Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Gemcitabine in Brief versus Prolonged Low-Dose Infusion, both Combined with Cisplatin, for Advanced Non-small Cell Lung Cancer: A Randomized Phase II Clinical Trial The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Safety and Resource Utilization by Non-small Cell Lung Cancer Histology: Results from the Randomized Phase III Study of Pemetrexed Plus Cisplatin versus Gemcitabine Plus Cisplatin in Chemonaïve Patients with Advanced Non-small Cell Lung Cancer Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. A phase III randomised study comparing two different dose-intensity regimens as induction chemotherapy followed by thoracic irradiation in patients with advanced locoregional non-small-cell lung cancer. Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. Phase II Randomized Trial of Erlotinib or Vinorelbine in Chemonaive, Advanced, Non-small Cell Lung Cancer Patients Aged 70 Years or Older Efficacy and safety analysis according to histology for S-1 in 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. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaïve patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study. Reliability of the PEDro scale for rating quality of randomized controlled trials. Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Squamous Non–Small-Cell Lung Cancer: Results From the Randomized Controlled MONET1 Study FDA drug approval summary: pemetrexed for injection (Alimta) for the treatment of non-small cell lung cancer. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. A retrospective analysis of outcomes across histological subgroups in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin for advanced non-small cell lung cancer. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. Survival advantage for carboplatin substituting cisplatin in combination with vindesine and mitomycin C for stage IIIB and IV squamous-cell bronchogenic carcinoma: a randomized phase III study. Treatment Outcomes by Tumor Histology in Eastern Cooperative Group Study E4599 of Bevacizumab with Paclitaxel/Carboplatin for Advanced Non-small Cell Lung Cancer Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2.
BACKGROUND The study compared the efficacy of a first-line treatment with day 1 i.v . vinorelbine ( NVBiv ) and day 8 oral vinorelbine ( NVBo ) versus docetaxel ( DCT ) in a cisplatin-based combination in advanced non-small-cell lung cancer , in terms of time to treatment failure ( TTF ) , overall response , progression-free survival ( PFS ) , overall survival ( OS ) , tolerance and quality of life ( QoL ) . METHODS Patients were r and omly assigned to receive cisplatin 80 mg/m2 with NVBiv 30 mg/m2 on day 1 and NVBo 80 mg/m2 on day 8 every 3 weeks , after a first cycle of NVBiv 25 mg/m2 on day 1 and NVBo 60 mg/m2 on day 8 ( arm A ) or cisplatin 75 mg/m2 and DCT 75 mg/m2 on day 1 every 3 weeks ( arm B ) , for a maximum of six cycles in both arms . RESULTS From 2 February 2004 to 1 January 2006 , 390 patients were entered in a r and omised study and 381 were treated . The patient characteristics are as follows ( arms A/B ) : metastatic ( % ) 80.5/84.8 ; patients with three or more organs involved  ( % ) 45.3/40.8 ; median age 59.4/62.1 years ; male 139/146 ; squamous ( % ) 34.2/33.5 ; adenocarcinoma ( % ) 41.6/39.3 ; median TTF ( arms A/B in months ) [ 95 % confidence interval ( CI ) ] : 3.2 ( 3.0 - 4.2 ) , 4.1 ( 3.4 - 4.5 ) ( P = 0.19 ) ; overall response ( arms A/B ) ( 95 % CI ) : 27.4 % ( 21.2 % to 34.2 % ) , 27.2 % ( 21.0 % to 34.2 % ) ; median PFS ( arms A/B in months ) ( 95 % CI ) : 4.9 ( 4.4 - 5.9 ) , 5.1 ( 4.3 - 6.1 ) ( P = 0.99 ) and median OS ( arms A/B in months ) ( 95 % CI ) : 9.9 ( 8.4 - 11.6 ) , 9.8 ( 8.8 - 11.5 ) ( P = 0.58 ) . The median survival for squamous histology was 8.87/9.82 months and for adenocarcinoma 11.73/11.60 months for arms A and B , respectively . Main haematological toxicity was grade 3 - 4 neutropenia : 24.4 % ( arm A ) and 28.8 % ( arm B ) . QoL as measured by the Lung Cancer Symptom Scale was similar in both arms . CONCLUSIONS Both arms provided similar efficacy in terms of response , time-related parameters and QoL , with an acceptable tolerance profile . In the current Global Lung Oncology Branch trial 3 , NVBo was shown to be effective as a substitute for the i.v . formulation . This can relieve the burden of the i.v . injection on day 8 and can optimise the hospital 's re sources and improve patient convenience BACKGROUND Necitumumab is a second-generation , recombinant , human immunoglobulin G1 EGFR antibody . In this study , we aim ed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer . METHODS We did this open-label , r and omised phase 3 study at 184 investigative sites in 26 countries . Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer , with an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion . Enrolled patients were r and omly assigned central ly 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block r and omisation scheme ( block size of four ) by a telephone-based interactive voice response system or interactive web response system . Chemotherapy was gemcitabine 1250 mg/m(2 ) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2 ) administered intravenously over 120 min on day 1 of a 3-week cycle . Necitumumab 800 mg , administered intravenously over a minimum of 50 min on days 1 and 8 , was continued after the end of chemotherapy until  disease progression or intolerable toxic side-effects occurred . R and omisation was stratified by ECOG performance status and geographical region . Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash -- a class effect of EGFR antibodies -- that would have unmasked most patients and investigators to treatment . The primary endpoint was overall survival , analysed by intention to treat . We report the final clinical analysis . This study is registered with Clinical Trials.gov , number NCT00981058 . FINDINGS Between Jan 7 , 2010 , and Feb 22 , 2012 , we enrolled 1093 patients and r and omly assigned them to receive necitumumab plus gemcitabine and cisplatin ( n=545 ) or gemcitabine and cisplatin ( n=548 ) . Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group ( median 11·5 months [ 95 % CI 10·4 - 12·6 ] ) vs 9·9 months [ 8·9 - 11·1 ] ; stratified hazard ratio 0·84 [ 95 % CI 0·74 - 0·96 ; p=0·01 ] ) . In the necitumumab plus gemcitabine and cisplatin group , the number of patients with at least one grade 3 or worse adverse event was higher ( 388 [ 72 % ] of 538 patients ) than in the gemcitabine and cisplatin group ( 333 [ 62 % ] of 541 ) , as was the incidence of serious adverse events ( 257 [ 48 % ] of 538 patients vs 203 [ 38 % ] of 541 ) . More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3 - 4 hypomagnesaemia ( 47 [ 9 % ] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [ 1 % ] of 541 in the gemcitabine and cisplatin group ) and grade 3 rash ( 20 [ 4 % ] vs one [ < 1 % ] ) . Including events related to disease progression , adverse events with an outcome of death were reported for 66 ( 12 % ) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 ( 11 % ) of 541 patients in the gemcitabine and cisplatin group ; these were deemed to be related to study drugs in 15 ( 3 % ) and ten ( 2 % ) patients , respectively . Overall , we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations . INTERPRETATION Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease . FUNDING Eli Lilly and Company INTRODUCTION We conducted this analysis to determine whether survival of advanced NSCLC patients treated with platin-based chemotherapy doublets involving paclitaxel , docetaxel or gemcitabine was dependent on histological subtypes and treatment regimen . METHODS We retrospectively analyzed data from E1594 , a front-line phase III study in which advanced NSCLC patients were r and omized to receive one of four regimens : cisplatin-paclitaxel , cisplatin-gemcitabine , cisplatin-docetaxel , and carboplatin-paclitaxel . Patients were classified into four histology groups : squamous cell ( SCC ) , adeno- ( AC ) , large cell ( LCC ) and others including not otherwise specified ( O/NOS ) carcinoma . Logrank test was performed to compare overall survival ( OS ) and progression free survival ( PFS ) distributions according to histology as well as treatment . RESULTS Of 1139 patients including 716 men and 423 women , AC was the most common subtype ( 56.8 % ) , followed by SCC ( 19.7 % ) , O/NOS ( 17.0 % ) and LCC ( 6.5 % ) . Men were more likely to have SCC and women were more likely to have AC ( p = 0.002 ) . Among the four histology groups , there was no imbalance in regard to race , performance status , weight loss , brain metastasis or treatment . In each histology group , we found no significant difference in OS and PFS between the four chemotherapy regimens . Conversely , in each treatment arm , the survival outcome was similar between the four histology subtypes . CONCLUSIONS Our analysis suggests that histology does not predict survival benefit in advanced NSCLC patients treated with first-line platin-based doublets involving paclitaxel , docetaxel or gemcitabine Objective : Gemcitabine in low dose in prolonged infusion is a treatment with documented activity against a variety of tumors . We here report the first r and omized trial to compare st and ard brief and low-dose prolonged infusion of gemcitabine . Patients and Methods : Eligible patients had non-small cell lung cancer in stage IIIB ( wet ) or IV , Karnofsky performance status 100 to 70 ( Eastern Cooperative Oncology Group 0–2 ) , measurable disease , were chemonaïve and fulfilled the st and ard criteria for chemotherapy . In arm A ( st and ard treatment ) , gemcitabine was given at 1250 mg/m2 in 20 to 30 minutes and in arm B ( prolonged infusion ) at 250 mg/m2 in 6 hours infusion . All patients received gemcitabine on days 1 and 8 and cisplatin at 75 mg/m2 on day 2 of a 3-week cycle for four cycles , followed by two cycles of gemcitabine as monotherapy . Results : A total of 249 patients ( 188 men and 61 women , median age 58 years ) were r and omized between arm A ( 125 patients ) and arm B ( 124 patients ) . Adenocarcinoma ( 53.9 % ) was the predominant histologic type ; 92 % of patients were in stage IV . The two groups were balanced for prognostic factors ; however , group A had fewer patients with significant weight loss and no patient with lung cancer as a second malignancy or after radiotherapy for brain metastases . Grade 3 or greater toxicity was rare : anemia in 0.8 and 3.2 % , neutropenia in 21.6 and 22.6 % , thrombocytopenia in 0 and 1.6 % , and nausea/vomiting in 4 and 8.1 % for arms A and B , respectively . Alopecia was seen in 54.5 % of patients in arm B , as compared with 9.7 % in arm A. No patient died of treatment-related toxicity . During cycle 5 , 47.7 % of patients in arm A and 60.7 % in arm B reported improved well-being , as compared with the status before chemotherapy . Patients in arm A had no complete remission , 32.8 % partial responses , 48 % minimal responses or stable disease , 13.6 % progressions , and 5.6 % were not evaluable . For arm B , the corresponding figures are as follows : complete remission 0.8 % , partial responses 46 % ( for overall response rate of 46.8 % ) , minimal responses or stable disease 36.3 % , progression 12.1 % , and not evaluable 4.8 % . Median progression-free survival was 5.5 and 6.0 months , median overall survival was 10.1 and 10.0 months , and 1-year survival was 46.6 and 41.1 % for arms A and B , respectively . For the 71 patients with squamous carcinoma , arm B seems superior to arm A , as seen by the higher overall response rate ( 51.3 versus 35.5 % ) , longer median progression-free survival ( 6.2 versus 4.9 months ) , and longer median survival ( 11.3 versus 8.5 months ) . However , because of the small number of patients , these differences did not reach the level of statistical significance . Conclusion : In the treatment of advanced non-small cell lung cancer , gemcitabine in low dose in prolonged infusion in combination with cisplatin has low toxicity and has activity comparable with gemcitabine in higher dose in st and ard brief infusion . Low-dose gemcitabine may be preferred for incurable cancer among economically deprivileged patients . In addition , apparent superior activity against squamous carcinoma opens new perspectives and deserves further research Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Platinum-containing two-drug combinations improve survival and cancer-related symptoms in patients with advanced non-small-cell lung cancer ( NSCLC ) . However , survival benefit is modest and platinum-containing regimens cause substantial toxic effects . We did a prospect i ve r and omised open-label phase III study to compare an experimental platinum-free , triplet , sequential regimen of vinorelbine plus gemcitabine followed by docetaxel with the st and ard platinum-containing , doublet regimen paclitaxel plus carboplatin in patients with advanced NSCLC . METHODS Between March , 2001 , and April , 2005 , patients with stage IIIB ( positive pleural effusion ) or IV NSCLC , performance status 0 to 1 , and adequate organ function , were r and omly assigned to experimental treatment or to st and ard treatment . R and omisation was done central ly by use of a dynamic balancing algorithm . Patients were stratified by weight loss , lactate dehydrogenase concentration , and disease stage . Patients in the experimental group were scheduled to receive intravenous vinorelbine ( 25 mg/m(2 ) ) plus gemcitabine ( 1000 mg/m(2 ) ) on days 1 and 8 every 21 days for three cycles , followed by intravenous docetaxel ( 60 mg/m(2 ) ) on day 1 every 21 days for three cycles . Patients in the st and ard group were scheduled to receive intravenous paclitaxel ( 225 mg/m(2 ) ) plus carboplatin ( area under the curve=6 ) for 3 h on day 1 , every 21 days for six cycles . The primary endpoint was overall survival , and secondary endpoints were progression-free survival , response , and toxic effects . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00079287 . FINDINGS Of the 401 patients enrolled and r and omised in the trial , five patients in the experimental group and three in the st and ard group were ineligible for analysis ; thus 196 patients in the experimental group and 197 in the st and ard group were included in analyses . Patient characteristics were well-balanced between the two groups with regard to major prognostic factors . Median overall survival was 13.6 months ( range 12.0 - 16.4 ) in the experimental group versus 14.1 months ( 11.9 - 17.5 ) in the st and ard group ( p=0.97 ) . 49 of 196 patients ( 25 % ) in the experimental group had a partial response compared with 73 of 197 patients ( 37 % ) in the st and ard group ( p=0.012 ) . There were no complete responses . Median progression-free survival was 5.5 months ( 95 % CI 4.9 - 6.3 ) in the experimental group compared with 5.8 months ( 5.3 - 6.1 ) in the st and ard group ( p=0.74 ) . The incidence of grade 3 and 4 neutropenia , neuropathy , arthralgia , and myalgia was lower in the experimental group than in the st and ard group , although the incidence of pulmonary toxic effects was higher . INTERPRETATION Although platinum-containing regimens remain the st and ard treatment for advanced NSCLC , non-platinum regimens could provide equivalent efficacy with a different toxicity profile Introduction : A prespecified analysis of the large , r and omized , phase III study in advanced non-small cell lung cancer showed significant improvement in survival for nonsquamous patients treated with pemetrexed/cisplatin versus gemcitabine/cisplatin .  Selected grade 3/4 toxicities and re source utilization favored pemetrexed in the overall population , but detailed safety results by histology have not been reported . Methods : Treated patients were included in this analysis of safety by histology . At each cycle , adverse events were assessed , and concomitant medications , transfusions , and hospitalizations were recorded . Measures were summarized by histology and compared between arms with Fisher 's exact test . Results : When analyzed by squamous and nonsquamous histology , safety and re source utilization for each treatment arm paralleled those of the overall population . Selected toxicities did not vary by histology . Concomitant medication use and hospitalizations were also very similar to the patterns observed in the overall population . Conclusions : Although previous efficacy analyses showed a significant pemetrexed treatment advantage for nonsquamous patients , results of this analysis indicate that safety and re source utilization do not vary by histology and are consistent with the overall population . The safety and re source utilization of patients treated with pemetrexed/cisplatin  are predictable , reproducible , and consistent with the established favorable safety profile of pemetrexed , regardless of histology PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin ( TC ) as first-line treatment of advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS This multicenter , open-label , phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB ( pleural effusion ) or IV NSCLC , without restrictions by histology or epidermal growth factor receptor expression . Patients were r and omly assigned to cetuximab/TC or TC . TC consisted of paclitaxel ( 225 mg/m(2 ) ) or docetaxel ( 75 mg/m(2 ) ) , at the investigator 's discretion , and carboplatin ( area under the curve = 6 ) on day 1 every 3 weeks for < or = six cycles ; cetuximab ( 400 mg/m(2 ) on day 1 , 250 mg/m(2 ) weekly ) was administered until progression or unacceptable toxicity . The primary end point was progression-free survival assessed by independent radiologic review committee ( PFS-IRRC ) ; overall response rate ( ORR ) , overall survival ( OS ) , quality of life ( QoL ) , and safety were key secondary end points . PFS and ORR assessed by investigators were also evaluated . Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC ( hazard ratio [ HR ] = 0.902 ; 95 % CI , 0.761 to 1.069 ; P = .236 ) . Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC ( HR = 0.890 ; 95 % CI , 0.754 to 1.051 ; P = .169 ) . ORR-IRRC was 25.7 % with cetuximab/TC versus 17.2 % with TC ( P = .007 ) . The safety profile of this combination was manageable and consistent with its individual components . CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point , PFS-IRRC . There was significant improvement in ORR by IRRC . The difference in OS favored cetuximab but did not reach statistical significance PURPOSE The aim of this study was to determine the role of chemotherapy dose intensity in patients with initially unresectable non-metastatic non-small-cell lung cancer ( NSCLC ) , with survival as primary end point , by testing two different regimens as induction chemotherapy followed by thoracic irradiation . PATIENTS AND METHODS Patients had pathologically proven NSCLC , an initially unresectable non-metastatic tumour without homolateral malignant pleural effusion , no prior history of malignancy and had received no prior therapy . Treatment was r and omised for chemotherapy between three courses of MIP ( mitomycin C 6 mg/m2 ; ifosfamide 3 g/m2 ; cisplatin 50 mg/m2 ) or SuperMIP ( mitomycin C 6 mg/m2 ; ifosfamide 4.5 g/m2 ; cisplatin 60 mg/m2 , carboplatine 200 mg/m2 ) , followed by chest irradiation ( 60 Gy ; five times per week , for 6 weeks ) . If the tumour became resectable after chemotherapy , surgery was performed , followed by mediastinal irradiation . RESULTS A total of 351 patients were eligible : 176 in the MIP arm and 175 in the SuperMIP arm , with 43 % and 51 % stages IIIA and IIIB , respectively . There was a significantly higher objective response rate with SuperMIP ( 46 % ) compared with MIP ( 35 % ) ( P=0.03 ) [ 95 % confidence interval ( CI ) for the difference between the response rates , 1 % to 22 % ] . After induction chemotherapy , surgery was performed in 54 ( 15 % ) patients ( 27 per arm ) and chest irradiation in 203 ( 57 % ) patients ( 102 in the MIP arm and 101 in the SuperMIP ) . In terms of survival , there was no statistically significant difference between the two study arms ( P=0.16 ) , with median survival times of , for MIP and SuperMIP , respectively , 12.5 ( 95 % CI 10.1 - 14.9 ) and 11.2 ( 95 % CI 9.7 - 12.8 ) months . Haematological toxicity and dosage reductions were higher with SuperMIP , which was nevertheless associated with a significantly increased absolute dose intensity . CONCLUSIONS High dose-intensity induction chemotherapy does not improve survival in initially unresectable non metastatic NSCLC Platinum-based chemotherapy is the st and ard treatment for patients with advanced non-small cell lung cancer ( NSCLC ) , but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials ; concern exists about tolerability and feasibility of st and ard chemotherapy in these patients . No prospect i ve r and omized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2 . CAPPA-2 was a multicenter , r and omized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC . Patients , aged 18 - 70 , were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes ( TNM VI edition ) and adequate organ function . Patients in st and ard arm received gemcitabine 1200 mg/m(2 ) days 1 and 8 . Patients in experimental arm received cisplatin 60 mg/m(2 ) day 1 plus gemcitabine 1000 mg/m(2 ) days 1 and 8 . All treatments were repeated every 3 weeks , up to 4 cycles , unless disease progression or unacceptable toxicity . Primary endpoint was overall survival ( OS ) . To have 80 % power of detecting hazard ratio ( HR ) 0.71 , corresponding to an increase in median OS from 4.8 to 6.8 months , 285 deaths were required . The study was stopped in June 2012 after the enrolment of 57 patients , due to the slow accrual and the report of positive results from a similar study . Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine ( HR 0.52 , 95 % CI 0.28 - 0.98 , p = 0.039 ) . Combination chemotherapy produced longer PFS ( median 1.7 vs. 3.3 months , HR 0.49 , 95 % CI 0.27 - 0.89 , p = 0.017 ) and higher response rate ( 4 % vs. 18 % , p = 0.19 ) , without substantial increase in toxicity . The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC PURPOSE This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 ( vadimezan ) , when combined with first-line platinum-based chemotherapy , improves survival in patients with advanced non-small-cell lung cancer ( NSCLC ) versus chemotherapy alone . PATIENTS AND METHODS Patients with advanced stage IIIB or IV NSCLC , stratified by sex and tumor histology , were r and omly assigned 1:1 to paclitaxel ( 200 mg/m(2 ) ) and carboplatin ( area under the curve , 6.0 ) with or without ASA404 ( 1,800 mg m(2 ) ) , given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo . Primary end point was overall survival ( OS ) ; secondary end points included overall response rate ( ORR ) and progression-free survival ( PFS ) . RESULTS One thous and two hundred ninety-nine patients were r and omly assigned . The trial was stopped for futility at interim analysis . At final analysis , there was no difference in OS seen between ASA404 ( n = 649 ) and placebo ( n = 650 ) arms : median OS was 13.4 and 12.7 months respectively ( hazard ratio [ HR ] , 1.01 ; 95 % CI , 0.85 to 1.19 ; P = .535 ) . Similarly , no OS difference was seen in the histologic ( squamous or nonsquamous ) and sex ( male or female ) strata . Median PFS was 5.5 months in both arms ( HR , 1.04 ; P = .727 ) , while ORR was 25 % in both arms ( P = 1.0 ) . Overall rate of adverse events ( AEs ) was comparable between the ASA404 and placebo arms . Grade 4 neutropenia ( 27 % v 19 % ) and infusion site pain ( 10 % v 0.5 % ) were reported more frequently in the ASA404 arm . CONCLUSION The addition of ASA404 to carboplatin and paclitaxel , although generally well tolerated , failed to improve frontline efficacy in advanced NSCLC Introduction : The primary objective of this study was to compare the response rates of elderly , chemonaive patients with advanced non-small cell lung cancer ( NSCLC ) treated with daily oral erlotinib versus oral vinorelbine . Methods : Chemonaive Taiwanese patients aged 70 years or older who had advanced NSCLC were r and omized to receive either oral erlotinib 150 mg ( E ) daily or oral vinorelbine 60 mg/m2 ( V ) on days 1 and 8 every 3 weeks . Results : From February 2007 to July 2008 , 116 patients were enrolled and 113 were included in the intent-to-treat population : 57 patients in the E group and 56 patients in the V group . Objective response rates were 22.8 % ( 13 of 57 ) in E and 8.9 % ( 5 of 56 ) in V ( p = 0.0388 ) . Median progression-free survival ( PFS ) was 4.57 months in E and 2.53 months in V ( p = 0.0287 ) , with an 80.6 % increase in median PFS for E compared with V. Median survival time was 11.67 months in E and 9.3 months in V ( p = 0.6975 ) . Toxicities were generally mild in both groups . Median PFS was longest for epidermal growth factor receptor gene (EGFR)-mutated patients in the E group , followed by EGFR-mutated patients in V , EGFR wild type in E , and EGFR wild type in V ( p = 0.0034 ) . Overall survival was longer for EGFR-mutated patients than for EGFR wild-type patients ( p < 0.0001 ) . Conclusions : Erlotinib is highly effective compared with oral vinorelbine in elderly , chemonaive , Taiwanese patients with NSCLC . EGFR-mutated patients had better survival than those with EGFR wild-type disease , regardless of the treatment received BACKGROUND A phase III study ( Lung Cancer Evaluation of TS-1 ) previously demonstrated noninferiority in terms of overall survival ( OS ) at interim analysis for carboplatin-S-1 compared with carboplatin-paclitaxel for first-line treatment of advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A total of 564 patients were r and omly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1 - 14 or carboplatin-paclitaxel on day 1 every 21 days . Up date d results and post hoc subgroup analysis according to tumor histology are presented . RESULTS The up date d analysis revealed a median OS of 15.2 months in the carboplatin-S-1 arm and 13.1 months in the carboplatin-paclitaxel arm , with a hazard ratio ( HR ) of 0.956 [ 95 % confidence interval ( CI ) 0.793 - 1.151 ] , consistent with the previous primary analysis . Median OS was 14.0 months in the carboplatin-S-1 arm and 10.6 months in the carboplatin-paclitaxel arm ( HR 0.713 ; 95 % CI 0.476 - 1.068 ) for patients with squamous cell carcinoma ( SCC ) , with corresponding values of 15.5 and 13.9 months ( HR 1.060 ; 95 % CI 0.859 - 1.308 ) for those with non-SCC . CONCLUSIONS These results establish the efficacy and safety of carboplatin-S-1 in patients with advanced NSCLC regardless of tumor histology BACKGROUND Findings from the phase 3 First-Line ErbituX in lung cancer ( FLEX ) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone ( hazard ratio [ HR ] 0·871 , 95 % CI 0·762 - 0·996 ; p=0·044 ) in patients with advanced non-small-cell lung cancer ( NSCLC ) . To define patients benefiting most from cetuximab , we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients . METHODS We used prospect ively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0 - 300 . We used response data to select an outcome -based discriminatory threshold immunohistochemistry score for EGFR expression of 200 . Treatment outcome was analysed in patients with low ( immunohistochemistry score < 200 ) and high ( ≥200 ) tumour EGFR expression . The primary endpoint in the FLEX study was overall survival . We analysed patients from the FLEX intention-to-treat ( ITT ) population . The FLEX study is registered with Clinical Trials.gov , number NCT00148798 . FINDINGS Tumour EGFR immunohistochemistry data were available for 1121 of 1125 ( 99·6 % ) patients from the FLEX study ITT population . High EGFR expression was scored for 345 ( 31 % ) evaluable patients and low for 776 ( 69 % ) patients . For patients in the high EGFR expression group , overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group ( median 12·0 months [ 95 % CI 10·2 - 15·2 ] vs 9·6 months [ 7·6 - 10·6 ] ; HR 0·73 , 0·58 - 0·93 ; p=0·011 ) , with no meaningful increase in side-effects . We recorded no corresponding survival benefit for patients in the low EGFR expression group ( median 9·8 months [ 8·9 - 12·2 ] vs 10·3 months [ 9·2 - 11·5 ] ; HR 0·99 , 0·84 - 1·16 ; p=0·88 ) . A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression ( p=0·044 ) . INTERPRETATION High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC . Assessment of EGFR expression could offer a personalised treatment approach in this setting . FUNDING Merck BACKGROUND In a large phase III study , cisplatin and pemetrexed had non-inferior efficacy and better tolerability compared with cisplatin and gemcitabine in chemonaïve patients with non-small cell lung cancer ( NSCLC ) . The current analysis characterised the clinical benefit ( i.e. survival ) relative to clinical risk ( i.e. drug-related toxicity ) of the doublets . PATIENTS AND METHODS A total of 1669 patients ( of 1725 r and omised ) received 500 mg/m(2 ) pemetrexed IV followed by 75 mg/m(2 ) cisplatin IV on day 1 or gemcitabine 1250 mg/m(2 ) on days 1 and 8 and 75 mg/m(2 ) cisplatin on day 1 , administered every 3 weeks for up to 6 cycles . Survival without toxicity ( i.e. clinical benefit to risk ) was defined as the time from r and omisation to the first occurrence of any grade 3 or 4 drug-related toxicity or death , and was analysed using Kaplan-Meier and Cox methods . RESULTS In the overall patient population , survival without grade 3 or 4 drug-related toxicity was significantly longer for patients treated with cisplatin and pemetrexed versus cisplatin and gemcitabine ( HR=0.70 ; P<0.001 ) , as was survival without grade 4 drug-related toxicity ( HR=0.83 ; P<0.001 ) . For patients with non-squamous NSCLC , survival without toxicity with cisplatin and pemetrexed was superior to cisplatin and gemcitabine for grade 3 or 4 drug-related toxicity ( HR=0.64 ; P<0.001 ) and for grade 4 drug-related toxicity ( HR=0.77 ; P<0.001 ) , whereas no treatment-arm difference was observed in the squamous subgroup . CONCLUSIONS Patients with non-squamous NSCLC treated with front-line cisplatin and pemetrexed have superior survival without toxicity ( i.e. clinical benefit-to-risk profile ) compared with patients treated with cisplatin and gemcitabine BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However , the reliability of data obtained with most quality assessment scales has not been established . This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions . METHOD In the first study , 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base . In the second study , 2 raters rated 120 RCTs r and omly selected from the PEDro data base , and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings . The process was repeated by independent raters to create a second set of individual and consensus ratings . Reliability of ratings of PEDro scale items was calculated using multirater kappas , and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ) . RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters . The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals , and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ) . DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from " fair " to " substantial , " and the reliability of the total PEDro score was " fair " to " good . Introduction : The phase 3 MONET1 study evaluated motesanib ( a small-molecule inhibitor of vascular endothelial growth factor receptors ) plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel as first-line therapy for advanced non – small-cell lung cancer ( NSCLC ) . Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received  motesanib . Enrollment of patients with nonsquamous histology was temporarily halted , but resumed following a protocol amendment ( Scagliotti et al. J Clin Oncol . 2012;30:2829–2836 ) . Herein , we report data from the squamous cohort . Methods : Patients with stage IIIB/IV or recurrent squamous NSCLC ( without prior systemic therapy for advanced disease ) received up to six 3-week cycles of chemotherapy ( carboplatin , area under the curve 6 mg/mL•min/paclitaxel , 200 mg/m2 ) and were r and omized 1:1 to receive motesanib 125 mg ( Arm A ) or placebo ( Arm B ) once daily . The primary end point was overall survival . Results : Three-hundred and sixty patients with squamous NSCLC were r and omized ( Arm A , n = 182 ; Arm B , n = 178 ) between July 2007 and November 2008 . Twenty-three patients ( 13 % ) in Arm A and 10 ( 6 % ) in Arm B had fatal adverse events within the first 60 days of treatment . Among these , six patients in Arm A , but none in Arm B , had fatal bleeding events . At final analysis , serious adverse events had occurred in 47 % of patients in Arm A and 29 % of patients in Arm B. Median overall survival was similar in Arms A and B ( 11.1 versus 10.7 months ) . Conclusions : Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC On August 19 , 2004 , pemetrexed for injection ( Alimta ) ; Eli Lilly and Company , Indianapolis , IN , http://www.lilly.com ) received accelerated approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer ( NSCLC ) who had received prior chemotherapy . Approval was primarily based on a single , controlled , unblinded trial . Five hundred seventy-one protocol -eligible patients were r and omized to receive either pemetrexed or docetaxel ( Taxotere ) ; Aventis Pharmaceuticals Inc. , Bridgewater , NJ , http://www.aventispharmaus.com ) . The primary efficacy end point was overall survival . The median survival times were 8.3 months in the pemetrexed arm and 7.9 months in the docetaxel arm . Neither superiority nor noninferiority for overall survival could be demonstrated , the latter because a reliable and consistent survival effect of docetaxel could not be estimated and because of significant crossover of pemetrexed-treated patients to docetaxel after tumor progression . Comparable response rates , 9.1 % for pemetrexed and 8.8 % for docetaxel , times to progressive disease , and progression-free survival times supported the conclusion that an effect of pemetrexed on survival was reasonably likely , however . In addition , pemetrexed was felt to have a more favorable safety profile than docetaxel . Of greatest importance , pemetrexed caused significantly less neutropenia , febrile neutropenia , neutropenic infections , and need for granulocyte/macrophage colony-stimulating factors BACKGROUND Use of cetuximab , a monoclonal antibody targeting the epidermal growth factor receptor ( EGFR ) , has the potential to increase survival in patients with advanced non-small-cell lung cancer . We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer . METHODS In a multinational , multicentre , open-label , phase III trial , chemotherapy-naive patients ( > or=18 years ) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were r and omly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy . Chemotherapy was cisplatin 80 mg/m(2 ) intravenous infusion on day 1 , and vinorelbine 25 mg/m(2 ) intravenous infusion on days 1 and 8 of every 3-week cycle ) for up to six cycles . Cetuximab-at a starting dose of 400 mg/m(2 ) intravenous infusion over 2 h on day 1 , and from day 8 onwards at 250 mg/m(2 ) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred . The primary endpoint was overall survival . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00148798 . FINDINGS Between October , 2004 , and January , 2006 , 1125 patients were r and omly assigned to chemotherapy plus cetuximab ( n=557 ) or chemotherapy alone ( n=568 ) . Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group ( median 11.3 months vs 10.1 months ; hazard ratio for death 0.871 [ 95 % CI 0.762 - 0.996 ] ; p=0.044 ) . The main cetuximab-related  adverse event was acne-like rash ( 57 [ 10 % ] of 548 , grade 3 ) . INTERPRETATION Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer . FUNDING Merck PURPOSE Cyclooxygenase-2 ( COX-2 ) protein expression in patients with non-small-cell lung cancer ( NSCLC ) may be not only a prognostic marker but also predictive for COX-2 inhibition . We hypothesized that COX-2 expression is associated with shorter survival and that celecoxib , being a potent COX-2 inhibitor , increases tumor response and survival . PATIENTS AND METHODS A phase III study was performed in patients with stage IIIb/IV NSCLC who had pathologic confirmation , no prior chemotherapy , Eastern Cooperative Oncology Group performance status of 0 to 2 , and adequate organ function . Treatment consisted of docetaxel and carboplatin every 3 weeks for five cycles . Patients were r and omly assigned to receive celecoxib 400 mg or placebo twice daily . COX-2 expression on tumor cells was detected by immunohistochemistry . Primary end point was overall survival ( OS ) . RESULTS From July 2003 to December 2007 , 561 patients were r and omly assigned .  Toxicity was mild , and no increase in cardiovascular events was observed . Tumor response was 38 % in the celecoxib arm and 30 % in the placebo arm ( P = .08 ) . Median progression-free survival was 4.5 months ( 95 % CI , 4.0 to 4.8 ) for the celecoxib arm and 4.0 months ( 95 % CI , 3.6 to 4.9 ) for the placebo arm ( hazard ratio [ HR ] , 0.8 ; 95 % CI , 0.6 to 1.1 ; P = .25 ) . Median OS was 8.2 months ( 95 % CI , 7.5 to 8.8 ) for both treatment arms ( HR , 0.9 ; 95 % CI , 0.6 to 1.2 ; P = .32 ) . COX-2 expression did not independently predict survival . Benefit from celecoxib , restricted to patients with low COX-2 expression , was not significant when adjusted for prognostic factors . CONCLUSION In advanced NSCLC , celecoxib does not improve survival . In this study , COX-2 expression was not a prognostic biomarker and had no predictive value when celecoxib was added to chemotherapy PURPOSE This phase III , multicenter , r and omized , placebo-controlled trial assessed the efficacy and safety of sorafenib , an oral multikinase inhibitor , in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Nine hundred twenty-six patients were r and omly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2 ) ( CP ) on day 1 , followed by either sorafenib 400 mg twice a day ( n = 464 , arm A ) or placebo ( n = 462 , arm B ) on days 2 to 19 . The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day . The primary end point was overall survival ( OS ) ; secondary end points included progression-free survival and tumor response . RESULTS Overall demographics were balanced between arms ; 223 patients ( 24 % ) had squamous cell histology . On the basis of a planned interim analysis , median OS was 10.7 months in arm A and 10.6 months in arm B ( hazard ratio [ HR ] = 1.15 ; 95 % CI , 0.94 to 1.41 ; P = .915 ) . The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point . A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B ( HR = 1.85 ; 95 % CI , 1.22 to 2.81 ) . Main grade 3 or 4 sorafenib-related toxicities included rash ( 8.4 % ) , h and -foot skin reaction ( 7.8 % ) , and diarrhea ( 3.5 % ) . CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC PURPOSE This phase III trial compared the efficacy and safety of albumin-bound paclitaxel ( nab-paclitaxel ) plus carboplatin with solvent-based paclitaxel ( sb-paclitaxel ) plus carboplatin in advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS In all , 1,052 untreated patients with stage IIIB to IV NSCLC were r and omly assigned 1:1 to receive 100 mg/m(2 ) nab-paclitaxel weekly and carboplatin at area under the concentration-time curve ( AUC ) 6 once every 3 weeks ( nab-PC ) or 200 mg/m(2 ) sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks ( sb-PC ) . The primary end point was objective overall response rate ( ORR ) . RESULTS On the basis of independent assessment , nab-PC demonstrated a significantly higher ORR than sb-PC ( 33 % v 25 % ; response rate ratio , 1.313 ; 95 % CI , 1.082 to 1.593 ; P = .005 ) and in patients with squamous histology ( 41 % v 24 % ; response rate ratio , 1.680 ; 95 % CI , 1.271 to 2.221 ; P < .001 ) . nab-PC was as effective as sb-PC in patients with nonsquamous histology ( ORR , 26 % v 25 % ; P = .808 ) . There was an approximately 10 % improvement in progression-free survival ( median , 6.3 v 5.8 months ; hazard ratio [ HR ] , 0.902 ; 95 % CI , 0.767 to 1.060 ; P = .214 ) and overall survival ( OS ; median , 12.1 v 11.2 months ; HR , 0.922 ; 95 % CI , 0.797 to 1.066 ; P = .271 ) in the nab-PC arm versus the sb-PC arm , respectively . Patients ≥ 70 years old and those enrolled in North America showed a significantly increased OS with nab-PC versus sb-PC . Significantly less grade ≥ 3 neuropathy , neutropenia , arthralgia , and myalgia occurred in the nab-PC arm , and less thrombocytopenia and anemia occurred in the sb-PC arm . CONCLUSION The administration of nab-PC as first-line therapy in patients with advanced NSCLC was efficacious and result ed in a significantly improved ORR versus sb-PC , achieving the primary end point . nab-PC produced less neuropathy than sb-PC PURPOSE Three phase III trials have shown pemetrexed to be associated with improved clinical outcomes among patients with adenocarcinoma and large cell histology compared with patients with squamous histology in advanced non-small cell lung cancer ( NSCLC ) . The current retrospective analysis examined whether differences were present by histology in a three-arm trial of gemcitabine-carboplatin ( GCb ) or gemcitabine-paclitaxel ( GP ) versus a st and ard regimen of paclitaxel-carboplatin ( PCb ) . MATERIAL S AND METHODS 1135 chemonaïve patients with stage IIIB or IV NSCLC were r and omly allocated to receive : gemcitabine 1000 mg/m(2 ) days 1 and 8 plus carboplatin area under the curve ( AUC ) 5.5 day 1 ( GCb ) ; or gemcitabine 1000 mg/m(2 ) days 1 and 8 plus paclitaxel 200mg/m(2 ) day 1 ( GP ) ; or paclitaxel 225 mg/m(2 ) plus carboplatin AUC 6.0 day 1 ( PCb ) . Cycles were repeated every 21 days up to 6 cycles or disease progression . Clinical results were retrospectively analyzed in by patient histology . RESULTS 202 patients ( 17.8 % ) had squamous , 555 ( 48.9 % ) had adenocarcinoma , 45 ( 4.0 % ) had large cell , and 333 ( 29.3 % ) had another histologic type . The overall response rate for squamous patients was greater than non-squamous ( 35.1 % versus 27.8 % , P=0.04 ) . Median survival ( 9.5 months for squamous and 8.3 months for non-squamous ) and median time to progression ( 5.0 months for squamous and 4.4 months for non-squamous ) did not significantly vary by histologic group . For squamous histology , median survival was 6.6 months for GCb , 10.2 months for GP , and 10.3 months for PCb . For non-squamous disease , median survival was 8.2 months for GCb , 8.4 months for GP , and 8.3 months for PCb . A formal test for a histology-by-treatment interaction effect between GCb and PCb was significant ( P=0.04 ) . CONCLUSION In this trial of commonly used agents for advanced NSCLC , overall survival and time to progression were similar when comparing patients across histologies . The effect of treatment , however , varied across histologies PURPOSE Cancer and Leukemia Group B conducted a r and omized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy ( TRT ) . PATIENTS AND METHODS Patients with unresectable stage III non-small-cell lung cancer ( NSCLC ) were r and omly assigned to carboplatin ( area under the curve , 5 ) and pemetrexed ( 500 mg/m(2 ) ) every 21 days for four cycles and TRT ( 70 Gy ; arm A ) or the same treatment with cetuximab administered concurrent only with TRT ( arm B ) . Patients in both arms received up to four cycles of pemetrexed as consolidation therapy . The primary end point was the 18-month overall survival ( OS ) rate ; if the 18-month OS rate was ≥ 55 % , the regimen(s ) would be considered for further study . RESULTS Of the 101 eligible patients enrolled ( 48 in arm A and 53 in arm B ) , 60 % were male ; the median age was 66 years ( range , 32 to 81 years ) ; 44 % and 35 % had adenocarcinoma and squamous carcinoma , respectively ; and more patients enrolled onto arm A compared with arm B had a performance status of 0 ( 58 % v 34 % , respectively ; P = .04 ) . The 18-month OS rate was 58 % ( 95 % CI , 46 % to 74 % ) in arm A and 54 % ( 95 % CI , 42 % to 70 % ) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed ( P = .667 ) . The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy . CONCLUSION The combination of pemetrexed , carboplatin , and TRT met the prespecified criteria for further evaluation . This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC PURPOSE Figitumumab ( CP-751,871 ) , a fully human immunoglobulin G2 monoclonal antibody , inhibits the insulin-like growth factor 1 receptor ( IGF-1R ) . Our multicenter , r and omized , phase III study compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histology received open-label  figitumumab ( 20 mg/kg ) plus paclitaxel ( 200 mg/m(2 ) ) and carboplatin ( area under the concentration-time curve , 6 mg · min/mL ) or paclitaxel and carboplatin alone once every 3 weeks for up to six cycles . The primary end point was overall survival ( OS ) . RESULTS Of 681 r and omly assigned patients , 671 received treatment . The study was closed early by an independent Data Safety Monitoring Committee because of futility and an increased incidence of serious adverse events ( SAEs ) and treatment-related deaths with figitumumab . Median OS was 8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone ( hazard ratio [ HR ] , 1.18 ; 95 % CI , 0.99 to 1.40 ; P = .06 ) ; median progression-free survival was 4.7 months ( 95 % CI , 4.2 to 5.4 ) and 4.6 months ( 95 % CI , 4.2 to 5.4 ) , respectively ( HR , 1.10 ; P = .27 ) ; the objective response rates were 33 % and 35 % , respectively . The respective rates of all-causality SAEs were 66 % and 51 % ; P < .01 ) . Treatment-related grade 5 adverse events were also more common with figitumumab ( 5 % v 1 % ; P < .01 ) . CONCLUSION Adding figitumumab to st and ard chemotherapy failed to increase OS in patients with advanced nonadenocarcinoma NSCLC . Further clinical development of figitumumab is not being pursued This communication represents the definitive report of a r and omized phase III study comparing cisplatin and carboplatin , in combination with vindesine and mitomycin C in stage IIIB and IV squamous-cell bronchogenic carcinoma . A total of 221 patients entered the study and were r and omized into two arms . Of these , 114 patients ( 109 evaluable for activity ) were r and omized to arm A , receiving cisplatin 120 mg/m(2 ) , mitomycin C 8 mg/m(2 ) and vindesine 3 mg/m(2 ) per cycle ; 107 patients ( 101 evaluable for activity ) were r and omized to arm B receiving carboplatin 500 mg/m(2 ) with the same doses of mitomycin C and vindesine per cycle . Patients with progressive disease ( PD ) were excluded from the study after the 2nd cycle , and those with stable disease ( SD ) , partial response ( PR ) and complete response ( CR ) received six cycles of chemotherapy ( or less in case of early progression ) . Patients were stratified according to the clinical stage ( IIIB vs. IV ) , performance status ( 0 + 1 vs. 2 + 3 ) and tumor histological grade ( I+II vs. III ) . In the cisplatin arm two patients ( 1.9 % ) achieved a CR , 38 ( 34.9 % ) a PR , 45 ( 41.2 % ) a SD and 24 ( 22.0 % ) had PD ; the overall response rate was 40/109 ( 36.8 % ) . In the carboplatin arm five patients ( 5.0 % ) achieved a CR , 31 ( 30.7 % ) a PR , 40 ( 39.6 % ) a SD , and 25 ( 24.7 % ) had PD ; the overall response rate was 36/101 ( 35.7 % ) . No statistically significant difference in response rate was present between the two arms , and the response rate was not influenced by performance status , histological grade or clinical stage . The Kaplan-Meyers curves displayed a significant advantage both for time to progression ( P=0.005 ) and overall survival ( P=0.008 ) for patients in the carboplatin arm . The advantage for patients receiving carboplatin instead of cisplatin appeared evident in univariate setting for patients with a good performance status and clinical stage IV , and occurred irrespectively of tumor histological grade ; response duration and survival of responders was identical in the two arms . Patients achieving a stable disease survived longer in the carboplatin than in the cisplatin arm ( P=0.012 ) . Thus , substitution of cisplatin by carboplatin in the combination chemotherapy regimen , although more hematologically toxic ( but less emetogenic ) result ed in a similar response rate , but a significantly longer time to progression and overall survival Introduction : The combination of paclitaxel/carboplatin ( PC ) and bevacizumab ( B ) was previously shown to extend overall survival ( OS ) in patients with advanced nonsquamous non-small cell lung cancer ( NSCLC ) . An analysis of survival and safety outcomes based on histology is presented here . Methods : Patients with cytologically or histologically confirmed metastatic NSCLC were treated with PC + B ( PCB ) or PC .  Median OS for all patients was determined using Kaplan-Meier methodology . Hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) were obtained using an unstratified Cox proportional hazards model . Histology-by-treatment interaction was tested with an unstratified multivariate Cox regression model . Results : A total of 444 patients were r and omized to PC , and 434 patients were r and omized to PCB ( the intent-to-treat population ) . Median OS times were 10.3 and 12.3 months for PC and PCB , respectively , with an HR for PCB of 0.80 ( 95 % CI : 0.69 - 0.93 ) . A total of 68.8 % of patients had adenocarcinoma histology ; 18.9 % had “ not otherwise specified ” ; 5.5 % had large cell undifferentiated ; 2.6 % had bronchoalveolar carcinoma ; and 3.9 % “ other . ” For adenocarcinoma , median OS was 10.3 months for PC treatment ( n = 302 ) and 14.2 months for PCB ( n = 300 ) , HR 0.69 ( 95%CI : 0.58 - 0.83 ) . Sample sizes for other specific histologic subtypes were too small for meaningful comparisons . Safety profiles among histologies were consistent with the overall safety profile , and there were no unexpected adverse event trends . Conclusions : Addition of B to PC is associated with increased survival in previously untreated patients with nonsquamous NSCLC . Adenocarcinoma was associated with an increased survival benefit of PCB treatment . Data for other histologies are inconclusive , primarily because of small patient sample sizes and large CIs PURPOSE A multicenter r and omized phase II trial to evaluate two treatment strategies in the first-line management of advanced non-small-cell lung cancer ( NSCLC ) patients with a performance status ( PS ) of 2 . PATIENTS AND METHODS Patients were assigned to erlotinib 150 mg orally daily until progression or to carboplatin ( area under the curve [ AUC ] 6 ) and paclitaxel ( 200 mg/m(2 ) day 1 every 3 weeks ) for up to four cycles . Patients who experienced progression or did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib . The primary end point was progression-free survival ( PFS ) . Secondary end points were response , survival , quality of life ( QOL ) , and a retrospective molecular correlation . RESULTS Fifty-two patients were r and omly assigned to erlotinib and 51 to chemotherapy .  Partial responses were 2 % and 12 % , respectively . Median PFS was 1.9 months in the erlotinib arm and 3.5 months in the chemotherapy arm ( hazard ratio [ HR ] = 1.45 ; 95 % CI , 0.98 to 2.15 ; P = .06 ) . Median survival times were 6.5 and 9.7 months , respectively ( HR = 1.73 ; 95 % CI , 1.09 to 2.73 ; P = .018 ) . Patients who crossed over to erlotinib had a median survival of 14.9 months . Sex , histology , skin rash , and smoking history predicted outcome with erlotinib .  Rash and diarrhea were more common with erlotinib ;  emesis , alopecia , peripheral neuropathy , and fatigue were more common with chemotherapy .  QOL was similar between the two arms . Molecular correlation was limited by available sample s. CONCLUSION Unselected patients with advanced NSCLC and PS 2 are best treated with combination chemotherapy as first-line therapy . Erlotinib may be considered in patients selected by clinical or molecular markers
Background The objectives of this systematic review and meta- analysis were to compare the survival , toxicity , and quality of life of patients treated with necitumumab in combination with gemcitabine and cisplatin .
These agents were investigated in published r and omized controlled trials ( RCTs ) of patients with squamous non-small cell lung cancer ( NSCLC ) in the first-line setting .