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Cetuximab combined with chemotherapy for Advanced Non-small
Cell Lung Cancer: A meta-analysis of Randomized Controlled Trials
Objective
Compared the efficacy and adverse events(AEs) of chemotherapy alone(Chem)
with chemotherapy plus cetuximab(Ce+chem) in advanced NSCLC patients.
Methods
This meta- analysis was carried out in the Bengbu Medical College,Anhui,China
between February 2014 and April 2014. Trials and references were screened t
hrough PubMed and Medline.Extracted data and the quality of the trials were a
ssessed independently by two investigators. The results included HR (Hazard r
atio)for OS (overall survival) and PFS(progression-free survival ), RR for efficac
y or ORR (overall response rate) ,and odds ratios (ORs) for toxicity. HR,RR,O
Rand their 95% confidence intervals (CIs) were pooled using STATA SE12.0 pa
ckage and RevMan5.2 software.
Results
Five trials involving 2,552 patients with advanced NSCLC were accord with the
inclusion criteria ultimately.Compare with chemotherapy alone,the pooled HR
for OS(HR=0.89;95% CI,0.83-0.95;p=0) was propitious to Ce-chem,while bring
a better efficacy(RR = 1.17, 95% CI:1.06-1.29,p=0.002).The pooled HR for PFS
(HR = 0.91,95% CI:0.83-0.99,p = 0.037)also was benifit to Ce-chem.More grad
e3/4 leukopenia,febrile-neutropenia,acneiform-rash,infusion-reaction,hypomagnese
mia (OR = 1.33,95% CI:0.94-1.88,p = 0.008;OR = 1.46,95% CI:1.06-2.01,p = 0.
002;OR = 51.22,95%CI:16.24-161.53,p < 0.00001;OR = 3.57,95% CI:1.81-7.02,p
= 0.0002;OR = 8.05, 95% CI: 2.83-22.89,p < 0.0001;respectively) were
recorded.
Conclusion
Our meta-analysis data show that cetuximab combined with chemotherapy can
prolong OS,PFS and ORR of patients with advanced NSCLC.Ce-chem may provide
a new option for clinical treament of patients with advanced NSCLC,althought it may
increse some treament related adverse events(AEs).
Key words：NSCLC;cetuximab;chemotherapy
Introduction
Lung cancer is a major cause of cancer related death worldwide 1and NSCLC
(non–small-cell lung cancer,including the histologic hypotypes of squamous cell
1
carcinoma,andadeno carcinoma,large cell carcinoma),occupy 80% to 85% of cases. 2
Therapy with a platinum-based of Double agent is standard regimen,although double
agent without platinum-based combinations are an acceptable alternative.3But
different agent combinations have similar efficacy4-6,and this has lead to the belief
that cytotoxic drug therapy has reached a bottleneck period with median survival
about one year and progression-free survival between 3.9 months to 6 months 7,8.So
we must find a new combination for the therapy of non-small cell lung cancer.
The overexpression of EGFR(epidermal growth factor receptor ) is common
in 40~89%9,10of patients with non-small cell lung cancer.EGFR-targeting agents
come in two main types:EGFR-targeted monoclonal antibodies and TKIs(EGFR
tyrosine kinase inhibitors). In non-small cell lung cancer,treament with TKIs is
effective as single agentsto refractory disease11,12but combined with first-line
cytotoxic treatment seldomly shown a benefit in the populations of unselected
patient13-16.Cetuximab(Erbitux®) is a monoclonal chimeric mouse-human antibody
directed against EGFR,and is approved to be applied to patients with colorectal
and head and neck cancers.by FDA .In addition,Cetuximab may also play a
part in mediating anti-tumour immune mechanisms17,18.
There are some phase II or phase III studies showed that cetuximab combined
withchemotherapy was active in advanced non-small cell lung cancer patients
.In 2007, Charles A.Butts et al.found that median PFS was 5.09 months(95%
CI,4.17-5.98)in Ce+chem(Gemcitabine+Cisplatin/Carbo-platin+Cetuximab)and 4.21
months (95% CI, 3.81 to 5.49) in Chem (Gemcitabine+Cisplatin/Carboplatin),
and that median OS was 11.99 months (95%CI,8.80 to 15.18) in Ce+chem and
9.26 months (95% CI,7.43-11.79) in Chem.19Another study in 2012,J.R.Fischer
et al.showed that Response rate (PR + SD) was 79.1%,while the 1-year rates
for PFS was11.2% and one-year rates of OS was 64.4% in Ce+chem.Median
PFS )and median OS were 4.8 months (95% CI,3.70–5.31 and 12.9 months (
95% CI 8.26–∞),respectively in arm Ce+chem.AEs were well tolerated.20
Patients and methods
Searching. This meta-analysis was carried out in the Bengbu Medical College,
Anhui, China between February 2014 and April 2014. Eligible trial publications
for our analysis were performed in June 10, 2014 in china.ThePubMed and M
edline were screened,using following keywords:"lung cancer/non-smallcell lung
cancer;NSCLC"and”chemotherapy”and.“cetuximab;ERBITUX”References of all
selected trials were retrieved for additional study.The ESMO(European Society
for Medical Oncology) and ASCO(American Society of Clinical Oncology) and a
nnual meeting abstracts were also scanned.
Selection of trials. Trials were manually included if they met the following inclusion
criteria:(1)chemotherapy
plus
cetuximab
versus
chemotherapy
alone;
(2)histologically or cytologically documented advanced non-small cell lung cancer
(stage III or stage IV) (3) Eastern Cooperative Oncology Group(ECOG) performance
status less than 2 or Karnofsky performance status(KPS) less than 60;(4)
2
Radiation untreated;(5) all tiais were RCT (randomized controlled trial).Language
was not restricted.
Basic characteristics and Quality evaluation. All trials which we slected wer
e assessed by the Jadad scale openly.
Data abstraction. All data of patients were extracted by two investigators with
a standardized method.In addition,we reach an agreement on all items..If
information of articals is not reported,we try to get additional information by
contacting the authors.We used a standardized form to extract the data from
each trial,,including quality grading,publication details,study characteristics(for
example groups,cases,gender,histology type,treament regimens,and stage,
performance status (PS)),evaluation index (RR for ORR, HRs for PFS and OS
and their 95 % CIs (confidence intervals),log-rank test p values). Grade3/4
adverse events were extracted including non-hematological and hematological
toxicities(Table 1).
Statistical analysis. RR,HR and RR were calculated using Review Manager (
RevMan,Version 5.2) or STATA 12.0.Analyses were performed in intention-totreatment for overall response rate,overall survival and progression-free survival,
and in treatment related analyses for toxicities.A p-value which is less than
0.05 for a statistical test was considered significant.RR >1 showed that more
OS was got in treament arm(Ce+chem),HR > 1 indicated that more deaths
or progression would occured in Ce+chem,and OR > 1 reflected more
treament related toxicities in Ce+chem.Statistical heterogeneity between trials
was assessed with the χ 2 test( with a p-value less than 0.1)for heterogeneity
and the I2 test for inconsistency21.The results of analyses were considered
inconsisten,when the I2 was more than 50%.We will use random-effect model
to analyse data,if there was significant statistical heterogeneity22.
Table.1. Quality evaluation of included trials
Results
Search Of The Published Literature
3
We found 415 publications on Cetuximab,and 27 trials were potentially eligible,
when we examined with key word “Cetuximab therapy in advanced NSCLC
patients”.Five trials met inclusion criteria finally,and all trials were performed
between 2007 and 2014,and the number of advanced NSCLC patients was
2,552 19,23-26.Three trials were phase III RCTs23,24,26and two trials were multicent
er trials23,24There was no double blind without being reported by Charles A et a
l.19(Figure.1). Five trials were included involving 2,552 patients for this
meta-analysis.They are divided into two groups,1272 in Ce+Chem and 1280 in
Chem.Four trials were with platinum-based doublets therapy :”GP” (gemcitabine
1250mg/m2 day1 and day8 plus cisplatin 75mg/m2 day1-day4, every 3 week
or gemcitabine 1000 mg/m2 (day1,day8) plus carboplatin(AUC=5,day1,every 3
week,six cycles at most))19;”NP” (Vinorelbine 25mg/m2 (day1+day8) plus
cisplatin 80mg/m2,(day1,every3 week,eight cycles25or six cycles23 at most);”TA”
(taxane ( paclitaxel 225mg/m2, three-hour IV or docetaxel 75mg/m2 one-hour IV)
+carboplatin (AUC =6, six cycles at most))24. One trial was received Docetaxel
or pemetrexed,not combine with platinum:docetaxel (75mg/m2) or pemetrexed (
500 mg/m2). In Ce-Chem arm of five trials,cetuximab (initial dose was 400
mg/m2 and followed by 250 mg/m2 every week,Day 1 of each 3 week)19,23-26
was intravenously infused till intolerable toxicity happened or disease
progressed(Table 2).
Table.2.The basic characteristics of included trials
4
Fig.1.Flow of identifying the trials comparing chemotherapy plus cetuximab with chemotherapy alone in patients with
advanced non-small-cell lung cancer.
Efficacy comparison
Five trails all have reported efficacy of Ce+Chem.The result of meta-analysis in
dicates that compared with Chem,a beneficial trend was showed in Ce+Chem
according to RR and there was statistical significance (RR = 1.17,95% CI:1.06
–1.29,p = 0.002). There was no evidence of heterogeneity between the trials (I
2 = 44%, p = 0.13) (Figure.2).
Fig.2.Meta-analysis of Efficient.The pooled RR showed that E-chemo might increase overall response rate inpatients with
advanced NSCLC (RR, 1.17; 95%CI, 1.06-1.29; p = 0.002).
OS(Overall survival)
Overall survival might be prolonged in terms of the pooled HR (HR = 0.89;95
%CI, 0.83–0.95;p = 0.00) in patients with advanced non-small cell lung cancer.
The evidence of heterogeneity was not found between two groups (I2 = 32.9%,
p = 0.202)(Figure.3A).
PFS(Progression-free Survival)
The result of meta-analysis indicates that a beneficial trend was showed in
Ce+Chem according to the pooled HR (HR = 0.91,95% CI: 0.83-0.99,p = 0.037
) in patients with advanced non-small cell lung cancer..There was no
heterogeneity between two groups(I2 = 0%,p = 0.202)(Figure.3B).
5
A
(OS)
B
(PFS)
Fig.3.Meta-analysis of the hazard ratios (HRs) between chemotherapy plus cetuximab (Ce-chemo) and chemotherapy alone
(Chemo) in OS,PFS.(A)The pooled HR showed that Ce-chemo might prolong OS in patients with advanced NSCLC (HR, 0.89;
95%CI, 0.83–0.95;p=0.00);(B)The pooled HR showed that Ce-chemo might prolong PFS in patients with advanced NSCLC (HR,
0.91; 95%CI, 0.83-0.99; p=0.037).
Adverse Events
Hematological Toxicity
Adverse Events was described as patients experiencing grade 3/4 toxicity.
Hematological toxicity were reported in all trials,inclued neutropenia,leukopenia,
thrombocytopenia,febrile-neutropenia,anemia.Five trials all reported neutropenia,
but there was no statistical significance (OR = 2.96;95% CI,0.71–12.46;p = 0.
14), and there was heterogeneity between two groups(I2 = 97%,p < 0.0001.).So
we selected Random model to analyse.Compared with Chem,a statistically
significant increase in leukopenia,thrombocytopenia and febrile neutropenia in
Ce+Chem(OR=1.33,95% CI:0.94–1.88,p = 0.10;OR = 1.34, 95% CI: 0.9-1.98,p
= 0.15;OR = 1.46,95% CI:1.06-2.01,p = 0.002,respectively).Only in anemia have
a decrease in Ce+Chem(OR = 0.96,95% CI:0.72-1.27,p = 0.75).The pooled O
6
Rs for hematological toxicity were performed with the Random model as a resu
lt of heterogeneities of neutropenia(Figure.4).
Fig.4.Meta-analysis of grade 3/4 hematological toxicity.Abbreviations: M-H, mantel-haenszel; CI, confidence
interval.
Non-hematological Toxicity
Acneiform rash were reported in all five trials,Ce+Chemo lead to more grade
3/4 rash(OR = 51.22,95% CI:16.24-161.53,p < 0.00001),and there was no
heterogeneities(I2 = 0,p = 0.73).Infusion reaction,hypomagnesemia and diarrhea
also caused more grade 3/4 adverse events(OR = 3.57,95% CI: 1.81-7.02,p =
0.0002;OR = 8.05,95% CI:2.83-22.89,p < 0.0001;OR = 1.95,95% CI:1.2-3.18,p
= 0.007 respectively).There was no marked difference of statistics in the grade
3/4 Nausea(OR=1.34,95%CI:0.75-2.38,p = 0.32).There was no heterogeneity
7
between all groups.The ORs for non-hematologictoxicity were pooled with the
fixed-effort model (Figure.5).
Fig.5.Meta-analysis of grade 3/4 non-hematological toxicity.Abbreviations: M-H, mantel-haenszel; CI,confidence .
Discussion
Cetuximab has been assessed in many studies of patients with advanced non-small
cell lung cancer.In a phase III study,23chemotherapy-naive patients with stage IIIB or
stage IV NSCLC were randomly divided into two groups (chemotherapy combined
with cetuximab or chemotherapy alone).Compared with those who received
chemotherapy alone,the outcomes of this study met its primary endpoint,with patients
receiving cetuximab experiencing improved OS(11.3 vs 10.1 months;HR = 0.871,95%
CI 0.762-0.996;p = 0.044).In BMS099,taxane plus carboplatin with cetuximab did not
improve the primary endpoint of PFS, but a significantly greater proportion of
patients achieved better ORR than those without cetuximab. 24OS of difference of this
magnitude with statistical significance was not detected in BMS099,but the HR for
death was similar to FLEX(BMS099HR=0.890 vs FLEX HR = 0.871).23,24InBMS099,
Selection of patients was not according to EGFR expression,but in FLEX,only EGFR
positive tumours of patients were
enrolled.23,24In another phase 3,
8
open-label,randomised trial,26the result is that Cetuximab combining with
chemotherapy is not best choice for patients who have been previously treated with
platinum-based therapy.Compared with pemetrexed alone,median PFS of Ce-chmo
was not obviously prolonged(2.9 months versus 2.8 months,HR = 1.03,95 %CI
0.87-1.21; p = 0.76 ).26The different result of trials may be because of status of
EGFR express-ion.But present studies might help us to delimit which patients might
benefit from combination.A study (SWOG S0819) is designed to directly investigate
the effect of combined EGFR and VEGF blockade together with chemotherapy,
incorporating EGFR FISH as a coprimary endpoint.27
Outcomes of our meta-analysis indicated that Chemotherapy combined with
cetuximab can prolong progression-free survival and overall survival of
advanced non-small cell cancer patients and improve overall reponse rate
obviously compared with chemotherapy alone.But Edward S Kim,et al.show that
the addition of cetuximab to pemetrexed did not improve progression-free
survival(PFS),nor were there improvements in any of other assessed efficacy or
Qol measures,including OS26.It was possible that patients who were enrolled
in this study had received a platinum-based regimen previously.Cetuximab
related adverse events (AEs) mainly include hematological toxicity and
non-hematological toxicity.More grade 3/4 acneiform rash was recorded
compared with chemotherapy aloneThe pooled ORs of hematological toxicity
except neutropenia and non-hematological toxicity were significant different
compared with Chemo.Additional of Cetuximab may be increase some toxicity
of chemotherapy.In addition,hypomagnesemia and rash acneiform even may be
considered as a predictive mark for sensitivity of cetuximab.
Studies showed that different results may be generated when cetuximab
combined with different chemotherapy regimens.Response rate were increased
in BMS-099 and FLEX,and it seems that the benefit of cetuximab did not
dependent on the platinum-based regimens23.In a phase 3,open-label,
randomised trial indicaed that the addition of cetuximab to chemotherapy did
not improve PFS obviously,26and in another multicenter phase 2 trial,it
demonstrated that the addition of cetuximab to carboplatin had a lower
response rate than double agent platinum-based treament.28We are puzzled by
the reasons which cetuximab combined with different chemotherapy regimens
have different outcomes.
In summary, our meta-analysis indicated that the addition of cetuximab to
chemotherapy may be considered as a new t option for treatmen of patients with
advanced non-small cell cancer.Although it may be increased some AEs.,It can
prolong PFS and OS obviously.We should have come up with an effective method to
reduce the treatment related adverse effects.We have many questions need to clarify
in the future,for example,biomarkers for the selection of population and the best time
to cetuximab therapy. To find a biomark for cetuximab treament is our future task.
Conflict of interest statement
We declare that we have no any conflict of interest swith other people or
organizations.
9
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