Do Current Lung Cancer Screening Guidelines Apply for Populations With High Prevalence of Granulomatous Disease? Results From the First Brazilian Lung Cancer Screening Trial (BRELT1).

BACKGROUND: Low-dose computed tomography (LDCT) screening for lung cancer has been demonstrated to be effective in reducing cancer mortality. However, these studies have not been undertaken in countries where the incidence of granulomatous disease is high. The First Brazilian Lung Cancer Screening Trial (BRELT1) has completed initial accrual and is now in the follow-up phase. We present results from the initial prevalence round of screening. METHODS: The inclusion criteria were the same as those for the National Lung Cancer Screening Trial (NLST). Pulmonary nodules larger than 4 mm were considered positive and required evaluation by a multidisciplinary team. Indeterminate nodules were evaluated with fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) or biopsy when indicated. Statistical analysis was performed with Fisher's exact test to compare our positive findings with those of the NLST. RESULTS: From January 2013 to July 2014, 790 participants were enrolled. Positive LDCT scans were reported in 312 (39.4%) participants, with a total of 552 nodules larger than 4 mm. The comparison between positive findings in the NLST (7,191 of 26,722 cases) and those in the BRELT1 (312 of 790 cases) showed a significant difference (p < 0.001). The positive predictive value was lower in BRELT1 than in the NLST (3.2% versus 3.8%, respectively). Follow-up imaging was indicated in 278 of 312 (89.1%) participants; 35 procedures were performed in 25 participants. In 15 cases, benign lesions were diagnosed. Non-small-cell lung cancer (NSCLC) was diagnosed in 10 patients (prevalence of 1.3%). In 8 patients (stage IA/IB disease), treatment was by resection only, in 1 patient neoadjuvant chemotherapy was used (stage IIIA), and in 1 patient advanced disease was diagnosed (stage IV). CONCLUSIONS: Using NSLT criteria, a larger number of patients had positive scans (nodules), compared with previous lung cancer screening studies. However, the number of participants requiring surgical biopsy procedures and who were ultimately identified as having cancer was similar to other reports. This supports the role of screening in patient populations with a high incidence of granulomatous inflammation.

Weekly and every 2 weeks cetuximab maintenance therapy after platinum-based chemotherapy plus cetuximab as first-line treatment for non-small cell lung cancer: randomized non-comparative phase IIIb NEXT trial.

The First-Line Erbitux in Lung Cancer (FLEX) trial showed that the addition of cetuximab to chemotherapy followed by weekly cetuximab maintenance significantly improved survival in the first-line treatment of advanced non-small cell lung cancer (NSCLC). The phase IIIb NSCLC Erbitux Trial (NEXT) trial (NCT00820755) investigated the efficacy and safety of weekly and every 2 weeks cetuximab maintenance therapy in this setting. Patients were treated with platinum-based chemotherapy plus cetuximab, and those progression-free after four to six cycles were randomized to every 2 weeks (500 mg/m(2)) or weekly (250 mg/m(2)) cetuximab maintenance. Randomization was stratified for tumor histology and response status. The primary endpoint for a regimen would be reached if the lower boundary of the 95 % confidence interval (CI) for the 1-year survival rate exceeded 55 %. A planned 480 patients were to be randomized. However, enrollment was curtailed following a negative opinion from the European Medicines Agency with regard to the use of cetuximab in this setting. After combination therapy, 311/583 (53.3 %) patients without progression were randomized to maintenance therapy: 157 to every 2 weeks cetuximab and 154 to weekly cetuximab. Baseline characteristics were balanced between these groups and exposure to cetuximab was similar. The 1-year survival rate was 62.8 % (95 % CI, 54.7-70.0) for every 2 weeks cetuximab and 64.4 % (95 % CI, 56.2-71.4) for weekly cetuximab. Safety profiles were similar, manageable, and in line with expectations. Therefore, in patients with advanced NSCLC who were progression-free after four to six cycles of first-line chemotherapy plus cetuximab, weekly and every 2 weeks cetuximab maintenance therapy were associated with similar survival outcomes.

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.

BACKGROUND: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 µg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING: Merck KGaA (Darmstadt, Germany).

Elderly subset analysis of randomized phase III study comparing pemetrexed plus carboplatin with docetaxel plus carboplatin as first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer.

BACKGROUND: Many physicians consider platinum-doublet chemotherapy inappropriate for elderly patients, regardless of their medical fitness. OBJECTIVE: This was a retrospective subgroup analysis of data from a multicenter, randomized, phase III clinical trial evaluating pemetrexed + carboplatin versus docetaxel + carboplatin in elderly chemo-naive patients with advanced, nonsquamous non-small cell lung cancer (NSCLC). METHODS: Data from elderly patients (aged ≥65 years and ≥70 years) were evaluated using the same statistical methods as those used in patients aged <70 years and qualified intent-to-treat (Q-ITT) populations. The primary objective of the clinical trial was comparison of pemetrexed + carboplatin with docetaxel + carboplatin in terms of survival without grade 3 or 4 toxicity in chemo-naive NSCLC patients. RESULTS: The ≥65- and ≥70-year age groups had 68 and 37 patients, respectively. Among patients aged ≥65 years, the adjusted hazard ratio (HR) for survival without grade 3-4 toxicity (HR 0.40, 95 % confidence interval [CI] 0.23-0.70) favored pemetrexed + carboplatin; this was similar to the HRs in patients aged ≥70 years (HR 0.43, 95 % CI 0.20-0.92), patients aged <70 years (HR 0.44, 95 % CI 0.32-0.62), and the Q-ITT population (HR 0.45, 95 % CI 0.34-0.61). The median values for overall survival (OS) and progression-free survival (PFS) were similar across all age-group subsets and the Q-ITT population. The HRs for OS and PFS were similar for all age-group subsets, except for the ≥70-year age group, which favored pemetrexed + carboplatin to a greater extent. The toxicity profile was similar across age groups, with the exception of diarrhea, mucosal inflammation, and grade 3-4 neutropenia and leukopenia, which were slightly more common in elderly patients in both treatment arms. Between-arm differences in the toxicity profiles for the ≥65-, ≥70- and <70-year age subgroups were similar to those in the Q-ITT population. There were no on-study deaths or unexpected toxicities. CONCLUSION: The benefits of pemetrexed + carboplatin were maintained, and toxicity was manageable in both elderly subgroups. The favorable risk-benefit profile of pemetrexed + carboplatin makes it an appropriate first-line treatment option for elderly patients with advanced nonsquamous NSCLC.

Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2.

PURPOSE: To compare single-agent pemetrexed (P) versus the combination of carboplatin and pemetrexed (CP) in first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. PATIENTS AND METHODS: In a multicenter phase III randomized trial, patients with advanced NSCLC, ECOG PS of 2, any histology at first and later amended to nonsquamous only, no prior chemotherapy, and adequate organ function were randomly assigned to P alone (500 mg/m(2)) or CP (area under the curve of 5 and 500 mg/m(2), respectively) administered every 3 weeks for a total of four cycles. The primary end point was overall survival (OS). RESULTS: A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. The response rates were 10.3% for P and 23.8% for CP (P = .032). In the intent-to-treat population, the median PFS was 2.8 months for P and 5.8 months for CP (hazard ratio [HR], 0.46; 95% CI, 0.35 to 0.63; P < .001), and the median OS was 5.3 months for P and 9.3 months for CP (HR, 0.62; 95% CI, 0.46 to 0.83; P = .001). One-year survival rates were 21.9% and 40.1%, respectively. Similar results were seen when patients with squamous disease were excluded from the analysis. Anemia (grade 3, 3.9%; grade 4, 11.7%) and neutropenia (grade 3, 1%; grade 4, 6.8%) were more frequent with CP. There were four treatment-related deaths in the CP arm. CONCLUSION: Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2.

Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study.

BACKGROUND: No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC. METHODS: Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m(2) on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825. FINDINGS: Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group). INTERPRETATION: Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC. FUNDING: AstraZeneca.

Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.

INTRODUCTION: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. METHODS: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. RESULTS: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. CONCLUSION: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

Randomized phase 2b study of pralatrexate versus erlotinib in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) after failure of prior platinum-based therapy.

INTRODUCTION: Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease. METHODS: In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) ≥1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more. RESULTS: A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%. CONCLUSIONS: Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit.

Chemotherapy beyond first-line in stage IV metastatic non-small cell lung cancer / Quimioterapia em câncer de pulmão não pequenas células metastático estádio IV: além da primeira linha

OBJECTIVE: Platinum-based doublet chemotherapy is considered the standard of care for advanced non-small cell lung cancer (NSCLC). However, prognosis after recurrent or progressive disease following first-line chemotherapy is usually poor. Maintenance chemotherapy, second line treatment and even third line chemotherapy are available for patients with advanced NSCLC. Unfortunately, few patients are candidates for chemotherapy beyond first line. The present study evaluated characteristics of patients with NSCLC and outcomes of the treatment of their metastatic disease, with emphasis on second and third-line chemotherapy. METHODS: This was a retrospective observational study of 2,673 patients with metastatic, stage IV, non-small cell lung cancer admitted for treatment in two São Paulo institutions. First-line chemotherapy was defined as the first chemotherapeutic approach administered to the patient. Second and third-line chemotherapy were defined as the systemic treatment administered after discontinuing first-line chemotherapy, either for intolerance or for progressive or recurrent disease. RESULTS: Most patients (57.9 percent) received first-line chemotherapy, and approximately 23.4 percent received second-line and 8 percent third-line regimens. Only 2.5 percent received fourth-line chemotherapy. Median overall survival (OS) was 8 months (95 percent CI: 8-9 months). At univariate analyses, gender (p < 0.05), histology, first-line chemotherapy, objective response to first-line chemotherapy and second-line chemotherapy (p < 0.01) were prognostic factors related to overall survival. At multivariate analysis, only performance status (p = 0.04), receiving any second-line chemotherapy (p < 0.01) and response to first-line chemotherapy (p < 0.01) were independent predictors of overall survival. CONCLUSION: Second-line chemotherapy is a therapeutic strategy that should be considered for a selected group of patients. Performance status and response to first-line chemotherapy could be determinant characteristics to select patients who might be treated beyond first-line chemotherapy.

OBJETIVO: A quimioterapia dupla com base em platina consiste no tratamento padrão para o câncer de pulmão não pequenas células (CPNPC) avançado. Contudo, o prognóstico dos pacientes com doença recorrente ou em progressão após a quimioterapia de primeira linha é ruim. Quimioterapia de manutenção, de segunda linha e até de terceira linha são tratamentos válidos para pacientes com CPNPC de estádio avançado. Infelizmente, poucos pacientes são candidatos para o tratamento quimioterápico além daquele de primeira linha. O presente estudo avalia as características de pacientes com CPNPC e os resultados do tratamento da doença metastática, com ênfase na quimioterapia de segunda e de terceira linha. MÉTODOS: Este é um estudo observacional e retrospectivo de 2.673 pacientes com CPNPC metastático, estádio IV, admitidos para tratamento em duas instituições de São Paulo, SP. A quimioterapia de primeira linha foi definida como a primeira abordagem quimioterápica administrada ao paciente. Quimioterapias de segunda e de terceira linha foram definidas como tratamento sistêmico administrado após a interrupção da quimioterapia de primeira linha, seja por intolerância ou por doença em progressão ou recorrente. RESULTADOS: A maioria dos pacientes (57,9 por cento) foi submetida à quimioterapia de primeira linha; aproximadamente 23,4 por cento receberam quimioterapia de segunda linha e 8 por cento de terceira. Apenas 2,5 por cento foram submetidos ao regime de quarta linha. A sobrevida global mediana (OS) foi de 8 meses (IC 95 por cento: 8-9 meses). Na análise univariada, sexo (p < 0,05), histologia, quimioterapia de primeira linha, resposta imparcial à quimioterapia de primeira linha e quimioterapia de segunda linha (p < 0,01) foram fatores prognósticos relacionados com a sobrevida global. Na análise multivariada, status de performance (p = 0,04), submissão do paciente a qualquer tipo de quimioterapia de segunda linha (p < 0,01) e resposta à quimioterapia de primeira linha (p < 0,01) foram os únicos fatores independentes preditivos de maior sobrevida. CONCLUSÃO: A quimioterapia de segunda linha é uma estratégia terapêutica a ser considerada em seletos grupos de pacientes. O status de performance e a resposta à quimioterapia de primeira linha poderiam ser alguns dos fatores determinantes durante o processo de seleção dos pacientes que deverão ser submetidos a regimes quimioterápicos além da primeira linha.

Chemotherapy beyond first-line in stage IV metastatic non-small cell lung cancer.

OBJECTIVE: Platinum-based doublet chemotherapy is considered the standard of care for advanced non-small cell lung cancer (NSCLC). However, prognosis after recurrent or progressive disease following first-line chemotherapy is usually poor. Maintenance chemotherapy, second line treatment and even third line chemotherapy are available for patients with advanced NSCLC. Unfortunately, few patients are candidates for chemotherapy beyond first line. The present study evaluated characteristics of patients with NSCLC and outcomes of the treatment of their metastatic disease, with emphasis on second and third-line chemotherapy. METHODS: This was a retrospective observational study of 2,673 patients with metastatic, stage IV, non-small cell lung cancer admitted for treatment in two São Paulo institutions. First-line chemotherapy was defined as the first chemotherapeutic approach administered to the patient. Second and third-line chemotherapy were defined as the systemic treatment administered after discontinuing first-line chemotherapy, either for intolerance or for progressive or recurrent disease. RESULTS: Most patients (57.9%) received first-line chemotherapy, and approximately 23.4% received second-line and 8% third-line regimens. Only 2.5% received fourth-line chemotherapy. Median overall survival (OS) was 8 months (95% CI: 8-9 months). At univariate analyses, gender (p < 0.05), histology, first-line chemotherapy, objective response to first-line chemotherapy and second-line chemotherapy (p < 0.01) were prognostic factors related to overall survival. At multivariate analysis, only performance status (p = 0.04), receiving any second-line chemotherapy (p < 0.01) and response to first-line chemotherapy (p < 0.01) were independent predictors of overall survival. CONCLUSION: Second-line chemotherapy is a therapeutic strategy that should be considered for a selected group of patients. Performance status and response to first-line chemotherapy could be determinant characteristics to select patients who might be treated beyond first-line chemotherapy.

Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer.

PURPOSE This phase III, multicenter, randomized, 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 randomly 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%), hand-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.

Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.

BACKGROUND: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. METHODS: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. FINDINGS: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001). INTERPRETATION: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. FUNDING: Eli Lilly.

Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I.

PURPOSE: This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted. RESULTS: A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm). CONCLUSION: The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.

Lung Cancer Symptom Scale outcomes in relation to standard efficacy measures: an analysis of the phase III study of pemetrexed versus docetaxel in advanced non-small cell lung cancer.

BACKGROUND: Patients with advanced non-small cell lung cancer (NSCLC) require care that emphasizes symptom palliation in addition to extending survival. The low response rates and minimal survival gains observed in second-line studies underscore the need to assess treatment efficacy with symptomatic end points. METHODS: To characterize the relationship between patient-reported health-related quality of life outcomes and efficacy end points (tumor response, overall survival [OS], progression-free survival [PFS]), retrospective analyses were performed on Lung Cancer Symptom Scale (LCSS) data (n = 488) from the phase III study of pemetrexed (500 mg/m2 once every 3 weeks) versus docetaxel (75 mg/m2 once every 3 weeks) in advanced NSCLC. The LCSS data consisted of patient ratings of six symptoms and three summary items using 100-mm visual analogue scales. The mean maximum improvement for each item was categorized according to best tumor response, with statistical analyses based on a two-factor interaction model (with treatment arm and response group as fixed factors). Additional analyses pooled data between treatment arms and examined correlation (nonparametric and Pearson's) of time to first worsening of symptoms (TWS) with PFS and OS. RESULTS: All LCSS items, except hemoptysis, showed mean maximum improvement over baseline for responders and patients with stable disease (p < 0.01), with greater improvement associated with response. Median TWS for each LCSS item ranged between 2.3 months (fatigue) and 7.0 months (cough), with correlation between TWS and PFS and OS (all p values

Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.

PURPOSE: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. METHODS: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). RESULTS: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. CONCLUSION: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.

Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.

BACKGROUND: Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer (NSCLC) is not known. We aimed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC. METHODS: 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were randomly assigned to observation (n=433) or to 30 mg/m(2) vinorelbine plus 100 mg/m(2) cisplatin (n=407). Postoperative radiotherapy was not mandatory and was undertaken according to every centre's policy. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN95053737. FINDINGS: 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment. 301 (36%) patients had stage IB disease, 203 (24%) had stage II disease, and 325 (39%) had stage IIIA disease. Tolerance to chemotherapy mainly included neutropenia in 335 (92%) patients and febrile neutropenia in 34 (9%); seven (2%) toxic deaths were also recorded. Compliance was greater with cisplatin than with vinorelbine (median dose intensity 89% [range 17-108] vs 59% [17-100]). After a median follow-up of 76 months (range 43-116), median survival was 65.7 months (95% CI 47.9-88.5) in the chemotherapy group and 43.7 (35.7-52.3) months in the observation group. Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls (hazard ratio 0.80 [95% CI 0.66-0.96]; p=0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). INTERPRETATION: Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, better defining indication of adjuvant chemotherapy.

Survival rates and tolerability of platinum-based chemotherapy regimens for elderly patients with non-small-cell lung cancer (NSCLC).

BACKGROUND: The combination therapy for non-small-cell lung cancer (NSCLC) with platinum-based treatment is well known, but its utility in elderly has not been explored systematically. AIM: To examine whether aging compromises survival or exacerbates toxicity in patients with advanced lung cancer receiving platinum-based treatment. METHODS: We performed a nested case-control study in a cohort of chemotherapy naïve patients enrolled January 1998-December 2003. Cases were consecutive patients over 70 at diagnosis with stage III or IV NSCLC. Controls were a subset of patients under 70 years matched by stage and year in which they had been treated. All patients received Cisplatin (80 mg/m2) or Carboplatin (4-6 AUC), every 4 weeks, followed by Vinorelbine (30 mg/m2) for a maximum of six courses. The medical history, physical examination and tumor imaging evaluation were performed at baseline and then monthly. Survival was calculated by Kaplan-Meier method and log-rank test was used for survival comparisons. Chi-squared test was used to compare side effects in the two groups. RESULTS: A total of 419 patients were identified for the case-control study (205 elderly/214 young) with 3.6 cycles per patient, on average. The 2- and 3-year survival rates were 20.5% and 6.8% for elderly patients and 9.8% and 2.3% for younger patients (p=0.017 and 0.014, respectively for 2 and 3 years). The proportion of patients with adverse effects, either grade 3 or 4, was the same in both groups at 2 years (43.9% versus 43.9%; p=0.99). CONCLUSIONS: Although elderly patients may self-select or be selected to be healthier, our findings suggest that elderly patients currently undergoing chemotherapy for lung cancer do as well or better than younger patients. Elderly age alone should not preclude patients from receiving platinum-based chemotherapy, since it seems well tolerated and effective in non-small-cell lung cancer among elderly patients.

Prospective randomized trial of silver nitrate vs talc slurry in pleurodesis for symptomatic malignant pleural effusions.

STUDY OBJECTIVES: To compare the efficacy and the safety of talc slurry and silver nitrate (SN) in the treatment of symptomatic malignant pleural effusions. PATIENTS AND METHODS: Sixty patients were enrolled into the study, and all received a chest tube (26F or 28F) that was placed using local anesthesia. The patients were randomized to receive either 5 g talc diluted to a total volume of 50 mL with saline solution or 20 mL 0.5% SN through the chest tube. Patients were clinically evaluated before and after treatment regarding pain, and were evaluated at monthly intervals with respect to the effectiveness of pleurodesis. Eleven patients did not return for their 30-day follow-up visit and were excluded from further analysis. Pleurodesis therapy was considered to be successful if there was no recurrence of the effusion. The patients who did not have a pleurodesis at one visit were excluded from subsequent visits. RESULTS: Forty-nine patients returned at 30 days for follow-up, including 24 patients who received SN and 25 who received talc. The groups were similar in age (p = 0.23), sex (p = 0.70), Karnofsky index (p = 0.94), and pathology (p = 0.68). After the induction of pleurodesis, neither the total mean (+/- SE) fluid drainage (SN, 901 +/- 125 mL; talc, 766 +/- 74 mL; p = 0.36) nor the level of pain (SN, 2.58 +/- 0.26; talc, 2.62 +/- 0.30; p = 0.91) differed significantly between the groups, and no patient in either group developed ARDS. The mean number of days spent in the hospital was nearly identical (SN group, 3.7 +/- 0.15 days; talc group, 3.6 +/- 0.13 days; p = 0.47). Both SN and talc were effective agents. Thirty days after the procedure, 23 of 24 patients (96%) who had received SN and 21 of 25 patients (84%) who had received talc showed an effective pleurodesis (p = 0.35). Similar results were observed after 60 days (SN group, 18 of 18 patients [100%]; talc group, 13 of 13 patients [100%]; p = > 0.99), 90 days (SN group, 16 of 16 patients [100%]; talc, 8 of 9 patients [89%]; p = 0.36), and 120 days (SN group, 4 of 4 patients [100%]; talc group, 4 of 4 patients [100%]; p > 0.99). CONCLUSIONS: The present study suggests that SN is an effective agent for producing a pleurodesis. In the present study, SN showed a tendency to be more effective than talc, but the power of the test to detect a significance difference was low in this small group of patients. The side effects of 0.5% SN appear to be minimal, but since only a small number of patients received SN and nearly 20% of the patients were lost to follow-up, significant long-term side effects cannot be excluded. Since SN appears to be as effective as talc, and since there is no evidence that it induces ARDS as has been reported with talc, it should be considered as an alternative to talc for the production of a pleurodesis.