adjuvant_cisplatin_vinorelbine_completelyresected

ORIGINAL ARTICLE

Adjuvant Cisplatin and Vinorelbine for Completely ResectedNon-small Cell Lung Cancer

Subgroup Analysis of the Lung Adjuvant Cisplatin Evaluation

Jean-Yves Douillard, MD, PhD,* Helene Tribodet, MSc,† Delphine Aubert, MSc,‡Frances A. Shepherd, MD,§ Rafael Rosell, MD, PhD,� Keyue Ding, PhD,¶ Anne-Sophie Veillard, MSc,†

Lesley Seymour, PhD,¶ Thierry Le Chevalier, MD,# Stephen Spiro, MD,** Richard Stephens,††Jean Pierre Pignon, MD, PhD,† and on behalf of the LACE Collaborative Group

Background: To evaluate the impact of adjuvant cisplatin-vinorelbinein completely resected non-small cell lung cancer and identify patientslikely to benefit from this regimen in the Lung Adjuvant CisplatinEvaluation (LACE) database. The overall LACE meta-analysis showedsurvival benefit with cisplatin-based adjuvant chemotherapy (5-yearsurvival benefit of 5.4%, hazard ratio �HR� 0.89, p � 0.004). Subgroupanalysis for the cisplatin-vinorelbine regimen was prespecified in theLACE statistical analysis plan. Patients randomized to cisplatin-vinorel-bine or observation were the largest subgroup (41%) and the mosthomogeneous in terms of drug doses and eligibility.Patients and Methods: The LACE-vinorelbine cohort included trialsevaluating cisplatin-vinorelbine versus observation. Overall survivalwas the primary end point. Other studies randomizing patients to otherchemotherapy or observation (LACE-other) were also evaluated.Results: The LACE-vinorelbine cohort included 1888 patients fromfour studies (Adjuvant Navelbine International Trialist Association, BigLung Trial, International Adjuvant Lung Cancer Trial, and National

Cancer Institute of Canada Clinical Trials Group JBR.10). Baselinecharacteristics were similar to the LACE-other but had fewer patientswith stage IA (2% versus 11%). Survival improvement at 5 years was8.9% with cisplatin-vinorelbine versus observation (HR 0.80, 95%confidence interval: 0.70–0.91, p �0.001). Stage was a significantpredictor for survival (test for trend, p � 0.02; benefit at 5 years: 14.7%�stage III�, 11.6% �stage II�, and 1.8% �stage I�). Similar benefits wereseen for disease-free survival (HR 0.75 �0.67–0.85, p �0.001�, stage III�HR 0.62, 0.50–0.76�, stage II �HR 0.69, 0.57–0.83�, and stage I �HR0.95, 0.76–1.19�). The overall result was statistically superior to LACE-other (LACE other HR 0.95, 0.86–1.05, interaction p � 0.04).Conclusion: In subgroup analyses, adjuvant cisplatin-vinorelbineprovides a superior survival benefit and can be recommended incompletely resected stages II and III non-small cell lung cancer.

Key Words: Non-small cell lung cancer, Adjuvant cisplatin-vi-norelbine, Meta-analysis.

(J Thorac Oncol. 2010;5: 220–228)

Lung cancer is the most frequent cause of cancer deathworldwide.1 Patients with completely resected stage I non-

small cell lung cancer (NSCLC) have a 5-year survival of�60%, whereas it falls to �10% for completely resected stageIII.2,3 The first meta-analysis published in 19954 showed anonsignificant 5% survival benefit at 5 years for patients receiv-ing cisplatin combinations (hazard ratio �HR� 0.87, p � 0.08). Inthe following years, doublet combinations of cisplatin with newagents improved survival in patients with metastatic disease, butonly one of these agents, vinorelbine, has been tested prospec-tively in combination with cisplatin in randomized adjuvanttrials. Several meta-analyses including newer cisplatin-basedregimens showed a small but consistent effect on survival.5–9

The more recent Lung Adjuvant Cisplatin Evaluation (LACE)10

is a meta-analysis based on individual patient data from the fivelargest adjuvant trials of cisplatin-based adjuvant chemotherapypublished after 1995.11–17 LACE showed a HR of 0.89 for death(95% confidence interval �CI�: 0.82–0.96, p � 0.004) corre-sponding to an absolute survival benefit of 5.4% at 5 years, inagreement with the 1995 meta-analysis.10

*Department of Medical Oncology, Centre R Gauducheau, St-Herblain; †Bio-statistics and Epidemiology Department, Institut Gustave Roussy, Paris;‡Department of Statistics, Institut de Recherche Pierre Fabre, Boulogne,France; §Department of Thoracic Oncology, Princess Margaret Hospital,Toronto, Canada; �Medical Oncology Department of Statistics, HospitalGermans Trias i Pujol, Barcelona, Spain; ¶Department of Biostatistics andEpidemiology, NCIC Clinical Trials Group, Queen’s University, Kingston,Ontario, Canada; #Department of Medicine, Institut Gustave-Roussy, Paris,France; **Department of Thoracic Medicine, The Middlesex Hospital; and††Cancer Division, MRC Clinical Trials Unit, London, United Kingdom.

Disclosure: F.A.S. was paid to speak on behalf of and consulted with PierreFabre Oncology and GlaxoSmithKline. L.S.’s employer received partialfunding from GlaxoSmithKline to support JBR10. R.S. received anhonorarium from Pierre Fabre Oncology to speak at a meeting. J.P.P.received unrestricted grants from Sanofi-Aventis and Pierre Fabre On-cology for this project.

Supplemental digital content is available for this article. Direct URL citationsappear in the printed text and are provided in the HTML and PDFversions of this article on the journal’s Web site (www.jto.org).

Address for correspondence: Jean-Yves Douillard, MD, PhD, Department ofMedical Oncology, Centre R. Gauducheau, Bd J. Monod, St. Herblain44805, France. E-mail: [email protected]

Copyright © 2010 by the International Association for the Study of LungCancerISSN: 1556-0864/10/0502-0220

Journal of Thoracic Oncology • Volume 5, Number 2, February 2010220

Patients randomized to cisplatin-vinorelbine or observa-tion constituted the largest subgroup (1888 of 4584 patients,41%) and the most homogeneous in terms of cisplatin dose. Aprospectively planned analysis of chemotherapy effect accord-ing to regimen in LACE revealed a statistical trend (interactionp � 0.11) for superiority of cisplatin-vinorelbine compared withthe other cisplatin-based doublets with vindesine, vinblastine, oretoposide and triplet combinations with mitomycin C, ifosf-amide, or vinblastine. Although not originally planned, theindirect comparison of cisplatin-vinorelbine to other combina-tions (pooled) demonstrated a significant interaction (i.e., varia-tion of the effect of chemotherapy compared with no treatmentaccording to the type of chemotherapy, p � 0.04) in favor ofcisplatin-vinorelbine. We report here the results of these sub-group analyses.

PATIENTS AND METHODS

Inclusion and Exclusion CriteriaThe LACE meta-analysis has been described previously.10

Briefly, eligible trials (a) were randomized trials performed afterthe NSCLC meta-analysis published in 1995, (b) included onlypatients with completely resected NSCLC, and (c) comparedcisplatin-based chemotherapy versus no chemotherapy. Trialswere excluded if they (a) used concomitant radiochemotherapyor preoperative chemotherapy; (b) included incompletely re-sected patients; and (c) were included in the 1995 NSCLCmeta-analysis. LACE prospectively planned evaluation of treat-ment effect according to types of chemotherapy received (cis-platin-vinorelbine, other cisplatin-based doublets, or triplets).

Trials included in LACE comparing cisplatin-vinorelbinewith observation were included in the LACE-vinorelbine cohortand included Adjuvant Navelbine International Trialist Associ-ation (ANITA), Big Lung Trial (BLT), International AdjuvantLung Cancer Trial (IALT), and JBR.10. All other trials or stratawithin trials were pooled into a “LACE-other” subgroup andwere compared with the LACE-vinorelbine subgroup.

AnalysesFor LACE-vinorelbine, the primary objective was overall

survival. Secondary objectives were (a) interaction betweenpredefined baseline covariates and the effect of cisplatin-vinorel-bine; (b) cause-specific mortality; (c) disease-free survival(DFS); and (d) chemotherapy-related severe toxicity. Each trialwas analyzed individually, and all data were pooled for theoverall analysis. In addition, the results for LACE-vinorelbinewere compared with those for the LACE-other subgroup.

PopulationAll patients, including ineligible patients, were analyzed

in the group to which they were randomized, independent of thechemotherapy actually received (intent-to-treat analysis).

Data ChecksAs described previously,10 individual patient data were

retrieved for each study. Systematic data checking and reanaly-sis were performed by the meta-analysis team at Institut GustaveRoussy.

Statistical AnalysesTimes to events were measured from the date of random-

ization. Survival was the time until death of any cause or lastknown alive date. DFS was the time until first recurrence ordeath of any cause or last disease evaluation date. Secondcancers were not considered as an event, and follow-up was notcensored after a second cancer. Median follow-up was computedusing the reverse Kaplan-Meier method.18

Survival and DFS per treatment group were estimatedusing Peto curves19 and their comparison summarized by HRsstratified by trial with their 95% CIs. The analysis of survivalwas based on a log-rank test stratified by trial. Chi-square testswere used to study heterogeneity among trials and groups. I2

statistic was also used.20 Test of heterogeneity used to comparethe HR of groups of trials is also called test for interaction.Cause-specific mortality (lung cancer, �death from other causeafter a lung cancer recurrence and death from unknown cause�versus nonlung cancer)10 was described by treatment arm andcompared using the log-rank test stratified by trial. As proposedby Peto,21 data were censored at the first recurrence for nonlungcancer mortality. The log-rank statistic for nonlung cancer mor-tality was subtracted from the log-rank statistic for mortalityfrom all causes to obtain the log-rank statistic of lung cancermortality.21 Variations in treatment effect were described usingforest plots of HRs. Multivariate Cox regression analysis wasperformed to estimate chemotherapy effect adjusted for pre-specified factors of age, type of surgery, histology, and stage.

Treatment Compliance and ToxicityThe actual doses of cisplatin and vinorelbine (available for

ANITA, JBR.10, and BLT) and time between surgery and startof chemotherapy were described. Grade 3, 4, or 5 toxicity wascollected in all trials except IALT, which collected only grades4 and 5 toxicity. Toxicities were not available from the BLTtrial.

LACE OrganizationA Steering Committee for LACE was constituted with

one clinician and one statistician from each trial, together withthe two statisticians from the data center in charge of the pooledanalysis (see Appendix). This committee validated the statisticalanalysis plan, selected the data to be included in the publication,and contributed to the writing of the manuscript. All analyseswere performed at the Institut Gustave-Roussy.

Role of the Funding SourceThe sponsors of the LACE meta-analyses and these

subgroup analyses had no role in the study design, datacollection, data analysis, data interpretation, or the writingof the report. The corresponding author had full access toall data in the study and had final responsibility for thedecision to submit for publication.

RESULTSFour studies from LACE were eligible for the LACE-

vinorelbine subgroup analyses with a total of 1888 patients(Tables 1 and 2). Two studies evaluated the cisplatin-vinorel-bine combination exclusively (ANITA and JBR.10). In theother two (IALT and BLT), the investigator could chooseamong several regimens; each center used only one regimen,

Journal of Thoracic Oncology • Volume 5, Number 2, February 2010 Adjuvant Cisplatin and Vinorelbine

Copyright © 2010 by the International Association for the Study of Lung Cancer 221

and patients were randomized by center. Median follow-upwas 5.2 years. The LACE-other subgroup consisted of 2696patients of whom 1347 received nonvinorelbine but cisplatin-based chemotherapy (Tables 1 and 2).

Patients aged �70 years were slightly more common inLACE-vinorelbine (10% versus 8%), and stage IA were morenumerous in LACE-other (11%) than in LACE-vinorelbine(2%). In both subgroups approximately two thirds of patients

TABLE 1. Overview of Studies Included in the LACE-Vinorelbine and LACE-Other Subgroups

No. of Patients Evaluated and Follow-Up

LACE, N

LACE-Vinorelbine LACE-Other

NRandomized to

Cisplatin Vinorelbine Follow-Upa (yr) NRandomized to

Other Chemotherapy Follow-Upa (yr)

ANITA 840 840 407 5.9 0 0 —

IALT 1867 500 248 4.1 1367 684 4.9

JBR.10 482 482 242 5.2 0 0 —

BLT 307 66 37 4.9 241 115 5.2

ALPI 1088 0 0 — 1088 548 5.4

Total 4584 1888 934 5.2 2696 1347 5.2

a Median.LACE, Lung Adjuvant Cisplatin Evaluation; ANITA, Adjuvant Navelbine International Trialists Association; IALT, International Adjuvant Lung Trial; BLT, Big Lung Trial.

TABLE 2. Patients Characteristics (%)

Characteristics


Chemotherapy(N � 934)

Observation(N � 954)



Age (yr)

Median 59 59 60 61

Range 27–81 18–77 27–83 30–79

Sex (%)

Male 79 80 81 81

Female 21 20 19 19

Unknown �1 �1 0 0

Pathological TNM stage (%)

IA 3 2 12 11

IB 34 33 26 28

II 37 39 33 33

III 26 26 29 28

Unknown 0 0 �1 �1

Type of surgery (%)

Pneumonectomy 33 31 27 28

Lobectomy/other 62 65 64 63

Unknown 4 3 9 9

Performance status (%)

0 49 50 31 31

1 47 47 23 24

2 3 2 5 5

Unknown 1 1 41 40

Histologic type (%)

Squamous cell 48 49 49 48

Adenocarcinoma 42 41 39 38

Other 10 10 12 14

Area of the world (%)

Europe 68 68 91 91

North America 26 26 1 1

Other 6 6 8 8

LACE, Lung Adjuvant Cisplatin Evaluation; TNM, tumor, node, metastasis.

Douillard et al. Journal of Thoracic Oncology • Volume 5, Number 2, February 2010

Copyright © 2010 by the International Association for the Study of Lung Cancer222

presented with stages II and III. No firm conclusions can bedrawn regarding the distribution of performance status amongsubgroups because the data were missing for approximately40% of patients in LACE-other. The majority of patients inLACE were evaluated in Europe, and most patients from NorthAmerica were in the LACE-vinorelbine subgroup (26% versus1% in LACE-other) as corresponding mostly to the JBR.10

study. Other baseline variables were similarly distributed be-tween LACE-vinorelbine and LACE-other.

Effect of Cisplatin-Vinorelbine on SurvivalFor the LACE-vinorelbine subgroup, 45.3% of cisplatin-

vinorelbine patients had died (versus 53.7% observation) with amedian follow-up of 5.2 years. Patients randomized to adjuvant

FIGURE 1. A, Forest plot of hazard ratios of overall survival and disease-free survival with cisplatin-vinorelbine versus observa-tion (control). B, Forest plot of hazard ratios of overall survival and disease-free survival with cisplatin-vinorelbine versus obser-vation (control) according to stage.



cisplatin-vinorelbine had a 20% reduction in the risk of death(HR 0.80, 95% CI: 0.70–0.91, p �0.001). The test of hetero-geneity among trials was not significant (p � 0.52) (Figure 1A).The absolute benefit was 6.8% at 3 years (64.3% versus 57.5%)and 8.9% at 5 years (55.1% versus 46.2%) (Figure 2A). In themultivariate Cox model chemotherapy (HR 0.76), squamoushistology (HR 0.69), pneumonectomy (HR 1.33), age (51–60years, HR 1.26, 61–69, HR 1.40, �70, HR 1.90), and stage(stage II, HR 1.72; stage III, HR 2.61) were significant prognos-tic factors. Sex showed a trend for better survival in females(p � 0.07; see Web Table 1, Supplemental Digital Content 1,http://links.lww.com/JTO/A13). There was a significant interac-tion of cisplatin-vinorelbine effect and stage (test for trend p �0.02) (Figure 1B): patients with stage I had no benefit fromchemotherapy (�1.2% at 3 years and �1.8% at 5 years),whereas the effect was significant for stage II (�10.5% at 3

years and �11.6% at 5 years) and stage III (�11.5% at 3 yearsand �14.7% at 5 years) (Figure 3).

The effect on survival was significantly higher (test ofinteraction p � 0.04) in LACE-vinorelbine (HR 0.80, mentionedabove) compared with LACE-other (HR 0.95, 95% CI: 0.86–1.05, p � 0.33). There was no significant interaction with stagein LACE-other. In LACE-vinorelbine, no significant interactionwas observed between chemotherapy and covariates of sex,performance status, age, histology, type of surgery, and plannedradiotherapy, and chemotherapy effect was not different withplanned doses of cisplatin or vinorelbine.

Effect of Cisplatin-Vinorelbine on DFSA significant difference in DFS was observed for pa-

tients receiving cisplatin-vinorelbine with a HR 0.75 (CI:0.67–0.85, p � 0.001) (Figure 1A). The absolute benefit at 3years was 10.0% and at 5 years 9.2%. A clear relationbetween chemotherapy effect and stage was also observed onDFS for LACE-vinorelbine, the effect was significant forstage II: HR 0.69 (CI: 0.57–0.83) and for stage III: HR 0.62(CI: 0.50–0.76) but not for stage I: HR 0.95 (CI: 0.76–1.19),test for trend, p � 0.008 (Figure 1B).

The effect on DFS was significantly higher (test forinteraction p � 0.02) in LACE-vinorelbine compared withLACE-other (HR 0.90 �0.82–0.99], p � 0.04). For LACE-other, the benefit at 5 years was 3.8%. No interaction withstage was demonstrated (data not shown).

Effect of Cisplatin-Vinorelbine on Complianceand Toxicity

In the cisplatin-vinorelbine subgroup, 7% of patientsdid not receive chemotherapy and 0.6% of patients in theobservation group did. The majority of patients were plannedto receive a total cisplatin dose �400 mg/m2 (Table 3). Themedian dose delivered was 303 mg/m2 for cisplatin and 236mg/m2 for vinorelbine, and the median relative dose intensi-ties were 95% and 69%, respectively. There were 371 pa-tients (43%) who did not complete chemotherapy because of

FIGURE 2. A, Survival curves for the cisplatin-vinorelbineand the observation (no chemotherapy) groups. Absolutebenefit (�1 standard deviation). B, Lung cancer-specific andnonlung cancer-related survival for the cisplatin-vinorelbineand the observation (no chemotherapy) groups.

FIGURE 3. Overall survival curves by stage for the cisplatin-vinorelbine versus the observation (no chemotherapy)groups.



patient refusal (42%), toxicity (30%), or unknown reasons(10%). The median time between surgery and initiation ofchemotherapy was 41 days with 6% of patients initiatingchemotherapy more than 2 months after surgery. Twentypercent of patients in ANITA, 17% in JBR.10, 11% in IALT,and 41% in BLT received only one cycle of chemotherapy.

For LACE-other, 9% of patients randomized to chemo-therapy did not receive it, whereas 2% randomized to obser-vation did. Planned doses of cisplatin were lower than for theLACE-vinorelbine subgroup (Table 3).

The incidence of grade �3 toxicity was collected intwo of the trials in LACE-vinorelbine (ANITA andJBR.10), whereas only grades 4 and 5 toxicity were inIALT. ALPI (LACE-other) collected only toxicity � grade3. No data were available for BLT. Neutropenia � grade 4was observed in 55% in LACE-vinorelbine and 10% ofpatients in LACE-other, but life threatening or fatal febrileneutropenia (� grade 4) was 0 in LACE-vinorelbine and�1% in LACE-other. There was no difference in periph-eral neurotoxicity grade �3. Overall, grades 4 � 5 toxic-ities were more frequent in LACE-vinorelbine (59% versus16% in LACE-other, Table 4).

Effect of Cisplatin-Vinorelbine on Cancer-Related and Noncancer-Related Deaths

As shown in Table 5, there were 13 (1.4%) reporteddrug-related deaths in the cisplatin-vinorelbine arm, mainlybecause of septic shock. The drug-related death rate forLACE-other was 0.4.

When considering the overall follow-up period, in theLACE-vinorelbine subgroup, noncancer-related death wasnot significantly different between the two arms (HR 1.31,�0.91–1.88� p � 0.15), whereas there was a highly statisti-cally significant difference in lung cancer-specific death (HR0.74 �0.65–0.85�, p �0.001) (Figure 2B). For LACE-other,there was a significant increase (p � 0.01) in nonlung cancerdeaths (HR 1.40 �1.08–1.82�).

A significant interaction over time was observed bothfor LACE-vinorelbine (p � 0.002) and LACE-other (p �TA

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TABLE 4. Incidence of Grades 3, 4, and 5 Toxicity andTherapy-Related Deaths in LACE Other and LACE-Vinorelbine

Toxicity

Vinorelbine Other

Grades3–5 (%)a

Grades4–5 (%)b

Grades3–5 (%)a

Grades4–5 (%)b

N 599 837 460 1077

Neutropenia 80 55 27 10

Febrile neutropenia 9 0 2 0

Thrombocytopenia 3 1 5 2

Neuropathy 3 0 3 0

Renal impairment 1 0 2 0

Nausea and vomiting 20 3 16 3

Infection 8 2 0 0

Constipation 4 1 1 0

a All studies except BLT and IALT.b All studies except BLT.IALT, International Adjuvant Lung Trial; BLT, Big Lung Trial.



0.03) with a significant increase of nonlung cancer death inthe first 6 months in both groups: 2.92 (1.54–5.51, p �0.001)for LACE-vinorelbine (29 versus 9 deaths) and 2.17 (1.33–3.53, p � 0.002) for LACE-other (45 versus 20 deaths). InLACE-vinorelbine, among the 29 early nonlung cancerdeaths observed in the cisplatin-vinorelbine arm, 13 (45%)were drug related and 12 (41%) related to cardiovascular orpulmonary disease. There were six cardiovascular or pulmo-nary deaths in the observation arm of nine early deaths. InLACE-other, there were six (13%) drug-related deaths and 28(62%) cardiovascular or pulmonary deaths among the 45early deaths in the chemotherapy arm. In the correspondingobservation arm, there were 15 cardiovascular or pulmonarydeaths of 20 early deaths.

Use of Adjuvant Postoperative RadiationTherapy

The impact of postoperative radiation therapy(PORT) was not assessable in either the LACE-vinorelbineor the LACE-other analysis, because the use and regimensof PORT varied among trials and was not mandatory orrandomized. PORT was planned for a similar percentage ofpatients in LACE-vinorelbine and LACE-other: 33% and31% for the observation groups and 30% and 32% in thechemotherapy groups, respectively.

DISCUSSIONWe have evaluated the effect of cisplatin-vinorelbine

on survival in patients with completely resected stages I toIII NSCLC within the LACE database. Baseline charac-teristics of the patients in the trials evaluating this combi-nation were similar to those included in the other LACEtrials, except for a slightly lower incidence of stage IA anda predominance of patients from North America.

Survival of patients receiving cisplatin-vinorelbinewas statistically superior to observation (absolute benefit8.9% at 5 years) and was also statistically superior to thebenefit observed in LACE-other (overall test for interac-tion p � 004). Baseline characteristics were similar andcould not account for these results. In LACE-vinorelbine,stage was a strong predictor. Patients with stage IIIAbenefited the most, closely followed by patients with stageII. Too few patients with stage IA were treated withcisplatin-vinorelbine to make a definitive interpretation,

whereas in stage IB (approximately 34% of the totalgroup), cisplatin-vinorelbine did not affect outcomes,when compared with observation. In LACE-other, therewas no variation of treatment effect with stage, although asignificant effect was observed in stage IB for DFS (HR0.75, 95% CI: 0.60 – 0.93) and a borderline effect forsurvival (HR 0.81, 95% CI: 0.64 –1.02). These results arein agreement with the Cancer and Leukemia Group B 9633trial using paclitaxel-carboplatin in stage IB showing asignificant benefit on failure-free survival but no signifi-cant difference on overall survival.22 However, in theupdated NSCLC meta-analysis of 30 trials and 8147 pa-tients, no interaction with stage was observed.23 Thus, theabsence of an effect of chemotherapy in stage I withcisplatin-vinorelbine reported here should be interpretedwith caution.

Although the planned cisplatin dose was higher inLACE-vinorelbine than LACE-other, the median dose ofcisplatin delivered in LACE-vinorelbine was lower than in-tended and close to the median dose delivered with othercisplatin doublets but higher than that delivered with cisplatintriplets in LACE.10

Toxicity observed with the cisplatin-vinorelbine regi-men was as expected for the combination, and was higher inLACE-vinorelbine than in LACE-other, in particular forgrade 4 neutropenia (80% grade �3). The incidence of febrileneutropenia grade 4 was similar in LACE-vinorelbine andLACE-other. Overall reported grade �3 toxicity was ob-served in 90% of patients receiving cisplatin-vinorelbineversus 49% in LACE-other. There seemed to be a smallincrease in chemotherapy-related deaths in LACE-vinorel-bine compared with LACE-other (1.4% versus 0.4%). Itshould be noted that these data are difficult to interpretbecause ANITA and JBR.10 collected laboratory and toxicitydata in a more rigorous fashion than other trials. A quantifi-cation of differences in tolerability between cisplatin-vinorel-bine and other regimens evaluated in LACE was not anobjective of the meta-analysis and cannot be addressed ade-quately. However, in the IALT study, vinorelbine was asso-ciated with a higher grades 4 to 5 toxicity rate than otherassociated drugs with an odds ratio adjusted on region of theworld and received dose of cisplatin at first cycle of 2.5(1.7–3.7) for vinorelbine versus other (A. Dunant et al.,personal communication).

TABLE 5. Causes of Death

Cause of Death






Total no. of deathsa 423 (45.3) 512 (53.7) 713 (52.9) 742 (55.0)

No. of lung cancer deaths (%)b 354 (83.7) 464 (90.6) 579 (81.2) 651 (87.7)

No. of nonlung cancer deaths (%)b 69 (16.3) 48 (9.4) 134 (18.8) 91 (12.3)

No. of drug- related deaths (%)c 13 (1.4) 6 (0.4)

a Percentage of the total number of patient randomized in the corresponding arm.b Percentage of the total number of deaths in the corresponding arm.c Included in the nonlung cancer deaths.LACE, lung adjuvant cisplatin evaluation.



The excess of early nonlung cancer deaths described inLACE10 was found in both LACE-vinorelbine and LACE-other. Possible explanations for this unexpected effect havebeen discussed previously and were mainly related to che-motherapy toxicity and lethal cardiopulmonary events.10

Addition of PORT to adjuvant chemotherapy withcisplatin-vinorelbine could not be assessed. A descriptiveanalysis in the ANITA trial suggested a possible benefit inpatients with N2 disease, whereas patients with N1 diseaseexperienced a potential detrimental effect.24 The role ofPORT in N2 disease is presently being evaluated in therandomized Lung Adjuvant Radiation Therapy trial.

Cisplatin-vinorelbine is the only third generation drug incombination with cisplatin tested so far to demonstrate a signif-icant survival benefit with a reduction in the risk of death of 20%

versus observation, despite an increase in toxicity. Indirectcomparison with other cisplatin-based combinations (3–8% re-duction) is in favor of cisplatin-vinorelbine. Based on theseresults, the evidence supports the selection of cisplatin-vinorel-bine as the adjuvant chemotherapy of choice for patients withcompletely resected stages II and IIIA.

ACKNOWLEDGMENTSSupported by Institut Gustave-Roussy, Programme

Hospitalier de Recherche Clinique, Ligue Nationale Contrele Cancer, Sanofi-Aventis (unrestricted grants), and PierreFabre Oncology (unrestricted grants). The contribution ofNCIC CTG is supported by the Canadian Cancer Society.JBR.10 was an Intergroup study, led by NCIC CTG and towhich CALGB, NCCTG, and SWOG contributed.

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APPENDIX. Members of the Steering Committee

Trials Clinician Statistician

ANITA Jean-Yves Douillard, Department of MedicalOncology, Centre R Gauducheau, Nantes

Patricia HIS, Institut de Recherche Pierre Fabre Boulogne,France

IALT Thierry Le Chevalier, Department of Medicine,Institut Gustave-Roussy, Paris

Jean-Pierre Pignon, Biostatistics and EpidemiologyDepartment, Institut Gustave-Roussy, Paris

JBR.10 Frances Shepherd, Princess Margaret Hospital,Toronto

Keyue Ding, NCIC Clinical Trials Group, Queen’sUniversity, Kingston

BLT Stephen Spiro, Department of Thoracic Medicine,The Middlesex Hospital, London

Richard Stephens, Cancer Division, MRC Clinical trialsUnit, London

LACE Secretariat Hélène Tribodet, Biostatistics and EpidemiologyDepartment, Institut Gustave-Roussy, Paris



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22. Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant paclitaxel pluscarboplatin compared with observation in stage IB non-small-cell lungcancer: CALGB 9633 with the Cancer and Leukemia Group B, Radia-tion Therapy Oncology Group, and North Central Cancer TreatmentGroup Study Groups. J Clin Oncol 2008;26:5043–5051.

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