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Objectives: To assess if induction radiochemotherapy followed by consolidation chemotherapy (arm A) will improve survival in comparison with the same chemotherapy given as induction followed by consolidation concurrent radiochemotherapy (arm B) in patients with unresectable non-metastatic non-small cell lung cancer (NSCLC)., Patients and Methods: Chemotherapy consisted in a combination of cisplatin with docetaxel, with one initial course for each patient, two courses in single modality therapy and weekly administration during chest irradiation (66 Gy)., Results: A total of 125 patients were randomised before early closure of the study because of poor accrual and an unplanned blind interim analysis which suggested that the continuation of the study would have been futile. Mature survival results showed no significant difference between both modalities with median survival times, respectively in arms A and B, of 19.6 months and 18.3 months, two years survival rates of 44% and 44% and five years survival rates of 23% and 26%. Toxicity was acceptable., Conclusions: Our randomised study did not demonstrate survival difference between induction concurrent radiochemotherapy followed by consolidation chemotherapy and induction chemotherapy followed by consolidation concurrent radiochemotherapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In May 2017, the second European Respiratory Society research seminar of the Thoracic Oncology Assembly entitled "Immunotherapy, a new standard of care in thoracic malignancies?" was held in Paris, France. This seminar provided an opportunity to review the basis of antitumour immunity and to explain how immune checkpoint inhibitors (ICIs) work. The main therapeutic trials that have resulted in marketing authorisations for use of ICIs in lung cancer were reported. A particular focus was on the toxicity of these new molecules in relation to their immune-related adverse events. The need for biological selection, currently based on immunohistochemistry testing to identify the tumour expression of programmed death ligand (PD-L)1, was stressed, as well as the need to harmonise PD-L1 testing and techniques. Finally, sessions were dedicated to the combination of ICIs and radiotherapy and the place of ICIs in nonsmall cell lung cancer with oncogenic addictions. Finally, an important presentation was dedicated to the future of antitumour vaccination and of all ongoing trials in thoracic oncology., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2018.)

Introduction: Classical therapeutic strategy for advanced and metastatic non-small cell lung cancer, without activable oncogenic driver mutation, has been based mainly on cytotoxic chemotherapy with modest benefits in terms of increased survival., Background: A better understanding of the mechanisms involved in the regulation of the immune system led to the development of antibodies directed against immune checkpoints such as PD-L1. The first encouraging clinical data from phase I studies assessing anti-PD1 and anti-PD-L1 antibodies have been confirmed in randomised phase III trials., Conclusions: These new drugs now constitute a standard second-line treatment for metastatic tumours and in the future, at least for pembrolizumab, in the first line. Their adjuvant role after locoregional treatment with curative intent is currently under investigation., (Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Brain metastases are a common complication of bronchial carcinoma (BC). There is no consensus as to the need to undertake a systematic search for these lesions during the initial assessment. The aim of this study was to evaluate the contribution of brain imaging in the initial evaluation of patients with CB., Methods: We undertook a retrospective analysis of patients treated in the Thoracic Oncology Clinic at the Institute Jules-Bordet between 01/09/2008 and 31/08/2013, who were treatment-naïve and were having a full diagnostic work-up including brain imaging., Results: Four hundred and sixty-three patients consecutively diagnosed with BC were included. Brain magnetic resonance imaging and/or CT-scan showed brain metastases in 101 patients (21.8%), of whom 67 had no symptoms suggestive of brain metastatic disease. The addition of a brain imaging into the work-up procedure resulted in a stage migration for 30 patients (6.5%), mainly otherwise staged IIIA (n=10) or IIIB (n=14) without brain imaging., Conclusion: The addition of brain imaging in the initial assessment of bronchial carcinoma allows the identification of brain metastases in one case among 5, of which 2/3 are asymptomatic. This leads to a change in staging, primarily for disease otherwise considered to be stage III., (Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: A working group has highlighted guidelines in thoracic oncology in Europe without study of their implementation, due to a lack of data., Methods: The records of 354 untreated lung cancer patients seen between January 2009 and December 2012 were reviewed. Any new treatment should have been proposed by a multidisciplinary consultation (MDC) in accordance with an oncology care program (OCP) based on the European Lung Cancer Working Party guidelines., Results: For the 354 patients, there were 636 MDC (332, 176, 81 and 47 in 1st, 2nd, 3rd and subsequent lines). For the first line, the MDC rate was 88%, in accordance with the OCP, and 75% of treatments were in agreement with the guidelines. For the 2nd and 3rd lines, the rates were 93% and 92% respectively (MDC), 90 and 89% (OCP), 55 and 63% (guidelines). In the first line, the main causes of non-compliance with the OCP were patient's refusal or doctor's choice and with guidelines a lack of adequate recommendations for specific situations such as comorbidities or the appearance of new treatments., Conclusion: The vast majority of patients are the subject of a MDC with a high rate of application of OCP. Guidelines should be updated regularly to incorporate new treatments., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: In a first study, we identified signatures of 3 mRNAs (semaphorin 3D [SEMA3D], cytokeratin 16 [KRT16] and UL16 binding protein 2 [ULBP2]) associated to response to a cisplatin-vinorelbin chemotherapy and to survival of advanced non-small cell lung cancers (NSCLC)., Material and Methods: The aim of this study was to develop immunohistochemistry tests for KRT16, ULBP2 and SEMA3D and to test proteins expression for prediction of response and survival in biopsies of the same patients., Results: We were not able to reproduce by the protein expression study the signature predicting response to chemotherapy in advanced NSCLC., Conclusion: We highlight the difficulties of translational research in thoracic oncology emphasizing the complexity in obtaining adequate tissue samples and the difficulties in conduction and transposing in routine practice high throughput technique for transcriptomic analyses., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor., Methods: Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease., Results: Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung., Conclusion: The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed., Trial Registration: ClinicalTrials.gov NCT00339586.

(18)F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I-II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22-1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I-III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27-1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I-III NSCLC, for squamous cell carcinoma and for adenocarcinoma., (Copyright ©ERS 2015.)

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are common in the therapeutic armentarium of lung cancer today. Initially tested in an unselected population, they have been of limited usefulness until the identification EGFR gene mutations. Activating mutations generate conformational changes that result in a shift toward an active state of the catalytic domain and are associated with sensitivity to first generation EGFR TKI. Other mutations have been associated with resistance to these drugs, but for rare mutations there is limited data concerning their role in predicting response to EGFR TKI. To date, four molecules have been approved for the treatment of EGFR mutated lung cancer. Gefitinib and/or erlotinib are available in almost all countries. Afatinib has been approved by the US Food and Drug Administration and by the European Medicines Agency, and icotinib has been approved only in China. Other, more active, third generation agents with a higher binding affinity for the receptor, or that are directed against specific mutations, are under development. EGFR TKIs have a favourable impact on progression-free survival when given as first line treatment in mutated patients, but may also have a moderate effect as a salvage therapy and in maintenance in an unselected population., (Copyright ©ERS 2015.)

Herein, we have reviewed and analysed recent literature, published in 2013 and early 2014, in the context of pre-existing data. Considered target therapies were tyrosine kinase inhibitors of active epidermal growth factor receptor mutations (e.g. erlotinib, gefinitib and afatinib), anaplastic lymphoma kinase rearrangements (e.g. crizotinib) or angiogenesis (drugs under development), or monoclonal antibodies against vascular endothelial growth factor (e.g. bevacizumab) or epidermal growth factor receptors (e.g. cetuximab). The therapeutic project has to consider tyrosine kinase inhibitors in the case of nonsmall cell lung cancer with active epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangement. However, these drugs should not be used in the absence of the targeted genetic abnormalities., (Copyright ©ERS 2015.)

The use of noninferiority randomised trials for patients with advanced non-small cell lung cancer has emerged during the past 10-15 years but has raised some issues related to their justification and methodology. The present systematic review aimed to assess trial characteristics and methodological aspects. All randomised clinical trials with a hypothesis of noninferiority/equivalence, published in English, were identified. Several readers extracted a priori defined methodological information. A qualitative analysis was then performed. We identified 20 randomised clinical trials (three phase II and 17 phase III), 11 of them being conducted in strong collaboration with industry. We highlighted some deficiencies in the reports like the lack of justification for both the noninferiority assumption and the definition of the noninferiority margin, as well as inconsistencies between the results and the authors' conclusions. CONSORT guidelines were better followed for general items than for specific items (p<0.001). Improvement in the reporting of the meth"odology of noninferiority/equivalence trials is needed to avoid misleading interpretation and to allow readers to be fully aware of the assumptions underlying the trial designs. They should be restricted to limited specific situations with a strong justification why a noninferiority hypothesis is acceptable., (Copyright ©ERS 2015.)

The objective of this review is to report the Clinical Year in Review proceedings in the field of thoracic oncology that were presented at the 2013 European Respiratory Society Annual Congress in Barcelona, Spain. Various topics were reviewed, including: epidemiology, screening, histology, and treatment of nonsmall cell lung cancer and small cell lung cancer.

Aim: While meta-analyses and clinical trials show improved survival in advanced NSCLC treated with platinum-containing chemotherapy, there are few data concerning front-line platinum-free ifosfamide-based regimens. We aimed to compare cisplatin-based chemotherapy to ifosfamide-gemcitabine (IG) with pre-defined second-line docetaxel., Patients and Methods: 693 Untreated advanced inoperable NSCLC cases were randomised to either GIP (gemcitabine, ifosfamide, cisplatin), DP (docetaxel, cisplatin) or IG. Primary outcome was overall survival., Results: Median age of the patients was 58 years with a predominance of males (75%), adenocarcinoma (56%), Karnofsky PS 80-100 (77%) and stage-IV disease (81%). Median survival times were 8.7, 8.8 and 8.3 months for IG, GIP and DP (p=0.79). GIP presented with (p<0.05) greater neutropenia, thrombopenia, vomiting, while greater cardiotoxicity, diarrhea, peripheral neuropathy were observed for DP and encephalopathy for IG., Conclusion: In advanced NSCLC, cisplatin-based CT is not superior to a platinum-free regimen (ifosfamide-gemcitabine) with a favourable toxicity profile.

Unlabelled: Clinical variables, like stage and performance status (PS), have predictive and prognostic values in advanced non-small cell lung cancer (NSCLC) patients treated with chemotherapy, not allowing adequate individual prediction. MicroRNA (miRNA) are non-coding RNAs regulating gene expression. In a prospective study, we assessed the predictive value for response and survival of tumour miRNA in NSCLC patients treated by 1st line cisplatin and vinorelbine. miRNA expression was analysed on a biopsy obtained during the diagnostic bronchoscopy, using TaqMan Low Density Arrays. The signature for response was derived using logistic regression with stepwise variable selection. The associations between overall survival and miRNA expression levels were estimated by using the Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models to estimate the hazard ratios. In total, 38 patients with adequate tumour biopsies, treated with cisplatin-vinorelbine were included: male (n = 27), 80-100 Karnofsky PS (n = 27), adenocarcinoma (n = 20), stage IV (n = 30). One patient was considered not assessable for response but remained included in the survival analyses. Out of the 37 patients assessable for response, 16 partial responses (43%) were observed. A two miRNA signature (miR-149 and miR-375) was found predictive for response and was also associated to progression-free survival (p = 0.05). Using a linear combination of the miR CT values with Cox's regression coefficients as weights, we constructed a prognostic score for overall survival including four miRNA (miR-200c, miR-424, miR-29c and miR-124). The signature distinguished patients with good (n = 18) and poor (n = 20) prognosis with respective median survival times of 47.3 months (95% CI 29.8-52.4) and 15.5 months (95% CI 9.1-22.8) (p < 0.001; hazard ratio 21.1, 95% CI 4.7-94.9)., Conclusions: miRNA signature allows predicting response and is of prognostic value for survival in patients with NSCLC treated with first line cisplatin and vinorelbine., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Induction cisplatin-based CT improves survival in resectable non-small cell lung cancer (NSCLC). We aimed to determine the respective activity of third-generation (gemcitabine-vinorelbine-cisplatin [GVP]) in comparison with second-generation drugs CT (mitomycine-ifosfamide-cisplatin [MIP]) and their cost-effectiveness as neoadjuvant CT before surgery in NSCLC. Patients with histologically proven initially untreated resectable stages I-III NSCLC were randomised between three courses of MIP or GVP followed by surgery. A two-stage Simon design was used for each arm with resectability rate as primary endpoint. A cost minimisation analysis, considering the direct medical costs, was performed in the Belgian and French social security systems. From 2001 to 2007, 140 patients (pts) were randomised (MIP 69, GVP 71). Main characteristics were: stage I/II/III in 52, 37 and 51 pts, squamous histology in 82 pts, male 114 pts, median PS 90. Objective response rates to induction CT were 60% (MIP) and 65% (GVP) (p=0.55). Complete resection rates were 77% (MIP) and 80% (GVP) (p=0.62). Median survival times were 47.2 months (MIP) and 36.6 months (GVP) (p=0.41). Cost-analyses showed significant incremental costs with GVP. In conclusion, while both neoadjuvant chemotherapy regimens shared similar efficacy in patients with resectable NSCLC, costs were significantly higher for third-generation regimens., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The present systematic review was performed under the auspices of the European Lung Cancer Working Party (ELCWP) in order to determine the role of early intermediate criteria (surrogate markers), instead of survival, in determining treatment efficacy in patients with lung cancer. Initially, the level of evidence for the use of overall survival to evaluate treatment efficacy was reviewed. Nine questions were then formulated by the ELCWP. After reviewing the literature with experts on these questions, it can be concluded that overall survival is still the best criterion for predicting treatment efficacy in lung cancer. Some intermediate criteria can be early predictors, if not surrogates, for survival, despite limitations in their potential application: these include time to progression, progression-free survival, objective response, local control after radiotherapy, downstaging in locally advanced nonsmall cell lung cancer (NSCLC), complete resection and pathological TNM in resected NSCLC, and a few circulating markers. Other criteria assessed in these recommendations are not currently adequate surrogates of survival in lung cancer.

Background: Registration trials demonstrated the activity of pemetrexed in non small cell lung carcinoma (NSCLC) either in combination with first-line agents or in monotherapy for salvage treatment. The aim of our implementation study was to verify, in an unselected population, the results obtained with pemetrexed salvage chemotherapy in clinical practice., Patients and Methods: The charts of all patients diagnosed with NSCLC, receiving pemetrexed for progressive disease after at least one previous course of chemotherapy, were retrospectively reviewed in two academic institutions. Response was assessed according to WHO and toxicity using the CTCAE and WHO criteria., Results: Between November 2004 and September 2009, 84 patients were given pemetrexed as second, third or greater than third line therapy (n=18/14/52). Intent-to-treat response rate was 11.9% (95% CI, 5%-18.8%). Median progression-free survival was 2.2 months and median survival time was 6.4 months. The most frequent grade 3-5 toxicity was neutropenia (23.9%)., Conclusion: Salvage chemotherapy with pemetrexed for progressing NSCLC confirmed, in an unselected population, who had been extensively treated previously, the level of activity observed in registration trials although a significant toxicity was noted., (Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Few data are available about the predictive value of FDG-PET-CT in the evaluation of the response to chemotherapy of patients with advanced NSCLC and its impact on subsequent survival., Methods: A retrospective study of patients with advanced NSCLC who underwent a FDG-PET-CT before treatment and after three cycles of first-line chemotherapy. Morphological and metabolic responses were assessed respectively using RECIST/OMS and EORTC criteria. The relation between response and survival was analysed through Cox regression models., Results: Fifty-nine patients were included in the study (stage IIIA/IIIB/IV: 9/11/39). Median survival was 40 weeks (44 deaths observed). The evaluation of treatment response (morphological or metabolic, taken alone or combined) in terms of survival failed to identify any difference between responders and patients with stable disease. Only patients with progressive disease had a significantly shorter survival. The negative predictive value of the metabolic response for the morphological response is 0.90 and that of metabolic progression for morphological progression is 0.98., Conclusion: Only progressive disease differs significantly from other types of response with a more sensitive and earlier detection by PET-CT., (Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: The clinical impact of c-erbB-3 has seldom been assessed in patients with non small cell lung cancer (NSCLC)., Patients and Methods: Forty-three NSCLC patients treated by erlotinib for c-erbB-3 and EGFR expression were investigated by immunohistochemistry analysis., Results: Two partial responses, one minor response, two stable diseases and twenty progressive diseases were observed at the first evaluation. Seventeen patients died before evaluation. Median EGFR expression was 70% of the cancer cells. Forty-two percent of the tumours co-expressed c-erbB-3 and EGFR without any difference according to histology or disease stage. There was no correlation between c-erbB-3 and EGFR expression. Median survival time was 2.6 months and the six months survival rate was 21%. There was no detectable impact of EGFR (p=0.94) or c-erbB-3 (p=0.93) expression on survival., Conclusion: In this small particular cohort of NSCLC patients receiving salvage therapy with erlotinib, there was no correlation between c-erbB-3 expression and clinical parameters, nor between cerbB-3/EGFR expression and outcome.

Introduction: Few validated prognostic factors are available for survival in patients with lung cancer. [F]-fluoro-2-deoxy-d-glucose positron emission tomography has been shown to be of additional value to conventional imaging for staging lung cancer. The prognostic value of this lung tumor metabolic activity was studied in a first systematic review of studies published until 2006., Methods: As further studies have appeared since 2006, this report has as objective to confirm and to estimate with less variability the prognostic value of primary tumor standardized uptake value (SUV) measured with [F]-fluoro-2-deoxy-d-glucose positron emission tomography on the basis of an updated search of eligible studies., Results: Ten additional studies were eligible for the updated review and eight of them provided, in the publication, data allowing survival results aggregation. All together, 21 studies were analyzed. Comparing patients with low and high SUV, using preferentially the median SUV value of each study as threshold, we obtained a poor prognostic value for high SUV compared with low SUV with an overall combined hazard ratio of 2.08, significantly different from one with a 95% confidence interval ranging from 1.69 to 2.56. No interaction between older and newer studies was detectable (P = 0.60) as well as between studies having selected non metastatic patients or studies without selection criterion related to stage (P = 0.46)., Conclusions: We confirmed the results of our previous review showing that SUV is potentially a very interesting factor for predicting patient outcome. We believe that a meta-analysis based on individual patient data would be of great value as allowing to assess the independent prognostic value, to take into account some factors responsible for heterogeneity between studies (SUV assessment method, disease stage, and histology), and to update survival data. We are planning to conduct such a meta-analysis on behalf of the International Association for the Study of Lung Cancer Staging Project.

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.

Cisplatin based chemotherapy for stage IV non small cell lung cancer patients with good performance status is associated with improved survival and better symptom control. Chemotherapeutic regimens should include cisplatin with at least one other active drugs as ifosfamide, mitomycin C, vindesine, vinblastine (second generation drugs) or gemcitabine, paclitaxel, docetaxel, irinotecan and/or vinorelbine (third generation drugs). If the other drug is a new one, there is no evidence for the addition of a third agent. Four to six cycles is proposed in responding patients. Non-platinum-based regimens may be used in cases where platinum-based chemotherapy is contra-indicated. Single agent chemotherapy may be considered in patients with poor performance status.

New biological factors have not been extensively studied in stage III NSCLC as yet. The aim of this retrospective study was to assess the association between the expression and the prognostic role on survival of four biological markers in stage III NSCLC. Clinical characteristics were retrieved from the patients charts. EGF-R, Mdm2, p53 and TTF-1 expressions were evaluated by immunohistochemistry by three independent observers. Cox multivariate model was used to assess the impact of clinical and biological factors on patients' survival. A total of 84 stage III NSCLC patients, treated between 03/1987 and 08/2003, were included in the study. There was a statistically significant association between the expression of TTF-1 and EGFR (p=0.01) or TTF-1 and Mdm2 (p=0.04). Positive expressions for EGFR or TTF-1 were almost mutually exclusive. The status EGFR+/TTF-1--was mainly found in squamous cell carcinoma (18 among 19tumours). In multivariate analysis, only treatment with curative intent was independently associated with better survival (p=0.0004). In stage III NSCLC, there was a significant association between TTF-1 and EGFR or TTF-1 and Mdm2. The status EGFR+/TTF-1--was associated with squamous cell carcinoma.

Meta-analyses dealing with the treatment of thoracic malignancies (non-small cell lung cancer, small cell lung cancer and mesothelioma) are reviewed including those performed in the context of a systematic review of the literature or based on individual patients data. Their results have been used as an effective tool for resolving various clinical questions, providing more reliable evidence for some clinical practice: (neo)adjuvant chemotherapy after surgery for resectable NSCLC, radiochemotherapy for patients with unresectable limited NSCLC and limited SCLC, advantage of chemotherapy for advanced NSCLC and identification of the most active drugs. However, it is important to understand the limits of their methodology in order to avoid inappropriate interpretations.

Hypothesis: The 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography is an imaging tool for assessing clinical tumor, node, metastasis in non-small cell lung cancer (NSCLC). Primary tumor standardized uptake value (SUV) has been studied as a potential prognostic factor for survival. However, the sample sizes are limited leading to conduct a meta-analysis to improve the precision in estimating its effect., Methods: We performed a systematic literature search. For each publication, we extracted an estimate of the hazard ratio (HR) for comparing patients with a low and a high SUV and we aggregated the individual HRs into a combined HR, using a random-effects model., Results: We found 13 eligible studies dedicated to NSCLC. Most of them included patients with stages I to III/IV and used a SUV assessment corrected for body weight. Number of patients ranged from 38 to 315 (total: 1474); 11 studies identified a high SUV as a poor prognostic factor for survival although two studies found no significant correlation between SUV and survival. SUV measurement and SUV threshold for defining high SUV were study dependent, eight studies looked for a so-called best cutoff (maximizing the logrank test statistic) without adjusting the p value for multiplicity. Overall, the combined HR for the 13 reports was 2.27 (95% confidence interval [CI]: 1.70-3.02); excluding the studies proposing a "best" cutoff, it was 2.08 (95% CI: 1.431-3.04)., Conclusion: Our meta-analysis suggests that the primary tumor SUV measurement has a prognostic value in NSCLC; these results should be confirmed in a meta-analysis on individual patients' data.

The aim of the present study was to determine the potential benefit of conventional cisplatin-based chemotherapy on patients with advanced nonsmall cell lung cancer (NSCLC) and poor performance status (PS), defined as 60-70 on the Karnofsky scale. Retrospective analysis was carried out of a randomised trial performed in advanced NSCLC where 485 patients received three courses of gemcitabine+ifosfamide+cisplatin induction chemotherapy. Of the patients, 80% had good PS (Karnofsky 80-100) and 20% poor PS. Response rates were 38 and 28%, respectively. Clinical improvement, defined as achieving a good PS during chemotherapy, was observed overall in 25% of the poor PS patients, with rates of 38, 20 and 14%, respectively, in case of response, no change and progression. PS improved more quickly in the responders. Survival of patients with poor PS was significantly worse, but survival of responders was similar, irrespective of the initial poor or good PS. Although nonfatal toxicity was almost similar, there were more toxic deaths (including vascular and cardiac fatalities) in the poor PS patients (9.2 versus 2.1%). In conclusion, combination chemotherapy is associated with clinical improvement in a substantial number of patients with advanced nonsmall cell lung cancer of poor performance status.

In the context of a phase III trial comparing in advanced non-small cell lung cancer (NSCLC) sequential to conventional administration of cisplatin-based chemotherapy and paclitaxel, we evaluated the activity of paclitaxel as second-line chemotherapy and investigated any relation of its efficacy with the type of failure after cisplatin. Patients received three courses of induction GIP (gemcitabine, ifosfamide, cisplatin). Non-progressing patients were randomised between three further courses of GIP or three courses of paclitaxel. Second-line paclitaxel was given to patients with primary failure (PF) to GIP and to those progressing after randomisation to further GIP (secondary failure or SF). One hundred sixty patients received second-line paclitaxel. Response rates were 7.7% for PF and 11.6% for SF (P=0.42). Median survival times (calculated from paclitaxel start) were 4.1 and 7.1 months for PF and SF (P=0.002). In multivariate analysis, three variables were independently associated with better survival: SF (hazard ratio (HR)=1.55, 95% confidence interval (CI) 1.08-2.22; P=0.02), normal haemoglobin level (HR=1.56, 95% CI 1.08-2.26; P=0.02) and minimal weight loss (HR=1.79, 95% CI 1.26-2.55; P=0.001). Paclitaxel in NSCLC patients, whether given for primary or for SF after cisplatin-based chemotherapy, demonstrates activity similar to other drugs considered active as second-line therapy.

Background: The purpose of this study is to determine whether in advanced non-small-cell lung cancer (NSCLC), the sequential administration of cisplatin-based chemotherapy and paclitaxel (Taxol) is superior to a cisplatin-based chemotherapy, followed by paclitaxel as salvage treatment., Patients and Methods: A total of 485 chemotherapy naive patients with advanced NSCLC were treated with three courses of GIP (gemcitibine + ifosfamide + cisplatin), consisting of cisplatin 50 mg/m(2) on day 1, ifosfamide 3 g/m(2) on day 1 and gemcitabine 1 g/m(2) on days 1 and 8. Patients with nonprogressive disease were then randomised to further similar courses of GIP or courses of paclitaxel (225 mg/m(2) over 3 h every 3 weeks)., Results: Objective response or nonprogression after induction GIP occurred in 174 and 115 patients, respectively. After randomisation, there were 140 patients in the GIP arm and 141 in the paclitaxel arm. In terms of postrandomisation survival, there was no statistically significant difference (P = 0.17) between the two arms. Median times were 9.7 [95% confidence interval (CI) 7.8-11.6] and 11.9 (95% CI 9.4-14.3) months for paclitaxel and GIP, respectively. Multivariate analysis demonstrated that sex and haemoglobin were independent prognostic factors. After adjustment for these factors, the observed hazard ratio was 0.81 (95% CI 0.63-1.04) in favour of GIP (P = 0.10). Toxicity was tolerable; there was a significantly higher rate of grades III/IV thrombocytopenia with GIP and more alopecia with paclitaxel., Conclusion: Sequential chemotherapy using cisplatin-based regimen followed by paclitaxel does not result in better outcome than cisplatin-based chemotherapy using taxane as salvage treatment.

Epidermal growth factor receptor tyrosine kinase inhibitors represent a new treatment option for patients with advanced nonsmall cell lung cancer (NSCLC). This retrospective study examined to what extent previous clinical trial experience matches large-scale Western community implementation of this treatment. In the Belgian expanded access programme, the data from 513 patients with advanced or metastatic NSCLC, not suitable for further chemotherapy and receiving oral gefitinib 250 mg.day(-1) until disease progression, death or unacceptable toxicity, were analysed. The median (range) duration of gefitinib treatment was 2.3 months (0.0-32.7). Its use was predominantly in second- or third-line treatment. The overall response and disease control rates were 8.9 and 41.2%, respectively. In univariate analysis, response was more common in females and never-smokers. In multivariate analysis, female sex was the only significant predictive factor (odds ratio (OR) (95% confidence interval (CI)) 0.329 (0.129-0.839)). Symptom improvement was reported in 108 patients of whom 32 (29.6%) had an objective response, 66 (61.1%) experienced disease stabilisation and 10 (9.3%) progressed. Gefitinib was well tolerated; only 7.8% of the patients reported grade 3 or 4 toxicity. The overall median survival was 4.7 months, with a 1-yr survival rate of 21%. Survival was strongly influenced by a better performance status (PS) (good PS: hazard ratio (HR) (95%CI) 0.110 (0.077-0.157)) and adenocarcinoma with bronchioloalveolar carcinoma features histology (HR (95%CI) 0.483 (0.279-0.834)). In conclusion, the activity of gefitinib was confirmed in the present large Western community implementation study. Response, present in a small subgroup, led to a rewarding survival and could be predicted by sex only. Baseline performance status and adenocarcinoma with bronchioloalveolar carcinoma features histology were significant factors for survival.

Cyclooxygenase-2 (COX-2) is overexpressed in lung cancer, especially in adenocarcinoma (ADC). Our aim was to determine the prognostic value of COX-2 on survival in patients with lung cancer. Studies evaluating the survival impact of COX-2 in lung cancer, published until December 2005, were selected. Data for estimation of individual hazard ratios (HR) for survival were extracted from the publications and combined in a pooled HR. Among 14 eligible papers, all dealing with non-small-cell lung cancer, 10 provided results for meta-analysis of survival data (evaluable studies). Cyclooxygenase-2 positivity was associated with reduced survival, improved survival or no statistically significant impact in six, one and seven studies, respectively. Combined HR for the 10 evaluable studies (1236 patients) was 1.39 (95% confidence intervals (CI): 0.97-1.99). In stage I lung cancer (six evaluable studies, 554 patients), it was 1.64 (95% CI: 1.21-2.24). No significant impact was shown in ADC. A slight detrimental effect on survival in patients with lung cancer is associated with COX-2 expression, but the statistical significance is not reached. This effect is statistically significant in stage I, suggesting that COX-2 expression could be useful at early stages to distinguish those with a worse prognosis.

Background: The relationships between EGF-R and c-erbB-2 with other factors involved in tumour regulation are not well understood. The aim of this study was to correlate the expression of these markers with tumour proliferation., Materials and Methods: The presence of EGF-R, c-erbB-2 and Ki-67 was evaluated by immunohistochemistry in non-small cell lung cancer (NSCLC) and preneoplastic lesions., Results: Forty-two percent of the tumours were positive for EGF-R, 22% for c-erbB-2 and 97% for Ki-67. No statistically significant correlation was found between EGF-R and Ki-67, EGF-R and c-erbB-2 or between c-erbB-2 and Ki-67. With regards to Ki-67, a significant difference in survival was noted in favour of patients who did not express the marker. In preneoplastic lesions, most of the low-grade lesions showed neither EGF-R nor Ki-67 staining. In contrast, most of the high-grade lesions stained positively for these proteins., Conclusion: EGF-R and c-erbB-2 do not seem to be correlated with Ki-67 in NSCLC.

Background: The MIP regimen (mitomycin, ifosfamide, cisplatin) demonstrated its effectiveness as first-line chemotherapy in phase II and III trials in NSCLC. We aimed to determine whether these results could be confirmed in a hospital population., Methods: Between 1987 and 2004, 204 patients with NSCLC received MIP in our institution. Patients treated in and off trials received the same combination of cisplatin (50 mg/m2), ifosfamide (3 g/m2) and mitomycin C (6 mg/m2) every three weeks and were staged and followed in a similar way., Results: Response rates for patients treated in or outside trials were 36.8% and 40.7%, respectively. After multiple logistic regressions, the only statistically significant factor predicting objective response was stage. The median survival time was 54.6 and 43.7 weeks respectively for patients treated in and outside trials. In multivariate analysis, four factors were statistically significantly associated with better survival: good performance status (p = 0.003), normal LDH value (p < 0.001), early stage (p = 0.01) and active smoking (p = 0.03)., Conclusion: Participation in a clinical trial was not associated with a significant difference in efficacy. This implementation study thus confirms the activity of the MIP regimen when used in the routine management of patients with NSCLC.

The recent publication of many randomised trials about (neo)adjuvant chemotherapy in resectable non-small cell lung cancer (NSCLC) has prompted our group to update a prior meta-analysis of the literature. Randomised studies published in French and English between 1965 and June 2004 were included in this analysis. A qualitative assessment of each trial was first performed using the European lung cancer working party (ELCWP) and the Chalmers' scales. In absence of statistically significant quality difference between positive and negative trials, a quantitative aggregation (meta-analysis) of the individual results was performed. Two trials for which data were available on ASCO virtual meeting website were also included in the meta-analysis. Twenty-five studies eligible for this analysis assessed chemotherapy as induction (n = 6) or adjuvant to surgery (n = 19). No quality difference was detected between positive and negative trials according to the two scores, whatever all trials were combined or only adjuvant chemotherapy studies were considered. The overall meta-analysis showed that the hazard ratio (HR) of the combined results was 0.66 (95% CI 0.48-0.93) in favour of the addition of induction chemotherapy to a standard surgical procedure and 0.84 (95% CI 0.78-0.89) in favour of adjuvant chemotherapy. The effect was significant for adjuvant chemotherapy in stages I and II with a HR of 0.88 (95% CI 0.83-0.94). It was not statistically significant in stage III although the trend was in favour of chemotherapy whatever adjuvant (HR = 0.85; 95% CI 0.69-1.04) or (neo)adjuvant (HR = 0.65; 95% CI 0.41-1.04) chemotherapy was tested. In conclusion, our meta-analysis shows the efficacy of adjuvant chemotherapy in stages I and II resected NSCLC. More data are needed to confirm such a role for induction chemotherapy. Further trials should separate stage III disease from earlier stages.

Salvage treatment with docetaxel after failure of cisplatin-based chemotherapy in non-small cell lung cancer (NSCLC) has already been tested in the context of clinical prospective trials but only dealing with selected patients. The aim of the present study is to assess the generalizability of these results in an unselected population. We retrospectively analysed the data of all patients not included in clinical studies and treated at the Jules Bordet Institute between September 1996 and July 2003 by docetaxel after a previous chemotherapy containing platinum. Patients were separated in two groups: eligible or not studies according to the selection criteria of the published phase II and III prospective trials. There were 27 patients treated by docetaxel after relapse or failure of prior first-line platinum-based chemotherapy. Among them, 15 were ineligible according to the criteria of published phase II and III trials. The global response rate was 7.41%. All responders had a partial response to first line chemotherapy. Toxicity consisted mainly in grade III/IV neutropenia and was similar between the two group of patients. The median survival time was 25 weeks. In conclusion, our implementation study confirms the activity of docetaxel as salvage therapy after failure of first line cisplatin-based chemotherapy in an unselected population of patients with NSCLC, with a response rate similar to that obtained in propective trials.

In order to analyse the genetic abnormalities and protein expression of c-erbB-1 and -2, we have performed fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in resected non-small cell lung carcinoma (NSCLC). By IHC (106 patients), 11% of the patients were positive both for c-erbB-1 and -2 protein expression and 47% negative for both proteins. FISH (69 patients) showed a balanced disomy for both c-erbB-1 and -2 in 38%, all other cases had genetic abnormalities in at least one of both genes. c-erbB-2 gene was amplified in less than 10% of the tumours and c-erbB-1 gene was never amplified. c-erbB-2 protein overexpression was observed in only three out of the six cases showing c-erbB-2 amplification. The negative predictive value (NPV) of IHC for gene abnormalities was high for both markers. Median survival time (MST) was respectively of 76 and 174 weeks for patients with or without c-erbB-2 overexpression. Patients with c-erbB-2 amplification had a shorter survival: 125 weeks versus 165 weeks. MST was respectively of 109 and 196 weeks for patients with or without EGFR overexpression and patients with EGFR gene abnormalities had also a shorter survival with MST 136 weeks versus 189 weeks. These differences were not significant. In conclusion, if the majority of NSCLC showed genetic abnormalities in the c-erbB-1 and/or c-erbB-2 gene receptor, amplification could be observed only in a few tumours and was not strictly correlated with protein expression. Finally, survival of patients expressing EGFR and/or c-erbB-2 was slightly shorter.

New biological factors have not been extensively studied in stage III nonsmall cell lung cancer (NSCLC). The aim of the present retrospective study was to determine the role of epidermal growth factor receptor (EGF-R) as a prognostic factor in stage III NSCLC, in addition to the stage and other known clinical factors. Clinical characteristics were retrieved from the patients' charts. Membrane immunostaining for EGF-R was evaluated by three independent observers. The Cox multivariate model, including all variables with a p-value of <0.2 in univariate analysis, was used to assess the impact of clinical and biological factors on patients survival. Between January 1987 and July 2002, 99 assessable stage III NSCLC patients were included in the study. A total of 23 patients were positive for EGF-R (squamous 39.6% versus nonsquamous 7.8%). In multivariate analysis, only three factors were statistically significantly associated with survival: performance status, surgery and creatinine. In conclusion, good performance status, surgical resection and creatinine were found to be independent favourable prognostic factors for survival in a retrospective analysis of stage III nonsmall cell lung cancer, while epidermal growth factor receptor was not even in the univariate analysis.

The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with meta-analysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using meta-analytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16-1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26-2.02) and in studies using PCR (HR 1.40; 95% CI 1.18-1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86-1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.

Substaging using molecular markers has been proposed to try to identify prognostic factors allowing to define groups of patients with lung cancer for whom specific therapy might be of benefit. The pre-operative assessment of these markers seems to be important specially in case of neoadjuvant chemotherapy. The aim of our study was to compare the expression of two potential prognostic factors (p53 and Ki-67) and two potential therapeutic targets (EGF-R and c-erbB-2) assessed on biopsy samples (B) of non-small cell lung cancer (NSCLC) with that of the corresponding resected tumor (RT). The expression of these biological markers was evaluated by immunohistochemistry on B and on the paired RT in 28 patients. The mean percentage of p53 positive cells was 28% in RT and 38% in B with 81% CR between B and RT and 19% FP on B. Considering RT results as standard, the positive (PPV) and negative predictive value (NPV) of the B were, respectively, 74 and 100%. The mean percentage of EGF-R positive cells was 11% in RT and 28% in B. With a cut-off of 1%, we found 85% concordant results (CR) between B and RT, 4% false negative (FN) and 11% false positive (FP) on B. The PPV and NPV values of the B were, respectively, 80 and 92%. The 8% B and 19% RT were considered as positive for c-erbB-2. We found 15% FN and 4% FP on B with 81% CR between B and RT for c-erbB-2. The NPV of the B was 83%. The mean percentage of Ki-67 positive cells was 32% in RT and 14% in B. We found 82% CR between B and RT, 14% FN and 4% FP on B. The PPV of the B was 96%. In conclusion, biopsies may provide reliable information about p53, EGF-R, c-erbB-2 and Ki-67 in lung carcinoma and could help to elaborate a therapeutic strategy.

The main critical factors for lung cancer patient management, apart from TNM staging, include expertise required to offer optimal management and conditions related to the patient, including performance status and weight loss and the presence of lung, cardiac or other comorbidities. Performance status and weight loss must be assessed for all patients. The minimal pulmonary functional evaluation should include spirometry. The minimal cardiac evaluation should consist of a clinical history and evaluation for cardiac risk factors and disease and at least preoperatively, and ECG. Age per se is not a contraindication for curative treatment.

Fragile histidine triad (FHIT) is a tumour suppressor gene, which is altered in a variety of epithelial tumours, including lung cancer. Biochemical and functional pathways of its tumourigenicity are not yet understood. Its role in tumour proliferation is particularly controversial. The purpose of this study was to correlate the expression of FHIT protein in nonsmall cell lung cancer (NSCLC) with tumour proliferation as estimated by Ki-67 antigen and with p53, a suppressor gene. FHIT, Ki-67 and p53 expression were evaluated by immunohistochemistry in 119 resected NSCLC. Altogether, 58 tumours were negative (expression <10%) for FHIT. The median expression in tumours was 15% positive cells, in comparison with 100% in normal matched lung tissue. The expression was as strong as in normal tissue in only 19 cases. FHIT expression was significantly lower in squamous cell carcinoma (SCC) (5%) than in adenocarcinoma (ADC) (64%). The median expression of Ki-67 was 20% and 69% of tumours were positives (expression >10%). Ki-67 expression was significantly higher in SCC (33.3%) than in ADC (10%). The loss of FHIT protein was not correlated with the expression of p53 (median: 7.5%, 58% of positive tumours for a cut-off of 10% of positive cells) or Ki-67. But percentage of labelled cells for p53 and Ki-67 were significantly correlated. The results suggest that for fragile histidine triad, the pathway of tumourigenesis is independent of p53 and of tumoural proliferation, as reported previously in vitro.

The process of angiogenesis is an important factor in tumour development. One of the principal factors implicated in this process is vascular endothelial growth factor (VEGF) which induces, among other things, an increase in vascular permeability. We have undertaken a systematic review of the English and French literature in order to clarify its effect on the survival of patients with small cell (SCLC) and non-small cell (NSCLC) lung cancer. To be eligible studies had to deal with the the evaluation of VEGF or its receptors in lung cancer and describe the relationship of their expression to survival. The survival figures were subject to meta-analysis after a methodological evaluation by means of a specific numerical scale evaluating the design of the study, the methodology (including laboratory techniques), and the analysis of results. Among the 20 studies selected 15 identified VEGF expression, using univariate analysis, as a statistically significant indicator of poor prognosis. 17 reported sufficient data to allow aggregation of the survival figures, of which 15 were devoted to NSCLC (1,549 patients). The median overall methodological score was 48.3% (range 21.8-72.4%), without significant difference (p=0.63) between studies eligible or non-eligible for meta-analysis. The meta-analysis, using the authors' threshold of positivity for VEGF, showed that VEGF is an unfavourable prognostic factor in NSCLC (HR=1.48; 95% confidence interval 1.27-1.72). The data were insufficient to determine the prognostic value of VEGF in SCLC and that of its two receptors Flt-1 and KDR, with 1, 2 and 1 published studies respectively. In conclusion the expression of VEGF in MSCLC is a factor indicating a poor prognosis.

A systematic review of the literature about the role of chemotherapy in comparison to local therapies--surgery or radiotherapy--in non-small cells lung cancers has identified 35 randomised trials. The methodological assessment has not shown significant difference for quality scores between negative or positive studies in term of survival effect. The aggregation (meta-analysis) shows a significant effect of survival improvement by chemotherapy, whatever all indications are considered or subgroups like adjuvant chemotherapy to surgery, neoadjuvant chemotherapy, concomitant radio-chemotherapy and induction chemotherapy prior to thoracic irradiation.

In order to clarify the role of mitomycin (MMC) in the treatment of NSCLC, we performed a systematic review of the literature and qualitatively assessed the selected studies using the ELCWP and Chalmers scales. 5 trials (202 patients) assessed the activity of MMC as single-agent chemotherapy in NSCLC. The overall response rate was 25% (95% Cl 19-31). In 10 randomized phase III trials (1769 patients), we studied the role of MMC in combination therapy. A meta-analysis, based on the available published data, failed to show any survival advantage of the MMC containing regimens (hazard ratio = 0.95; 95% Cl 0.83-1.10). Finally, 4 eligible trials (139 patients) assessed the activity of MMC regimens as salvage therapy, 3 in combination with vindesine and one with cisplatin and vinblastine. The overall response rate for the MMC-vindesine regimen was 10.5% (95% Cl 1.7-19.4). In conclusion, MMC is an active drug for NSCLC but does not improve survival when combined with other active drugs, particularly cisplatin. Its use for salvage therapy appears to be associated with marginal activity only., (Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.)