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Lung Cancer 74 (2011) 89– 97

Contents lists available at ScienceDirect

Lung Cancer

j our na l ho me p age: www.elsev ier .com/ locate / lungcan

fficacy of bevacizumab (Bev) plus chemotherapy (CT) compared to CT alone inreviously untreated locally advanced or metastatic non-small cell lung cancerNSCLC): Systematic review and meta-analysis

obias Engel Ayer Botrel1, Otávio Clark ∗, Luciana Clark1, Luciano Paladini1,néas Faleiros1, Bruna Pegoretti1

videncias Consulting, Rua Tranquillo Prosperi, 143, Campinas, São Paulo ZIP: 13084-778, Brazil

r t i c l e i n f o

rticle history:eceived 21 June 2010eceived in revised form0 December 2010ccepted 30 January 2011

eywords:hemotherapyevacizumabon-small cell lung cancerystematic revieweta-analysis

a b s t r a c t

Objective: To perform a systematic review and meta-analysis of all randomized controlled trials compar-ing the efficacy of chemotherapy (CT) plus Bevacizumab (Bev) versus CT alone in previously untreatedlocally advanced or metastatic non-small cell lung cancer (NSCLC).Methods: Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. Theendpoints were overall survival (OS), progression-free survival (PFS) and side effects. We performeda meta-analysis (MA) of the published data, using a fixed effects model and an additional random effectsmodel, when applicable. The results of the MA are expressed as hazard ratio (HR) or risk ratio (RR),with their corresponding 95% confidence intervals (CI95%). We analyzed the use of Bev in the doses of7.5 mg/kg and 15 mg/kg.Results: The final analysis included 4 trials, comprising 2200 patients. The response rate was higherin patients who received the combination of CT plus Bev 7.5 mg/kg (RR = 0.58; CI95% = 0.46–0.74;p < 0.00001) and Bev 15 mg/kg (RR = 0.53; CI95% = 0.45–0.63; p < 0.00001) with moderate heterogene-ity at dose of 15 mg/kg (Chi2 = 4.30, df = 3 (P = 0.23); I2 = 30%). The PFS length was longer in patients whoreceived CT plus Bev 7.5 mg/kg (HR = 0.78, CI95% = 0.68–0.90; p = 0.0005) and Bev 15 mg/kg (HR = 0.72,CI95% = 0.65–0.80; p < 0.00001) with moderate heterogeneity (Bev 7.5 mg/kg: Chi2 = 1.43, df = 1 (P = 0.23);I2 = 30% and Bev 15 mg/kg: Chi2 = 7.43, df = 3 (P = 0.06); I2 = 60%). Differences in these end points remainedin favor of CT plus Bev when made the analysis by random-effects model. Overall survival was longer

in patients who received CT plus Bev 15 mg/kg (HR = 0.89, CI95% = 0.80–1.00; p = 0.04), with moderateheterogeneity (Chi2 = 5.09, df = 3 (P = 0.17); I2 = 41%). The random-effects model analysis for this endpointdid not confirmed the difference seen in the fixed effects model analysis (HR = 0.90, CI95% = 0.76–1.07;p = 0.23). Severe haematologic toxicities (grade > 3), neutropenia and febrile neutropenia were morecommon among the patients that received Bev.

ion oh res

Conclusion: The combinatpatients with NSCLC. Wit

. Background

Non-small cell lung cancer (NSCLC) represents the most com-on cause of cancer-related deaths in Western countries [1]. For

atients with advanced/metastatic NSCLC, systemic chemother-

py constitutes the standard of care [2]. Both qualitative anduantitative benefits are noted with platinum-based two-drugombinations for advanced NSCLC patients with a good perfor-ance status [2–5].

∗ Corresponding author. Tel.: +55 19 8149 5375, fax: +55 19 3287 8310.E-mail address: clark@evidencias.com.br (O. Clark).

1 Tel.: +55 19 8149 5375, fax: +55 19 3287 8310.

169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.lungcan.2011.01.028

f CT plus Bev increased the response rate and progression-free survival ofpect to overall survival the benefits of Bev remains uncertain.

© 2011 Elsevier Ireland Ltd. All rights reserved.

Some combinations of chemotherapy (cisplatin/paclitaxel,cisplatin/docetaxel, cisplatin/gemcitabine, and carbo-platin/paclitaxel) for front-line therapy of advanced NSCLCdemonstrated similar efficacy [6].

Unfortunately, the response rates for CT are low: less than 40%of patients show significant tumor reduction. Five-year survivalremains unacceptably low in the order of 15% [7]. Opportuni-ties exist to improve the clinical benefit of first-line treatment forpatients before disease progression [8].

Bevacizumab (Bev) is a recombinant humanized monoclonalantibody against VEGF that was approved in the United States ofAmerica for the first-line treatment of patients with unresectable,locally advanced, recurrent or metastatic non-squamous NSCLC [9].In Europe and more recently in Brazil, Bev was also approved for

90 T.E.A. Botrel et al. / Lung Cancer 74 (2011) 89– 97

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se in the first-line treatment of advanced non-squamous NSCLC,ssociated to CT [7].

From 2004, clinical studies have shown that the addition of Bevo chemotherapy significantly increased progression-free survivalnd response rate of patients diagnosed with advanced lung cancer10,11].

However, results in overall survival remain controversial: Therst randomized study, published in full in 2006, showed an

ncrease of 2 months in median overall survival in favor of thessociation of CT with Bev [10]. Two years later the final resultsf overall survival of the study AVAiL (Avastin® in Lung) [12,13]ere presented. No differences were observed in overall survival

etween the groups studied.A recently published meta-analysis, showed that the use of CT

lus Bev (at a dose of 15 mg/kg), increased the two year survivalate of patients diagnosed with advanced lung cancer, when com-ared to CT alone [14]. But, this meta-analysis has some limitations:he authors included patients in different lines of treatment (pre-iously untreated and treated with prior CT); the survival analyses

ere performed at fixed times, as defined by the authors (first and

econd year) and were reported as dichotomous events. Also, inhe survival analysis at two years, heterogeneity of 38% (moderate)as noted and no additional attempt to better explore this fact wasresented. These limitations make this study prone to the occur-

able 1haracteristics of included studies.

Study Design N Patients H

Johnson et al. [11] Randomized, double-blindactive-controlled, parallelarm

99 Recurrent oradvancednon-small-cell lungcancer (stage IIIB orIV)

ALSO

Sandler et al. [10] Randomized, double-blind,active-controlled, parallelarm

878 Recurrent oradvancednon-small-cell lungcancer (stage IIIB orIV)

AoLBO

Reck et al. [13,29] Randomized, double-blind,active-controlled, parallelarm

1043 Recurrent oradvancednon-small-cell lungcancer (stage IIIB orIV)

ALMpacO

Nishio et al. [30,31] Randomized, open label,multicenter

180 Advanced orrecurrentnon-squamous

U

bbreviations: CT – chemotherapy; Bev – bevacizumab.a Carboplatin and paclitaxel.b Gemcitabine and cisplatin.

tion flow.

rence of bias and other meta-analysis should be performed to betterclarify these issues.

Our objective is to analyze all published randomized controlledclinical trials (RCTs) that compared the efficacy of CT plus Bev (low-dose: 7.5 mg/kg and high-dose: 15 mg/kg) compared to CT alonefor lung cancer in non-small cell, inoperable, locally advanced (IIIB,with supraclavicular lymph node metastasis or malignant pleuralor pericardial effusion), metastatic (IV) or recurrent in front-linetherapy.

2. Methods

2.1. Study selection criteria

2.1.1. Types of studiesRCTs with parallel design, that compared the use of chemother-

apy regimens associated or not to the use of Bevacizumab(low-dose: 7.5 mg/kg and high-dose: 15 mg/kg).

2.1.2. Types of participantsPatients with non-small cell lung cancer (NSCLC) previously

untreated locally advanced or metastatic (IIIB, with supraclavicularlymph node metastasis or malignant pleural or pericardial effusionor IV).

istology Interventions Primary endpoint

denocarcinomaarge-cell anaplasticquamous cellther

CTa alone or, CTa plus Bev7.5 mg/kg or, CTa plus Bev15 mg/kg

Time toprogression andtumor responserate

denocarcinoma or notther-wise specifiedarge-cellronchioloalveolarther

CTa alone or, CTa plus Bev15 mg/kg

Overall survival

denocarcinomaarge-cellixed (with

redominantlydenocarcinomaomponent)ther

CTb alone or, CTb plus Bev7.5 mg/kg or, CTb plus Bev15 mg/kg

Progression-freesurvival

ninformed CTa alone or, CTa plus Bev15 mg/kg

Progression-freesurvival

T.E.A. Botrel et al. / Lung Cancer 74 (2011) 89– 97 91

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ig. 2. comparative effect in objective response rates of CT with Bev versus CT alone measurable lesion are assessed.

.1.3. Search strategy for identification of studiesA wide search of the main computerized databases of interest

as conducted, including EMBASE, LILACS, MEDLINE, SCI, CENTRAL,he National Cancer Institute Clinical Trials service, and The Clinicalrials Register of Trials Central. In addition, the abstracts publishedn the proceedings of the American Society of Clinical OncologyASCO), American Society of Hematology (ASH), the European Soci-ty for Medical Oncology (ESMO) and International Association forhe Study of Lung Cancer (IASLC) were also searched.

For MEDLINE, we used the search strategy methodology forandomized controlled trials [15] recommended by the Cochraneollaboration [16]. For EMBASE, we used adaptations of this sametrategy [15], and for LILACS, we used the search strategy method-logy reported by Castro et al. [17]. We performed an additionalearch on the SCI database looking for studies that were cited onhe included studies. We added the specific terms pertinent tohis review to the overall search strategy methodology for eachatabase.

The overall search strategy was a follows: #1 (“beva-izumab”(Substance Name) OR “bevacizumab”(All Fields));2 (“lung”(MeSH Terms) OR “lung”(All Fields)) AND (“neo-

lasms”(MeSH Terms) OR “neoplasms”(All Fields)); #3 Random*.

Searches of electronic databases combined the terms: #1 AND2 AND #3 for these study designs: Humans, Clinical Trial, Meta-nalysis, Practice Guideline, Randomized Controlled Trial, andeview.

Fig. 3. Comparative effect in progression-free survival of CT wit

eviations: CT – chemotheraphy. Observation: Sandler et al. [10]: only patients with

2.2. Critical evaluation of the selected studies

All the references retrieved by the search strategies had theirtitle and abstract evaluated by two of the researchers. Every ref-erence with the least indication of fulfilling the inclusion criteriawas listed as pre-selected. We retrieved the complete article ofall pre-selected references. They were analyzed by two differentresearchers and included or excluded according to the previouslyreported criteria. The excluded trials and the reason of their exclu-sion are listed in this article. Data was extracted from all theincluded trials.

Details regarding the main methodology characteristics empir-ically linked to bias [18] were extracted with the methodologicalvalidity of each selected trial assessed by two reviewers(T.E.A.B. and O.C.). Particular attention was given to some itemssuch as: the generation and concealment of the sequence ofrandomization, blinding, application of intention-to-treat anal-ysis, sample size pre-definition, loss of follow-up description,adverse events reports, if the trial was multi-centric and thesponsorship.

2.3. Data extraction

Two independent reviewers extracted data. The name of the firstauthor and year of publication were used to identify the study. Alldata were extracted directly from the text or calculated form avail-

h Bev versus CT alone. Abbreviations: CT – chemotherapy.

92 T.E.A. Botrel et al. / Lung Cancer 74 (2011) 89– 97

Fig. 4. Comparative effect in overall survivalof with Bev versus CT alone (fixed-effect model analysis). Abbreviations: CT – chemotherapy.

Fig. 5. Comparative effect in overall survival of CT with Bev versus CT alone (random-effects model analysis). Abbreviations: CT – chemotherapy.

Fig. 6. Comparative effect haematologic toxicities CT with Bev (7.5 mg/kg) versus CT alone. Abbreviations: CT – chemotherapy. The event represents the observed number ofpatients.

T.E.A. Botrel et al. / Lung Cancer 74 (2011) 89– 97 93

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ig. 7. Comparative effect non–haematologic toxicities of CT with Bev (7.5 mg/kg)umber of patients.

ble information when necessary. The data of all trials were basedn the intention-to-treat principle, so they compared all patients

llocated one treatment with all those allocated the other.

The primary endpoints were overall survival (OS) androgression-free survival (PFS). Definition of PFS: time from ran-omization to either death or disease progression, whicheverccurs first.

s CT alone. Abbreviations: CT – chemotherapy. The event represents the observed

Other clinical outcomes were also evaluated: overall responserate and the number of patients that presented adverse

events (grade ≥ 3): haematological (neutropenia, thrombocy-topenia, anemia, febrile neutropenia) and non-haematological(haemoptysis, hypertension, proteinuria, venous thromboembolicevents, vomiting, rash or desquamation, epistaxis and bleedingevents).

94 T.E.A. Botrel et al. / Lung Cancer 74 (2011) 89– 97

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ig. 8. Comparative effect haematologic toxicities CT with Bev (15 mg/kg) versus Catients.

.4. Analysis and presentation of results

Data were analyzed using the Review Manager 5.0.24 statisticalackage (Cochrane Collaboration Software) [19].

Dichotomous clinical outcomes are reported as risk ratio (RR)nd survival data as hazard ratio (HR) [20]. The corresponding5% confidence interval (CI95%) was calculated, considering P val-es less than 5% (p < 0.05). A statistic for measuring heterogeneityas calculated through I2 method (25% was considered low-leveleterogeneity, 25–50% moderate-level heterogeneity and >50%igh-level heterogeneity [14,21].

To estimate the absolute gains in PFS and OS, we calculatedeta-analytic survival curves as suggested by Parmar et al. [20].

pooled estimate of the HR was computed by a fixed-effect modelccording to the inverse-variance method [22]. Thus, for effective-ess an HR or RR greater than one favors the standard arm (CTlone) whereas an HR or RR less than 1 favors the CT plus Bevreatment.

If statistical heterogeneity was found in the meta-analysis, weerformed an additional analysis using the random-effects modelescribed by DerSimonian and Laird [23], that provides a moreonservative analysis.

To assess the possibility of publication bias, we performed theunnel plot test described by Egger et al. [24]. When the pooled

esults were significant, the number of patients needed to treatNNT) to cause or to prevent one event was calculated by pool-ng absolute risk differences in trials included in meta-analyses25–27]. For all the analyses, a forest plot was generated to displayesults.

e. Abbreviations: CT – chemotherapy. The event represents the observed number of

In the analysis of OS, a subgroup analysis was planned to eval-uate the effect of the combination of CT plus Bev for those patientswith squamous cell histology.

3. Results

The diagram represents the flow of identification and inclusionof trials, as recommended by the QUOROM statement [28] (Fig. 1).

Overall, 545 references were identified and screened.Sixty-seven studies were selected and retrieved for full-text

analysis. Of these studies, 63 were excluded for various reasons,described on Table S1 (additional material).

The final analysis included 4 trials comprising 2200 patients.Bev was associated with two different CT regimens (carbo-platin/paclitaxel or cisplatin/gemcitabine) (Table 1).

Two publications were a three-arm study of CT aloneor combined to two different doses of Bev (Bev 7.5 mg/kgand Bev 15 mg/kg) [11,13,29]. Only one study allowed thecrossover between the arms [11], after a progression have beendetected.

The meta-analysis showed an higher overall response rate inpatients who received the combination of CT plus Bev at 7.5 mg/kgdoses (fixed effect: RR = 0.58; CI95% = 0.46–0.74; p < 0.00001;NNT = 7) as well as at Bev at 15 mg/kg (RR = 0.53; CI95% = 0.45–0.63;

p < 0.00001; NNT = 6). This last analysis showed a moderate hetero-geneity (Chi2 = 4.30, df = 3 (P = 0.23); I2 = 30%) (Fig. 2).

As planned, we performed a random-effects model analysis: theresults remained favorable to CT plus Bev in both doses: 7.5 mg/kg(random effects: RR = 0.58; CI95% = 0.46–0.74; p < 0.00001)

T.E.A. Botrel et al. / Lung Cancer 74 (2011) 89– 97 95

Fig. 9. Comparative effect non–haematologic toxicities of CT with Bev (15 mg/kg) versus CT alone. Abbreviations: CT–chemotherapy. The event represents the observednumber of patients.

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5 mg/kg (random effects: RR = 0.54; CI95% = 0.44–0.67; < 0.00001).

The PFS was longer in patients who received CT plusev at 7.5 mg/kg (fixed effect: HR = 0.78, CI95% = 0.68–0.90;

= 0.0005; NNT = 4) and Bev at 15 mg/kg (fixed effect: HR = 0.72,I95% = 0.65–0.80; p < 0.00001; NNT = 3) both with heterogene-

ty (Bev 7.5 mg/kg: Chi2 = 1.43, df = 1 (P = 0.23); I2 = 30% and Bev5 mg/kg: Chi2 = 7.43, df = 3 (P = 0.06); I2 = 60%) (Fig. 3). The ben-fit for PFS is sustained when we use a random-effects modelnalysis: CT plus Bev at 7.5 mg/kg (random effects: HR = 0.80;I95% = 0.66–0.97; p = 0.02) and Bev at 15 mg/kg (random effects:R = 0.70; CI95% = 0.58–0.85; p = 0.0003).

The OS was similar in patients who received CT plus Bevt 7.5 mg/kg (fixed effect: HR = 0.92, CI95% = 0.77–1.09; p = 0.33)nd longer for patients who received CT plus Bev at 15 mg/kgfixed effect: HR = 0.89, CI95% = 0.80–1.00; p = 0.04; NNT = 9), butith moderate heterogeneity (Chi2 = 5.09, df = 3 (P = 0.17); I2 = 41%)

Fig. 4). However, when the analysis is performed by the random-ffects model no significant difference is seen (random effects:R = 0.90, CI95% = 0.76–1.07; p = 0.23) (Fig. 5).

We tried to better explore this heterogeneity by excluding thetudy published by Johnson et al. [11], due to the fact that thisrial was the only one that allowed the inclusion of patients withquamous cell histological type. There was no change in the het-rogeneity (fixed effect: Chi2 = 4.98, df = 2 (P = 0.08); I2 = 60%). Otherttempts to diminish the heterogeneity by excluding studies, basedn clinical characteristics also failed.

We planned to perform a subgroup analysis according to theistological type of the patients included. It was not possible, asnly one study included patients with squamous cell histologicalype [11], and even there, only 19 patients with this particular typef tumor were included.

Regarding the haematological toxicities (grade > 3), the groupeceiving CT plus Bev in the dose of 7.5 mg/kg had more patientsith neutropenia (fixed effect: RR = 0.79; CI95% = 0.65–0.96;

= 0.02). No differences were seen in the rates of patientsith thrombocytopenia (fixed effect: RR = 0.86; CI95% = 0.66–1.12;

= 0.27). Only one study [13,29] evaluating CT plus Bev7.5 mg/kg) reported the proportion of anemia and febrile neu-ropenia (RR = 1.31; CI95% = 0.86–1.99; p = 0.21 and RR = 0.81;I95% = 0.22–2.98; p = 0.75, respectively) (Fig. 6).

The non-haematologic toxicities reported the group receivingT plus Bev in the dose of 7.5 mg/kg had more patients withypertension (fixed effect: RR = 0.30; CI95% = 0.13–0.73; p = 0.007)nd bleeding events (fixed effect: RR = 0.40; CI95% = 0.16–0.97;

= 0.04). The proportion of patients with haemoptysis (fixedffect: RR = 0.30; CI95% = 0.07–1.20; p = 0.09), venous thromboem-olic events (fixed effect: RR = 0.93; CI95% = 0.54–1.59; p = 0.79),nd vomiting (fixed effect: RR = 0.52; CI95% = 0.27–1.01; p = 0.05),ere similar (Fig. 7).

The group that received CT plus Bev at 15 mg/kg had moreeutropenia (fixed effect: RR = 0.77; CI95% = 0.65–0.91; p = 0.002)nd febrile neutropenia (fixed effect: RR = 0.44; CI95% = 0.23–0.84;

= 0.01). The proportion of thrombocytopenia (fixed effect:R = 0.91; CI95% = 0.69–1.20; p = 0.5) and anemia (fixed effect:R = 1.41; CI95% = 0.93–2.13; p = 0.1) were similar (Fig. 8).

The non-haematologic toxicities reported were also wereore frequent in the group of patients that receiving CT

lus Bev at 15 mg/kg: haemoptysis (fixed effect: RR = 0.31;I95% = 0.10–0.92; p = 0.03), hypertension (fixed effect: RR = 0.14;I95% = 0.07–0.28; p < 0.00001), proteinuria (fixed effect: RR = 0.05;

I95% = 0.01–0.41; p = 0.005), vomiting (fixed effect: RR = 0.41;I95% = 0.22–0.77; p = 0.005), rash or desquamation (fixed effect:R = 0.19; CI95% = 0.04–0.88; p = 0.03), and bleeding events (fixedffect: RR = 0.27; CI95% = 0.13–0.56; p = 0.0004). Venous throm-oembolic events (fixed effect: RR = 0.87; CI95% = 0.51–1.47; p = 0.6)

cer 74 (2011) 89– 97

and epistaxis (fixed effect: RR = 0.32; CI95% = 0.03–3.10; p = 0.33)were similar (Fig. 9). Nishio et al. [30,31] reported only the data ofhaemoptysis and hypertension.

According to the funnel plot analysis [24] the possibility of pub-lication bias was low for all of the end points.

4. Discussion

Presently many oncology guidelines recommend the use of CTplus Bev for front-line therapy of advanced NSCLC [3,32].

In our meta-analysis, progression-free survival and responserate favored the combination of Bev plus CT in patients with NSCLC.In the analysis of OS, we observed a difference in favor of thecombination of CT plus Bev at 15 mg/kg in a fixed effects modelanalysis but with an important heterogeneity. When a random-effects model analysis was performed this difference disappeared.

The discrepancy between a clear benefit in PFS and a not soclear benefit in OS is not unexpected, as, in lung cancer, the cor-relation between these two measures are not yet completely clearand validation studies for the use of PFS as surrogate to OS are stilllacking [33]. There is a possibility that the treatments used after theprogression in these patients could have an influence in this lackof clear benefit in OS, but, with the data published, we could notanalyze this possibility.

As the random-effects models provides a more conservativeestimate of the average treatment effect when trials are statisti-cally heterogeneous [23], we cannot rule out a benefit in OS, for theuse of Bev. A definitive answer will come only after more studiescome to be published.

The results of this study is not divergent of those from othermeta-analysis previously published [14]. There are differences inthe methods used, but in overall, both studies points to a benefitof Bev, although in a different extent. Both meta-analysis showed abetter response rate and PFS for Bev. In our study there was no clearbenefit for Bev in OS as that showed in the meta-analysis publishedby Yang [14]. This major point of disagreement can be attributedto the methods used: while in this meta-analysis we used HR asa measure of association, Yang et al. used RR. As the HR is a moreappropriate method to measure time to event data [20], we can saythat the results presented here are more reliable.

Overall, there were more side effects in the group that usedBev. Recently two large studies have concluded for an increasedsecurity with the use of bevacizumab in combination with differ-ent chemotherapy schedules [34,35], what apparently contradictsour results. As these studies were not randomized, one should stillbe concerned for a greater incidence of side effects when treatinga patient with Bev.

As there was an increase in toxicity, attention should be givento patients that have an increased risk of bleeding, recent or cur-rent use of aspirin or oral and/or parenteral anticoagulants. Also,patients with central nervous system (CNS) metastasis an activeinfection, radiation therapy within 21 days before enrollment ormajor surgery within 28 days before enrollment, should not useBev, given the increased risk of bleeding [34].

Hypertension, proteinuria and headache are usually control-lable events and do not require permanent discontinuation ofbevacizumab [10].

5. Conclusion

The combination of CT plus Bev increased the response rate andprogression-free survival of patients with NSCLC. With respect tooverall survival its benefit remains uncertain. As the number of pub-lished studies is still small, future assessments should be conductedto better clarify the real role of Bev in patients with advanced lung

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onflict of interest statement

None of the authors have stocks, patents or shares from anyrganizations that can benefit from these findings. The source ofunding was internal.

ppendix A. Supplementary data

Supplementary data associated with this article can be found, inhe online version, at doi:10.1016/j.lungcan.2011.01.028.

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