1. Chin Med J 2013;126 (17)
3348
Meta analysis
Chemotherapy with or without gefitinib in patients with advanced
non-small-cell lung cancer: a meta-analysis of 6844 patients
ZHOU Hang, ZENG Chao, WANG Li-yang, XIE Hua, ZHOU Jin, DIAO Peng, YAO Wen-xiu, ZHAO Xin and WEI Yang
Keywords: non-small-cell-lung cancer; gefitinib; meta-analysis
Background Gefitinib is widely used in patients with advanced non-small-cell lung cancer (NSCLC), in whom
chemotherapy had failed. Previous trials reported inconsistent findings regarding the efficacy of gefitinib on overall survival
(OS) and progression free survival (PFS). This study was to evaluate the effects of chemotherapy plus gefitinib versus
chemotherapy alone on survival of patients with NSCLC.
Methods We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference
lists of articles, and proceedings of major meetings for relevant literature. Randomized controlled trials (RCTs) comparing
chemotherapy with and without gefitinib in the treatment of patients with advanced NSCLC were included in our analysis.
The primary endpoints were OS and PFS.
Results Of 182 relevant studies, 12 were included in the final analysis, which consisted of 6844 patients with NSCLC.
Overall, we noted that gefitinib therapy had an 8% improvement in the OS as compared to the gefitinib-free therapy, but
this difference was not statistically significant (HR, 0.92; 95% CI: 0.85–1.00; P=0.051). Furthermore, gefitinib therapy had
significantly longer PFS compared to gefitinib-free therapy (HR, 0.72; 95% CI 0.60–0.87, P=0.001). Patients receiving
gefitinib therapy also had a more frequent objective response rate (ORR) than the control arm (OR, 2.51; 95% CI, 1.67–
3.78, P <0.001). Rashes, diarrhea, dry skin, pruritus, paronychia, and abnormal hepatic function were more frequent in the
gefitinib therapy group.
Conclusions Treatment with gefitinib had a clear effect on PFS and ORR, and it might contribute considerably to the OS.
Furthermore, there was some evidence of benefit for gefitinib therapy among patients with adenocarcinoma.
Chin Med J 2013;126 (17): 3348-3355
N
on-small-cell lung cancer (NSCLC) accounts
for approximately 80%–85% of all cases of lung
cancer, and is the most common cause of cancer death in
industrialized countries.1,2 In patients with locally advanced
and metastatic NSCLC short-lived responses to aggressive
chemotherapy are observed in approximately 30% of the
patients; the impact on the patients’ survival has been
modest.1,3
The treatment armamentarium for advanced NSCLC has
expanded to include molecular targeted therapies that act
specifically against key components of cellular pathways
involved in tumor growth, progression, and cell death.4,5
Gefitinib is an orally administered tyrosine kinase inhibitor
of the epidermal growth factor receptor (EGFR), which has
already clinically validated therapeutic targets in NSCLC.
It inhibits growth and causes regressions in the human
tumor xenografts with EGFR overexpression. Furthermore,
unlike conventional chemotherapy, gefitinib did not cause
myelosuppression, neuropathy, or significant alopecia.5-7
Despite all of these improvements, the benefits associated
with gefitinib are modest and serve to stress the need for
novel therapeutic approaches. In addition, several largescale randomized controlled trials investigating the use
of gefitinib therapy have been performed. Some studies
illustrated that gefitinib therapy had beneficial effects
on the OS or PFS when compared to the traditional
chemotherapy,8-13 while others showed little effect and
some trials even found that gefitinib therapy could induce
some harmful effects.14-19 To better understand the effect of
gefitinib therapy on OS and PFS in patients with NSCLC,
data from these recent trials need to be evaluated to
formulate a conclusion regarding the efficacy of gefitinib
therapy. We therefore undertook a meta-analysis to update
the results and resolve the uncertain efficacy of gefitinib in
patients with NSCLC. Furthermore, we also reported the
efficacy of gefitinib treatment in some specific subgroups.
METHODS
Publication search
For inclusion in our research, randomized controlled
trials of gefitinib therapy in English literature were
eligible for inclusion in our meta-analysis, regardless
of the publication status (published, unpublished, in
press, and in progress). Relevant trials were identified
by the following procedure: (1) Electronic searches: we
DOI: 10.3760/cma.j.issn.0366-6999.20122920
Department of Chemotherapy, Sichuan Cancer Hospital, Chengdu,
Sichuan 610041, China (Zhou H, Wang LY, Xie H, Zhou J, Diao P,
Yao WX, Zhao X and Wei Y)
Department of Gastroenterology, Third People’s Hospital of
Chengdu, Chengdu, Sichuan 610031, China (Zeng C)
Correspondence to: Dr. YAO Wen-xiu, Department of Chemotherapy,
Sichuan Cancer Hospital, Chengdu, Sichuan 610041, China (Tel &
Fax: 86-28-85420847. Email: yaowenxiu_2011@126.com)

2. Chinese Medical Journal 2013;126 (17)
searched the electronic databases Medline, EmBase, and
the Cochrane Central Register of Controlled Trials for
articles up to 20 January 2012, using “gefitinib”, “clinical
trial” and “randomized controlled trial” as the search
terms. All reference lists from reports on non-randomized
controlled trials were searched manually for additional
eligible studies; (2) Other sources: we contacted authors
to obtain any possible additional published or unpublished
data, and searched the proceedings of annual meetings in
the Cochrane Cardiovascular Disease Group Specialized
Register. The relevant reviews and meta-analyses regarding
the role of gefitinib therapy for NSCLC patients were
examined for potential inclusive trials. In addition, we
searched for ongoing randomized controlled trials, which
had been registered as completed but not yet published,
in the metaRegister of Controlled Trials. Medical subject
headings and methods, patient population, and intervention
were used to identify the relevant trials.
Inclusion criteria
The literature search was undertaken independently by
three authors (Zhou H, Zeng C, and Wang LY) with a
standardized approach, and any disagreement between
these three authors was settled by a fourth author (Yao WX)
until a consensus was reached. All completed randomized
controlled trials assessing the effects of gefitinib therapy
compared to the effects of a non-gefitinib therapy, and
reporting at least one of the primary outcomes were
included as eligible trials.
Data extraction and quality assessment
Two investigators (Xie H and Zhou J) independently
extracted and collected data using a standardized dataextraction protocol. Disagreements were adjudicated by
a third reviewer (Wei Y) after referring to the original
articles.
The data collected included baseline patient characteristics
(number of patients, age, sex, pre-existing diseases,
interventions, disease status, treatment status, and duration
of follow-up), publication details, and methodological
components. The outcomes investigated included overall
survival (OS), progression free survival (PFS), objective
tumor response rate (ORR), and possible drug-correlated
adverse reactions. The quantitative 5-point Jadad score20
was used to assess the quality of the inclusive trials based
on randomization, concealment of treatment allocation,
blinding, completeness of follow-up, and use of intentionto-treat analysis (Diao P and Zhao X).
Statistical analysis
The primary efficacy outcomes of our meta-analysis
were OS and PFS. The log hazard ratios (HRs) and their
variances were estimated using the methods proposed
by Parmar21 and confidence intervals (CIs) of HRs were
reported. The summary of HRs and their 95% CIs were
estimated using a general variance-based method. For ORR
and possible drug-correlated adverse reactions, the pooled
estimation plotted as odd ratios (ORs) were obtained. The
3349
subgroup analyses were prospectively planned according
to number of patients, median age, gender, control drug,
treatment status, follow-up, smoker, racial, disease status,
pre-existent disease, EGFR FISH, and Jadad score.
Heterogeneity between trials was evaluated by the Chisquare test and I-squared statistic. These indices assess
the percentage of variability across studies attributable to
heterogeneity rather than chance. Statistical heterogeneity
was considered significant when P <0.10.22 Although the
fixed-effects model and random-effects model yielded
similar conclusions, we chose to use the random-effects
model, which assumed that the true underlying effect
varied among included trials. Moreover, many investigators
consider the random-effects model to be a more natural
choice than the fixed effects model in medical decisionmaking contexts.23,24 The probability of publication bias
was assessed with the funnel plots and the Egger test.25 All
reported P values were two-sided and P values less than
0.05 were regarded as statistically significant. Statistical
analyses were carried out using STATA 10.0 (StataCorp,
USA).
RESULTS
Search of the published literature
We identified 182 potentially relevant trials from our
initial electronic search, and excluded 136 trials after a
preliminary review. The remaining 46 studies were assessed
in detail and 12 randomized controlled trials met the
inclusion criteria (Figure 1), which included 6844 patients
with NSCLC. All the included trials were published in full
text. Table 1 summarized the baseline characteristics of the
participants and the design of the studies included.
Characteristics of the included studies
The trials included in this study compared gefitinib therapy
with the non-gefitinib control. The follow-up for patients
ranged from 7.2 to 60.0 months, with a mean of 33 months.
The population of the trials ranged from 161–1692 patients,
with a mean of 570. Jadad scale was used to assess the
quality of the included trials. Seven trials had a score of 4,
Figure 1. Diagram of the literature search and trial selection
process.

3. Chin Med J 2013;126 (17)
3350
Table 1. Baseline characteristics for included trials
Trials
ISEL (2005)14
INVITE (2008)15
V-15-32 (2008)16
SWOG S0023 (2008)17
INTEREST (2008)18
INSTEP (2009)19
IPASS (2009)8
Number of Median age Sex, male Stage IIIB
Patients
(years)
(%)
or IV (%)
1692
62
67
81
196
74
76
100
489
20 years or older
62
83
243
61
63
52
1466
61
65
79
201
75
61
NG
1217
57
21
100
ISTANA (2010)9
WJTOG 3405 (2010)10
161
172
57
64
61
31
100
59
North-East Japan (2010)11
230
63
36
91
WJTOG 0203 (2010)12
604
62
64
100
EORTC 08021/ILCP
01/03 (2011)13
173
62
77
100
and the remaining five trials had a score of 3.
Overall survival
Data for OS were available from 11 trials, which consisted
of 6614 patients with NSCLC. We noted that gefitinib
therapy had an 8% improvement in the OS as compared
to the gefitinib-free treatment arm (HR, 0.92; 95% CI:
0.85–1.00; P=0.051; Figure 2) under a random-effect
model, but was not associated with a statistically significant
Second line
First line
First line
Second line
Second line
Second line
First line
Follow-up
(months)
7.2
20
36
60
7.6
24
24
OS, ORR
OS, PFS, ORR
OS, PFS, ORR
OS, PFS
OS, PFS, ORR
OS, PFS, ORR
OS, PFS, ORR
4
3
3
3
4
4
4
Second line
Second line
15
40
OS, PFS, ORR
OS, PFS, ORR
3
3
First line
42
PFS, ORR
4
First line
60
OS, PFS, ORR
4
Second line
60
OS, PFS, ORR
4
Intervention
Treatment status
Gefitinib; placebo
Gefitinib; vinorelbine
Gefitinib; docetaxel
Gefitinib; placebo
Gefitinib; docetaxel
Gefitinib; placebo
Gefitinib;
carboplatin plus paclitaxel
Gefitinib; docetaxel
Gefitinib; cisplatin plus
docetaxel
Gefitinib; paclitaxel and
carboplatin
Gefitinib; platinumdoublet chemotherapy
Gefitinib; placebo
Main endpoint Jadad score
improvement in the OS. In addition, heterogeneity was
observed in the magnitude of the effect across the trials
included. According to a sensitivity analysis, we excluded
the V-15-32 study.16 This trial specifically included patients
were more younger, and the proportion of IIIB or IV
was less than other trials. After this, we could conclude
that gefitinib therapy yielded a clinically and statistically
significant 9% improvement in OS compared with gefitinibfree therapy (HR, 0.91; 95% CI: 0.84–0.98; P=0.015;
Table 2. Summary of the odds ratios of all toxicities outcomes assessed
Outcomes
Rash
Diarrhoea
Nausea
Anorexia
Vomiting
Dry skin
Constipation
Pruritus
Pyrexia
Asthenic condition
Cough
Dyspnea
Stomatitis
Hemoptysis
Pneumonia
Cancer pain
Edema peripheral
Paronychia
Fatigue
Anemia
Hypokalemia
Neutropenia
Leukopenia
Febrile neutropenia
Upper abdominal pain
Abnormal hepatic function
Insomnia
Alopecia
Myalgia
Neurotoxicity
Arthralgia
Dyspepsia
Dizziness
Sensory disturbance
Thrombocytopenia
Included studies
8–16,18,19
8–16,18,19
8–10,12,14–16,18,19
8,9,11,12,14–16,18,19
8,9,11,12,14–16,18,19
8,9,11,12,14–16,18,19
8–10,12,14–16,18,19
8,9,14,16,19
14–16,18
8,9,14,15,18
9,13,14,18
9,10,13–15,18,19
8–10,12,14,16,18,
9,14
11–14,18,19
9,13,14
14–16,18,19
8–10,14,16
10–13,15,16,19
10–13,15,18,19
13,15
10–13,15,16,18
10,12,15,16
8,12,15,16,18
9,15,19
13,16
9,16,19
8–10,16,18
8,9,16,18
8,9,13,16
8,9,13
9,11,13
9,13
10–12
10–13
OR and 95% CI
8.73 (6.13, 12.45)
2.63 (1.96, 3.52)
0.47 (0.28, 0.79)
0.70 (0.47, 1.06)
0.88 (0.54, 1.45)
10.37 (5.98, 18.01)
0.56 (0.40, 0.78)
3.03 (1.67, 5.49)
0.79 (0.41, 1.53)
0.45 (0.25, 0.80)
0.94 (0.76, 1.17)
0.96 (0.79, 1.17)
1.24 (0.77, 2.00)
1.34 (0.86, 2.11)
0.97 (0.70, 1.34)
0.69 (0.37, 1.28)
0.47 (0.33, 0.68)
14.00 (1.14, 171.75)
0.35 (0.19, 0.63)
0.29 (0.14, 0.61)
0.34 (0.09, 1.34)
0.05 (0.01, 0.28)
0.08 (0.01, 0.69)
0.19 (0.05, 0.70)
0.61 (0.20, 1.82)
5.76 (3.15, 10.55)
1.36 (0.60, 3.10)
0.06 (0.05, 0.09)
0.18 (0.14, 0.24)
0.19 (0.05, 0.65)
0.15 (0.04, 0.55)
0.45 (0.05, 3.89)
1.09 (0.40, 2.93)
0.13 (0.02, 0.77)
0.37 (0.20, 0.71)
P values
<0.001
<0.001
0.004
0.09
0.62
<0.001
<0.001
<0.001
0.48
0.006
0.59
0.68
0.38
0.20
0.85
0.24
<0.001
0.04
<0.001
0.001
0.12
<0.001
0.02
0.01
0.37
<0.001
0.46
<0.001
<0.001
0.008
0.004
0.47
0.87
0.02
0.003
Heterogeneity (%)
77
73
93
87
87
64
76
79
85
91
0
0
79
0
13
31
38
87
78
84
0
98
97
88
53
0
66
38
4
95
83
88
0
86
51
P values for heterogeneity
<0.001
<0.001
<0.001
<0.001
<0.001
0.004
<0.001
<0.001
<0.001
<0.001
0.61
0.79
<0.001
0.37
0.33
0.23
0.17
<0.001
<0.001
<0.001
0.38
<0.001
<0.001
<0.001
0.12
0.68
0.05
0.17
0.37
<0.001
0.003
<0.001
0.45
<0.001
0.11

4. Chinese Medical Journal 2013;126 (17)
3351
Overall, we noted that gefitinib
therapy yielded a clinically and
statistically significant 28%
improvement in PFS as compared
to the traditional chemotherapy
without gefitinib (HR, 0.72; 95%
CI 0.60–0.87, P=0.001, Figure
3). Although there was some
evidence of heterogeneity across
the studies included, however,
after sequential exclusion of each
trial from all pooled analysis, the
results were not affected by the
exclusion of any specific trial.
Overall response rate
Data for ORR was available
from 11 trials including 6601
patients. Overall, we noted that
gefitinib therapy increased the
objective response rate by 151%
when compared to gefitinibfree therapy (OR, 2.51; 95% CI:
1.67‒3.78, P <0.001, Figure 4).
Furthermore, there was a evidence
of heterogeneity for ORR among
the included trials (Figure 4).
A sensitivity analysis indicated
that the results were not affected
by sequential exclusion of any
particular trial from all pooled
analysis.
Toxicity
Data concerning AEs were
e x t r a c t e d f r o m 11 t r i a l s ; a
summary of the drug-related
toxicities was shown in
Table 2. Overall, the pooled
OR of each kind of toxicity
indicated that a significant
increase associated with
gefitinib therapy was observed
for ashes, diarrhea, dry skin,
pruritus, paronychia, abnormal
hepatic function compared
to traditional chemotherapy.
C o n v e r s e l y, w e a l s o n o t e d
that gefitinib protected against
nausea, constipation, asthenic
condition, peripheral edema,
Figure 2. Comparison of the overall survival between gefitinib therapy and gefitinib-free therapy.
Figure 3. Comparison of the progression-free survival between gefitinib therapy and gefitinib-free fatigue, anemia, neutropenia,
therapy.
leukopenia, febrile neutropenia,
Figure 4. Comparison of the objective response rate between gefitinib therapy and gefitinib-free
alopecia, myalgia, neurotoxicity,
therapy.
arthralgia, sensory disturbance,
and thrombocytopenia, when compared to gefitinib-free
Figure 2).
therapy. Furthermore, we noted that heterogeneity among
trials was found in these analyses, possibly due to the
Progression-free survival
use of different agents at various dosages and the use of
Eleven trials including 5152 patients provided PFS results.

5. Chin Med J 2013;126 (17)
3352
Table 3. Subgroup analysis for the effect of Gefitinib therapy on OS and PFS
Variables
OS
Number of patients
≥1000
<1000
Median age
<64
≥64
Gender (male, %)
>65%
<65%
Control drug
Traditional chemotherapy
Placebo
Treatment status
First line
Second line
Follow-up
≥36 months
<36 months
Smoker
Never smoker
Current/former smoker
Racial
Asian
Non-Asian
Disease status (IIIB or IV)
≥90%
<90%
Pre-existent diseases
Adenocarcinoma
Non-adenocarcinoma
EGFR FISH
Positive
Negative
Jadad score
4
<4
PFS
Number of patients
≥1000
<1000
Mean age
<64
≥64
Gender (male, %)
>65%
<65%
Drug
Traditional chemotherapy
Placebo
Treatment status
First line
Second line
Follow-up
≥36 months
<36 months
Smoker
Never smoker
Current/former smoker
Racial
Asian
Non-Asian
Disease status (IIIB or IV)
≥90%
<90%
Pre-existent diseases
Adenocarcinoma
Non-adenocarcinoma
EGFR FISH
Positive
Negative
Jadad score
4
<4
Hazard ratio (HR)
P values
Heterogeneity (%)
P values for heterogeneity
0.95 (0.87−1.04)
0.90 (0.78−1.03)
0.266
0.110
16.1
32.2
0.304
0.171
0.92 (0.84−1.00)
0.96 (0.73−1.26)
0.061
0.761
36.1
19.5
0.141
0.289
0.95 (0.88−1.04)
0.90 (0.79−1.03)
0.282
0.126
0
39.5
0.414
0.128
0.97 (0.89−1.06)
0.85 (0.76−0.95)
0.517
0.004
7.7
0
0.369
0.397
0.94 (0.84−1.06)
0.90 (0.79−1.02)
0.319
0.085
11.9
40.0
0.333
0.125
0.90 (0.73−1.12)
0.94 (0.87−1.02)
0.345
0.124
59.6
0
0.042
0.666
0.76 (0.59−0.98)
−
0.034
−
19.0
−
0.291
−
0.91 (0.78−1.06)
0.87 (0.78−0.97)
0.216
0.015
48.5
0
0.084
0.409
0.88 (0.79−0.98)
0.96 (0.81−1.13)
0.025
0.593
0
62.6
0.964
0.030
0.85 (0.76−0.95)
−
0.005
−
0
−
0.599
−
1.14 (0.18−7.16)
0.89 (0.59−1.33)
0.14
0.59
87.9
0
0.004
0.539
0.93 (0.86−0.99)
0.94 (0.73−1.21)
0.031
0.646
0
55.2
0.505
0.063
0.88 (0.63−1.23)
0.68 (0.54−0.86)
0.447
0.001
92.8
83.8
<0.001
<0.001
0.70 (0.56−0.87)
0.79 (0.49−1.27)
0.002
0.329
89.4
83.6
<0.001
0.002
0.92 (0.65−1.29)
0.66 (0.54−0.81)
0.623
<0.001
82.5
82.3
0.003
<0.001
0.71 (0.56−0.91)
0.73 (0.61−0.89)
0.006
0.001
90.7
7.7
<0.001
0.339
0.70 (0.51−0.95)
0.75 (0.58−0.95)
0.024
0.017
90.9
79.6
<0.001
<0.001
0.60 (0.45−0.81)
0.88 (0.72−1.08)
0.001
0.228
86.2
78.5
<0.001
0.001
0.48 (0.33−0.70)
−
<0.001
−
0
−
0.832
−
0.62 (0.48−0.79)
0.83 (0.63−1.08)
<0.001
0.161
86.6
64.5
<0.001
0.037
0.66 (0.50−0.86)
0.81 (0.62−1.06)
0.002
0.128
87.4
80.8
<0.001
0.001
0.63 (0.42−0.93)
−
0.021
−
76
−
0.041
−
0.76 (0.22−2.65)
1.29 (0.53−3.15)
0.665
0.579
91.0
90.9
<0.001
<0.001
0.67 (0.50−0.88)
0.80 (0.62−1.03)
0.005
0.080
92.2
70.2
<0.001
0.009

6. Chinese Medical Journal 2013;126 (17)
different control arms. No other significant differences
were identified between the effect of gefitinib therapy and
control for adverse events.
Subgroup analysis
Subgroup analyses were carried out for overall survival and
progression free survival. Overall, we noted that gefitinib
therapy was associated with an improvement of the overall
survival when compared to placebo, never smoker, nonAsian, IIIB or IV ≥90%, patients with adenocarcinoma,
or Jadad score more than 3. Similarly, gefitinib therapy
produced a statistically significant improvement of PFS
when the number of patients was <1000, mean age <64,
the proportion of male <65%, compared to traditional
chemotherapy/placebo, first-line, second-line, followup more than 36 months, never smoker, Asian, IIIB or IV
≥90%, patients with adenocarcinoma, or Jadad score more
than 3.
Publication bias
We used Egger’s test25 to check for potential publication
bias, which showed no evidence of publication bias for
the outcomes of OS (P value for Egger’s test, 0.643) , PFS
(P value for Egger’s test, 0.170), and ORR (P value for
Egger’s test, 0.105).
DISCUSSION
The goal of the treatment of NSCLC was to prolong
survival time and prevent disease recurrence after therapy.5
Current third-line chemotherapy regimens provide little
benefit, and the small survival benefits obtained with
these treatment regimens are commonly balanced by their
substantial toxic effects. For patients who are refractory
to or intolerant of the current chemotherapy regimens,
currently treatment options are limited and new therapies
are needed.5,26,27
Several strategies were proposed to overcome this lowvalid. The most important one was that gefitinib therapy,
which was the first targeted drug to enter clinical use for the
treatment of lung cancer.28,29 However, several randomized
controlled trials reported an inconsistent conclusion on
OS, PFS, and ORR by gefitinib therapy in patients with
NSCLC as compared to the traditional chemotherapy or
placebo. Therefore, the goal of our research was to perform
a comprehensive, updated meta-analysis of randomized
controlled trials, which included all currently available
clinical trials.
This large quantitative review included 6844 patients
with NSCLC in 12 trials with a broad range of baseline
characteristics. The main finding of our research suggested
that gefitinib therapy had a clear effect on PFS and
ORR; furthermore, a sensitivity analysis and subgroup
analysis indicated that gefitinib therapy might contribute
an important role for OS. In addition, gefitinib was
associated with significantly less toxicity than traditional
chemotherapy and improved quality-of-life.
3353
In contrast with previous research, 30 these findings
supported that as an adjunctive therapy gefitinib does
not have significant benefits or harm in OS; however,
subgroup analysis demonstrated that gefitinib therapy had
a clear effect in the improvement of OS when compared
to placebo. The reason for these could be that although
traditional chemotherapy contributed a little, which are
commonly a balanced gefitinib effect on the overall
survival. Similarly, we also noted that gefitinib produced
an important role for OS in patients who previously never
smoke. The reason could be that patients currently smoking
or who were formerly smoking with impaired lung
function, could contribute an important role in the lessened
therapy effect by gefitinib. Furthermore, gefitinib produced
a clear effect when proportion of IIIB or IV ≥90%, and
patients with adenocarcinoma, the reason could be that
gefitinib has emerged as a new drug commonly used for
advanced NSCLC. Our research also supported that nonAsian patients gained more benefit from gefitinib in times
of treatment failure. These results are also consistent with
previous randomized controlled trials.
The results of our research demonstrated that gefitinib
yielded a statistically significant benefit in PFS as compared
to gefitinib-free therapy; however, it should be noted that
progression-free survival was not improved when the
number of patients was more than 1000, median age was
more than 64, the proportion of male was more than 65, the
follow-up time was less than 36 months, non-Asian, the
proportion of IIIB or IV was lesser than 90, EGFR FISH
positive or negative, Jadad score less than 4. The reason
could be that less trials reported progression-free survival
data in some subsets, while other reasons similarly to the
overall survival. In contrast with previous meta-analysis,
improvement in the objective response rate also detected
between gefitinib and gefitinib-free therapies. Previous
research31,32 indicated that gefitinib was active in NSCLC,
with confirmed objective response rates of 12%–18%. The
significant improvements in time to treatment failure and
objective response rate seen with gefitinib in our research
are consistent with these previous studies.
Some drug-related toxicity was significantly more frequent
in patients who received gefitinib therapy. We noted
that rashes, diarrhea, dry skin, pruritus, paronychia, and
abnormal hepatic function were more frequent in the
gefitinib therapy group. In addition, gefitinib also protected
against nausea, constipation, asthenia condition, peripheral
edema, fatigue, anemia, neutropenia, leucopenia, febrile
neutropenia, alopecia, myalgia, neurotoxicity, arthralgia,
sensory disturbance, and thrombocytopenia as compared
to traditional chemotherapy. We easily concluded that
gefitinib was a promising therapy in patients with NSCLC,
which contributed to less toxicity than the traditional
chemotherapy and significantly improved the quality-oflife.
Although the benefit of gefitinib therapy may be lessened or
balanced by some drug-related toxicity, however, gefitinib

7. Chin Med J 2013;126 (17)
3354
as an adjunctive therapy could improve PFS, ORR, and
could lessen drug-related toxicities compared to traditional
chemotherapy. In addition, we should considered patients’
baseline characteristics before any therapeutic decision is
made to ensure the patients with the best therapy.
The main purpose of our research was to present all
available evidence in a systematic, quantitative, and
unbiased fashion. The findings of this meta-analysis
suggested that gefitinib therapy produced a significant
improvement in the progression-free survival, objective
response rate, and it might also play an important role
in the overall survival. Compared to previous research,
our research provided a more detailed conclusion on OS
and drug-related toxicities information. As compared to
individual trials, our research provided a conclusion for
the effect of gefitinib therapy in patients with advanced
NSCLC.
The limitations of our research are as follows: (1)
although subgroup analysis suggested that gefitinib
significantly improved the OS and PFS for patients with
adenocarcinoma, however, these results may be variable
because of the small number of trials (only three trials)
that provided such a subset of survival data; (2) data on
quality of life were rarely available in these trials and no
conclusions could be drawn; (3) inherent assumptions made
for any meta-analysis, because the analysis used pooled
data either published or provided by individual study
authors, and individual patients survival data or original
data were unavailable, which restricted us from doing a
more detailed and relevant analysis and obtaining more
comprehensive results.
In conclusion, the findings of this study also supported
previous findings that the gefitinib therapy had a clear effect
on the PFS and ORR. A sensitivity analysis and subgroup
analysis also demonstrated that gefitinib therapy might
play an important role on the OS. Future focus will be on
the identification of predictive markers which may enable
treatments to be targeted to specific patient groups and
thereby translate it into improved outcomes. Furthermore,
subgroup analysis in individual trial needs a more detailed
and formulated report.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
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(Received October 23, 2012)
Edited by CUI Yi