): 19 trials (2728 participants, Table 2) com-

paring 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 chemo-

therapy, in combination with etoposide in three; three used con-

current docetaxel or paclitaxel; one used hydroxyurea and one hy-

droxycomptothecin. Chemotherapy was administered on each ra-

diotherapy 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 radiother-

apy 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 time-

to-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 didn’t cause

relevant changes in metanalysis results.

Risk of bias in included studies

Overall, risk of bias in the 19 trials of concurrent chemoradiother-

apy 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 rea-

sons 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 pub-

lished 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 chemora-

diotherapy, 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 chemora-

diotherapy, 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 analy-

sis. 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 in-

eligibility, 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 par-

ticipants) 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-contain-

ing 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 (com-

parison 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 two-

year 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 chemo-

therapy 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 (com-

parison 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 differ-

ences 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 ra-

diotherapy dose (up to or more than 60 Gy). Thirteen trials used

low doses of radiotherapy from 50 Gy to 60 Gy on 1691 partici-

pants (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 signif-

icant (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 reli-

able. 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 be-

tween 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 locorre-

gional 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 con-

current treatment (RR 1.76; 95% CI 1.34 to 2.31; I2 0%; 17 tri-

als, 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 signifi-

cantly increased and confidence intervals were wide. A single case

of radiation myelopathy was reported in a patient receiving radio-

therapy alone (Landgren 1974). Neutropenia (grade 3 or worse)

was reported in 7 trials (837 participants), 3 of which used induc-

tion 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 neutrope-

nia 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 con-

current 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 sig-

nificant benefit of concurrent over sequential treatment with re-

spect 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 follow-

up 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 sur-

vival, 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 out-

come.

- 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 im-

puted 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 compari-

son, 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.

D I S C U S S I O N

Summary of main results

In 2004 as a result of the meta-analysis of chemotherapy in

NSCLC (NSCLCCG 1995), the combination of (sequential) che-

motherapy 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 sequen-

tial 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 ad-

ditional trials but benefits also from full publication of the pre-

vious concurrent versus sequential comparisons and this has con-

solidated 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 origi-

nal 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



(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 radia-

tion alone. There was a significant benefit from concurrent ther-

apy, which also held for the analysis at two years but there was sub-

stantial 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 dif-

ferent 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 ofevidence

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 che-

motherapy regimens between the two arms. This is not an indi-

vidual 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 individ-

ual 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. Al-

though we have limited inclusion to radiotherapy regimens deliv-

ering 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 sub-

stantially in recent years with improved imaging, PET staging and

definition of treatment volumes and continually evolving tech-

niques 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 che-

motherapy 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 demon-

strated in this review for both comparisons for the use of concur-

rent chemoradiation. In one study (Reinfuss 2005) 21% of pa-

tients 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 pneumoni-

tis 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 (approxi-

mately 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 platinum-

based chemotherapy although there was considerable clinical het-

erogeneity 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 carbo-

platin. 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 un-

certain with the combined analysis of data from the two three-

armed trials (Jeremic 1995; Schaake-Koning 1992). The prin-

ciple underlying concurrent chemotherapy is that local control

can be improved by radiosensitisation and that in reducing mi-

crometastatic disease the risk of systemic relapse is also reduced.

Low dose chemotherapy might be adequate to achieve radiosensi-

tisation without the increase in toxicity seen with full dose com-

bination 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 ra-

diotherapy 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 hy-

pofractionated accelerated radiotherapy with concurrent low dose

cisplatin which produced favourable survival figures but the study



closed early and was underpowered. The CHART trial of hyper-

fractionated 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 chemother-

apy.

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 qual-

ity 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 ap-

pear 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 sup-

ports the confidence on the review conclusions.

Agreements and disagreements with otherstudies or reviews

Individual patient data meta-analyses can estimate treatment ef-

fects 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 com-

paring concurrent chemoradiation with radiation alone, demon-

strating 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 se-

quential 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-anal-

ysis 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 com-

plete the scheduled treatment. In the Zatloukal trial only 58% of

patients in the sequential group completed chemotherapy com-

pared to 83% in the concurrent group (Zatloukal 2003). More im-

portantly only 64% of the sequential group received radiotherapy

treatment against 94% of concurrent group. Similarly in the Four-

nel 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 ob-

served 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 tu-

mours more resistant to subsequent irradiation, further contribut-

ing to the difference in effectiveness of concurrent and sequential

chemoradiotherapy. It is possible that longer conventional frac-

tionation schedules over 6 to 7 weeks (in contrast to accelerated

regimens of 4 weeks or less) may be particularly vulnerable to ac-

celerated repopulation.

In summary, concurrent chemoradiotherapy appears more effec-

tive 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 administra-

tion 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 ra-

diosensitisation 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 con-

current chemoradiation regimes, addressing ways of reducing tox-

icity and evaluating the optimal chemotherapy combinations and

optimal radiotherapy schedules, using modern, quality assured ra-

diotherapy techniques.

A U T H O R S ’ C O N C L U S I O N S

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



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 sur-

vival and the optimal radiotherapy schedule remains uncertain.

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 ad-

ministration;

* compare platinum- and taxane-based chemotherapy;

* investigate the impact of anaemia on the benefits of chemora-

diotherapy.

A C K N O W L E D G E M E N T S

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 transla-

tions, to Dr David Ball and Dr Harry Groen for additional data

and to colleagues for support and comment. They also acknowl-

edge the useful contributions of Gian Luca Di Tanna and Mia

Schmidt-Hansen, who peer-reviewed the manuscript. The origi-

nal version of the review was possible with the support of Maid-

stone & Tunbridge Wells NHS Trust and Beatson Oncology Cen-

tre.

R E F E R E N C E S

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):195–201.

Ball 1999 once daily {published data only}∗ Ball D, Bishop J, Smith J, O’Brien 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):129–36.

Ball 1999 twice daily {published data only}∗ Ball D, Bishop J, Smith J, O’Brien P, Davis S, Ryan





Oncology 1999;52(2):129–36.

Blanke 1995 {published data only}

Ansari R, Tokars R, Fisher W, Pennington K, Mantravadi R,

O’Connor 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

Group Protocol. Proceedings of the American Society of

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Fisher W, et al.Phase III trial of thoracic irradiation with or

without cisplatin for locally advanced unresectable non-

small-cell lung cancer: a Hoosier Oncology Group Protocol.

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Bonner 1998 {published data only}∗ Bonner JA, McGinnis WL, Stella PJ, Marschke FR,

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hyperfractionated thoracic radiotherapy in the treatment of

locally advanced non-small lung carcinoma. Cancer 1996;

82(6):1037–48.

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:

309–16.

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):4–11.

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.



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 d’Oncologie

Thoracique-Groupe Francais de Pneumo-Cancerologie

NPC 95-01 Study. Journal of Clinical Oncology 2005;23

(25):5910–7.

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

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cancer (GFPC-GLOT 95-01). Annals of Oncology 2006;17

(8):1269–74.

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):73–81.

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

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Groen HJM, van der Leest AHW, Snoek WJ, Nossent GD,

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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, Pöllinger 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):

4397–404.

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):452–8.

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):1065–70.

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:

1598–1601.

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):156–8.

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):

48–50.

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):248–9.

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



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

94:1375–82. [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):942–3.

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):200–6.

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):524–30.

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 non-

small cell lung cancer. Seminars in Oncology 1988;15 Suppl

7(6):20–5.

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):11–5.

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):283–5.

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):75–80.

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):87–98.

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, O’Brien P, Bernshaw

D, et al.A phase III study of radiotherapy with or without

continuous-infusion fluorouracil as palliation for non-

small-cell lung cancer. British Journal of Cancer 1997;75(5):

690–7.

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 08972-

22973). European Journal of Cancer 2007;43(1):114–21.

Chan 1976 {published data only}∗ Chan PYM, Byfield JE, Kagan AR, Aronstam EM.

Unresectable squamous cell carcinoma of the lung and its

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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):47–51.

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sequential radiotherapy in combination with mitomycin,

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Guschall 2000 {published data only}∗ Gurschall W-R, Schneemann-Heinze S, Floegel R,

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small cell lung cancer: radiotherapy vs radio-chemotherapy.

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advanced non-small cell lung cancer. Journal of B.U.ON:

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prospective study of radiation versus radiation plus ACNU



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1989;63(2):249–54.

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kanserinde hiperfraksiyone radyoterapi ile cisplatin+5FU

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Komaki 2002 {published data only}∗ Komaki R, Seiferheld W, Ettinger D, Lee JS, Mosvas

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inoperable non-small-cell lung cancer: long-term follow-

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LePar 1967 {published data only}∗ LePar E, Faust DS, Brady LW, Beckloff GL. Clinical

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Misirlioglu 2006 {published data only}

Misirlioglu CH, Erkal H, Elgin Y, Ugur I, Altundag K.

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tocopherol with radiotherapy on the clinical outcome of

patients with stage IIIB non-small cell lung cancer: A

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2006;23(2):185–9.

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versus radiotherapy with paclitaxel concomitantly in non-

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sequential chemotherapy in non-small cell lung cancer.

Radiation Medicine 2000;18:93–6.

References to studies awaiting assessment

Zhang 2006 {published data only}

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hydroxycamplothecin (HCPT) for radiosensitization on

local advanced non-small cell lung cancer]. Chinese Journal

of Clinical Oncology 2006;33(8):458–61.

References to ongoing studies

NCRI SOCCAR {published data only}

SOCCAR Trial Cisplatin and Vinorelbine for NSCLC

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

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C H A R A C T E R I S T I C S O F S T U D I E S

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


Adequate sequence generation? Yes ”Randomisation within each stratum was based on an adaptative

biased coin procedure weighted to achieve approximate balance

between the four treatment arms. However, because fo the large



Ball 1999 once daily (Continued)

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

were slightly imbalanced.”

Allocation concealment? Yes Randomised by telephone to the central trial office.


All outcomes

Yes 208 patients were randomised. ”All patients were analysed

according to their randomised treatment arm (“intention-to-

treat”), 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 in-

eligible 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 randomisa-

tion 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


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


Adequate sequence generation? Yes ”Randomisation within each stratum was based on an adaptative

biased coin procedure weighted to achieve approximate balance

between the four treatment arms. However, because fo the large

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

were slightly imbalanced.”

Allocation concealment? Yes Randomised by telephone to the central trial office.


All outcomes

Yes 208 patients were randomised. ”All patients were analysed

according to their randomised treatment arm (“intention-to-

treat”), except for the exclusion from the toxicity analysis of three

patients who received no treatment and one patient who received



Ball 1999 twice daily (Continued)

only 6 Gy. “ “Response rates were calculated as percentages of

all randomised patients.””All patients were followed up to Jan-

uary 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 effu-

sions 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


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


Adequate sequence generation? Yes “Patients were stratified”. “Permuted-blocks randomization was

used to assign patients within the strata”



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-to-

treat 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“



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


Adequate sequence generation? Yes ”Randomization to one of the three treatment arms was per-

formed by a dynamic allocation procedure that balanced the

marginal distributions of the stratification factors among the

study arms. “

Allocation concealment? Yes “Patients were randomized at a centralized NCCTG random-

ization center.”


All outcomes

Yes ”110 patients entered the study. Eleven patients were declared

ineligible on the basis of the eligibility criteria listed above, leav-

ing 99 patients with analyzable data.”

Cakir 2004

Methods Randomised


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


Adequate sequence generation? Unclear ”A stratified randomisation procedure was performed; the stages

(III-A,III-B) were used as a stratifying factor. The patients having

these two stages allocated to treatment arms equally.”




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 radio-

therapy alone) were subsequently found to be ineligible and were

excluded. The reasons for exclusion were the patient’s admis-

sion in another protocol, and presence of other malignant con-

ditions, or patient’s 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


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


Adequate sequence generation? Unclear ”Randomization was stratified by stage so that an equal propor-

tion of clinical stage IIIA and IIIB patients would be assigned

to each treatment arm”



All outcomes

Yes ”Of the 283 patients registered onto the trial, 137 were random-

ized 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 treat-

ment. 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



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


Adequate sequence generation? Unclear Not reported.



All outcomes

Unclear Numbers are presented, although causes of patients loss and

groups they belong to aren’t. “610 enrolled patients, 595 ana-

lyzable 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)


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


Adequate sequence generation? Unclear It’s not clear how patients were randomised. “Patients were strat-

ified by stage (IIIA-N2/IIIB) and were then randomly assigned

to receive sequential or concurrent therapy.”



Fournel 2001 (Continued)

Allocation concealment? Unclear It’s not clear whether randomisation was centralized. “The cen-

tral office stratified patients according to institute and stage (II-

IAN2/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


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





All outcomes

Yes All 60 randomised patients were analysed.

Groen 1999

Methods Randomised


Interventions Daily RT to 60Gy v RT with carboplatin continuous infusion


Notes



Groen 1999 (Continued)

Risk of bias


Adequate sequence generation? Yes ”Patients were stratified according to stage, performance status

and hospital. Block randomization was used “

Allocation concealment? Yes ” treatment allocation was performed by telephone into either

carboplatin and radiation, or radiation alone.”


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


Notes

Risk of bias


Adequate sequence generation? Yes ”Random assignment after response evaluation allocated pa-

tients to radiotherapy alone or to chemoradiotherapy by stratifi-

cation according to center and stage using computer-generated

random lists of permuted blocks of varying size.”

Allocation concealment? Yes ”The study center in Munich, Germany, was responsible for

central random assignment based on patient details the centers

had submitted.”


All outcomes

Yes ”The analysis of time to progression and overall survival was

based on the intent-to-treat population.” “Two hundred nine-

teen patients were randomly assigned (115 patients to radio-

therapy alone and 104 patients to simultaneous chemoradio-

therapy). After careful review, five patients were excluded (three

patients were randomly assigned despite progressive disease, and



Huber 2003 (Continued)

two patients showed brain metastasis before the start of treat-

ment), 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 receiv-

ing radiotherapy alone; Fig 1).”

Jeremic 1995

Methods Randomised


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

carboplatin and etoposide alternate weeks

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

2-year survival 25% v 35% v 27%;

3-year survival 6.6% v 23% v 16%.

Notes More toxicity in alternate week chemotherapy arm resulting in more treatment inter-

ruptions

Risk of bias





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


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


2-year survival 26% v 43%;




Jeremic 1996 (Continued)

Notes

Risk of bias





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



Notes Only 64% completed RT as planned

Risk of bias





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



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





All outcomes

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

don’t 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



Allocation concealment? 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

don’t specify the group they belong to



Manegold 2003

Methods Randomised


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


Adequate sequence generation? Unclear Not described although “patients stratified according to centre

and disease stage.”



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 contraindica-

tion for radiotherapy owing to the high risk of developing life-

threatening pulmonary haemorrhage) (one patient each)).”

Rao 2007

Methods Randomised


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




Rao 2007 (Continued)

Adequate sequence generation? Yes Randomisation by number table.

Allocation concealment? 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%”

It’s 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


Adequate sequence generation? Yes Used randomisation tables.

Allocation concealment? 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 1-year survival 46% v 44% v 54%;

2-year survival 13% v 19% v 26%;

3-year survival 2% v 13% v 16%.

Notes

Risk of bias



Schaake-Koning 1992 (Continued)



Allocation concealment? 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


Notes

Risk of bias





All outcomes

Yes 95 randomised patients ”Two patients in the RT group were lost

too early to follow-up /.../ so they were excluded from analysis

of progression-free interval and survival.”

Trovo 1992

Methods Randomised

Participants 173 patients with stage IIIA/B NSCLC

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

Outcomes 2-year survival 14% v 15%.



Trovo 1992 (Continued)

Notes

Risk of bias





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


Adequate sequence generation? Yes Randomisation table

Allocation concealment? No Randomisation table


All outcomes

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



Yadav 2005

Methods Randomised


Interventions 50Gy/25 alone vs with weekly cisplatin

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

Notes

Risk of bias


Adequate sequence generation? Yes Randomisation by table of Tippet (random numbers table).

Allocation concealment? 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


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)


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


Adequate sequence generation? Unclear Not described, although randomisation was by envelope method

Allocation concealment? Yes ”Randomisation by envelope method was used”



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



(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 radiother-

apy 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



NCRI SOCCAR (Continued)

Contact information Dr Joseph Maguire

Clatterbridge Centre for Oncology

Bebington

Wirral

Liverpool

United Kingdom

CH63 4JY

Notes



D A T A A N D A N A L Y S E S

Comparison 1. Concurrent chemoradiotherapy vs Radiotherapy alone

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Overall survival 9 1607 Hazard Ratio (Random, 95% CI) 0.71 [0.64, 0.80]

2 Overall survival 2-years 20 2587 Risk Difference (M-H, Random, 95% CI) -0.08 [-0.12, -0.03]

3 Progression-free survival 7 1145 Hazard Ratio (Random, 95% CI) 0.69 [0.58, 0.81]

4 Progression-free survival 2-years 9 1405 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.86, 0.97]

5 Locoregional progression-free

survival

2 345 Hazard Ratio (Fixed, 95% CI) 0.67 [0.54, 0.82]


survival 2-years

5 872 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.72, 0.98]

7 Toxicity 19 Risk Ratio (M-H, Random, 95% CI) Subtotals only

7.1 Treatment-related deaths 14 2075 Risk Ratio (M-H, Random, 95% CI) 1.38 [0.51, 3.72]

7.2 Acute pneumonitis 9 1179 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.58, 1.93]

7.3 Acute oesophagitis 17 2227 Risk Ratio (M-H, Random, 95% CI) 1.76 [1.34, 2.31]

7.4 Pulmonary fibrosis 4 596 Risk Ratio (M-H, Random, 95% CI) 1.27 [0.34, 4.64]

7.5 Late oesophagitis 2 300 Risk Ratio (M-H, Random, 95% CI) 1.72 [0.32, 9.33]

7.6 Neutropenia 7 837 Risk Ratio (M-H, Random, 95% CI) 3.53 [1.84, 6.77]

7.7 Anaemia (grade 3 to 4) 5 822 Risk Ratio (M-H, Random, 95% CI) 4.17 [1.13, 15.35]

7.8 Anaemia (grade 1 to 4) 9 887 Risk Ratio (M-H, Random, 95% CI) 1.99 [1.49, 2.64]

Comparison 2. Concurrent vs Sequential chemoradiotherapy


studies

No. of


1 Overall survival 3 702 Hazard Ratio (Random, 95% CI) 0.74 [0.62, 0.89]

2 Overall survival 2-years 5 937 Risk Difference (M-H, Random, 95% CI) -0.10 [-0.18, -0.02]

3 Progression-free survival 1 201 Hazard Ratio (Random, 95% CI) 0.67 [0.30, 1.50]


5 Locoregional PFS 2-years 1 402 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.64, 1.10]






6.5 Anaemia 2 292 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.41, 2.21]



Comparison 3. Subgroup analysis Chemoradiotherapy vs Radiotherapy


studies

No. of


1 Chemotherapy regime 20 2587 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.86, 0.97]

1.1 Platinum-containing

regimes


1.2 Taxane-containing

regimes


1.3 Other regimes 2 113 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.56, 1.36]

2 Frequency of chemotherapy

administration

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

2.1 Daily administration 7 840 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.84, 1.05]

2.2 Weekly administration 7 1013 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.84, 0.96]

2.3 Two- to four-weekly

administration


3 Platinum dose 16 2173 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.86, 0.98]

3.1 High dose 9 1145 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.84, 1.00]

3.2 Low dose 7 1028 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.84, 1.03]

4 Radiotherapy fractionation 20 2587 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.86, 0.97]

4.1 Once daily fractionation 15 2065 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.85, 0.97]

4.2 Twice daily fractionation 5 522 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.79, 1.08]

5 Dose of radiotherapy 20 2587 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.86, 0.97]



6 Duration of follow-up 20 2587 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.86, 0.97]

6.1 Minimum follow-up 22

months or more



months or less


6.3 Duration of follow-up

uncertain


Comparison 4. Subgroup analysis Concurrent vs Sequential


studies

No. of


1 Dose of radiotherapy 5 937 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.78, 0.97]



2 Duration of follow-up 5 937 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.78, 0.97]


months or more



months or less




2.3 Duration of follow-up

uncertain

0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable

Comparison 5. More frequent versus less frequent chemotherapy


studies

No. of


1 Frequency of chemotherapy 2 325 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.80, 1.03]

Comparison 6. Sensitivity fixed: Concurrent vs Radiotherapy


studies

No. of


1 Overall survival 9 Hazard Ratio (Fixed, 95% CI) 0.71 [0.64, 0.80]

2 Overall survival 2-years 20 2587 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.86, 0.94]

3 Progression-free survival 7 Hazard Ratio (Fixed, 95% CI) 0.70 [0.62, 0.79]

4 Progression-free survival 2-years 9 1405 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.87, 0.95]


survival

2 Hazard Ratio (Fixed, 95% CI) 0.67 [0.54, 0.82]


survival 2-years

5 872 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.76, 0.91]

7 Toxicity 19 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

7.1 Treatment-related deaths 14 2075 Risk Ratio (M-H, Fixed, 95% CI) 1.51 [0.60, 3.79]

7.2 Acute pneumonitis 9 1179 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.57, 1.74]

7.3 Acute oesophagitis 17 2227 Risk Ratio (M-H, Fixed, 95% CI) 1.96 [1.50, 2.57]

7.4 Pulmonary fibrosis 4 596 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.56, 2.60]

7.5 Late oesophagitis 2 300 Risk Ratio (M-H, Fixed, 95% CI) 1.94 [0.53, 7.14]

7.6 Neutropenia 7 837 Risk Ratio (M-H, Fixed, 95% CI) 4.29 [2.28, 8.07]

7.7 Anaemia (grade 3 to 4) 5 822 Risk Ratio (M-H, Fixed, 95% CI) 4.96 [1.82, 13.51]

7.8 Anaemia (grade 1 to 4) 9 887 Risk Ratio (M-H, Fixed, 95% CI) 1.95 [1.46, 2.61]

Comparison 7. Sensitivity fixed: Concurrent vs Sequential


studies

No. of


1 Overall survival 3 Hazard Ratio (Fixed, 95% CI) 0.74 [0.62, 0.89]

2 Overall survival 2-years 5 937 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.81, 0.96]

3 Progression-free survival 1 Hazard Ratio (Fixed, 95% CI) 0.67 [0.30, 1.50]

4 Progression-free survival 2-years 2 378 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.83, 1.00]


survival 2-years

1 402 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.64, 1.10]

6 Toxicity 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only



6.1 Treatment-related deaths 5 950 Risk Ratio (M-H, Fixed, 95% CI) 2.09 [0.95, 4.57]

6.2 Acute pneumonitis 5 947 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.60, 1.46]

6.3 Acute oesophagitis 5 947 Risk Ratio (M-H, Fixed, 95% CI) 4.97 [3.28, 7.53]

6.4 Neutropenia 5 947 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.97, 1.20]

Comparison 8. Sensitivity ITT: Concurrent vs Radiotherapy


studies

No. of


1 Overall survival 2-years 20 2691 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.87, 0.97]



survival 2-years


Comparison 9. Sensitivity ITT: Concurrent vs Sequential


studies

No. of




Comparison 10. Sensitivity fully published: Concurrent vs Sequential


studies

No. of


1 Overall survival 2 Hazard Ratio (Random, 95% CI) 0.63 [0.44, 0.90]









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

survival.

Review: Concurrent chemoradiotherapy in non-small cell lung cancer

Comparison: 1 Concurrent chemoradiotherapy vs Radiotherapy alone

Outcome: 1 Overall survival

Study or subgroupConcurrentchemoRT Radiotherapy log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio

N N (SE) IV,Random,95% CI 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 -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 ]

Schaake-Koning 1992 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 ]

Total (95% CI) 100.0 % 0.71 [ 0.64, 0.80 ]

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 1 2 5 10

Favours chemoRT Favours RT



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

survival 2-years.



Outcome: 2 Overall survival 2-years

Study or subgroup RT + chemo RT aloneRisk

Difference WeightRisk

Difference

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Atagi 2005 15/23 17/23 2.2 % -0.09 [ -0.35, 0.18 ]

Ball 1999 once daily 32/54 39/53 4.2 % -0.14 [ -0.32, 0.03 ]

Ball 1999 twice daily 39/51 31/46 4.1 % 0.09 [ -0.09, 0.27 ]

Blanke 1995 85/104 97/111 8.3 % -0.06 [ -0.15, 0.04 ]

Bonner 1998 24/32 24/33 3.2 % 0.02 [ -0.19, 0.24 ]

Cakir 2004 68/88 84/88 8.2 % -0.18 [ -0.28, -0.08 ]

Clamon 1999 92/130 89/120 7.3 % -0.03 [ -0.14, 0.08 ]

Gouda 2006 11/20 18/20 2.4 % -0.35 [ -0.60, -0.10 ]

Groen 1999 66/82 56/78 6.1 % 0.09 [ -0.04, 0.22 ]

Huber 2003 63/99 88/113 6.6 % -0.14 [ -0.26, -0.02 ]

Jeremic 1995 75/108 46/61 5.7 % -0.06 [ -0.20, 0.08 ]

Jeremic 1996 37/65 49/66 4.8 % -0.17 [ -0.33, -0.01 ]

Landgren 1974 25/28 22/25 4.4 % 0.01 [ -0.16, 0.18 ]

Li 2008 14/30 20/30 2.5 % -0.20 [ -0.45, 0.05 ]

Lu 2005 27/47 30/45 3.6 % -0.09 [ -0.29, 0.11 ]

Manegold 2003 29/43 38/46 4.1 % -0.15 [ -0.33, 0.03 ]

Schaake-Koning 1992 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 ]

Total (95% CI) 1365 1222 100.0 % -0.08 [ -0.12, -0.03 ]

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 0 1 2

favours chemoRT favours RT alone



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

Progression-free survival.



Outcome: 3 Progression-free survival



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 -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 ]

Total (95% CI) 100.0 % 0.69 [ 0.58, 0.81 ]




0.01 0.1 1 10 100

Favours experimental Favours control




Progression-free survival 2-years.



Outcome: 4 Progression-free survival 2-years

Study or subgroupConcurrentchemoRT Radiotherapy Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Clamon 1999 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 ]

Total (95% CI) 716 689 100.0 % 0.91 [ 0.86, 0.97 ]

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



0.5 0.7 1 1.5 2





Locoregional progression-free survival.



Outcome: 5 Locoregional progression-free survival


N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI

Cakir 2004 88 88 -0.63 (0.16) 45.0 % 0.53 [ 0.39, 0.73 ]

Jeremic 1995 56 0 -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 ]

Total (95% CI) 100.0 % 0.67 [ 0.54, 0.82 ]

Heterogeneity: Chi2 = 4.95, df = 2 (P = 0.08); I2 =60%



0.01 0.1 1 10 100





Locoregional progression-free survival 2-years.



Outcome: 6 Locoregional progression-free survival 2-years


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Schaake-Koning 1992 150/217 92/114 29.6 % 0.86 [ 0.75, 0.97 ]

Total (95% CI) 510 362 100.0 % 0.84 [ 0.72, 0.98 ]




0.1 0.2 0.5 1 2 5 10




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



Outcome: 7 Toxicity

Study or subgroup Favours experimental Radiotherapy Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Treatment-related deaths

Atagi 2005 3/23 1/23 3.00 [ 0.34, 26.76 ]

Ball 1999 once daily 0/54 0/53 0.0 [ 0.0, 0.0 ]

Ball 1999 twice daily 2/51 3/46 0.60 [ 0.11, 3.44 ]

Blanke 1995 2/104 0/111 5.33 [ 0.26, 109.80 ]

Bonner 1998 0/32 0/33 0.0 [ 0.0, 0.0 ]

Clamon 1999 2/130 2/120 0.92 [ 0.13, 6.45 ]

Groen 1999 0/82 0/78 0.0 [ 0.0, 0.0 ]

Huber 2003 0/99 0/113 0.0 [ 0.0, 0.0 ]

Jeremic 1995 0/108 0/61 0.0 [ 0.0, 0.0 ]

Jeremic 1996 0/65 0/66 0.0 [ 0.0, 0.0 ]

Landgren 1974 0/26 0/25 0.0 [ 0.0, 0.0 ]

Schaake-Koning 1992 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 ]

Subtotal (95% CI) 1109 966 1.38 [ 0.51, 3.72 ]

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 1 10 100


(Continued . . . )



(. . . Continued)Study or subgroup Favours experimental Radiotherapy Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Landgren 1974 1/26 0/25 2.89 [ 0.12, 67.75 ]

Soresi 1988 1/45 0/50 3.33 [ 0.14, 79.64 ]

Subtotal (95% CI) 610 569 1.06 [ 0.58, 1.93 ]




3 Acute oesophagitis

Atagi 2005 0/23 0/23 0.0 [ 0.0, 0.0 ]

Ball 1999 once daily 11/53 6/51 1.76 [ 0.70, 4.42 ]

Ball 1999 twice daily 24/50 15/46 1.47 [ 0.89, 2.44 ]

Blanke 1995 3/104 3/111 1.07 [ 0.22, 5.17 ]

Bonner 1998 4/32 3/33 1.38 [ 0.33, 5.66 ]

Clamon 1999 13/130 4/120 3.00 [ 1.01, 8.95 ]

Gouda 2006 5/20 1/20 5.00 [ 0.64, 39.06 ]

Groen 1999 8/82 2/78 3.80 [ 0.83, 17.36 ]

Huber 2003 13/99 6/113 2.47 [ 0.98, 6.26 ]

Jeremic 1995 4/108 3/61 0.75 [ 0.17, 3.25 ]

Jeremic 1996 5/65 4/66 1.27 [ 0.36, 4.52 ]

Landgren 1974 10/26 8/25 1.20 [ 0.57, 2.55 ]

Lu 2005 10/47 2/45 4.79 [ 1.11, 20.66 ]

Manegold 2003 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 ]

Subtotal (95% CI) 1187 1040 1.76 [ 1.34, 2.31 ]




4 Pulmonary fibrosis

Atagi 2005 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 ]

Subtotal (95% CI) 326 270 1.27 [ 0.34, 4.64 ]

0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,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 ]

Subtotal (95% CI) 173 127 1.72 [ 0.32, 9.33 ]




6 Neutropenia

Atagi 2005 10/23 0/23 21.00 [ 1.30, 338.51 ]

Ball 1999 once daily 7/53 0/51 14.44 [ 0.85, 246.55 ]

Ball 1999 twice daily 1/50 0/46 2.76 [ 0.12, 66.22 ]

Clamon 1999 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 ]

Subtotal (95% CI) 418 419 3.53 [ 1.84, 6.77 ]




7 Anaemia (grade 3 to 4)

Ball 1999 once daily 0/53 1/51 0.32 [ 0.01, 7.70 ]

Ball 1999 twice daily 0/50 0/46 0.0 [ 0.0, 0.0 ]

Clamon 1999 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 ]

Subtotal (95% CI) 414 408 4.17 [ 1.13, 15.35 ]





Atagi 2005 16/23 8/23 2.00 [ 1.07, 3.72 ]

Ball 1999 once daily 20/53 6/51 3.21 [ 1.40, 7.34 ]

Ball 1999 twice daily 15/50 8/46 1.73 [ 0.81, 3.68 ]

Cakir 2004 8/88 7/88 1.14 [ 0.43, 3.02 ]

0.01 0.1 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Subtotal (95% CI) 447 440 1.99 [ 1.49, 2.64 ]




0.01 0.1 1 10 100


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


Comparison: 2 Concurrent vs Sequential chemoradiotherapy


Study or subgroupConcurrentchemoRT Sequential chemoRT log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio


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 ]

Zatloukal 2003 52 50 -0.49 (0.22) 18.5 % 0.61 [ 0.40, 0.94 ]

Total (95% CI) 100.0 % 0.74 [ 0.62, 0.89 ]




0.01 0.1 1 10 100

Favours concurrent Favours sequential



Analysis 2.2. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 2 Overall survival 2-

years.




Study or subgroup Concurrent SequentialRisk

Difference WeightRisk

Difference

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 0 1 2

favours concurrent favours sequential

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

survival.




Study or subgroupConcurrentchemoRT Sequential chemoRT log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio


Fournel 2001 100 101 -0.4 (0.41) 100.0 % 0.67 [ 0.30, 1.50 ]

Total (95% CI) 100.0 % 0.67 [ 0.30, 1.50 ]

Heterogeneity: not applicable



0.01 0.1 1 10 100




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

survival 2-years.




Study or subgroup Concurrent Sequential Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 1 1.5 2


Analysis 2.5. Comparison 2 Concurrent vs Sequential chemoradiotherapy, Outcome 5 Locoregional PFS 2-

years.



Outcome: 5 Locoregional PFS 2-years


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Curran 2003 64/201 76/201 100.0 % 0.84 [ 0.64, 1.10 ]

Total (95% CI) 201 201 100.0 % 0.84 [ 0.64, 1.10 ]




0.2 0.5 1 2 5




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



Outcome: 6 Toxicity

Study or subgroup Concurrent Sequential Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


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 ]

Subtotal (95% CI) 470 480 2.02 [ 0.90, 4.52 ]




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 ]

Wu 2006 13/40 8/40 1.63 [ 0.76, 3.49 ]

Zatloukal 2003 2/51 1/48 1.88 [ 0.18, 20.09 ]

Subtotal (95% CI) 469 478 0.99 [ 0.51, 1.91 ]





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 ]

Wu 2006 19/40 10/40 1.90 [ 1.01, 3.56 ]

0.02 0.1 1 10 50


(Continued . . . )



(. . . Continued)Study or subgroup Concurrent Sequential Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Zatloukal 2003 9/51 2/48 4.24 [ 0.96, 18.62 ]

Subtotal (95% CI) 469 478 4.96 [ 2.17, 11.37 ]




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 ]

Subtotal (95% CI) 469 478 1.18 [ 0.90, 1.55 ]




5 Anaemia

Fournel 2001 19/93 28/100 0.73 [ 0.44, 1.21 ]

Zatloukal 2003 6/51 3/48 1.88 [ 0.50, 7.11 ]

Subtotal (95% CI) 144 148 0.95 [ 0.41, 2.21 ]




0.02 0.1 1 10 50




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

Chemotherapy regime.


Comparison: 3 Subgroup analysis Chemoradiotherapy vs Radiotherapy

Outcome: 1 Chemotherapy regime

Study or subgroup favours chemoRT RT alone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Platinum-containing regimes

Atagi 2005 15/23 17/23 2.0 % 0.88 [ 0.60, 1.30 ]

Ball 1999 once daily 32/54 39/53 3.5 % 0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily 39/51 31/46 4.0 % 1.13 [ 0.88, 1.46 ]

Blanke 1995 85/104 97/111 9.6 % 0.94 [ 0.83, 1.05 ]

Bonner 1998 24/32 24/33 3.2 % 1.03 [ 0.77, 1.38 ]

Cakir 2004 68/88 84/88 9.2 % 0.81 [ 0.72, 0.91 ]

Clamon 1999 92/130 89/120 7.5 % 0.95 [ 0.82, 1.11 ]

Gouda 2006 11/20 18/20 1.7 % 0.61 [ 0.40, 0.93 ]

Groen 1999 66/82 56/78 6.4 % 1.12 [ 0.94, 1.34 ]

Jeremic 1995 75/108 46/61 5.8 % 0.92 [ 0.76, 1.11 ]

Jeremic 1996 37/65 49/66 3.9 % 0.77 [ 0.59, 0.99 ]

Lu 2005 27/47 30/45 2.7 % 0.86 [ 0.62, 1.19 ]

Schaake-Koning 1992 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 ]

Subtotal (95% CI) 1165 1008 82.5 % 0.92 [ 0.86, 0.98 ]

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 ]

Subtotal (95% CI) 142 159 10.4 % 0.82 [ 0.71, 0.94 ]



0.5 0.7 1 1.5 2


(Continued . . . )



(. . . Continued)Study or subgroup favours chemoRT RT alone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


3 Other regimes

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 ]

Subtotal (95% CI) 58 55 7.1 % 0.88 [ 0.56, 1.36 ]




Total (95% CI) 1365 1222 100.0 % 0.91 [ 0.86, 0.97 ]




0.5 0.7 1 1.5 2




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

of chemotherapy administration.



Outcome: 2 Frequency of chemotherapy administration


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Daily administration

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 ]

Schaake-Koning 1992 79/107 99/114 20.9 % 0.85 [ 0.74, 0.97 ]

Trovo 1992 73/84 72/85 21.9 % 1.03 [ 0.91, 1.16 ]

Subtotal (95% CI) 419 421 100.0 % 0.94 [ 0.84, 1.05 ]




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 ]

Schaake-Koning 1992 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 ]

Subtotal (95% CI) 494 519 100.0 % 0.90 [ 0.84, 0.96 ]




3 Two- to four-weekly administration

Ball 1999 once daily 32/54 39/53 9.4 % 0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily 39/51 31/46 10.6 % 1.13 [ 0.88, 1.46 ]

0.5 0.7 1 1.5 2


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Subtotal (95% CI) 452 457 100.0 % 0.90 [ 0.81, 0.99 ]




0.5 0.7 1 1.5 2




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

dose.



Outcome: 3 Platinum dose


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 High dose

Ball 1999 once daily 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 ]

Subtotal (95% CI) 595 550 56.0 % 0.91 [ 0.84, 1.00 ]




2 Low dose

Atagi 2005 15/23 17/23 2.5 % 0.88 [ 0.60, 1.30 ]

Ball 1999 twice daily 39/51 31/46 4.8 % 1.13 [ 0.88, 1.46 ]

Clamon 1999 92/130 89/120 9.0 % 0.95 [ 0.82, 1.11 ]

Gouda 2006 11/20 18/20 2.1 % 0.61 [ 0.40, 0.93 ]

Schaake-Koning 1992 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 ]

Subtotal (95% CI) 570 458 44.0 % 0.93 [ 0.84, 1.03 ]




Total (95% CI) 1165 1008 100.0 % 0.92 [ 0.86, 0.98 ]




0.5 0.7 1 1.5 2




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

Radiotherapy fractionation.



Outcome: 4 Radiotherapy fractionation


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Once daily fractionation

Atagi 2005 15/23 17/23 2.0 % 0.88 [ 0.60, 1.30 ]

Ball 1999 once daily 32/54 39/53 3.5 % 0.81 [ 0.61, 1.06 ]

Blanke 1995 85/104 97/111 9.6 % 0.94 [ 0.83, 1.05 ]

Cakir 2004 68/88 84/88 9.2 % 0.81 [ 0.72, 0.91 ]

Clamon 1999 92/130 89/120 7.5 % 0.95 [ 0.82, 1.11 ]

Gouda 2006 11/20 18/20 1.7 % 0.61 [ 0.40, 0.93 ]

Groen 1999 66/82 56/78 6.4 % 1.12 [ 0.94, 1.34 ]

Huber 2003 63/99 88/113 6.3 % 0.82 [ 0.68, 0.98 ]

Landgren 1974 25/28 22/25 5.7 % 1.01 [ 0.84, 1.23 ]

Lu 2005 27/47 30/45 2.7 % 0.86 [ 0.62, 1.19 ]

Manegold 2003 29/43 38/46 4.1 % 0.82 [ 0.64, 1.04 ]

Schaake-Koning 1992 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 ]

Subtotal (95% CI) 1079 986 81.7 % 0.91 [ 0.85, 0.97 ]




2 Twice daily fractionation

Ball 1999 twice daily 39/51 31/46 4.0 % 1.13 [ 0.88, 1.46 ]

Bonner 1998 24/32 24/33 3.2 % 1.03 [ 0.77, 1.38 ]

Jeremic 1995 75/108 46/61 5.8 % 0.92 [ 0.76, 1.11 ]

Jeremic 1996 37/65 49/66 3.9 % 0.77 [ 0.59, 0.99 ]

0.5 0.7 1 1.5 2


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Li 2008 14/30 20/30 1.5 % 0.70 [ 0.44, 1.11 ]

Subtotal (95% CI) 286 236 18.3 % 0.92 [ 0.79, 1.08 ]




Total (95% CI) 1365 1222 100.0 % 0.91 [ 0.86, 0.97 ]




0.5 0.7 1 1.5 2


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

radiotherapy.



Outcome: 5 Dose of radiotherapy

Study or subgroup Favours experimental RT alone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Low dose

Atagi 2005 15/23 17/23 2.0 % 0.88 [ 0.60, 1.30 ]

Ball 1999 once daily 32/54 39/53 3.5 % 0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily 39/51 31/46 4.0 % 1.13 [ 0.88, 1.46 ]

Bonner 1998 24/32 24/33 3.2 % 1.03 [ 0.77, 1.38 ]

Clamon 1999 92/130 89/120 7.5 % 0.95 [ 0.82, 1.11 ]

Gouda 2006 11/20 18/20 1.7 % 0.61 [ 0.40, 0.93 ]

Groen 1999 66/82 56/78 6.4 % 1.12 [ 0.94, 1.34 ]

Huber 2003 63/99 88/113 6.3 % 0.82 [ 0.68, 0.98 ]

0.5 0.7 1 1.5 2


(Continued . . . )



(. . . Continued)Study or subgroup Favours experimental RT alone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Manegold 2003 29/43 38/46 4.1 % 0.82 [ 0.64, 1.04 ]

Schaake-Koning 1992 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 ]

Subtotal (95% CI) 895 796 61.7 % 0.93 [ 0.86, 1.01 ]

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 ]

Subtotal (95% CI) 470 426 38.3 % 0.88 [ 0.81, 0.95 ]




Total (95% CI) 1365 1222 100.0 % 0.91 [ 0.86, 0.97 ]




0.5 0.7 1 1.5 2




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

of follow-up.



Outcome: 6 Duration of follow-up


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Minimum follow-up 22 months or more

Ball 1999 once daily 32/54 39/53 3.5 % 0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily 39/51 31/46 4.0 % 1.13 [ 0.88, 1.46 ]

Blanke 1995 85/104 97/111 9.6 % 0.94 [ 0.83, 1.05 ]

Cakir 2004 68/88 84/88 9.2 % 0.81 [ 0.72, 0.91 ]

Huber 2003 63/99 88/113 6.3 % 0.82 [ 0.68, 0.98 ]

Landgren 1974 25/28 22/25 5.7 % 1.01 [ 0.84, 1.23 ]

Schaake-Koning 1992 168/217 99/114 10.5 % 0.89 [ 0.81, 0.99 ]

Subtotal (95% CI) 641 550 48.6 % 0.90 [ 0.83, 0.97 ]




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 ]

Subtotal (95% CI) 176 183 15.9 % 0.99 [ 0.85, 1.15 ]




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 1 1.5 2


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Subtotal (95% CI) 548 489 35.5 % 0.89 [ 0.79, 0.99 ]




Total (95% CI) 1365 1222 100.0 % 0.91 [ 0.86, 0.97 ]




0.5 0.7 1 1.5 2




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


Comparison: 4 Subgroup analysis Concurrent vs Sequential

Outcome: 1 Dose of radiotherapy

Study or subgroup Favours experimental RT alone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Low dose

Zatloukal 2003 34/52 43/50 17.1 % 0.76 [ 0.61, 0.95 ]

Subtotal (95% CI) 52 50 17.1 % 0.76 [ 0.61, 0.95 ]




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 ]

Subtotal (95% CI) 413 422 82.9 % 0.89 [ 0.79, 1.01 ]




Total (95% CI) 465 472 100.0 % 0.87 [ 0.78, 0.97 ]




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

0.5 0.7 1 1.5 2




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


Comparison: 4 Subgroup analysis Concurrent vs Sequential

Outcome: 2 Duration of follow-up


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Minimum follow-up 22 months or more

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 ]

Subtotal (95% CI) 303 304 51.0 % 0.88 [ 0.79, 0.99 ]




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 ]

Subtotal (95% CI) 162 168 49.0 % 0.84 [ 0.66, 1.06 ]




3 Duration of follow-up uncertain

Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]



Test for overall effect: not applicable

Total (95% CI) 465 472 100.0 % 0.87 [ 0.78, 0.97 ]




0.5 0.7 1 1.5 2




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

chemotherapy.


Comparison: 5 More frequent versus less frequent chemotherapy

Outcome: 1 Frequency of chemotherapy

Study or subgroup

morefrequent

chemo less frequent chemo Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Jeremic 1995 34/52 41/56 24.6 % 0.89 [ 0.69, 1.15 ]

Schaake-Koning 1992 79/107 89/110 75.4 % 0.91 [ 0.79, 1.05 ]

Total (95% CI) 159 166 100.0 % 0.91 [ 0.80, 1.03 ]

Total events: 113 (more frequent chemo), 130 (less frequent chemo)



0.5 0.7 1 1.5 2

more frequent chemo less frequent chemo



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


Comparison: 6 Sensitivity fixed: Concurrent vs Radiotherapy


Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio

(SE) IV,Fixed,95% CI 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 ]

Total (95% CI) 100.0 % 0.71 [ 0.64, 0.80 ]

Heterogeneity: Chi2 = 8.77, df = 9 (P = 0.46); I2 =0.0%



0.1 0.2 0.5 1 2 5 10

Favours chemoRT Favours RT



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

years.




Study or subgroup RT + chemo RT alone Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Atagi 2005 15/23 17/23 1.7 % 0.88 [ 0.60, 1.30 ]

Ball 1999 once daily 32/54 39/53 3.9 % 0.81 [ 0.61, 1.06 ]

Ball 1999 twice daily 39/51 31/46 3.3 % 1.13 [ 0.88, 1.46 ]

Blanke 1995 85/104 97/111 9.4 % 0.94 [ 0.83, 1.05 ]

Bonner 1998 24/32 24/33 2.4 % 1.03 [ 0.77, 1.38 ]

Cakir 2004 68/88 84/88 8.4 % 0.81 [ 0.72, 0.91 ]

Clamon 1999 92/130 89/120 9.3 % 0.95 [ 0.82, 1.11 ]

Gouda 2006 11/20 18/20 1.8 % 0.61 [ 0.40, 0.93 ]

Groen 1999 66/82 56/78 5.7 % 1.12 [ 0.94, 1.34 ]

Huber 2003 63/99 88/113 8.2 % 0.82 [ 0.68, 0.98 ]

Jeremic 1995 75/108 46/61 5.9 % 0.92 [ 0.76, 1.11 ]

Jeremic 1996 37/65 49/66 4.9 % 0.77 [ 0.59, 0.99 ]

Landgren 1974 25/28 22/25 2.3 % 1.01 [ 0.84, 1.23 ]

Li 2008 14/30 20/30 2.0 % 0.70 [ 0.44, 1.11 ]

Lu 2005 27/47 30/45 3.1 % 0.86 [ 0.62, 1.19 ]

Manegold 2003 29/43 38/46 3.7 % 0.82 [ 0.64, 1.04 ]

Schaake-Koning 1992 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 ]

Total (95% CI) 1365 1222 100.0 % 0.90 [ 0.86, 0.94 ]




0.5 0.7 1 1.5 2




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

survival.






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 ]

Total (95% CI) 100.0 % 0.70 [ 0.62, 0.79 ]




0.01 0.1 1 10 100




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

survival 2-years.






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 ]

Clamon 1999 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 ]

Total (95% CI) 716 689 100.0 % 0.91 [ 0.87, 0.95 ]





0.01 0.1 1 10 100




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

progression-free survival.



Outcome: 5 Locoregional progression-free survival



Cakir 2004 -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 ]

Total (95% CI) 100.0 % 0.67 [ 0.54, 0.82 ]




0.01 0.1 1 10 100




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

progression-free survival 2-years.






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 ]

Schaake-Koning 1992 150/217 92/114 38.6 % 0.86 [ 0.75, 0.97 ]

Total (95% CI) 510 362 100.0 % 0.84 [ 0.76, 0.91 ]





0.01 0.1 1 10 100




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



Outcome: 7 Toxicity

Study or subgroupConcurrentchemoRT Radiotherapy Risk Ratio Risk Ratio



Atagi 2005 3/23 1/23 3.00 [ 0.34, 26.76 ]

Ball 1999 once daily 0/54 0/53 0.0 [ 0.0, 0.0 ]

Ball 1999 twice daily 2/51 3/46 0.60 [ 0.11, 3.44 ]

Blanke 1995 2/104 0/111 5.33 [ 0.26, 109.80 ]

Bonner 1998 0/32 0/33 0.0 [ 0.0, 0.0 ]

Clamon 1999 2/130 2/120 0.92 [ 0.13, 6.45 ]

Groen 1999 0/82 0/78 0.0 [ 0.0, 0.0 ]

Huber 2003 0/99 0/113 0.0 [ 0.0, 0.0 ]

Jeremic 1995 0/108 0/61 0.0 [ 0.0, 0.0 ]

Jeremic 1996 0/65 0/66 0.0 [ 0.0, 0.0 ]

Landgren 1974 0/26 0/25 0.0 [ 0.0, 0.0 ]

Schaake-Koning 1992 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 ]

Subtotal (95% CI) 1109 966 1.51 [ 0.60, 3.79 ]




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 1 10 100


(Continued . . . )



(. . . Continued)



Landgren 1974 1/26 0/25 2.89 [ 0.12, 67.75 ]

Soresi 1988 1/45 0/50 3.33 [ 0.14, 79.64 ]

Subtotal (95% CI) 610 569 1.00 [ 0.57, 1.74 ]





Atagi 2005 0/23 0/23 0.0 [ 0.0, 0.0 ]

Ball 1999 once daily 11/53 6/51 1.76 [ 0.70, 4.42 ]

Ball 1999 twice daily 24/50 15/46 1.47 [ 0.89, 2.44 ]

Blanke 1995 3/104 3/111 1.07 [ 0.22, 5.17 ]

Bonner 1998 4/32 3/33 1.38 [ 0.33, 5.66 ]

Clamon 1999 13/130 4/120 3.00 [ 1.01, 8.95 ]

Gouda 2006 5/20 1/20 5.00 [ 0.64, 39.06 ]

Groen 1999 8/82 2/78 3.80 [ 0.83, 17.36 ]

Huber 2003 13/99 6/113 2.47 [ 0.98, 6.26 ]

Jeremic 1995 4/108 3/61 0.75 [ 0.17, 3.25 ]

Jeremic 1996 5/65 4/66 1.27 [ 0.36, 4.52 ]

Landgren 1974 10/26 8/25 1.20 [ 0.57, 2.55 ]

Lu 2005 10/47 2/45 4.79 [ 1.11, 20.66 ]

Manegold 2003 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 ]

Subtotal (95% CI) 1187 1040 1.96 [ 1.50, 2.57 ]




4 Pulmonary fibrosis

Atagi 2005 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 ]

Subtotal (95% CI) 326 270 1.21 [ 0.56, 2.60 ]

0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)






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 ]

Subtotal (95% CI) 173 127 1.94 [ 0.53, 7.14 ]




6 Neutropenia

Atagi 2005 10/23 0/23 21.00 [ 1.30, 338.51 ]

Ball 1999 once daily 7/53 0/51 14.44 [ 0.85, 246.55 ]

Ball 1999 twice daily 1/50 0/46 2.76 [ 0.12, 66.22 ]

Clamon 1999 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 ]

Subtotal (95% CI) 418 419 4.29 [ 2.28, 8.07 ]





Ball 1999 once daily 0/53 1/51 0.32 [ 0.01, 7.70 ]

Ball 1999 twice daily 0/50 0/46 0.0 [ 0.0, 0.0 ]

Clamon 1999 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 ]

Subtotal (95% CI) 414 408 4.96 [ 1.82, 13.51 ]





Atagi 2005 16/23 8/23 2.00 [ 1.07, 3.72 ]

Ball 1999 once daily 20/53 6/51 3.21 [ 1.40, 7.34 ]

Ball 1999 twice daily 15/50 8/46 1.73 [ 0.81, 3.68 ]

Cakir 2004 8/88 7/88 1.14 [ 0.43, 3.02 ]

0.01 0.1 1 10 100


(Continued . . . )



(. . . Continued)



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 ]

Subtotal (95% CI) 447 440 1.95 [ 1.46, 2.61 ]




0.01 0.1 1 10 100


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


Comparison: 7 Sensitivity fixed: Concurrent vs Sequential




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 ]

Zatloukal 2003 -0.49 (0.22) 18.5 % 0.61 [ 0.40, 0.94 ]

Total (95% CI) 100.0 % 0.74 [ 0.62, 0.89 ]




0.01 0.1 1 10 100




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






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 ]




0.5 0.7 1 1.5 2


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

survival.






Fournel 2001 -0.4 (0.41) 100.0 % 0.67 [ 0.30, 1.50 ]

Total (95% CI) 100.0 % 0.67 [ 0.30, 1.50 ]




0.01 0.1 1 10 100




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

survival 2-years.






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 ]




0.01 0.1 1 10 100


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







Curran 2003 64/201 76/201 100.0 % 0.84 [ 0.64, 1.10 ]

Total (95% CI) 201 201 100.0 % 0.84 [ 0.64, 1.10 ]




0.2 0.5 1 2 5




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



Outcome: 6 Toxicity




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 ]

Subtotal (95% CI) 470 480 2.09 [ 0.95, 4.57 ]




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 ]

Wu 2006 13/40 8/40 1.63 [ 0.76, 3.49 ]

Zatloukal 2003 2/51 1/48 1.88 [ 0.18, 20.09 ]

Subtotal (95% CI) 469 478 0.94 [ 0.60, 1.46 ]





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 ]

Wu 2006 19/40 10/40 1.90 [ 1.01, 3.56 ]

Zatloukal 2003 9/51 2/48 4.24 [ 0.96, 18.62 ]

Subtotal (95% CI) 469 478 4.97 [ 3.28, 7.53 ]




0.01 0.1 1 10 100


(Continued . . . )





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 ]

Subtotal (95% CI) 469 478 1.08 [ 0.97, 1.20 ]




0.01 0.1 1 10 100


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

years.


Comparison: 8 Sensitivity ITT: Concurrent vs Radiotherapy


Study or subgroup RT + chemo RT alone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Atagi 2005 15/23 17/23 1.8 % 0.88 [ 0.60, 1.30 ]

Ball 1999 once daily 34/56 39/53 3.4 % 0.83 [ 0.63, 1.08 ]

Ball 1999 twice daily 41/53 31/46 3.8 % 1.15 [ 0.90, 1.47 ]

Blanke 1995 98/117 109/123 10.3 % 0.95 [ 0.85, 1.05 ]

Bonner 1998 28/36 28/37 3.7 % 1.03 [ 0.80, 1.32 ]

Cakir 2004 72/92 89/93 9.3 % 0.82 [ 0.73, 0.92 ]

Clamon 1999 108/146 106/137 8.3 % 0.96 [ 0.84, 1.09 ]

Gouda 2006 11/20 18/20 1.5 % 0.61 [ 0.40, 0.93 ]

0.5 0.7 1 1.5 2


(Continued . . . )



(. . . Continued)Study or subgroup RT + chemo RT alone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Schaake-Koning 1992 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 ]

Total (95% CI) 1420 1271 100.0 % 0.92 [ 0.87, 0.97 ]




0.5 0.7 1 1.5 2




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

survival 2-years.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Total (95% CI) 744 714 100.0 % 0.92 [ 0.86, 0.98 ]




0.01 0.1 1 10 100




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






n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 ]

Schaake-Koning 1992 150/217 92/114 28.4 % 0.86 [ 0.75, 0.97 ]

Total (95% CI) 526 376 100.0 % 0.85 [ 0.74, 0.99 ]




0.01 0.1 1 10 100




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


Comparison: 9 Sensitivity ITT: Concurrent vs Sequential



n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 1 1.5 2


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

2-years.


Comparison: 9 Sensitivity ITT: Concurrent vs Sequential



n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

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 1 10 100




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

survival.


Comparison: 10 Sensitivity fully published: Concurrent vs Sequential



(SE) IV,Random,95% CI IV,Random,95% CI

Fournel 2001 -0.4 (0.34) 29.5 % 0.67 [ 0.34, 1.31 ]

Zatloukal 2003 -0.49 (0.22) 70.5 % 0.61 [ 0.40, 0.94 ]

Total (95% CI) 100.0 % 0.63 [ 0.44, 0.90 ]




0.01 0.1 1 10 100




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

survival 2-years.





n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Fournel 2001 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 ]




0.5 0.7 1 1.5 2




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



Outcome: 3 Toxicity


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


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 ]

Subtotal (95% CI) 269 279 2.45 [ 0.81, 7.43 ]




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 ]

Wu 2006 13/40 8/40 1.63 [ 0.76, 3.49 ]

Zatloukal 2003 2/51 1/48 1.88 [ 0.18, 20.09 ]

Subtotal (95% CI) 268 277 1.22 [ 0.57, 2.65 ]





Fournel 2001 30/93 3/100 10.75 [ 3.40, 34.05 ]

Reinfuss 2005 7/84 0/89 15.88 [ 0.92, 273.84 ]

Wu 2006 19/40 10/40 1.90 [ 1.01, 3.56 ]

Zatloukal 2003 9/51 2/48 4.24 [ 0.96, 18.62 ]

Subtotal (95% CI) 268 277 4.85 [ 1.52, 15.45 ]




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 1 10 100


(Continued . . . )




n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Wu 2006 26/40 17/40 1.53 [ 1.00, 2.34 ]

Zatloukal 2003 33/51 19/48 1.63 [ 1.09, 2.45 ]

Subtotal (95% CI) 268 277 1.35 [ 0.79, 2.32 ]




0.01 0.1 1 10 100


A D D I T I O N A L T A B L E S

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

author study name N analized / ran-

domized

date accrued minimum follow-up comparators

Atagi 2005 JCOG9812 46/46 1999-2001 unclear concurrent v RT alone

Ball 1999 Australian

multicentre

204/208 1989-1995 32 months concurrent v RT alone

Blanke 1995 Hoosier Oncology

Group


Bonner 1998 North Central Can-

cer Treatment

Group


Cakir 2004 Turkey (Samsun

and Ankara)


Clamon 1999 CALGB/ECOG 250/283 >1991 uncertain concurrent v RT alone

Gouda 2006 Egypt 60/60 1998-2000 uncertain concurrent v RT alone

Groen 1999 Netherlands 160/160 1994-1998 uncertain concurrent v RT alone

Huber 2003 BROCAT 212/219 not stated 3 years (except for

2 patients lost)

concurrent v RT alone

Jeremic 1995 Kragujevac (single

centre)

169/178 1988-1989 uncertain concurrent v RT alone



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

Jeremic 1996 Kragujevac (single

centre)


Landgren 1974 MDAnderson 53/54 1970-1971 24 months concurrent v RT alone

Li 2008 China 58/60 not stated (median 24 months) concurrent v RT alone

Lu 2005 China 85/92 2001-2003 uncertain concurrent v RT alone

Manegold 2003 European multicen-

tre (8 centres)


Schaake-Koning

1992

EORTC 331/331 1984-1989 22 months concurrent v RT alone

Soresi 1988 Milan 93/95 1986-1987 uncertain

(median 12 months)


Trovo 1992 GOCCNE 167/173 1987-1991 6 months concurrent v RT alone

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) concurrent v sequential

Rao 2007 China 53/55 not stated 4 months concurrent v sequential

Reinfuss 2005 Poland 173/173 2001-2004 12 months concurrent v sequential

Wu 2006 China --/80 not stated uncertain concurrent v sequential

Zatloukal 2003 Czech Lung Cancer

Group

102/102 not stated 18 months concurrent v sequential

Table 2. Concurrent chemoradiotherapy versus radiotherapy alone: treatment details

trial induction

chemo

RT dose & frac-

tions

chemo

frequency

chemo details total platinum

dose

chemo post RT

Atagi 2005

no

60Gy in 30 frac-

tions in 6 weeks

daily Daily carbo-

platin 30mg/m2

for first 20 frac-

600mg/m2 car-

boplatin in CRT

arm

no



Table 2. Concurrent chemoradiotherapy versus radiotherapy alone: treatment details (Continued)

tions

Ball 1999 - once

daily

no 60Gy in 30 daily

fractions over 6

weeks

4-weekly carbo-

platin 70mg/m2

days 1-5 weeks 1

& 5

700mg/m2 no

Ball 1999 - twice

daily

no 60Gy in 30 frac-

tions

(twice daily) over

3 weeks

3-weekly carbo-

platin 70mg/m2

days 1-5 week 1

350mg/m2 no

Blanke 1995 no 60-65Gy in daily

fractions of 1.8-

2Gy (6-7 weeks)

3-weekly cisplatin 70mg/

m2 weeks 1,4 &

7

210mg/m2 no

Bonner 1998 no 60Gy in 40 frac-

tions of 1.5Gy

(twice daily) split

over 6 weeks

4-weekly cisplatin 30mg/

m2 + etoposide

100mg/m2 days

1-3, weeks 1 & 5

180mg/m2 no

Cakir 2004 no 64Gy in 32 frac-

tions over 6.5

weeks

3-weekly cis-

platin 20mg/m2

days 1-5 weeks 2

& 6

200mg/m2 no

Clamon 1999 cisplatin 100mg/

m2 days 1 & 29 +

vinblastine 5mg/

m2 days 1,8,15,

22,29

60Gy in 30 daily

fractions over 6

weeks

weekly car-

boplatin 100mg/

m2 weekly

600mg/m2 no

Gouda 2006

No

60 Gy

at “conventional

fractionation”

in 30 fractions

2 to 4-weekly Pacli-

taxel175mg/m2

Carbo

AUC6 D1 and

D28 concur with

RT

Carbo AUC6 x2

in group B

No

Groen 1999 no 60Gy in 30 daily

fractions over 6

weeks

continuous infu-

sion

carboplatin

840mg/m2 con-

tinuous infusion

over 6 weeks

840mg/m2 no

Huber 2003 carboplatin

AUC6 + pacli-

taxel 200mg/

m2; 3-weekly, 2

cycles

60Gy in 30 daily

fractions over 6

weeks

weekly paclitaxel 60mg/

m2 weekly

- no




Jeremic 1995 no 64.8Gy in 54

fractions of 1.

2Gy (twice daily)

over 5.5 weeks

weekly OR alter-

nate weeks

car-

boplatin 100mg

total dose days

1,2 + etoposide

100mg total dose

days 1-3 each

week OR car-

boplatin 200mg

total dose days

1,2 + etopside

100mg total dose

days 1-5 weeks 1,

3, & 5

1200mg total

(approx 700mg/

m2)

no

Jeremic 1996 no 69.6Gy in 58

fractions of 1.

2Gy (twice daily)

over 6 weeks

daily carbo-

platin 50mg to-

tal dose + etopo-

side 50mg total

dose daily

1450mg total

(approx 850mg/

m2)

no

Landgren 1974 no 60Gy in 20 daily

fractions split

over 8 weeks

daily hydroxyurea

30mg/kg daily

- no

Li 2008 no 1.

2 Gy bd. AP/PA

to 38.4 Gy then

changed field an-

gles to continue

to total RT dose.

62.4-67.2 GY

Daily Hydroxy-

comphothecin

10 mg/d for 1st

and last week of

radiotherapy

- no

Lu 2005

2 cycles both

arms

40 Gy/20 AP/

PA with subse-

quent boost to

tumour avoiding

cord to total dose

60-65Gy

2 to 4-weekly Vinorelbine 15-

18 mg/m2 D1

and D8

Cisplatin 60mg/

m2 D1

q 3w

4-6 cycles

240-360mg/m2

2-4 cycles chemo

Manegold 2003 cisplatin 40mg/

m2 days 1,2 +

docetaxel 85mg/

m2 day 1; 3-

weekly, 2 cycles

60Gy in 30 daily

fractions over 6

weeks

weekly docetaxel 20mg/

m2 weekly

- no

Schaake-Koning

1992

no 55Gy in 20 daily

fractions split

over 7 weeks

weekly OR daily cisplatin 30mg/

m2 weekly OR

cisplatin 6mg/

m2 daily

120mg/m2 no




Soresi 1988 no 50.4Gy in 28

fractions over 5.

5 weeks

weekly cisplatin 15mg/

m2 weekly

90mg/m2 no

Trovo 1992 no 45Gy in 15 daily

fractions over 3

weeks

daily cisplatin 6mg/

m2 daily

90mg/m2 no

Yadav 2005

No

50 Gy in 25 #

AP/PA with cord

shielding last five

fractions ? same

treatment both

arms

weekly cisplatin 30mg/

m2 IV weekly

150mg/m2 no

Table 3. Concurrent versus sequential chemoradiotherapy : treatment details

trial chemotherapy RT dose & frac-

tions

concurrent RT sequential RT notes

Curran 2003 cisplatin 100mg/

m2 days 1,29 +

vinblastine 5mg/m2

days1,8,15,22,29

63 Gy once daily

fractions

RT starting day 1 RT starting day 50

Fournel 2001 sequential: cisplatin

120mg/m2 days 1,

29,57 + vinorelbine

30mg/m2

weekly; concurrent:

cisplatin 20mg/m2

+ etoposide days 1-

5 & 29-33 followed

by cisplatin 80mg/

m2 days 78 & 106 +

vinorelbine weekly

days 78-127

66 Gy in 33 daily

fractions over 6.5

weeks

RT starting day 1 RT starting day 85 total cisplatin dose

same in both arms

Rao 2007 vinorel 25mg/m2

D1, D8

cisplatin 25mg/m2

D1-3 q 3w

36 Gy/18 AP/PA

with tumour boost

26-34Gy avoiding

cord

RT starting day 1 RT starting after 2

cycles chemo ap-

prox D42

Reinfuss 2005 cisplatin

100mg/m2 D1, vi-

norel 20mg/m2 D1,

D8 q4wks 2 cycles

50.4 Gy/28# with

boost 19.8 Gy/11#

same schedule both

arms

RT starting day 1 RT starting day 8

second course

cisplatin 200mg/

m2 both arms



Table 3. Concurrent versus sequential chemoradiotherapy : treatment details (Continued)

Wu 2006 vi-

norelbine 12.5mg/

m2 and cisplatin

40mg/m2 D1, 8, 29

and 36 during RT

40 Gy/20-22 AP/

PA then avoiding

cord to total dose of

60Gy/30-33

RT starting day 1 RT starting D1 with

chemo given subse-

quent to RT

Zatloukal 2002,

2003

cisplatin 80mg/m2

day 1 + vinorelbine

25mg/m2 days 1,8,

15 (12.5mg/m2 in

cycles 2 & 3) 4-

weekly cycles x4

60 Gy

in 30 daily fractions

over 6 weeks

RT starting day 4

cycle 2

RT starting day 113

(approx)

A P P E N D I C E S

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



#26 radiotherap* 11360

#27 irradiat* 4696

#28 (#25 OR #26 OR #27) 13583

#29 (#20 AND #24 AND #28) 677

#30 (#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 exp lung non small cell cancer/ (23516)

2 (non small cell adj3 lung).mp. (26227)

3 nsclc.mp. (9972)

4 1 or 2 or 3 (26470)

5 exp radiotherapy/ (162634)

6 radiotherap*.mp. (130110)

7 irradiat*.mp. (120294)

8 (radiation adj2 therapy).mp. (34853)

9 8 or 6 or 7 or 5 (266901)

10 exp chemotherapy/ (196505)

11 exp antineoplastic agent/ (764918)

12 chemotherap*.mp. (265018)

13 (adjuvant adj3 therapy).mp. (41008)

14 11 or 13 or 10 or 12 (857609)

15 4 and 9 and 14 (4547)

16 Clinical trial/ (558947)

17 Randomized controlled trials/ (174578)

18 Random Allocation/ (27087)

19 Single-Blind Method/ (8587)

20 Double-Blind Method/ (74328)

21 Cross-Over Studies/ (21843)

22 Placebos/ (132301)



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

24 RCT.tw. (2950)

25 Random allocation.tw. (647)

26 Randomly allocated.tw. (10529)

27 Allocated randomly.tw. (1372)

28 (allocated adj2 random).tw. (565)

29 Single blind$.tw. (7704)

30 Double blind$.tw. (86977)

31 ((treble or triple) adj blind$).tw. (142)

32 Placebo$.tw. (113396)

33 Prospective Studies/ (86261)

34 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)

35 Case study/ (6429)

36 Case report.tw. (123578)

37 Abstract report/ or letter/ (513341)

38 35 or 36 or 37 (640898)

39 34 not 38 (708199)

40 animal/ not human/ (14494)

41 39 not 40 (708103)

42 synchronous.ti,ab. (13207)

43 concurrent.ti,ab. (43027)

44 concomitant.ti,ab. (82547)

45 sequential.ti,ab. (61371)

46 45 or 44 or 42 or 43 (196219)

47 46 and 15 (990)

48 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



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



W H A T ’ S N E W

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.

H I S T O R Y

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

C O N T R I B U T I O N S O F A U T H O R S

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.

D E C L A R A T I O N S O F I N T E R E S T

None known.



S O U R C E S O F S U P P O R T

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

I N D E X T E R M S

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



Concurrent ChemoRT in NSCLC

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