Crinò, L

De Marinis, F

Gridelli, C

Liepa, Am

Peterson, P

Ricci, S

Rinaldi, Mauro

Scagliotti, Giorgio Vittorio

Tonato, M.

Zhao, Yd

English

Institutional Research Information System University of Turin

BRIEF REPORTThe Role of Histology with Common First-line Regimens forAdvanced Non-small Cell Lung CancerA Brief Report of the Retrospective Analysis of a Three-armRandomized TrialGiorgio V. Scagliotti, MD,* Filippo De Marinis, MD,† Massimo Rinaldi, MD,‡ Lucio Crino`, MD,§Cesare Gridelli, MD, Sergio Ricci, MD,¶ Yan D. Zhao, PhD,# Astra M. Liepa, PharmD,#Patrick Peterson, PhD,# and Maurizio Tonato, MD**Introduction: Although histology has not consistently been associ-ated with treatment outcome in advanced non-small cell lung cancer,a recent phase III trial comparing pemetrexed plus cisplatin andgemcitabine plus cisplatin (GC) demonstrated better efficacy forpemetrexed plus cisplatin in nonsquamous (adenocarcinoma andlarge cell carcinoma) carcinoma than in squamous cell carcinoma.Herein, retrospective analysis is used to explore the potential pre-dictive and prognostic role of non-small cell lung cancer histology inpatients treated with three first-line, platinum-based regimens.Methods: Survival and time to progression (TTP) data from a phaseIII trial comparing paclitaxel plus carboplatin (PCb), GC, andvinorelbine plus cisplatin (VC) were analyzed. Using Cox multipleregression, factors for one model included treatment (PCb, GC, andVC), histology (squamous, adenocarcinoma, large cell, and other),gender, Eastern Cooperative Oncology Group performance status(0/1 and 2), stage (IIIB and IV), number of metastatic sites (1 and1), and smoking history (yes or no). In another model, histologywas simply considered as squamous versus nonsquamous. An inter-action value of p  0.10 was considered significant.Results: Baseline patient and disease characteristics for the 607treated patients were balanced among the arms. No significanttreatment-by-histology interaction was seen in either model foreither end point. Nevertheless, histology was a significant prognosticfactor for survival in the first model (p  0.0183) and marginallysignificant for TTP (p  0.0783). Subsequent pairwise comparisonsof histology groups demonstrated a survival advantage for squamouscell carcinoma over adenocarcinoma (p  0.0021).Conclusions: Histology was not predictive of PCb, GC, or VC treat-ment effect for either survival or TTP. Histology was prognostic forsurvival, with better outcomes associated with squamous cell carci-noma.Key Words: Predictive factor, Prognostic factor, Histology, Non-small cell lung cancer.(J Thorac Oncol. 2009;4: 1568–1571)Tumor histology has not consistently been identified as aprognostic factor in patients with advanced non-small celllung cancer (NSCLC).1–3 Nevertheless, a preplanned subsetanalysis by histology in a recent, large, phase III studyshowed longer survival for pemetrexed plus cisplatin thangemcitabine plus cisplatin (GC) in patients with nonsqua-mous NSCLC histology, whereas patients with squamous cellcarcinoma had shorter survival with pemetrexed/cisplatincompared with GC.4 Similarly, phase II and III studiesshowed that patients with nonsquamous NSCLC experiencebetter efficacy with pemetrexed-containing regimens.5–8These findings indicate that histology is a predictive factor forefficacy outcomes of pemetrexed-containing regimens in pa-tients with advanced NSCLC.Because histology has been associated with efficacy forpemetrexed-containing regimens, the question remainswhether histology is predictive of outcomes for other cyto-toxic regimens. This retrospective analysis explored the po-tential predictive and prognostic role of histology in a phaseIII study comparing three first-line, platinum-based regimens*Department of Clinical and Biological Sciences, University of Torino, Orbas-sano, Italy; †Pulmonary-Oncological Unit 1st San Camillo Hospital, Rome,Italy; ‡Oncologia Medica B, Instituto Nazionale Tumori Regina Elena,Rome, Italy; §Medical Oncology, Silvestrini Hospital, Perugia, Italy; Divi-sion of Medical Oncology, SGMoscati Hospital, Avellino, Italy; ¶OncologyDepartment, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; #EliLilly and Company, Indianapolis, Indiana; and **Regional Cancer Center,Perugia, Italy.Disclosure: G. Scagliotti served as an adviser to Eli Lilly and Company. Hereceived honoraria from Astra Zeneca, Eli Lilly and Company, GlaxoSmithkline, Millenium, Roche, and Sanofi Aventis. C. Griddeli served asa consultant and advisor to Eli Lilly and Company and has receivedhonoraria from Eli Lilly and Company. F. de Marinis, M. Rinaldi, L.Crinò, S. Ricci, and M. Tonato have no relevant disclosures. A. Liepa, Y.Zhao, and P. Peterson are employees of Eli Lilly and Company, and assuch, hold stock in Lilly.Address for correspondence: Giorgio Scagliotti, MD, Department of Clinicaland Biological Sciences, University of Torino, S. Luigi Hospital, Re-gione Gonzole, 10, Orbassano (Torino), Italy 10043. E-mail: giorgio.scagliotti@unito.itThe analysis presented here has been previously disclosed at the ChicagoMultidisciplinary Symposium in Thoracic Oncology, Chicago, IL, No-vember 13–15, 2008.Copyright © 2009 by the International Association for the Study of LungCancerISSN: 1556-0864/09/0412-1568Journal of Thoracic Oncology • Volume 4, Number 12, December 20091568for advanced NSCLC: GC, paclitaxel plus carboplatin (PCb),and vinorelbine plus cisplatin (VC).9METHODSPatientsThis retrospective analysis was conducted using thepatient database of a previously published study9 in whichpatients were considered eligible according to the followingcriteria: chemonaive, histologically or cytologically con-firmed stage IIIB (wet or dry) or stage IV NSCLC, 1measurable lesion (World Health Organization criteria), anEastern Cooperative Oncology Group performance status(PS) of 0 to 2, and adequate organ function. Study design andtreatment schema were previously published. Patients re-ceived up to six cycles of gemcitabine 1250 mg/m2 on days1 and 8 plus cisplatin 75 mg/m2 on day 2 of a 21-day cycle(GC); paclitaxel 225 mg/m2 plus carboplatin AUC 6 mg/ml/min, both on day 1 every 21 days (PCb); or vinorelbine 25mg/m2 on days 1, 8, 15, and 22 plus cisplatin 100 mg/m2 onday 1 every 28 days (VC).Statistical MethodsThis retrospective analysis incorporated all randomizedpatients who received treatment. Cox-adjusted analyses of over-all survival (OS) (measured from randomization to death) andtime to progression (TTP) (measured from randomization todisease progression or death) were used to determine the effectsof the following factors: treatment (PCb, GC, and VC), gender,Eastern Cooperative Oncology Group PS (0/1 and 2), diseasestage (IIIB and IV), number of metastatic sites (1 and 1),smoking history (yes or no), and histology (model 1: squamouscarcinoma, adenocarcinoma, large cell carcinoma, or other;model 2: squamous or nonsquamous). Median survival wasestimated using the Kaplan-Meier method.10 Predictive associ-ations were concluded if there was a significant (p  0.10)treatment-by-characteristic interaction within the regressionmodels. Prognostic associations were determined if there was asignificant (p  0.05) characteristic main effect within theregression models. Pairwise comparisons were performed usingCox-adjusted analysis.RESULTSA total of 612 patients entered the study betweenAugust 1998 and May 2000 and were randomized; 607 weretreated (205 GC, 201 PCb, and 201 VC). Baseline character-istics were well balanced among treatment arms (Table 1).When the baseline characteristics were examined by histol-ogy, independent of treatment received, each characteristicvaried slightly with the exception of disease stage. For ex-ample, patients with squamous cell carcinoma were morelikely (approximately 10%) to be male, have PS of 0/1, not tohave multiple metastatic sites, and have a history of smoking(data not shown). Analyses of efficacy endpoints (adjustedand unadjusted) showed no significant differences betweentreatment arms.9Using Cox multiple regression analysis of OS and TTP,the potential predictive and prognostic role of histology wasexamined using two histology models (Table 2). No signifi-cant treatment-by-histology interaction was seen in eithermodel for either end point (Table 2, column 4, all values p 0.10), confirming that histology was not predictive of efficacyoutcomes for any of the three regimens. Considering thetreatment effect (Table 2, column 2), neither model showedany significant differences between treatments. In model 1,histology was a significant prognostic factor for OS (p 0.0183) and was marginally significant for TTP (p  0.0783)(Table 2, column 3). Nevertheless, model 2 did not identifyhistology as a prognostic factor. Additional Cox regressionanalyses identified gender, PS, number of metastatic sites,and smoking history as significant prognostic factors for OS(p  0.05) in both models; the same factors, except gender,were also significant for TTP (p  0.05).After histology was identified as a significant prognos-tic factor using model 1 (p 0.018), pairwise comparisons ofhistologic groups for survival were performed (Table 3). Thecomparisons revealed a statistically significant survival ad-TABLE 1. Baseline Patient and Disease CharacteristicsCharacteristicsPercentage of PatientsGC(N  205)PCb(N  201)VC(N  201)Male 81 76 78ECOG performancestatus 0 or 195 92 92Stage IV disease 81 82 81HistologyAdenocarcinoma 50 48 55Squamous cellcarcinoma33 32 27Large cell carcinoma 6 10 6NSCLC not otherwisespecified (NOS)/other11 10 111 Metastatic sitea 26 28 33Smoking history 80 77 82a N  167 for GC, 164 for PCb, and 163 for VC.ECOG, Eastern Cooperative Oncology Group; GC, gemcitabine/cisplatin; NSCLC,non-small cell lung cancer; PCb, paclitaxel/carboplatin; VC, vinorelbine/cisplatin.TABLE 2. Cox Regression Results (p)aTreatment HistologyTreatment-by-HistologyInteractionModel 1 (four histologicgroupsb)Survival 0.6302 0.0183 0.2326TTP 0.2629 0.0783 0.3397Model 2 (nonsquamous vs.squamous)Survival 0.6089 0.1005 0.5235TTP 0.2590 0.7196 0.1674a Bold p is significant.b The four histologic groups in model 1 were squamous cell carcinoma, adenocar-cinoma, large cell carcinoma, or other.Nonsquamous, all non-small cell lung cancer histologic types except squamous cellcarcinoma; squamous, squamous cell carcinoma; TTP, time to progression.Journal of Thoracic Oncology • Volume 4, Number 12, December 2009 Role of Histology with Common First-Line RegimensCopyright © 2009 by the International Association for the Study of Lung Cancer 1569vantage for squamous cell carcinoma over adenocarcinoma(p  0.0021). To a lesser extent, “other” histology wasassociated with longer survival than adenocarcinoma. Otherpairwise comparisons were not significant. Survival by his-tology was plotted for the combined treatment arms to illus-trate these findings (Figure 1).DISCUSSIONThis retrospective analysis of the phase III trial9 did notidentify any significant difference in the efficacy of threecytotoxic chemotherapy regimens according to histology.Among common cytotoxic therapies for advanced NSCLC,histology may only be a predictive factor of efficacy forpemetrexed-containing regimens. Although a mechanistic un-derstanding of this phenomenon is not entirely clear, thedifferential expression of thymidylate synthase in adenocar-cinoma and squamous cell carcinoma11 might contribute tothe differential efficacy of pemetrexed by histology. As anagent that inhibits thymidylate synthase and other enzymesinvolved in purine and pyrimidine synthesis,12 pemetrexedwould be less efficacious when these targeted, folate-depen-dent enzymes are highly expressed,13 as they are in squamouscell carcinoma.This analysis also investigated a potential prognosticrole for histology in advanced NSCLC. Histology was foundto be prognostic for survival, with better outcomes associatedwith squamous cell carcinoma and poorer outcomes withadenocarcinoma. Although previous studies have also sug-gested a prognostic role for histology, this has not beenconsistently reported.3 As summarized by other authors,3among studies which tested chemotherapy in advancedNSCLC and identified a possible prognostic role for histol-ogy, approximately half concluded that squamous cell carci-noma (or nonadenocarcinoma) was associated with betteroutcomes, and half concluded that adenocarcinoma ornonsquamous histology was associated with better out-comes.3 These different outcomes may well have to do withdifferences in subsequent lines of therapy, including the useof epidermal growth factor receptor (EGFR) tyrosine kinaseinhibitors that have been shown to improve the survival ofpatients with EGFR mutations, which are usually seen inpatients with adenocarcinoma.14 Nevertheless, EGFR-inhibi-tors would not have impacted the study results presented hereas they were not in general use during the years these datawere collected (1998–2000).In this analysis, histology was identified as a prognosticfactor only when analyzed as four separate groups (model 1)but not when analyzed as two groups (model 2). This under-scores the need to use multiple models when investigatingthese associations. Differential outcomes were confined to thetwo most distinct histologic groups, with squamous cellcarcinoma performing significantly better than adenocarci-noma. When adenocarcinoma was analyzed in combinationwith large cell carcinoma and other histologic groups (col-lectively referred to as nonsquamous), the separation ofadenocarcinoma and squamous was less pronounced. Al-though combining histologic groups is often necessary andappropriate, initial analysis using separate histologic groupsmay yield additional insight.Interpretation of the presented results must acknowl-edge the limitations of this analysis, including the limitedsample size, especially in the large cell and “other” histologicgroups; a study population derived from a single country (allItalian study sites); and data derived from a study thatFIGURE 1. Kaplan-Meier plot of overall survival by histol-ogy for combined treatment arms.TABLE 3. Pairwise Comparisons of NSCLC Histologic Groups for Survival: Hazard Ratiosaand pbSquamous(n  187)Adenocarcinoma(n  310)Large cell(n  54)Other(n  65)Squamous — 0.0021 0.1607 0.9724Adenocarcinoma 1.42 (1.14–1.78) — 0.6953 0.0239Large cell 1.32 (0.89–1.96) 0.93 (0.64–1.34) — 0.2090Other 0.99 (0.71–1.39) 0.70 (0.51–0.95) 0.75 (0.48–1.17) —a Hazard ratios with 95% confidence intervals (in parentheses) are provided in the lower left data grouping. Reference histologic group incolumn heading; hazard ratios 1 indicate lower risk of death in histologic group in the column heading.b Comparison p are provided in the upper right data grouping. Bold p are significant.Large cell, large cell carcinoma; NSCLC, non-small cell lung cancer; squamous, squamous cell carcinoma.Scagliotti et al. Journal of Thoracic Oncology • Volume 4, Number 12, December 2009Copyright © 2009 by the International Association for the Study of Lung Cancer1570enrolled patients a decade ago. Regarding the latter point,evidence suggests that advanced NSCLC presentation andresponsiveness have been affected over time by multiplefactors. For example, changes in cigarette composition anddesign over the last few decades are thought to have influ-enced NSCLC histologic distribution.15 Additionally, the def-initions of NSCLC histologic categories have been refined inthe last several years, potentially altering the composition ofsome categories of NSCLC histologic types.3In conclusion, this retrospective analysis identified aprognostic role for histology in advanced NSCLC, with betteroutcomes associated with squamous cell carcinoma; how-ever, histology did not predict differential efficacy for PCb,GC, or VC. Evidence presented here and in other recentreports5–8 suggests that studies should continue to investigatehistology and its possible association with efficacy outcomesin patients with advanced NSCLC.ACKNOWLEDGMENTSSupported by Eli Lilly and Company, Indianapolis, IN.The authors thank Mary Dugan Wood, who provided medicalwriting services on behalf of Eli Lilly and Company, andNoelle Gasco, employed by Eli Lilly and Company, forassistance with manuscript preparation.REFERENCES1. Stanley KE. Prognostic factors for survival in patients with inoperablelung cancer. J Natl Cancer Inst 1980;65:25–32.2. Pfister DG, Johnson DH, Azzoli CG, et al; American Society of ClinicalOncology. American Society of Clinical Oncology treatment of unre-sectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol2004;22:330–353.3. Hirsch FR, Spreafico A, Novello S, Wood MD, Simms L, Papotti M.The prognostic and predictive role of histology in advanced non-smallcell lung cancer: a literature review. J Thorac Oncol 2008;3:1468–1481.4. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparingcisplatin plus gemcitabine with cisplatin plus pemetrexed in chemother-apy-naive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol 2008;26:3543–3551.5. Peng G, Zinner RG, Wang Y, et al. Comparison of patient outcomesstratified by histology among pemetrexed (P)-treated patients (pts) withstage IIIB/IV non-small cell lung cancer (NSCLC) in two phase II trials.J Clin Oncol 2008;26(Suppl):Abstract 8096.6. Ohe Y, Ichinose Y, Nakagawa K, et al. Efficacy and safety of two dosesof pemetrexed supplemented with folic acid and vitamin B12 in previ-ously treated patients with non-small cell lung cancer. Clin Cancer Res2008;14:4206–4212.7. Belani CP, Brodowicz T, Ciuleanu T, et al. Maintenance pemetrexed(Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC:a randomized phase III study in advanced non-small cell lung cancer(NSCLC). J Clin Oncol 2009;27(Suppl 18S):Abstract CRA8000.8. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy ofpemetrexed according to NSCLC histology: a review of two Phase IIIstudies. Oncologist 2009;14:253–263.9. Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trialcomparing three platinum-based doublets in advanced non-small-celllung cancer. J Clin Oncol 2002;20:4285–4291.10. Kaplan EL, Meier P. Nonparametric estimation from incomplete obser-vations. J Am Stat Assoc 1958;53:457–481.11. Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of thelung compared with other histotypes shows higher messenger RNA andprotein levels for thymidylate synthase. Cancer 2006;107:1589–1596.12. Mendelsohn LG, Shih C, Chen VJ, Habeck LL, Gates SB, ShackelfordKA. Enzyme inhibition, polyglutamation, and the effect of LY231514(MTA) on purine biosynthesis. Semin Oncol 1999;26:42–47.13. Schultz RM, Chen VJ, Bewley JR, Roberts EF, Shih C, Dempsey JA.Biological activity of the multitargeted antifolate, MTA (LY231514), inhuman cell lines with different resistance mechanisms to antifolatedrugs. Semin Oncol 1999;26:68–73.14. Giaccone G. Epidermal growth factor receptor inhibitors in the treatmentof non-small-cell lung cancer. J Clin Oncol 2005;23:3235–3242.15. Gabrielson E. Worldwide trends in lung cancer pathology. Respirology2006;11:533–538.Journal of Thoracic Oncology • Volume 4, Number 12, December 2009 Role of Histology with Common First-Line RegimensCopyright © 2009 by the International Association for the Study of Lung Cancer 1571

The role of histology with common first-line regimens for advanced non-small cell lung cancer: a brief report of the retrospective analysis of a three-arm randomized trial.

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The role of histology with common first-line regimens for advanced non-small cell lung cancer: a brief report of the retrospective analysis of a three-arm randomized trial.

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