Phase 2 Study of S-1 and Carboplatin Plus Bevacizumabpdf

Phase2Study of S-1and Carboplatin Plus Bevacizumab Followed by Maintenance S-1and Bevacizumab for Chemotherapy-Naive Patients With Advanced NonsquamousNon–Small Cell Lung CancerYoshiko Urata,MD,PhD1;Isamu Okamoto,MD,PhD2;Masayuki T akeda,MD,PhD3;Yoshihiro Hattori,MD1;Keiko Okuno,MD1;T emiko Shimada,MD,PhD1;T akayasu Kurata,MD,PhD2;Hiroyasu Kaneda,MD,PhD2;Masaki Miyazaki,MD,PhD2;Masaaki T erashima,MD,PhD2;Kaoru T anaka,MD,PhD2;Satoshi Morita,PhD4;Kazuhiko Nakagawa,MD,PhD2;Shunichi Negoro,MD1;and Miyako Satouchi,MD,PhD1BACKGROUND:A previous phase3trial demonstrated noninferiority in terms of overall survival for combined S-1(an oral fluoropyri-midine)and carboplatin compared with combined paclitaxel and carboplatin as first-line treatment for advanced non–small cell lung cancer(NSCLC).In the current study,the authors evaluated the efficacy and safety of combined S-1,carboplatin,and bevacizumab followed by maintenance with S-1and bevacizumab in chemotherapy-naive patients with advanced nonsquamous NSCLC.METHODS: Patients received carboplatin(area under the concentration-time curve,5mg mL21per minute)and bevacizumab(15mg/kg)on day 1plus oral S-1(80mg/m2per day)on days1through14every21days for up to6cycles.For patients without disease progression,S-1 and bevacizumab were continued until disease progression or unacceptable toxicity developed.RESULTS:Forty-eight patients were enrolled in the phase2study;of these,35patients(72.9%)completed at least4cycles.Most toxicities of grade 3were hematologic, and no increase in relative incidence associated with maintenance with S-1and bevacizumab was observed.The objective response rate was54.2%(95%confidence interval,39.2%-68.6%),and the median progression-free survival was6.8months(95%confidence interval,4.3-8.2months).CONCLUSIONS:The regimen of combined S-1,carboplatin,and bevacizumab followed by maintenance with S-1and bevacizumab was active and feasible as first-line treatment for advanced nonsquamous NSCLC.Cancer2013;119:2275-81.V C2013American Cancer Society.KEYWORDS:bevacizumab;carboplatin;chemotherapy;maintenance;non–small cell lung cancer;S-1.INTRODUCTIONLung cancer is the leading cause of death related to cancer worldwide,with non–small cell lung cancer(NSCLC)account-ing for85%of lung cancer cases.1For individuals with advanced or metastatic NSCLC,platinum-based chemotherapy is the mainstay of first-line treatment2,3on the basis of the moderate improvement in survival and quality of life it affords compared with best supportive care alone.4A phase3study,the Eastern Cooperative Oncology Group(ECOG)E4599trial,demonstrated that bevacizumab,a humanized monoclonal antibody specific for vascular endothelial growth factor,5given with paclitaxel and carboplatin resulted in significant improvements in the overall response rate(ORR),progression-free survival(PFS),and overall sur-vival(OS)compared with paclitaxel and carboplatin alone in individuals with advanced nonsquamous NSCLC.6A Japa-nese phase2study also indicated that bevacizumab in combination with paclitaxel and carboplatin improved the ORR and PFS compared with paclitaxel and carboplatin alone.7In a confirmatory phase3study(the Avastin in Lung[AVAiL] trial),the addition of bevacizumab to cisplatin and gemcitabine resulted in a significant improvements in the ORR and PFS.8,9These observations provide a rationale for combining bevacizumab with platinum-doublet chemotherapy in indi-viduals with advanced nonsquamous NSCLC.Corresponding author:Miyako Satouchi,MD,PhD,Department of Thoracic Oncology,Hyogo Cancer Center,13-70Kitaoji-cho,Akashi City,Hyogo673-8558, Japan;Fax:(011)81-78-929-2387;satouchi@hp.pref.hyogo.jp1Department of Thoracic Oncology,Hyogo Cancer Center,Akashi,Japan;2Department of Medical Oncology,Kinki University Faculty of Medicine,Osaka-Sayama, Japan;3Department of Medical Oncology,Kishiwada City Hospital,Kishiwada,Japan;4Department of Biostatistics and Epidemiology,Yokohama City University Medical Center,Yokohama,Japan.We thank all participating sites and investigators for their support with this clinical study.DOI:10.1002/cncr.28048,Received:October23,2012;Revised:January5,2013;Accepted:January11,2013,Published online April4,2013in Wiley Online Library()S-1(TS-1;Taiho Pharmaceutical Company Ltd., Tokyo,Japan)is an oral fluoropyrimidine agent that con-sists of tegafur(a prodrug of5-fluorouracil),5-chloro-2,4-dihydroxypyridine,and potassium oxonate.10It has demonstrated activity and acceptable tolerability in phase 2studies of patients with advanced NSCLC.11Our previ-ous phase3study demonstrated the noninferiority in terms of OS as well as a favorable toxicity profile for S-1 and carboplatin compared with standard paclitaxel-carbo-platin as first-line treatment for patients with advanced NSCLC.12Thus,our results indicated that the combina-tion of S-1and carboplatin is a valid option for the first-line treatment of such patients.In addition to the enhanced efficacy of cytotoxic chemotherapy observed with bevacizumab,preclinical studies indicate that the combination of bevacizumab with5-fluorouracil derivatives results in increased antitu-mor activity.13,14Therefore,we have now performed a multicenter phase2study to evaluate the efficacy and safety of S-1and carboplatin in combination with bevaci-zumab followed by maintenance therapy with S-1and bevacizumab alone in chemotherapy-naive patients with advanced nonsquamous NSCLC.MATERIALS AND METHODSEligibilityEligible patients were required be aged 20years and to have histologically or cytologically confirmed stage IIIB or IV nonsquamous NSCLC(diagnosed according to the seventh edition of the International Union Against Can-cer cancer staging manual)or recurrence of this condition after surgery.The patients also were required to have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors(RECIST)(version 1.1); adequate hematologic,hepatic,and renal function;an ECOG performance status of0or1;and no tumor inva-sion into the trachea,main bronchi,or major vessels. Exclusion criteria included hemoptysis(>2.5mL of red blood per episode),radiologic evidence of tumor invasion or tumor abutting of major blood vessels,evidence of a brain metastasis>1cm,current or recent use of full-dose anticoagulants,medically uncontrolled hypertension or a history of thrombotic or hemorrhagic disorders,intersti-tial pneumonia recognized on a chest x-ray,supporting radiation therapy occupying the pulmonary region in the 3months before enrollment,and major surgery within 28days before enrollment.The study was performed according to good clinical practices and ethical principles outlined in the Declaration of Helsinki.The study proto-col was approved by the institutional review board at each participating center,and all patients signed written informed consent forms before enrollment.The trial has been registered under University Medical Hospital Infor-mation Network(UMIN)Clinical Trials Registry Identi-fier UMIN000003698.Study Design and TreatmentThe study was designed as a prospective,multicenter, single-arm phase2trial of first-line combination therapy with S-1,carboplatin,and bevacizumab followed by continuous maintenance therapy with S-1and bevacizu-mab.The primary endpoint was treatment efficacy measured as the ORR in patients who received at least1 course of the initial combination therapy.OS,PFS,the disease control ratio,and adverse events also were eval-uated as secondary endpoints.Patients received S-1orally at a dose of80mg/m2 per day on days1through14as well as carboplatin at a dose calculated to produce an area under the concentra-tion-time curve of5mg mL21per minute and bevacizu-mab at a dose of15mg/kg as an intravenous infusion on day1.The combination therapy was repeated every21 days for up to4to6cycles unless there was evidence of disease progression or intolerance of the study treatment. After4to6cycles of treatment with S-1,carboplatin, and bevacizumab,patients who attained a complete response(CR),a partial response(PR),or stable disease (SD)continued to receive cycles of maintenance therapy with S-1and bevacizumab every21days until they had evidence of disease progression or developed unaccept-able toxicity.Administration of S-1during the mainte-nance phase was interrupted if patients developed grade 4neutropenia,a platelet count<50,000/l L,a serum creatinine concentration 1.5mg/dL,a serum total bili-rubin concentration 2.0mg/dL,a putative infection with fever of at least38 C,or severe diarrhea or stomati-tis(grade2or higher).Treatment with S-1and bevacizu-mab was resumed if the neutrophil count was 1500/ l L,the platelet count was 100,000/l L,the serum total bilirubin concentration was<1.5mg/dL,there was no infection with fever of at least38 C,and diarrhea or sto-matitis was grade1or lower.Subsequent cycles of treatment were withheld until the following criteria were satisfied:neutrophil count, 1500/l L;platelet count, 100,000/l L;performance status,0to2;serum total bilirubin concentration, 1.5mg/dL;weight loss,grade2or lower abnormal electrolytes,peripheral nerve damage,and hepatotoxicity (based on aspartate aminotransferase,alanine amino-transferase,and total bilirubin levels);grade3or lowerhypertension;grade2or lower proteinuria;grade0 hemoptysis or bleeding;and no infection with fever of at least38 C.The study therapy was stopped if grade2 or higher hemoptysis developed or if bleeding persisted after treatment of hemorrhage.Patients also were to be removed from the study if the next treatment cycle had not started within42days of the previous dosing as a result of toxicity.Baseline and Treatment AssessmentsBaseline evaluations included medical history,physical ex-amination,electrocardiogram,ECOG performance sta-tus,and laboratory puted tomography (CT)scans of the chest and abdomen,magnetic resonance imaging(MRI)studies of the brain,and bone scintigra-phy or positron emission tomography(PET)-CT studies were performed for tumor assessment within28days of initiation of the study treatment.CT scans of the chest and abdomen were repeated every2cycles,brain MRI studies were repeated every3months or on the appear-ance of any neurologic symptoms,and bone scintigraphy or PET-CT studies were performed every6months or on the appearance of any bone-related symptoms.All treat-ment responses were defined according to RECIST ver-sion1.1.If a patient had a documented a CR or a PR, then the respective response had to be confirmed4weeks later.A patient was considered to have SD if their response was confirmed and sustained for at least6weeks. PFS was calculated from the date of enrollment to the date of confirmation of progressive disease or the date of death from any cause.PFS from the start of maintenance therapy was calculated by subtracting the period of the initial combination therapy from overall PFS.OS was cal-culated from the date of initial treatment to the date of death from any cause.For patients with unknown death status,OS was censored at the last date the patient was known to be alive.Patients were assessed for toxicity according version4.0of the National Cancer Institute Common Toxicity Criteria.Statistical AnalysisWe assumed that an ORR of50%for the study regimen in eligible patients would indicate potential usefulness, whereas an ORR of30%would be the lower limit of in-terest.On the basis of these assumptions,our study was designed to have a power of80%and a1-sided level of type I error of0.05,resulting in a requirement for45 patients.A Simon2-stage design(MiniMax)was adopted. Nineteen patients were to be initially assessed for response,and if more than6patients manifested a PR or a CR,then26additional patients would be added to the assessment.Efficacy and safety analyses were planned for patients who received at least1cycle of the treatment. PFS and OS were analyzed using the Kaplan-Meier method to estimate the median points with95%confi-dence intervals(CIs).RESULTSPatient CharacteristicsBetween April2010and October2011,a total of48 patients with recurrent or newly diagnosed,advanced nonsquamous NSCLC were enrolled at3participating centers.The baseline characteristics of all assigned patients are provided in Table1.The median age for the treated patients was65.5years(range,35-77years),33patients (68.8%)were men,42patients(87.5%)had adenocarci-noma histology,40patients(83.3%)had stage IV disease, and16patients(33.3%)were never-smokers.Epidermal growth factor receptor mutation status was evaluated in 42patients(87.5%),and4individuals had activating mutations identified.Treatment DeliveryPatient disposition is illustrated in Figure1.Overall,35 patients(72.9%)completed at least4cycles of S-1and carboplatin combined with bevacizumab,and29patients (60.4%)were shifted to subsequent maintenance therapy with S-1and bevacizumab and received a median of4 cycles(range,1-18cycles).In the initial combination phase,13of48patients(27.1%)experienced dose TABLE1.Baseline Characteristics of the Study Patients,n548Characteristic No.of Patients(%) Age:Median[range],y65.5[35-77]SexMen33(68.8) Women15(31.3) ECOG PS015(31.3)133(68.8) Disease stageIIIB3(6.3)IV40(83.3) Recurrence5(10.4) HistologyAdenocarcinoma42(87.5) Large cell carcinoma1(2.1) Others5(10.4) Smoking statusNever-smoker16(33.3) Former or current smoker32(66.7) Abbreviations:ECOG PS,Eastern Cooperative Oncology Group perform-ance status.S-1–CBDCA Plus Bevacizumab for NSCLC/Urata et alreductions,and 34patients (70.8%)experienced a treat-ment delay because of adverse events,mostly related to myelosuppression.Among the 29patients who received maintenance therapy with S-1and bevacizumab,2indi-viduals (6.9%)underwent a dose reduction,and 20indi-viduals (69%)had a treatment delay.EfficacyForty-eight patients were deemed eligible for evaluation of treatment response.Twenty-six patients attained a PR,and no patients attained a CR,yielding an ORR of 54.2%(95%CI,39.2%-68.6%)(Table 2).Eleven patients (22.9%)had SD,yielding a disease control ratio (CR 1PR 1SD)of 77.1%(95%CI,67.2%-88%).Eleven patients (22.9%)had progressive disease as their best response.At a median follow-up of 13.9months (range, 2.0-27.5months),the median PFS was 6.8months (95%CI,4.3-8.2months)(Fig.2),and the me-dian OS was 22.8months (lower limit of 95%CI,13.1months).Thirty-seven patients (77.1%)received subse-quent chemotherapy regimens as poststudy treatment.Safety AnalysisAll 48patients who received the study treatment were deemed eligible for safety analysis.The major adverse events for each treatment phase (initial and maintenance phases)are listed in Table 3.During treatment with the combination of S-1,carboplatin,and bevacizumab,gradeFigure 1.This is a Consolidated Standards of Reporting Trials (CONSORT)diagram for the current study.TABLE 2.Treatment Outcomes for the Study Patients,,n 548OutcomeNo.of Patients (%)Complete response 0(0)Partial response 26(54.2)Stable disease11(22.9)Progressive disease11(22.9)Overall response rate [95%CI],%54.2[39.2-68.6]Disease control rate [95%CI],%77.1[67.2-88]Abbreviations:CI,confidenceinterval.Figure 2.This Kaplan-Meier curve illustrates progression-free survival (PFS).CI indicates confidence interval.Original Article3and higher hematologic toxicities included neutropenia (31.3%),thrombocytopenia(16.7%),anemia(10.5%), and leukopenia(8.3%).Among the29patients who con-tinued with S-1plus bevacizumab during the mainte-nance phase,4patients(13.8%)had grade3neutropenia, and1patient(3.4%)had grade3anemia during the pe-riod.Most nonhematologic adverse events were of mild to moderate intensity(grade1or2);those that were grade3 or higher during the initial phase of the study treatment included hypertension(8.3%),appetite loss(6.3%),diar-rhea(6.3%),fatigue(2.1%),and intestinal perforation (2.1%);whereas those during the maintenance phase included proteinuria(6.9%),mucositis(3.4%),and diar-rhea(3.4%).There were no clinically relevant bleeding events during either treatment phase for any patient,and there were no treatment-related deaths.DISCUSSIONThis multicenter phase2study is the first to evaluate the efficacy and safety of a new regimen,S-1and carboplatin combined with bevacizumab followed by maintenance S-1and bevacizumab,for first-line treatment of patients with advanced nonsquamous NSCLC.We observed that the combination was active,with an ORR of54.2%(95% CI,39.2%-68.6%),which met the primary objective of the study.At a median follow-up of13.9months,the me-dian PFS was6.8months,and the median OS was22.8 months.Our previous phase3study demonstrated that the combination of S-1and carboplatin was not inferior relative to a standard paclitaxel-carboplatin regimen in terms of OS for chemotherapy-naive patients with advanced NSCLC.12The ORR for S-1and carboplatin, however,was significantly lower than that for paclitaxel-carboplatin(20.4%vs29%;P5.019).This difference in ORR also was apparent for patients who had nonsqua-mous NSCLC(18.8%vs27.6%;P5.027).15It is believed that bevacizumab is targets the tumor vascula-ture,reducing interstitial pressure and increasing vessel permeability,thereby resulting in enhanced tumor sensi-tivity to cytotoxic chemotherapy.16,17Although there are limitations to comparisons of results among different studies,the ORR(54.2%)obtained in the current trial is indicative of increased antitumor activity of S-1and car-boplatin with the addition of bevacizumab.Our trial also indicates a favorable toxicity profile for the study treatment.All toxicities were manageable with symptomatic treatment and dose reduction or inter-ruption.In our previous phase3study,the combination of S-1and carboplatin was associated with significantly lower rates of neutropenia,leukopenia,and febrile neutro-penia compared with paclitaxel and carboplatin.12Con-sistent with these results,most patients enrolled in the current study had only mild hematologic toxicities,and no cases of febrile neutropenia occurred.Thus,no obvious exacerbation of chemotherapy-induced myelosuppression by the addition of bevacizumab to S-1and carboplatin was apparent.There also was no increase in the relative incidence of hematologic toxicities associated with main-tenance therapy with S-1and bevacizumab.With regard to nonhematologic toxicities,there were no grade3or4TABLE3.Incidence of Adverse Events in the Study PatientsNo.of Patients(%)Initial Treatment Phase,n548Maintenance Phase,n529 Adverse Event All Grades Grade3Grade4All Grades Grade3Grade4 Hematologic AEsLeukopenia43(89.6)4(8.3)0(0)17(58.6)0(0)0(0) Neutropenia44(91.7)12(25)3(6.3)16(55.2)4(13.8)0(0) Anemia37(77.1)2(4.2)3(6.3)25(86.2)1(3.4)0(0) Thrombocytopenia43(89.6)5(10.4)3(6.3)11(37.9)0(0)0(0) Nonhematologic AEsFatigue36(75)1(2.1)0(0)14(48.3)0(0)0(0) Appetite loss31(64.6)3(6.3)0(0)12(41.4)0(0)0(0) Proteinuria25(52.1)0(0)0(0)9(31)2(6.9)0(0) Nausea21(43.8)0(0)0(0)9(31)0(0)0(0) Mucositis17(35.4)0(0)0(0)9(31)1(3.4)0(0) Hypertension14(29.2)4(8.3)0(0)5(17.2)0(0)0(0) Diarrhea11(22.9)3(6.3)0(0)4(13.8)1(3.4)0(0) Hemoptysis6(12.5)0(0)0(0)1(3.4)0(0)0(0) Intestinal perforation2(4.2)0(0)1(1.1)1(3.4)0(0)0(0) Interstitial pneumonia0(0)0(0)0(0)0(0)0(0)0(0) Abbreviations:AEs,adverse events.S-1–CBDCA Plus Bevacizumab for NSCLC/Urata et altoxicities encountered in>10%of patients throughout the study d or moderate fatigue and gastro-intestinal adverse effects were the most frequent nonhe-matologic toxicities,consistent with findings from previous studies with combined S-1and carboplatin.12 Hypertension and proteinuria have been associated with bevacizumab administration6,8and also were observed in the current study.Two patients experienced grade3pro-teinuria in the maintenance period;however,both cases were fully reversible without dose reduction or cessation of treatment.Because clinically significant(grade 3) hemoptysis was observed in0.9%to1.9%of patients who received bevacizumab in the ECOG E4599and AVAiL trials,6,8the lack of fatal bleeding events and treat-ment-related deaths in the current study also is notewor-thy.Patients with brain metastases have been excluded from most clinical trials of bevacizumab for fear of intra-cranial hemorrhage.6,8However,recent data suggest that the risk of developing intracranial hemorrhage is inde-pendent of bevacizumab therapy in patients with NSCLC who have brain metastases.18Conversely,another study suggested that intracranial hemorrhage is more likely to become clinically symptomatic in larger(>2cm)brain metastases.19On the basis of these data,patients with brain metastases that measured<1cm were eligible for the current study.Indeed,2patients who had asymptom-atic,small(<1cm)brain metastases were enrolled in the study,but no intracranial hemorrhage was observed.Bevacizumab is used in the maintenance setting for patients with advanced nonsquamous NSCLC on the ba-sis of the results from the ECOG E4599and AVAiL trials, in which bevacizumab monotherapy after induction ther-apy with bevacizumab plus platinum doublets was admin-istered until patients developed disease progression.6,8 More recently,a large phase3trial(PARAMOUNT) demonstrated that maintenance therapy with pemetrexed after induction therapy with pemetrexed and cisplatin resulted in a significant improvement in PFS and OS.20 Furthermore,an ongoing ECOG phase3trial is compar-ing bevacizumab alone,pemetrexed alone,and the peme-trexed-bevacizumab combination for maintenance therapy after initial therapy with paclitaxel,carboplatin, and bevacizumab(National Clinical Trials identifier NCT01107626).Thus,extensive efforts are under way to examine the effects of the combination of bevacizumab and chemotherapy during the maintenance phase of treat-ment for advanced nonsquamous NSCLC.On the basis of the low level of toxicity accumulation for S-1,21we explored the efficacy and feasibility of continued mainte-nance therapy with S-1and bevacizumab in the current study.The favorable tolerability profile of maintenance with S-1and bevacizumab after induction therapy with S-1,carboplatin,and bevacizumab is reflected in out obser-vation that60%of patients were able to continue on S-1 and bevacizumab for a median of4cycles(range,1-18 cycles).Among the29patients who received maintenance therapy with S-1and bevacizumab,the median PFS of8.2 months(95%CI,7.4-9.6months)from the beginning of induction treatment is encouraging and compares favor-ably with that of6.9months reported in the PARA-MOUNT study for maintenance with pemetrexed monotherapy.Despite the limitations to comparisons of results from different studies,these data may stimulate further interest in the clinically relevant efficacy of main-tenance therapy with S-1and bevacizumab.In conclusion,here,we have presented results from the first phase2study of combined S-1,carboplatin,and bevacizumab followed by maintenance therapy with S-1 and bevacizumab.Although our study was not random-ized,the promising efficacy and favorable toxicity profile of the study treatment justify further development of regi-mens that contain S-1and bevacizumab.A large random-ized phase3trial comparing single-agent S-1with docetaxel in previously treated patients with advanced NSCLC in Asian countries is currently under way(JPRN-JapicCTI-101155).We believe that further randomized trials are warranted comparing S-1,carboplatin,and beva-cizumab with the current standard of care(paclitaxel,car-boplatin,and bevacizumab)in previously untreated patients with advanced nonsquamous NSCLC. FUNDING SUPPORTNo specific funding was disclosed.CONFLICT OF INTEREST DISCLOSURESThe authors made no disclosures.REFERENCES1.Siegel R,Naishadham D,Jemal A.Cancer statistics2012.CA Can-cer J Clin.2012;62:10-29.2.Ohe Y,Ohashi Y,Kubota K,et al.Randomized phase III study ofcisplatin plus irinotecan versus carboplatin plus paclitaxel,cisplatin plus gemcitabine,and cisplatin plus vinorelbine for advanced non-small-cell lung cancer:Four-Arm Cooperative Study in Japan.Ann Oncol.2007;18:317-323.3.Schiller JH,Harrington D,Belani CP,et parison of4chem-otherapy regimens for advanced non-small-cell lung cancer.N Engl J Med.2002;346:92-98.4.Burdett S,Stephens R,Stewart L,et al.Chemotherapy in additionto supportive care improves survival in advanced non-small-cell lung cancer:a systematic review and meta-analysis of individual patient data from16randomized controlled trials.J Clin Oncol.2008;28: 4617-4625.5.Ferrara N,Kerbel RS.Angiogenesis as a therapeutic target.Nature.2005;438:967-974.Original Article6.Sandler A,Gray R,Perry MC,et al.Paclitaxel-carboplatin alone orwith bevacizumab for non-small-cell lung cancer.N Engl J Med.2006;355:2542-2550.7.Niho S,Kunitoh H,Nokihara H,et al.Randomized phase II studyof first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer.Lung Cancer.2012;27:362-367.8.Reck M,Von Pawel J,Zatloukal P,et al.Phase III trial of cisplatinplus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer:AVAiL.J Clin Oncol.2009;27:1227-1234.9.Reck M,von Pawel J,Zatloukal P,et al.Overall survival with cispla-tin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer:results from a randomised phase III trial(AVAiL).Ann Oncol.2010;21:1804-1809.10.Shirasaka T,Nakano K,Takechi T,et al.Antitumor activity of1Mtegafur-0.4M5-chloro-2,4-dihydroxypyridine-1M potassium oxo-nate(S-1)against human colon carcinoma orthotopically implanted into nude rats.Cancer Res.1996;56:2602-2606.11.Kawahara M,Furuse K,Segawa Y,et al.Phase II study of S-1,anovel oral fluorouracil,in advanced non-small-cell lung cancer.Br J Cancer.2001;85:939-943.12.Okamoto I,Yoshioka H,Morita S,et al.Phase III trial comparingoral S-1plus carboplatin with paclitaxel plus carboplatin in chemo-therapy-naive patients with advanced non-small-cell lung cancer: results of a West Japan Oncology Group study.J Clin Oncol.2010;28:5240-5246.13.Nukatsuka M,Saito H,Nakagawa F,et bination therapyusing oral S-1and targeted agents against human tumor xenografts in nude mice.Exp Ther Med.2012;3:755-762.14.Shaked Y,Henke E,Roodhart J,et al.Rapid chemotherapy-inducedacute endothelial progenitor cell mobilization:implications for anti-angiogenic drugs as chemosensitizing agents.Cancer Cell.2008;14: 263-273.15.Yoshioka H,Okamoto I,Morita S,et al.Efficacy and safety analysisaccording to histology for S-1in combination with carboplatin as first-line chemotherapy in patients with advanced non-small cell lung cancer:updated results of the West Japan Oncology Group LETS study[published online ahead of print February4,2013].Ann Oncol.2013.16.Willett CG,Boucher Y,di Tomaso E,et al.Direct evidence that theVEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.Nat Med.2004;10:145-147.17.Dickson PV,Hamner JB,Sims TL,et al.Bevacizumab-induced tran-sient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy.Clin Cancer Res.2007;13:3942-3950.18.Besse B,Lasserre S,Compton P,et al.Bevacizumab safety inpatients with central nervous system metastases.Clin Cancer Res.2010;16:269-278.19.Srivastava G,Vishal R,Wallace S,et al.Risk of intracranial hemor-rhage and cerebrovascular accidents in non-small cell lung cancer brain metastasis patients.J Thorac Oncol.2009;4:333-337.20.Paz-Ares L,de Marinis F,Dediu M,et al.Maintenance therapywith pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cispla-tin for advanced non-squamous non-small-cell lung cancer(PARA-MOUNT):a double-blind,phase3,randomized controlled trial.Lancet Oncol.2012;13:247-255.21.Totani Y,Saito Y,Hayashi M,et al.A phase II study of S-1mono-therapy as second-line treatment for advanced non-small cell lung cancer.Cancer Chemother Pharmacol.2009;64:1181-1185.S-1–CBDCA Plus Bevacizumab for NSCLC/Urata et al。