Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data
The Lancet, Early Online Publication, 25 February 2014
Summary
Background
Individual
participant data meta-analyses of postoperative chemotherapy have shown
improved survival for patients with non-small-cell lung cancer (NSCLC).
We aimed to do a systematic review and individual participant data
meta-analysis to establish the effect of preoperative chemotherapy for
patients with resectable NSCLC.
Methods
We
systematically searched for trials that started after January, 1965.
Updated individual participant data were centrally collected, checked,
and analysed. Results from individual randomised controlled trials (both
published and unpublished) were combined using a two-stage fixed-effect
model. Our primary outcome, overall survival, was defined as the time
from randomisation until death (any cause), with living patients
censored on the date of last follow-up. Secondary outcomes were
recurrence-free survival, time to locoregional and distant recurrence,
cause-specific survival, complete and overall resection rates, and
postoperative mortality. Prespecified analyses explored any variation in
effect by trial and patient characteristics. All analyses were by
intention to treat.
Findings
Analyses
of 15 randomised controlled trials (2385 patients) showed a significant
benefit of preoperative chemotherapy on survival (hazard ratio [HR]
0·87, 95% CI 0·78—0·96, p=0·007), a 13% reduction in the relative risk
of death (no evidence of a difference between trials; p=0·18, I2=25%).
This finding represents an absolute survival improvement of 5% at 5
years, from 40% to 45%. There was no clear evidence of a difference in
the effect on survival by chemotherapy regimen or scheduling, number of
drugs, platinum agent used, or whether postoperative radiotherapy was
given. There was no clear evidence that particular types of patient
defined by age, sex, performance status, histology, or clinical stage
benefited more or less from preoperative chemotherapy. Recurrence-free
survival (HR 0·85, 95% CI 0·76—0·94, p=0·002) and time to distant
recurrence (0·69, 0·58—0·82, p<0·0001) results were both
significantly in favour of preoperative chemotherapy although most
patients included were stage IB—IIIA. Results for time to locoregional
recurrence (0·88, 0·73—1·07, p=0·20), although in favour of preoperative
chemotherapy, were not statistically significant.
Interpretation
Findings,
which are based on 92% of all patients who were randomised, and mainly
stage IB—IIIA, show preoperative chemotherapy significantly improves
overall survival, time to distant recurrence, and recurrence-free
survival in resectable NSCLC. The findings suggest this is a valid
treatment option for most of these patients. Toxic effects could not be
assessed.
Funding
Medical Research Council UK.
Introduction
Worldwide, roughly 1·5 million new cases of lung cancer are diagnosed annually1 with about 85% being non-small-cell lung cancers (NSCLCs).2 Surgery is thought the best treatment option, but only about 20—25% of tumours are suitable for potentially curative resection.3 Two individual participant data meta-analyses4 showed that postoperative chemotherapy, with or without radiotherapy, improved survival.
Preoperative
chemotherapy has the potential to reduce tumour size, increase
operability, and eradicate micrometastases. Chemotherapy might also be
more effective when the blood supply to the tumour is still intact
before surgical resection, and chemotherapy might be better tolerated if
patients are not recovering from major surgery. However, preoperative
chemotherapy will delay surgery, and if ineffective, tumours can become
unresectable.
The findings of several reviews, based on aggregate data from randomised controlled trials,5—9
have suggested preoperative chemotherapy improves survival. However,
these reviews all included different combinations of trials, some of
which were confounded by the use of chemotherapy in both arms or
radiotherapy in one arm, making the specific effects of preoperative
chemotherapy difficult to discern. Furthermore, analyses of other
outcomes and how effects vary by patient characteristics were not
possible with the aggregate data. Therefore, we did a systematic review
and meta-analysis of individual participant data to provide more
reliable and up-to-date evidence on the effect of preoperative
chemotherapy on survival and other key outcomes and whether this varies
by patient subgroup.
Methods
Design and study selection
Methods
were prespecified in a protocol (available on request). Randomised
trials comparing chemotherapy with subsequent surgery versus surgery
alone were eligible if they started after Jan 1, 1965, and aimed to
include chemotherapy-naive NSCLC patients, suitable for surgery, without
any previous malignancy. Trials that planned to use postoperative
radiotherapy in both arms, or postoperative chemotherapy in the
preoperative arm only, were also eligible.
Published
and unpublished trials were sought, with no language restrictions,
using randomised trial search filters for Medline and Embase10
with additional terms for NSCLC and chemotherapy. These searches were
supplemented by searching trial registers, conference proceedings,
review articles, and reference lists of trial publications (appendix). Collaborators were asked if they knew of any additional trials. Searches were regularly updated until May, 2013.
Data collection
For
all eligible trials and all patients who were randomised, data were
sought on the date of randomisation, treatment allocation, type of
chemotherapy and number of cycles, age, sex, histology, performance
status, date of surgery, extent of resection, clinical and pathological
tumour stage, clinical and pathological response, recurrence, survival,
cause of death, and date of last follow-up. Standard methods were used
to identify missing data and to assess data validity and consistency.11
Patterns of treatment allocation and the balance of baseline
characteristics by treatment group were used to check randomisation
integrity and follow-up of surviving patients was checked to ensure it
was up to date and balanced by arm and fed into a risk of bias
assessment for each trial.12 Any inconsistencies were resolved and the final dataset verified by the relevant trial contact.
Definition of outcomes
Our
primary outcome, overall survival, was defined as the time from
randomisation until death (any cause), with living patients censored on
the date of last follow-up. Secondary outcomes were recurrence-free
survival, time to locoregional and distant recurrence, cause-specific
survival, complete and overall resection rates, and postoperative
mortality. There were concerns that for patients receiving their surgery
immediately in the surgery-alone arm, any recurrences could be
identified sooner than in the preoperative chemotherapy arm. This might
erroneously suggest a benefit of chemotherapy. Thus, analyses of
recurrence outcomes were calculated from a landmark time of 6 months
from the date of randomisation to allow for all patients to have
completed their allocated treatment.13
Events arising within 6 months of randomisation were regarded as events
at this landmark time. Recurrence-free survival was defined as time
from the landmark date until locoregional recurrence, distant
recurrence, or death, whichever happened first. Patients alive without
recurrence were censored on the date of last follow-up. To avoid bias
from under-reporting of subsequent events, time to locoregional
(distant) recurrence was defined as time from the landmark date to first
locoregional (distant) recurrence, and patients experiencing previous
distant (local) recurrences were censored on the date of distant (local)
recurrence. Patients experiencing a locoregional and distant recurrence
on the same date were counted in both analyses. For trials that only
recorded the first recurrence, patients having a local (distant)
recurrence were censored in the analysis of distant (local) recurrence;
all other patients without recurrence were censored on the date of death
or last follow-up.
We used data on cause
of death to assess the effects of chemotherapy on lung and non-lung
cancer survival. However, although eight trials supplied these data,
only two provided sufficiently detailed information to discriminate
between treatment-related and other non-cancer causes, making it
impossible to define these outcomes accurately.
The
overall resection rate was defined as the proportion of patients having
either a complete or incomplete resection. The complete resection rate
was defined as the proportion of patients having a complete resection.
Postoperative mortality was defined as the proportion of patients dying
within 30 days of surgery, and early mortality was defined as death
within 6 months of date of randomisation, to allow for completion of all
treatment in each arm.
Statistical analysis
Unless
otherwise stated, all analyses were prespecified in the protocol, and
done on an intention-to-treat basis. For time-to-event outcomes, we used
the log-rank expected number of events and variance to calculate hazard
ratio (HR) estimates of effect for each individual trial, which were
then combined across trials using a stratified-by-trial, two-stage,
fixed-effect model.14 The random-effects model15 was used to assess the robustness of the results. χ2
heterogeneity tests were used to assess differences in the effect of
treatment or treatment by covariate interactions across trials. Results
for time-to-event outcomes are also presented as non-stratified
Kaplan-Meier curves.16 The median follow-up was computed for all patients using the reverse Kaplan-Meier method.17
For dichotomous outcomes, such as resection rate, the numbers of events
and patients were used to calculate Peto odds ratio (OR) estimates of
effect14 for trials, which were then pooled across trials, using a fixed-effect model.
To
explore any effect of trial-level characteristics on the effect of
chemotherapy, pooled HRs were calculated for each prespecified trial
group. χ2 tests for interaction and the F
ratio were used to assess differences in treatment effect across trial
groups. To investigate the effect of patient characteristics on the
effect of chemotherapy, the relevant treatment by patient covariate
interaction term was included in a Cox regression for each trial. The
resulting within-trial interactions (HRs) were then pooled across trials
using the stratified-by-trial, fixed-effect model.18 These analyses are focused on the primary outcome of survival.
Absolute differences in outcome at 5 years were calculated from the HR and the control group baseline event rate.19 All p values are two-sided.
Role of the funding source
The
sponsors of the study had no role in study design, data collection,
data analysis, data interpretation, or writing of the report. The
corresponding author had full access to all the data in the study and
had final responsibility for the decision to submit for publication.
Results
We identified 19 eligible randomised controlled trials; 17 published20—36 and two unpublished 37, 38 (appendix). Data could not be supplied for three trials,34—36 and one trial only recruited two patients.37
Although data were obtained for all 24 patients excluded from the
investigators' original analyses, and reinstated in this meta-analysis,
data for two other patients could not be obtained. Therefore, this
meta-analysis is based on data from 15 trials20—33,38
(2385 patients), representing 92% of patients who were randomised, from
all known eligible trials. Any risk of bias associated with the
randomisation procedure and completeness of outcome data in these 15
trials was judged to be low and the effects of early stopping were
minimised by the collection of updated follow-up and investigated in the
analyses.
Ten trials22,24—30,32,33 gave chemotherapy only preoperatively and five trials20, 21, 23, 31, 38
used chemotherapy preoperatively and then postoperatively, usually to
responders. All trials used platinum-based chemotherapy, except one,26 which used docetaxel alone (table 1). Seven trials20—24,27,32 used cisplatin, four29, 30, 33, 38 carboplatin, and three25, 28, 31 either cisplatin or carboplatin. Eight trials21—24,27,28,30,33 used postoperative radiotherapy in both arms.
Data on age, sex, histology, and stage were provided for all but one trial,20 and performance status for 11 trials (table 2).21,23,25—30,32,33,38
Based on the available data, patients were mostly men (80%) with a
median age of 62 years (IQR 55—68) and good performance status (88%).
They had mainly clinical stage IB—IIIA tumours (93%) that were
predominantly squamous cell carcinomas (50%) or adenocarcinomas (29%).
The median follow-up of all patients was 6 years (IQR 4·2—8·2; table 1).
Survival
results were based on 15 randomised controlled trials (2385 patients,
1427 deaths) and show a clear benefit of preoperative chemotherapy (HR
0·87, 95% CI 0·78—0·96; p=0·007; Figure 1, Figure 2).
This represents a 13% reduction in the relative risk of death,
translating to a 5% absolute improvement in survival at 5 years (from
40% to 45%). Despite design differences between trials, for example, a
variety of chemotherapy regimens, exclusive use of preoperative
chemotherapy, use of postoperative radiotherapy in both arms, and
inclusion of all stages of patients or only a specific stage of patient,
there was no clear evidence of statistical heterogeneity (p=0·18).
Figure 1 Full-size image (30K) Download to PowerPoint
Effect of preoperative chemotherapy on survival
Each
square denotes the HR for that trial comparison with the horizontal
lines showing the 95% and 99% CIs. The size of the square is directly
proportional to the amount of information contributed by the trial. The
black diamond gives the pooled HR from the fixed effect model; the
centre of this diamond denotes the HR and the extremities the 95% CI.
O—E=observed minus expected. HR=hazard ratio. MIP=mitomycin,
ifosphamide, cisplatin. SWOG=South West Oncology Group. JCOG=Japanese
Cancer Oncology Group. MRC=Medical Research Council. BLT=Big Lung Trial.
ChEST=Chemotherapy for Early Stages Trial. NATCH=Neoadjuvant/Adjuvant
Trial of Chemotherapy. df=degrees of freedom. *Number of events/number
entered.
Figure 2 Full-size image (46K) Download to PowerPoint
Kaplan-Meier curves (non-stratified) of the effect of preoperative chemotherapy on time to survival
There
is no clear evidence that the effect of chemotherapy on survival
differed according to whether chemotherapy was given preoperatively or
both preoperatively and postoperatively (interaction p=0·23), the number
of preoperative chemotherapy cycles (interaction p=0·68), the type of
chemotherapy regimen (interaction p=0·94), the number of chemotherapy
agents per regimen (interaction p=0·84), or both the type of
chemotherapy regimen and number of agents (interaction p=0·79; table 3).
Analyses of the type of regimen, the number of agents per regimen, and
both the type of regimen and number of agents were repeated only in
those trials that gave platinum-based regimens, and gave similar results
(interactions p=0·91, p=0·60, and p=0·62 respectively; table 3).
We did not identify evidence of a difference in effect of chemotherapy
on survival by whether regimens were cisplatin or carboplatin-based
(interaction p=0·48) or whether postoperative radiotherapy was used
(interaction p=0·87; table 3).
Although
the interaction test is not significant there is some suggestion of a
larger relative effect in trials where postoperative chemotherapy is
given to responders (HR 0·78, 95% CI 0·64—0·95, p=0·02) than in those
giving preoperative chemotherapy alone. Exploratory analyses examining
whether such an approach modifies the effect of chemotherapy on time to
local recurrence showed a similar pattern (preoperative chemotherapy HR
0·94, 95% CI 0·75—1·18, p=0·60; preoperative plus postoperative
chemotherapy HR 0·73, 95% CI 0·50—1·07, p=0·11), but again no clear
evidence of an interaction (p=0·26). However, for time to distant
recurrence, there is evidence of a difference in effect by chemotherapy
scheduling (p=0·05), with a substantially greater relative benefit in
trials giving postoperative chemotherapy (HR 0·53, 95% CI 0·39—0·73,
p<0·001) than in those using just preoperative chemotherapy (HR 0·78,
95% CI 0·63—0·96, p=0·02).
12 trials did not reach their target accrual. Two21, 22 closed early after recording a benefit of chemotherapy, one20 due to high progression rates in the chemotherapy arm, six due to poor accrual24—27,31,38 and three due to positive results in postoperative chemotherapy trials.29, 30, 32
Based on all trials, although we found some evidence of a difference in
effect by the reason for early stopping of trials, small trials with
extreme positive and negative estimates seem to strongly affect this
result (table 3). An exploratory analysis, excluding smaller trials (100 patients or fewer), was based on 80% of the data (77% of all deaths),23, 28, 29, 32, 33
and showed no clear difference in effect between trials stopping early
and those reaching their target accrual (interaction p=0·24).
We
did not identify clear evidence that the effect of preoperative
chemotherapy on survival differed by age, age group, performance status,
or histology (figure 3). Although, overall, there is no evidence of a difference in effect by sex, there is heterogeneity in the interaction (figure 3).
Some trials suggest the effect might be greater in women and others in
men, but it is not clear why. Also, there was a significant interaction
between the effect of preoperative chemotherapy and stage in the ChEST
trial,32 but not in the other trials, or across all trials (interaction p=0·83; appendix).
An exploratory analysis, splitting clinical stage I disease into IA and
IB, also identified an interaction between the treatment effect and
clinical stage in the ChEST trial, but not across trials (p=0·64,
heterogeneity p=0·22). Thus, the overall HR of 0·87 was applied to the
control group survival for each stage, giving an absolute survival
improvement at 5 years of 5% for all stages, taking it from 50% to 55%
in stage I, from 30% to 35% in stage II, and from 20% to 25% in stage
III. However, most patients in stage I are IB (89%), in stage II are IIB
(92%), and in stage III are IIIA (98%), therefore we can be most
confident of results for these patients.
Figure 3 Full-size image (38K) Download to PowerPoint
Forest plot of the interactions between the effect of preoperative chemotherapy on survival and covariates
The
circles represent (fixed effect) meta-analyses of the HRs representing
the interactions between the effect of chemotherapy and patient
characteristics; the horizontal line shows the 95% CI. HR=hazard ratio.
Mortality within 30 days of surgery could be calculated for nine trials,23,25,26,28—32,38 (1611 patients, 52 deaths) that supplied date of surgery. Four of these26, 30, 31, 38
had no deaths within 30 days of surgery in either arm and an OR was not
estimable. Overall, we did not identify a difference between treatment
arms (OR 1·48, 95% CI 0·85—2·58, p=0·17; heterogeneity p=0·45, appendix).
Based on all 15 trials (2381 patients, 254 deaths), we also did not
identify a deleterious effect of preoperative chemotherapy on mortality
within 6 months of randomisation (OR 0·88, 95%CI 0·67—1·14, p=0·33;
heterogeneity p=0·60).
11 trials21,23—26,28—32,38
(1778 patients) provided data on extent of resection. For the overall
resection rate, ORs could not be estimated for four trials21, 23, 29, 31 because they had 100% resection rates in both arms. The remaining seven trials24—26,28,30,32,38
represented less than half of the total data and, with possible
variation in the classification of extent of incomplete resection, this
analysis was deemed unreliable. Based on all 11 trials, there was no
evidence of an effect of preoperative chemotherapy on complete resection
(OR 0·88, 95% CI 0·68—1·14, p=0·33; appendix),
but the effect did vary between trials (heterogeneity p=0·006). This
variation might relate to differences in the types of patients or
surgery, because the baseline complete resection rate for control
patients ranged from 67% to 95%, with the exception of one trial21 where it was substantially lower (31%).
Recurrence-free survival data were available for 14 trials20,21,23—33,38
(2326 patients, 1524 events). The findings provide clear evidence of a
benefit of preoperative chemotherapy (HR 0·85, 95% CI 0·76—0·94,
p=0·002, heterogeneity p=0·41, figure 4), translating to an absolute improvement in recurrence-free survival of 6% at 5 years, taking it from 30% to 36%.
Figure 4 Full-size image (116K) Download to PowerPoint
Kaplan-Meier
curves (non-stratified) of the effect of preoperative chemotherapy on
time to distant and locoregional recurrence and recurrence-free survival
Analyses
of recurrence outcomes were calculated from a landmark time of 6 months
from the date of randomisation; for this reason time on the x-axis
starts at 6 months.
Data on both time to locoregional recurrence and distant recurrence were available for 13 trials20,21,23—32,38
and 1913 patients (426 events and 526 events respectively). In these
patients, 630 (33%) were alive and free from disease. For the remaining
1283 patients, the first events recorded were locoregional recurrence
for 305 (24%), distant recurrence for 397 (31%), both locoregional and
distant recurrence for 115 (9%), and death without recurrence for 466
(36%; appendix).
There is clear evidence of a benefit of preoperative chemotherapy on
time to distant recurrence (HR 0·69, 95% CI 0·58—0·82; p<0·001;
heterogeneity p=0·40; figure 4), but the effect on time to locoregional recurrence was less clear (HR 0·88, 95% CI 0·73—1·07; p=0·20; heterogeneity p=0·89; figure 4).
These findings translate into an absolute improvement in time to
distant recurrence of 10% at 5 years (from 60% to 70%). There is a
potential improvement on time to locoregional recurrence of 3% at 5
years.
Discussion
Based
on data from 15 randomised trials (92% of all patients who were
randomised), we have shown a 5% absolute benefit of preoperative
chemotherapy on 5 year survival in patients with resectable NSCLC. There
was no clear evidence of a difference in this effect by treatment type,
scheduling, trial design differences, or by patient characteristics,
although the results are most reliable for stage IB—IIIA. There seemed
to be no excess of early mortality in the preoperative chemotherapy arm
as a result of deferred surgery.
Although
this meta-analysis included most patients known to have been
randomised, four eligible trials (198 patients) could not be included.
We could estimate an HR39 for survival for one trial of 90 patients,36 but not the remaining three trials. Two of these34, 35 (106 patients) did not report the appropriate information, and one (two patients) was unpublished.37
When the single estimated HR was combined with the overall result for
the meta-analysis, the effect on survival remained the same (HR 0·87,
p=0·006), but being based on 96% of patients who were randomised, it
provides more convincing evidence of a benefit of preoperative
chemotherapy. This systematic review and meta-analysis will be updated
if further eligible trials are identified.
One
reason for using preoperative chemotherapy is that it might make
tumours more operable, potentially improving the likelihood of a
complete resection. Conversely, delays to surgery could make it harder
to achieve a complete resection. However, we did not identify clear
evidence of a positive or negative effect of chemotherapy on the
complete resection rate or a benefit on locoregional recurrence.
However, we did note a 10% absolute benefit of preoperative chemotherapy
on distant recurrence at 5 years, suggesting that it might have greater
potential to eradicate micrometastases than postoperative chemotherapy,
where the absolute benefit was 5% at 5 years.4
Comparing
the effect of preoperative and postoperative chemotherapy directly,
using data from this meta-analysis and two previous ones of
postoperative chemotherapy in NSCLC proved problematic. Although it was
possible to make the datasets comparable in terms of the regimens used,
we could not make them comparable in terms of their patient
characteristics, particularly stage. Only pathological stage was
available for the postoperative chemotherapy meta-analysis, and
agreement between clinical and pathological staging in the control group
patients of the current meta-analysis was only around 60%. However,
survival in the control group of the present meta-analysis is somewhere
between that noted for patients receiving surgery alone and those
receiving surgery plus radiotherapy as definitive treatment,4
suggesting that the present population spans the two. Although this
difference makes a formal indirect comparison of the effects of
preoperative and postoperative chemotherapy difficult, the benefit noted
is on a similar scale. Others have attempted formal comparison based on
aggregate data8
and concluded the effect of chemotherapy on overall or recurrence-free
survival is similar, irrespective of chemotherapy timing. However, they
did not include key large trials, published more recently, and have
included a trial confounded by the use of radiotherapy in only one arm.40
We included one three-arm trial (NATCH33)
with both preoperative and postoperative chemotherapy arms, but because
it was underpowered, the authors did not report their direct
comparison. Nevertheless, they provided us with analyses showing similar
effects of preoperative and postoperative chemotherapy on survival (HR
0·93, 95% CI 0·71—1·23, p=0·61) and recurrence-free survival (HR 0·88,
95% CI 0·68—1·13, p=0·31; Rosell R, unpublished). Similarly, a recent
trial41
(198 patients), of preoperative versus postoperative chemotherapy
reported no difference in disease-free survival (HR 0·88, 95% CI
0·58—1·33, p=0·54), although power could also be an issue in this trial.
The findings of NATCH33
showed a difference in treatment compliance between the preoperative
(90%) and the postoperative (60%) chemotherapy arms. Of the trials
included in our report, the ten20,22—26,28,29,32,33
that reported the number of patients receiving all scheduled
preoperative chemotherapy (2—3 cycles), identified a similarly high
compliance rate with preoperative chemotherapy (mean compliance rate
85%, range 71—100%). By contrast, for the 14 trials in the postoperative
chemotherapy systematic review4
that reported patients receiving scheduled chemotherapy (2—6 cycles),
the mean compliance rate was somewhat lower (62%, range 41—98%). This
implies that patients might receive more of their planned chemotherapy
if it is given before surgery.
The
results so far seem to suggest similar effects with either preoperative
or postoperative chemotherapy, giving a choice of treatment options.
Clinicians might consider that preoperative chemotherapy is preferable
for poorer prognosis patients with larger, more advanced stage tumours,
less able to tolerate chemotherapy after surgery, or in regions where
surgery waiting lists are longer. Postoperative chemotherapy might be
preferred by surgeons and by patients wishing to have potentially
curative treatment immediately, or for those with earlier stage disease.
It also allows for more reliable pathological staging to establish if
subsequent chemotherapy is appropriate.
Because this meta-analysis shows that preoperative chemotherapy has a greater effect on metastases, and a previous one4
shows that postoperative chemotherapy has a greater effect on local
control, it is tempting to speculate that combined preoperative and
postoperative chemotherapy would confer a greater benefit on local and
distant control and survival. This is not entirely borne out by the
present survival results by chemotherapy scheduling and generally only
those patients responding to preoperative chemotherapy were also given
postoperative chemotherapy such that most would have received
preoperative chemotherapy alone. However, exploratory analyses do
suggest a synergistic effect of combining preoperative and postoperative
chemotherapy on time to metastases. However, it should be noted that
more cycles of chemotherapy were planned in the trials of combined
preoperative and postoperative chemotherapy (2—3 plus 2—3 cycles
postoperatively) compared with those of just preoperative chemotherapy
(2—3). Moreover, a recently reported trial that compared the use of
preoperative chemotherapy plus postoperative chemotherapy42
to responders with postoperative chemotherapy in 528 similar patients
identified no evidence that preoperative plus postoperative chemotherapy
was better (HR 1·01, 95% CI 0·79—1·30, p=0·92). Nevertheless, further
head-to-head comparisons of these approaches might be warranted.
The
potential benefit of preoperative chemotherapy would need to be
balanced against possible toxic effects. However, although we were
unable to assess toxic effects at the patient level in this study, trial
reports for 13 of the included trials described mild or acceptable
toxic effects and that chemotherapy was generally well tolerated.
Further questions regarding which drugs to use, the duration of
chemotherapy, and if the effect might be modified by predictive genetic
biomarkers will need to be answered by new or ongoing trials.
Nevertheless, these results provide the most complete evidence so far of
the effects of preoperative chemotherapy, showing a significant
improvement in overall survival, time-to-distant recurrence, and
recurrence-free survival.
Correspondence
to: Sarah Burdett, MRC Clinical Trials Unit at UCL, Meta-analysis
Group, Aviation House, 125 Kingsway, London WC2B 6NH, UK sarah.burdett@ucl.ac.uk
Contributors
AA,
SB, TLC, CLP, J-PP, LHMR, and JFT, with the help of the members of the
Advisory Group, contributed to the conception of the study. SB and LHMR
collected and checked the data with the help of the trial investigators
who validated the reanalysis of their trials. SB and LHMR did the
statistical analysis. The report was drafted by SB, LHMR, and JFT and
submitted for comments to the members of the Project Management Group
and the Advisory Group. The investigators contributed to the
interpretation of the results during the investigators' meeting and
various revisions of the report.
NSCLC Meta-analysis Collaborative Group
Project Management Group:
Sarah Burdett, Larysa HM Rydzewska, Jayne F Tierney (Meta-analysis
Group, MRC Clinical Trials Unit at UCL, London, UK); Anne Auperin,
Cécile Le Pechoux (Service de Biostatistique et d'Epidemiologie,
Institut Gustave-Roussy, Villejuif, France); Thierry Le Chevalier,
Jean-Pierre Pignon (Department of Lung Cancer, Institut Gustave-Roussy,
Villejuif, France).
International Advisory Group:
Rodrigo Arriagada (Karolinska Institutet, Stockholm, Sweden; Institut
Gustave-Roussy, Villejuif, France); David H Johnson (Department of
Internal Medicine, UT Southwestern School of Medicine, Dallas, TX, USA);
Jan van Meerbeeck (Multidisciplinary Oncological Center, Thoracic
Oncology, University Hospital Antwerp, Belgium); Mahesh KB Parmar,
Richard J Stephens (retired) (MRC Clinical Trials Unit at UCL, London,
UK); Lesley A Stewart (Centre for Reviews and Dissemination, University
of York, York, UK).
Writing group (Project Management Group and International Advisory Group):
Rodrigo Arriagada, Anne Auperin, Sarah Burdett, David H Johnson,
Thierry Le Chevalier, Cécile Le Pechoux, Mahesh KB Parmar, Jean-Pierre
Pignon, Larysa HM Rydzewska, Richard J Stephens, Lesley A Stewart, Jayne
F Tierney, Jan van Meerbeeck.
Collaborators who supplied individual patient data:
Paul A Bunn (School of Medicine, Division of Oncology, University of
Colorado, Denver, CO, USA; SWOG S9015; NCI grant CA32102, CA38926,
CA42777; with support from Bristol-Myers Squibb); Bertrand Dautzenberg
(Service de Pneumologie et Réanimation, Groupe Hospitalier
Pitié-Salpêtrière, Paris, France; France 1990); David Gilligan
(Department of Oncology, Addenbrooke's Hospital, Cambridge, UK; MRC
LU22); Harry J M Groen (Department of Pulmonary Diseases, University
Medical Centre Groningen, Groningen, Netherlands; Netherlands 2000);
Aija H Knuuttila (Department of Pulmonary Medicine, Helsinki University
Central Hospital, Helsinki, Finland; Finland 2003); Katherine M Pisters
(Department of Thoracic/Head and Neck Medical Oncology, University of
Texas MD Anderson Cancer Centre, Houston, TX, USA; SWOG S9900; NCI grant
CA32102, CA38926, CA105409; with support from Bristol-Myers Squibb);
Rafael Rosell (Department of Medical Oncology, Catalan Institute of
Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain; Spain 1994,
NATCH); Jack Roth (Department of Thoracic and Cardiovascular Surgery,
University of Texas MD Anderson Cancer Centre, Houston, TX, USA; MD
Anderson 1994); Giorgio Scagliotti (Department of Clinical and
Biological Sciences, University of Turin, San Luigi Hospital, Torino,
Italy; ChEST); Masahiro Tsuboi (Division of Thoracic Surgery, Yokohama
City University Medical Centre, Yokohama, Japan; JCOG 9209); David A
Waller (Department of Thoracic Surgery, Glenfield Hospital, Leicester,
UK; MRC BLT); Virginie Westeel (Service de Pneumologie, Centre
Hospitalier Universitaire, Besançon, France; MIP-91); Yi-Long Wu
(Division of Pulmonary Oncology, Guangdong Lung Cancer Institute,
Guangdong General Hospital and Guangdong Academy of Medical Sciences,
Guangzhou, China; China 2002); Xue-Ning Yang (Division of Pulmonary
Oncology, Guangdong Lung Cancer Institute, Guangdong General Hospital
& Guangdong Academy of Medical Sciences, Guangzhou, China; China
2005).
Declaration of interests
HJMG
has served as a consultant for Eli Lilly, Pfizer, and Roche. VW has
received honoraria from Roche, Lilly, GlaxoSmithKline, AstraZeneca,
Chugai, Boehringer Ingelheim, and Amgen; travel grants from AstraZeneca,
Lilly, and Roche; and a research grant from Roche. The other authors
declare that they have no competing interests.
Acknowledgments
The
NSCLC Collaborative Group thanks all patients who took part in the
trials and contributed to this research. The meta-analysis would not
have been possible without their participation or without the
collaborating institutions that provided their trial data. The MRC
Project Management Group was funded by the UK Medical Research Council
and the IGR Project Management Group was supported by Institut
Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05
209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis (unrestricted
grants). We thank Valter Torri for his assistance with data retrieval
and David Fisher and Jack Bowden for their help on particular analyses.
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