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International audience; In the setting of small cell lung cancer (SCLC), the development of immuno-oncological agents, particularly those targeting Programmed cell Death protein 1 (PD-1) and Programmed cell Death protein Ligand 1 (PD-L1), is still at an early stage. Two critical elements need to be considered : the current data are extracted from Phase I and Phase II trials and the level of evidence from phase III trials has not been reached as it has been for non-small cell lung cancer (NSCLC) or for malignant melanoma ; The second aspect is the slow development of predictive factors for response to the immuno-oncological agents targeting the PD-1 receptor and its ligand. The clinical data are still too fragmentary to produce recommendations, although the improvement in progression-free survival seen in different phase II studies is promising. The expectation of clinicians dealing withSCLC is an indication of the challenge that this disease currently poses to oncology and justifies a focused clinical research effort.

International audience

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options.

Both quality of life (QoL) and comorbidity influence therapy and prognosis of non-small-cell lung cancer (NSCLC). We previously developed a lung cancer disease-specific simplified comorbidity score (SCS) and demonstrated the prognostic impact of this disease-specific instrument. This study aimed at validating the SCS in a prospective bicentric NSCLC population by measuring its relative prognostic determinant impact taking into account well-established variables such as QoL, performance status (PS), Charlson comorbidity index (CCI) and disease stage.Prognostic values of different pretherapeutic features were tested in univariate and multivariate analyses in a population of 301 NSCLC.Median survival was 17 months. One-third of patients reporting difficulties in their normal daily activities and an overall poor QoL. The following pretreament variables were independent determinants of a shorter overall survival: advanced disease, SCS, Lung Cancer Symptoms Scale global symptoms score, anaemia, hyponatremia, serum alkaline phosphatases level, serum CYFRA 21-1 and serum neuron-specific enolase.In this extended validation population, the SCS is more informative than the CCI in predicting NSCLC patient outcome as the former is also more disease specific. Combination of both SCS comorbidity score and LSCC QoL yields a more accurate information that conventional analysis of PS.

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Resume Introduction Les syndromes neurologiques paraneoplasiques associes aux anticorps anti-Hu sont rares et de pronostic severe. La recherche et le traitement d’un cancer associe, un carcinome pulmonaire a petites cellules le plus souvent, demeure la meilleure approche therapeutique. Observation Les auteurs decrivent l’evolution clinique d’un patient atteint d’une neuronopathie sensitive subaigue associee aux anticorps anti-Hu chez un fumeur actif traite par une chimiotherapie precoce active contre un carcinome pulmonaire a petites cellules bien qu’aucune tumeur n’ait pu etre identifiee lors de bilans repetes. En depit de ce traitement, l’etat neurologique s’est aggrave avec l’apparition d’une degenerescence cerebelleuse et d’une encephalite limbique responsables d’une perte d’autonomie et definissant une encephalomyelite. Un carcinome pulmonaire a petites cellules fut identifie et traite 65 mois apres le debut des symptomes neurologiques. Le traitement du cancer associe, lorsqu’il est identifie, reste le traitement optimal des syndromes neurologiques paraneoplasiques. Malgre l’absence de cancer identifie initialement, nous avons traite notre patient par une chimiotherapie probabiliste, active contre le cancer le plus frequemment associe aux syndromes des anti-Hu chez un fumeur, sans obtenir de benefices. Conclusion La recherche active et repetee d’un cancer associe a un syndrome neurologique anti-Hu et son traitement sont indispensables. Le traitement probabiliste d’un cancer suppose n’ayant pas fait sa preuve n’a pas empeche l’aggravation neurologique chez ce patient. En l’absence de cancer identifie par les techniques d’imagerie de premiere intention, un FDG-PET scanner precoce puis regulier en cas de normalite initiale devrait donc etre propose.

The Region Languedoc-Roussillon is the umbrella organisation for an interconnected and integrated project on AHA covering the 3 pillars of the European Innovation Partnership on Active and Healthy Ageing. All sub-activities (A1: electronic pharmaceutical file, A2: falls prevention initiative, A3: frailty, B3: chronic respiratory diseases, chronic diseases with comorbidities, oral health and hepatitis virus C chronic infection, C2 and D4 active and independent living and handicap) are included in MACVIA-LR that has a strong political commitment and includes all stakeholders (public, private, patients, policy makers). It is one of the Reference Sites of the European Innovation Partnership on Active and Healthy Ageing built around chronic diseases, ageing and handicap. The framework of MACVIA-LR has the vision that the prevention and management of CDs is essential for AHA promotion and for the reduction of handicap. The main objective of MACVIA-LR is to develop innovative solutions for a network of Living Labs in order to improve the care of patients affected by CDs in the Languedoc-Roussillon area and to disseminate the innovation.

Background This multicenter, randomized, phase III study compared the efficacy, including progression-free survival (PFS), and safety of gemcitabine–docetaxel (GD) combination versus cisplatin–vinorelbine (CV) in the treatment of advanced non-small-cell lung cancer (NSCLC). Patients and methods Chemonaive patients with stage IIIB or IV NSCLC were treated with GD (gemcitabine 1000 mg/m2 days 1 and 8 plus docetaxel 85 mg/m2 day 8, every 3 weeks for eight cycles) or CV (cisplatin 100 mg/m2 day 1 plus vinorelbine 30 mg/m2, days 1, 8, 15 and 22, every 4 weeks for six cycles). Results A total of 311 patients were enrolled (155 GD and 156 CV). Neither PFS nor overall survival differed significantly between the two arms (median PFS 4.2 and 4 months; median survival 11.1 and 9.6 months; 1-year survival 46% and 42%, for GD and CV, respectively). For the GD arm compared with the CV arm, the hazard ratio for PFS was 1.04 [95% confidence interval (CI) 0.83–1.32], and for overall survival, it was 0.90 (95% CI 0.70–1.16). Objective response rates did not differ significantly (31% for GD, 35.9% for CV). Myelosupression, emesis and frequency of febrile neutropenia were less pronounced on the GD arm, whereas fluid retention and pulmonary events were more pronounced. The CV arm experienced a higher number of serious adverse events and a lower compliance with the protocol. There was no quality of life (QoL) difference between arms. Median time to definite impairment of health-related QoL was 153 and 168 days in GD and CV arms, respectively. Conclusions There was no advantage in PFS with GD compared with CV; however, the CV regimen had higher rate of toxic events, mainly myelosuppression. The herein, non-platinum-containing regimen could be considered as a rational alternative to the cisplatin-based doublet.

Background Taxotere® (docetaxel) at the dose of 75 mg/m2 every 3 weeks is a standard therapy for pretreated non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the safety profile of two schedules of docetaxel administration (every 3 weeks versus weekly) in patients with pretreated NSCLC. Patients and methods From February 2000 to February 2001, 125 patients with locally advanced or metastatic NSCLC were randomised after failure of a previous platinum-based regimen to receive either docetaxel 75 mg/m2 administered every 3 weeks (Dq3w) or docetaxel 40 mg/m2 given weekly for 6 weeks followed by 2 weeks of rest (Dqw). Safety evaluations focused on grade 3–4 neutropenia, febrile neutropenia, nausea-vomiting and asthenia. Results Patients' characteristics were well balanced between arms. The most common National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3–4 toxicity was neutropenia, which occurred in 48.4% of Dq3w patients versus 15.9% of Dqw patients (P = 0.001). In addition, febrile neutropenia were observed in 6.5% of patients in Dq3w versus 0% in Dqw. Grade 3–4 asthenia was more frequent in Dqw. Other non-haematological toxicities were very rare. Regarding efficacy, there was a trend towards a better disease control rate in Dq3w: 32.2% versus 25.4% in Dqw. Median time to progression and survival were rather similar in both arms, respectively: 2.1 months (range 2–3.2) and 5.8 months (range 4.0–7.0) in Dq3w and 1.8 months (range 1.6–2.3) and 5.5 months (range 3.7–6.6) in Dqw. Conclusions While both schedules had a favourable safety profile, a significant lower rate of severe neutropenia was observed in the weekly arm. Both regimens had similar efficacy. The weekly regimen could be considered as a good alternative for patients at risk of severe neutropenia.

Background The survival benefit associated with first-line chemotherapy in advanced lung cancer led to the need for second-line chemotherapy. Docetaxel (Taxotere®) has proven efficacy in both settings. This study evaluated the safety and efficacy of two doses of docetaxel in patients with non-small-cell lung cancer who had failed first-line platinum-based chemotherapy. Patients and methods In total, 182 patients from 24 French centres were randomised and treated with either docetaxel 75 mg/m2 (arm A) or 100 mg/m2 (arm B) every 3 weeks. Baseline characteristics were well balanced, except more patients in arm A had metastatic disease (91.4% versus 78.7%) and therefore the median number of sites involved for arm A was three compared with two for arm B. Results Median time to treatment failure was 1.34 months [95% confidence interval (CI) 1.28–1.64] for arm A and 1.64 months (95% CI 1.34–2.62) for arm B. Median overall survival was 4.7 months (95% CI 3.8–5.9) for arm A versus 6.7 months (95% CI 4.8–7.1) for arm B. According to a blinded expert panel, disease control was achieved in 35 (43.8%) patients in arm A and 39 (49.4%) patients in arm B. More patients in arm B experienced grade 3–4 neutropenia (B: 72.7% versus A: 44.0%), asthenia (B: 20.2% versus A: 10.8%) and infection (B: 6.7% versus A: 2.2%). Three treatment-related deaths were reported in each arm. Conclusions The optimal docetaxel dosage in this second-line setting is 75 mg/m2, as it has a more favourable safety profile and on balance a similar efficacy to the 100 mg/m2 dose.

Objectives Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed–cisplatin (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed–cisplatin without disease progression. Methods Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan–Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population. Results Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1–44) following 4 cycles of pemetrexed–cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed–cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT. Conclusions The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed–cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed–cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.

Context The 'Standards, Options and Recommendations' (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French cancer centres and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. Objectives To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for the management of stage I and II non small cell lung carcinoma treated by radiotherapy alone. Methods Data were identified by searching Medline and personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to independent reviewers, and to the medical committees of the 20 French cancer centres. Results The main recommendations for the management of stage I and II non small cell lung carcinoma treated by radiotherapy alone are: 1) The curative external irradiation with a continual course is an alternative to surgery only in the case of medically inoperable tumors or because the patient refuses surgery; 2) The external irradiation of the primary tumor only without the mediastinum could be proposed in peripheral stage IA. In proximal stage IA and IB, external irradiation should be carried out only as part of prospective randomised controlled trials comparing a localised irradiation of the primary tumor with a large irradiation of the mediastinum and the primary tumor. The treated volume must include the macroscopic tumoral volume with or without the microscopic tumoral volume and with a security margin from 1.5 to 2 cm; 3) There is a benefit to delivering a total dose in the primary tumor higher than 60 Gy in so far as the proposed irradiation, taking into account the respiratory function, does not increase the likelihood of severe adverse events due to radiation; and 4) The change in fractionation, the radiochemotherapy combination, the endobronchial brachytherapy with high dose rate alone or with external irradiation could be proposed only as part of prospective controlled trials for tumors classified as stage IB or II.

Contexte. - La Federation nationale des centres de lutte contre le cancer (FNCLCC) et les Centres regionaux de lutte contre le cancer (CRLCC), en collaboration avec des partenaires des secteurs public (CHU, CHG), prive et certaines societes savantes ont entrepris depuis 1993 d'elaborer des recommandations pour la pratique clinique en cancerologie: les « Standards, Options et Recommandations » (SOR). L'objectif de l'operation SOR est d'ameliorer la qualite et l'efficience des soins aux patients atteints de cancer en fournissant aux praticiens une aide a la decision facilement utilisable. La methodologie d'elaboration des SOR repose sur une revue et une analyse critique des donnees de la litterature scientifique par un groupe d'experts pluridisciplinaire, permettant de definir, sur la base du niveau de preuve scientifique et du jugement argumente des experts, des « Standards », des « Options » et des « Recommandations ». Avant publication, les SOR sont revus par des experts independants. Objectifs. - Definir, sur la base d'une revue de la litterature et de l'accord d'experts, des Standards, Options et Recommandations pour la prise en charge des patients atteints de cancer broncho-pulmonaire primitif de stade I ou Il traites par irradiation exclusive. Methodes. - Un groupe de travail multidisciplinaire mis en place par la Federation nationale des centres de lutte contre le cancer (FNCLCC) a revu les donnees scientifiques disponibles concernant la prise en charge des patients atteints de cancer broncho-pulmonaire primitif non a petites cellules de stade I et Il traites par irradiation exclusive. Apres selection des articles, synthese des resultats et redaction des SOR, le document a ete soumis pour relecture et approbation a des relecteurs. Resultats.- Les principales recommandations sont: 1) l'irradiation externe exclusive continue a visee curative, avec un fractionnement conventionnel, n'est une alternative a la chirurgie d'exerese qu'en cas de contre-indications a un acte chirurgical liees au terrain medical ou de refus du malade de tout acte chirurgical; 2) l'irradiation externe du volume tumoral primitif seul, sans le mediastin, peut etre proposee dans les formes classees stade IA, de topographie peripherique. Dans les formes classees stade IA proximal et IB, elle ne peut se concevoir que dans le cadre d'un essai therapeutique prospectif randomise et controle comparant une irradiation localisee au volume tumoral et une irradiation large mediastino-tumorale. Le volume traite doit inclure le volume tumoral macroscopique avec ou sans le volume tumoral microscopique, avec une marge de securite de 1,5 a 2 cm; 3) il y a un benefice a delivrer une dose totale dans le volume tumoral superieure a 60 Gy dans la mesure ou la technique d'irradiation proposee tenant compte de la fonction respiratoire du malade, n'augmente pas la probabilite de risque de complications severes radio-induites; 4) les modifications du fractionnement, l'association radiochimiotherapie concomitante, la curietherapie endoluminale a haut debit de dose seule ou en association a une irradiation externe, ne peuvent etre proposees que dans le cadre d'essais prospectifs controles pour des formes classees de stade IB ou II.

A multi-centre retrospective study involving 4 French university institutions has been conducted in order to identify routine pre-therapeutic prognostic factors of survival in patients with previously untreated non-small cell lung cancer and brain metastases at the time of presentation. A total of 231 patients were recorded regarding their clinical, radiological and biological characteristics at presentation. The accrual period was January 1991 to December 1998. Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The median survival of the whole population was 28 weeks. Univariate analysis (log-rank), showed that patients affected by one of the following characteristics proved to have a shorter survival in comparison with the opposite status of each variable: male gender, age over 63 years, poor performance status, neurological symptoms, serum neuron-specific enolase (NSE) level higher than 12.5 ng ml−1, high serum alkaline phosphatase level, high serum LDH level and serum sodium level below 132 mmol l−1. In the Cox's model, the following variables were independent determinants of a poor outcome: male gender: hazard ratio (95% confidence interval): 2.29 (1.26–4.16), poor performance status: 1.73 (1.15–2.62), age: 1.02 (1.003–1.043), a high serum NSE level: 1.72 (1.11–2.68), neurological symptoms: 1.63 (1.05–2.54), and a low serum sodium level: 2.99 (1.17–7.62). Apart from 4 prognostic factors shared in common with other stage IV NSCLC patients, whatever the metastatic site (namely sex, age, gender, performance status and serum sodium level) this study discloses 2 determinants specifically resulting from brain metastasis: i.e. the presence of neurological symptoms and a high serum NSE level. The latter factor could be in relationship with the extent of normal brain tissue damage caused by the tumour as has been demonstrated after strokes. Additionally, the observation of a high NSE level as a prognostic determinant in NSCLC might reflect tumour heterogeneity and understimated neuroendocrine differentiation. © 2001 Cancer Research Campaignhttp://www.bjcancer.com

PURPOSE AND METHODS We investigated whether a high-dose chemotherapy regimen of cyclophosphamide 1,800 mg/m2, 4'-epidoxorubicin 60 mg/m2, etoposide 330 mg/m2, and cisplatin 120 mg/m2 given monthly for four cycles with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) support (5 micrograms/kg daily for 10 days) could improve the survival of patients with extensive-stage small-cell lung cancer (SCLC) compared with a standard-dose regimen (cyclophosphamide 1,200 mg/m2, 4'-epidoxorubicin 40 mg/m2, etoposide 225 mg/m2, and cisplatin 100 mg/m2) given monthly for six cycles. Planned cumulative doses of the drugs were the same in both treatment arms except for cisplatin (which was 80% in the higher-dose plus rhGM-CSF group). RESULTS At the time of the preplanned interim analysis, 125 patients, 60 in the standard-dose group and 65 in the higher-dose plus rhGM-CSF group, had entered the study; 116 were eligible, 55 in the standard-dose group and 61 in the higher-dose group. All patients were included in the analyses. The cumulative doses of each drug actually delivered were significantly higher in the standard-dose group. No difference in response rates was observed between the two groups. There were significantly greater hematologic toxicities, documented infections, and transfusions of RBCs and platelets in the higher-dose plus rhGM-CSF group. Patients in this group proved to have a shorter survival duration and a shorter time to relapse than patients in the standard-dose group (median overall survival: standard-dose, 10.8 months; higher-dose, 8.9 months; log-rank test with adjustment for prognostic variables, P = .0005; respective probabilities of relapse at 1 year, 77 +/- 0.6 and 96 +/- 2.2; log-rank test, P = .013). CONCLUSION A 50% increase in dose-intensity for this four-drug regimen could not be achieved with GM-CSF due to excessive toxicity in patients with extensive-stage SCLC.

In a previous study we found that tumor responses as assessed by CT scan and fiberoptic bronchoscopy are sometimes discordant. We hypothesize that the response-survival relationship might vary according to the method of tumor response assessment. In a multivariate analysis of survival using the landmark method, we evaluated the prognostic significance of tumor response assessed by CT scan or fiberoptic bronchoscopy together with bronchial tumor location and histology of bronchial biopsies at restaging. A total of 133 lung cancer patients (50 small cell lung cancers and 83 non-small cell lung cancers) were entered in controlled chemotherapy trials and prospectively evaluated for chest tumor response by CT scan and fiberoptic bronchoscopy (FOB). Only 106 patients were fully evaluable for response by both methods. For these patients, a statistical concordance was observed between the two tests (kappa = 0.271; p0.001). There was a significant correlation between response and survival whatever the test used. However, only CT scan evaluation resulted in a classification showing that the more unfavorable the response stage was, the worse the survival became with no intersection between survival curves. Cox's hazard model demonstrated that CT-evaluated progression, proximal bronchial location at second FOB (intermediate, main bronchus or trachea) and positive histologic status at restaging were all prognostic determinants of poor survival. In conclusion, CT-evaluated response led to the best response-survival relationship as this method classified patients into four groups with different outcomes. Fiberoptic bronchoscopy should be avoided in patients who were found to have no endobronchial lesion during the pretreatment staging. For patients with pretreatment assessable endobronchial lesions, the decision of a second FOB depends on the results of CT restaging: FOB is probably unnecessary in patients for whom progression is disclosed by CT scan. In patients for whom CT scan discloses tumor response or stabilization, bronchial tumor location and histology of bronchial biopsies at second FOB are independent prognostic factors.

A phase II study was designed to evaluate objective response rate and toxicity of fotemustine as single-drug chemotherapy in non-small-cell lung cancer. Eighty-seven patients with unresectable non-small-cell lung cancer took part in the study. Seventy-seven were evaluable for response. Of these, 60% had received prior chemotherapy and 74% had metastatic disease. Moreover, 22 patients had central nervous system metastases (of whom 12 were evaluable for this site). Treatment consisted of fotemustine 100 mg m-2 administered on days 1 and 8 followed by a 5 week rest period. Afterwards, responding or stabilised patients received fotemustine 100 mg m-2 every 3 weeks as a maintenance therapy. Toxicity and quality of life were recorded during therapy. Thirteen patients (17%; 95% CI 9-25%) had an objective response (11% for pretreated, 26% for non-pretreated) with a median duration of 22 weeks (range 7-41 weeks). Two objective responses were observed among the 12 patients with evaluable brain metastases. No response was observed among the 14 patients with adenocarcinoma. Haematological, gastrointestinal, hepatic and renal toxicities were mild to moderate and manageable. The most frequent biological adverse reactions were delayed thrombocytopenia and neutropenia. Quality of life did not significantly decrease during the first 6 treatment weeks. Moreover, it remained stable during the study period in patients with response or stabilisation, whereas it significantly decreased in patients who experienced progression of the disease. Fotemustine is feasible for single-drug chemotherapy in non-small-cell lung cancer even though poor prognostic variables such as brain metastases are present. It can be administered on an outpatient basis and toxicity is moderate and manageable. Thus, fotemustine can be considered as a putative drug in further combinations.

PURPOSE We designed a prospective randomized trial to compare vinorelbine and cisplatin (NVB-P) with vindesine and cisplatin (VDS-P) and to evaluate whether the best of these regimens affords a survival benefit compared with vinorelbine alone (NVB), an outpatient regimen, in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Forty-five centers included 612 patients in this study: 206 on NVB-P, 200 on VDS-P, and 206 on NVB. Vinorelbine was administered at a dose of 30 mg/m2 weekly, cisplatin at 120 mg/m2 on days 1 and 29 and then every 6 weeks, and vindesine at 3 mg/m2 weekly for 6 weeks and then every other week. Treatment was continued until progression or toxicity. Four percent of the patients entered were ineligible and 59% had metastatic disease. RESULTS An objective response rate was observed in 30% of patients in the NVB-P arm versus 19% in the VDS-P arm (P = .02) and 14% in the NVB arm (P < .001). The median duration of survival was 40 weeks in the NVB-P arm, compared with 32 weeks in the VDS-P arm and 31 weeks in the NVB arm. Comparison of survival among the three groups demonstrated an advantage for NVB-P compared with VDS-P (P = .04) and NVB (P = .01). Neutropenia was significantly higher in the NVB-P group (P < .001), and neurotoxicity was more frequent with VDS-P (P < .004). CONCLUSION Since our results have demonstrated that NVB-P yields a longer survival duration and a higher response rate than VDS-P or NVB alone, with acceptable toxicity, this combination should be considered a relevant regimen in advanced NSCLC.

Non-small cell lung carcinoma (NSCLC), which accounts for 80% of lung cancers, is the first cause of mortality from cancer in males in western countries [l]. Its curative treatment is surgery. In most cases, however, the disease is inoperable at the time of presentation because of either locally advanced tumor (stage III) or distant metastasis (stage IV). Sixty to 70% of patients with locally advanced NSCLC will die from intrathoracic disease, with or without distant metastases [2,3] and the median survival of such patients is less than 6 months without treatment 141. A complete radiologic response can be obtained in 7 to 30% of cases after radical radiotherapy [5] but, even in the case of apparent local control, long-term survival remains disappointing because of the high rate of distant metastases [6]. Better local control and a decrease in distant metastases are required to improve survival. There is, however, a need for an optimal definition of locoregional staging which would facilitate the design of a therapeutic strategy which might include surgery, radiotherapy (RT) and/or chemotherapy (CT). The purpose of this paper is to summarize the experience of French groups conducting randomized trials on the combined management of NSCLC.

Forty small cell lung cancer (SCLC) patients took part in a phase II study of cyclophosphamide, adriamycin and vincristine combination chemotherapy (CAV) alternating with cisplatin and etoposide (PE). There were 35 men and 5 women with a mean age of 60 years. Most of them had poor prognostic factors: extensive disease (ED) in 26 (65%), poor performance status in 41% and weight loss in 50%. Chemotherapy consisted of three cycles of CAV (cycles 1, 3, and 5) alternating with three cycles of PE (cycles 2, 4, and 6). Objective responses were obtained in 33/40 patients (overall response rate 83%). Among these 17 (43%) achieved complete response (CR) and 16 (40%) partial response (PR). The respective CR and PR rates were 43% and 50% for limited disease (LD) and 42% and 35% for ED. Haematological toxicity was mild-to-moderate and manageable. In particular, a neutropenia occurred in 85% of the patients inducing fever in 23%. Overall median survival was 48 weeks (88 weeks for the LD group and 45 weeks for the ED group; P

Mast cells and histamine-mediated reactions may be altered in patients with cancer. In an attempt to characterize the possible skin defects in patients with cancer, we tested 22 patients suffering from lung cancers, 30 from breast cancers, and 30 age-matched normal individuals, using several compounds, in investigating the pathophysiology of the skin response. Histamine hydrochloride (10 and 100 mg/ml) and codeine phosphate (9%) were tested by prick test. Substance P (50 and 500 ng per injection site), phentolamine (20 micrograms per injection site), and carbachol (1 microgram per injection site) were tested by intradermal skin tests. Skin mast cells were also microscopically examined in 10 patients with lung cancer, five with breast cancer, and 10 normal subjects. The mean wheal sizes induced by all the tested substances were similar in patients with cancer and chronic bronchitis and in normal individuals. The flare to histamine, codeine phosphate, and substance P was completely abolished in 7/22 patients with lung cancer, but the lack of flare was not related to the age of the patients, nor to the staging of cancer, nor to metastasis. The mean numbers of alcian blue-stained or toluidine blue-stained positive mast cells were similar in normal subjects and in subjects with cancer. This study does not confirm the skin hyporeactivity of patients with cancer.

Summary Patients and methods Twenty patients with lung cancer and brain metastasis were prospectively included in this feasibility study (four small-cell and 16 non-small-cell lung cancers). There were two previously untreated patients and 18 pretreated patients for whom brain metastases constituted the first re lapse after a treatment-free interval followmg chemotherapy for the primary lung cancer. Most of the patients had neuro logical symptoms and an ECOG performance index over 2. Treatment consisted of three courses of whole brain radio therapy (18 Gy in 10 fractions) and ifosfamide: 3 g/m2 daily from day 1 through day 4, i.e., during the first four days of radiotherapy with uromitexan uroprotection and haemato poietic support (r-HuG-CSF). Results Seventeen patients completed the three-cycle programme. Sixteen patients had grade 4 neutropema and six of them experienced a febrile episode. Other toxicities were mild to moderate and manageable. The received dose-intensity of ifosfamide was 90%. Response evaluation demonstrated stable disease for two patients, partial response for eight, complete response for six and progression for four. All responders benefited by a remission of symptoms and improvement of performance index. Median survival from start of protocol was 13 months. Conclusion Brain radiotherapy plus high-dose ifosfamide is feasible in patients suffering from brain recurrences of lung cancer.

PURPOSE: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally. DESIGN: Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes. RESULTS: A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).

Objectives The PARAMOUNT trial showed that continuation maintenance therapy with pem after induction therapy with pem plus CP significantly reduced the risk of disease progression (HR = 0.62) and death (HR = 0.78) in patients (pts) with advanced NS-NSCLC. The purpose of this abstract is to present the updated safety and patients' QoL results from the continuation maintenance treatment of the PARAMOUNT trial. Methods In this phase III, randomized, double-blind, PBO-controlled study, 939 pts were treated with pem (500 mg/m2) plus CP (75 mg/m2) on day 1 of four 21-day cycles. Patients (n = 539) who had not progressed and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1, were randomized (2:1; stratified for PS, induction response, and disease stage) to maintenance pem (500 mg/m2, day 1) plus BSC (n = 359) or PBO plus BSC (n = 180) until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. All randomized pts were qualified for the maintenance phase safety analyses, which included summaries of the incidence of adverse events by maximum Common Terminology Criteria Adverse Events, version 3, grade. All enrolled patients that had provided baseline and at least 1 subsequent measurement for EuroQol 5-dimensional (EQ-5D) scale were included in the analysis of patient-reported outcomes. Results Safety and the QoL analyses in the continuation maintenance therapy will be presented. Conclusions The long-term and low-grade toxicities of continuation maintenance therapy with pem will be discussed. Disclosure C.M. Visseren-Grul: Employed by and own stock in Eli Lilly and Company. L. Paz-Ares: I have advisory board relationship and honararia to disclose with Eli Lilly and Company, Bayer, Roche, Pfizer. I. M. Dediu: Advisory Board - Eli Lilly and Company. M. Thomas: Advisory Board - Eli Lilly and Company Corporate Sponsored Trial - Eli Lilly and Company. N. Chouaki: Employed by and own stock in Eli Lilly and Company. A. Zimmermann: Employed by and own stock in Eli Lilly and Company. J. Pujol: Advisory Board - Eli Lilly and Company. C. Gridelli: Advisory Board, corporate-sponsored research, and honoraria/speaker bureau with Eli Lilly and Company. All other authors have declared no conflicts of interest.

Events associated with decreased renal function are reported in ≥1% and

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.

High serum NSE and advanced tumour stage are well-known negative prognostic determinants of small cell lung cancer (SCLC) when observed at presentation. However, such variables are reversible disease indicators as they can change during the course of therapy. The relationship between risk of death and marker level and disease state during treatment of SCLC chemotherapy is not known. A total of 52 patients with SCLC were followed during cisplatin-based chemotherapy (the median number of tumour status and marker level assessments was 4). The time-homogeneous Markov model was used in order to analyse separately the prognostic significance of change in the state of the serum marker level (NSE, CYFRA 21-1, TPS) or the change in tumour status. In this model, transition rate intensities were analysed according to three different states: alive with low marker level (state 0), alive with high marker level (state 1) and dead (absorbing state). The model analysing NSE levels showed that the mean time to move out of state ‘high marker level’ was short (123 days). There was a 44% probability of the opposite reversible state ‘low marker level’ being reached, which demonstrated the reversible property of the state ‘high marker level’. The relative risk of death from this state ‘high marker level’ was about 2.24 times greater in comparison with that of state 0 ‘low marker level’ (Wald's test; P < 0.01). For patients in state ‘high marker level’ at time of sampling, the probability of death increased dramatically, a transition explaining the rapid decrease in the probability of remaining stationary at this state. However, a non-nil probability to change from state 1 ‘high marker level’ to the opposite transient level, state 0 ‘low marker level’, was observed suggesting that, however infrequently, patients in state 1 ‘high marker level’ might still return to state 0 ‘low marker level’. Almost similar conclusions can be drawn regarding the three-state model constructed using the tumour response status. For the two cytokeratin markers, the Markov model suggests the lack of a true reversible property of these variables as there was only a very weak probability of a patient returning to state ‘low marker level’ once having entered state ‘high marker level’. In conclusion, The Markov model suggests that the observation of an increase in serum NSE level or a lack of response of the disease at any time during follow-up (according to the homogeneous assumption) was strongly associated with a worse prognosis but that the reversion to a low mortality risk state remains possible. © 1999 Cancer Research Campaign

We examined two recently described cytokeratin markers, CYFRA 21-1 (cytokeratin fragment recognized by KS 19-1 and BM 19-21 antibodies) and TPS (specific M3 epitope of the tissue polypeptide antigen), in 405 lung cancer patients (91 small-cell and 314 non-small-cell lung cancers) and 59 patients presenting with nonmalignant pulmonary disease. Sensitivity-specificity relationship, as analyzed by receiver operating characteristic curves, demonstrated a higher accuracy of CYFRA 21-1 in comparison with TPS in both small-cell and non-small-cell lung cancers. Thresholds of 3.6 ng/ml and 140 U/L for CYFRA 21-1 and TPS respectively gave a 90% to 95% specificity. Sensitivity of CYFRA 21-1 was the highest in squamous-cell carcinomas (0.61) and the lowest in small-cell lung cancers (0.36), whereas sensitivity of TPS did not vary significantly according to histology (overall sensitivity, 0.40). In non-small-cell lung cancers, both serum CYFRA 21-1 and serum TPS distributions varied significantly according to Mountain's stage of the disease, nodal status, tumor status, and performance status, inasmuch as the worse each above-mentioned variable became, the higher the median and interquartile serum marker level was. Neither CYFRA 21-1 nor TPS was able to accurately discriminate between stage IIIa (marginally resectable) and stage IIIb (unresectable) non-small-cell lung cancers, however. In both small-cell and non-small-cell lung cancers, univariate survival analyses demonstrated that either a CYFRA 21-1 level over 3.6 ng/ml or a TPS level over 140 U/L significantly indicated a poor survival rate. In the whole population, taking into account other significant variables, Cox's model analysis demonstrated that a poor performance index, an advanced stage of the disease, the presence of metastases, elevated serum lactate dehydrogenase, and high serum CYFRA 21-1 (odds ratio, 1.74; 95% confidence interval, [1.33-2.27] were independent prognostic variables. We concluded that CYFRA 21-1 is a significant determinant of survival. Other applications of cytokeratin markers in lung cancer are still limited.

"Asthmaexpert" was produced at the special request of several clinicians in order to obtain a better understanding of the medical decisions taken by clinical experts in the management of asthmatic patients. In order to assess the severity of asthma, a new score called Artificial Intelligence score (AI score), produced by Asthmaexpert, was compared with three other scores (Aas, Hargreave and Brooks). One hundred patients were enrolled prospectively in the study during their first consultation in the out-patient clinic. Distribution of severity level according to the different scores was studied, and the reliability between AI and other scores was evaluated by Kappa and MacNemar tests. Correlations with functional parameters were performed. The AI score assessed higher levels of severity than the other scores (Kappa = 18, 28 and 10% for Aas, Hargreave and Brooks, respectively) with significant MacNemar test in all cases. There was a significant correlation between AI score and forced expiratory volume in one second (FEV1) (r = 0.73). These data indicate that the AI score is a severity score which defines higher levels of severity than the chosen scores. Correlations for functional parameters are good. This score appears easy to use for the first consultation of an asthmatic patient.

Background Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1–3. In the phase III AXIS study in second-line metastatic renal cell carcinoma (mRCC), axitinib demonstrated significant improvement in progression-free survival (PFS) compared with sorafenib (median PFS, 6.7 versus 4.7 months; hazard ratio [HR] 0.665; one-sided P Methods Eligible patients had clear-cell mRCC; progressive disease per RECIST after one prior systemic first-line therapy; and Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Patients were stratified by PS and prior therapy, then randomized 1:1 to receive axitinib or sorafenib. Tumour imaging was assessed by an independent review committee. Results Of the 723 enrolled patients, 158 were Asian (axitinib arm: n = 77; sorafenib arm: n = 81). Of the Asian patients, 74% were male, median age was 61 years, and 59% had PS = 0; prior therapies were 54% cytokine-, 41% sunitinib-, 4% bevacizumab-, and 1% temsirolimus-based regimens. Median PFS in the Asian patients was 10.3 months in the axitinib arm and 4.7 months in the sorafenib arm (HR 0.578; 95% confidence interval, 0.362–0.924; one-sided P = 0.0096). The objective response rate (ORR) was 31.2% versus 7.4% (one-sided P = 0.0003) in the Asian patients receiving axitinib and sorafenib, respectively. Common adverse events (AEs) in the Asian patients receiving axitinib were hypertension (53%), diarrhoea (53%), hand-foot syndrome (47%), fatigue (45%), decreased appetite (36%), dysphonia (36%), and hypothyroidism (31%). Common AEs in the Asian patients receiving sorafenib were hand-foot syndrome (70%), diarrhoea (46%), hypertension (34%), and alopecia (30%). Conclusions Axitinib is effective and well tolerated in the Asian patients with mRCC. Consistent with global phase III trial results, PFS and ORR were higher with axitinib versus sorafenib in the Asian patients.

Background As previously reported, the PARAMOUNT trial showed that pemetrexed (pem) continuation maintenance therapy after pem–cisplatin induction therapy significantly reduced the risk of disease progression over placebo (HR = 0.62; 95% CI: 0.49–0.79; P = 0.00007) in patients with advanced nonsquamous NSCLC. Here we present the final OS data. Methods In a double-blind, placebo-controlled study, 939 patients were treated with induction therapy [four cycles of induction pem (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle], after which 539 patients who had not progressed and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1 were randomized (2:1; stratified for PS, induction response, disease stage) to maintenance pem (500 mg/m2, day 1 of a 21-day cycle) plus BSC (n = 359) or placebo plus BSC (n = 180) until disease progression. All patients received vitamin B12, folic acid, and dexamethasone. After 390 deaths, the final analysis of OS was done on randomized patients and was based on a nominal alpha level of 0.0498. Results Patient characteristics were balanced between the arms: median age = 61 years; 58% male; 32% PS 0; 91% stage IV; 95% Caucasian; 86% adenocarcinoma; and 45% complete/partial response (CR/PR) to induction. (No OS data available.) Conclusions (Conclusion will be presented based on updated data.)

7007 Background: No survival differences was observed between any arms in the 528 early stage NSCLC randomized patients of the IFCT-0002 phase III trial comparing two chemotherapy timing, all pre- ...

CRA7510 Background: The PARAMOUNT trial investigated whether pem continuation maintenance therapy improves progression-free survival (PFS) after pem-cisplatin induction therapy in patients (pts) with advanced nonsquamous NSCLC. Methods: In this double-blind, placebo-controlled trial, 939 pts participated in the induction phase, specified as four cycles of induction pem (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Pts who had not progressed during pem-cisplatin induction and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1 (n=539; 57.4%) were randomized (2:1, stratified for disease stage, PS, and induction response) to maintenance pem (500 mg/m2 on day 1 of a 21-day cycle) plus BSC (n=359) or placebo plus BSC (n=180) until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. The primary endpoint was PFS (target: HR=0.65, two-sided alpha=0.05; 90% power with minimum of 238 events). Results: Pt characteristics were balanced between arms: median age=61 years; 58% male; 95% Caucasian; 32% PS 0; 91% stage IV; 87% adenocarcinoma; and 45% induction complete/partial response. Pem continuation maintenance resulted in a 36% reduction in the risk of progression (HR=0.64, 95% CI: 0.51-0.81; P=0.00025). The median independently reviewed PFS (472 pts, 297 events), measured from randomization, was 3.9 months (95% CI: 3.0-4.2) on the pem arm, and 2.6 months (95% CI: 2.2-2.9) on the placebo arm. The disease control rate (% pts with response/stable disease) was 71.8% on the pem arm, and 59.6% on the placebo arm (P=0.009). The drug-related serious adverse event (AE) rate was 8.9% on the pem arm, and 9.2% of pts had grade 3/4 laboratory Common Toxicity Criteria AEs. On the placebo arm, the rates were 2.8% and 0.6%, respectively. Discontinuations due to AEs were 5.3% on the pem arm, 3.3% on the placebo arm. Conclusions: PARAMOUNT met its primary endpoint and showed that pem continuation maintenance following pem-cisplatin induction is an effective and well tolerated treatment for pts with advanced nonsquamous NSCLC.

7530 Background: Association of surgery and CT is standard for early-stage NSCLC. Meta-analyses showed comparable efficacy of adjuvant and neoadjuvant CT. The primary objective was to compare survival between two different CT strategies: all before surgery (PRE) versus perioperative (PERI). Methods: Between 2001 and 2005, 528 patients with a stage IA-II resectable NSCLC were randomized to 4 parallel arms (A: 2 GP + 2 GP in responders, then surgery, B:2 GP - surgery + 2 GP in responders, C: 2 TC + 2 TC in responders then surgery, D: 2 TC - surgery + 2 TC in responders; GP: Gemcitabine 1250 mg/m2/d1, 8 and cisplatin 75 mg/m2/d1 q3 wk; TC: Paclitaxel 200 mg/m2/d1 and carboplatin AUC 6, q3 wk). Results: 501 patients were operated on, 96.2% in the preoperative CT arms (PRE: A+C) and 95.8% in the perioperative CT arms (PERI: B+D). Ninety- day postoperative mortality was 4.9% and 4.2%, respectively. Pathological complete response was not significantly influenced by the number of preoperative cycles (PRE:8.6%, PERI:6.4%). In an intent-to-treat analysis, 3-yr survival was 67.8% and 68.6%, respectively (p=0.96). In responders, despite a dramatic difference in CT compliance (90.4% and 75.2% having received the 4 cycles, respectively, p=0.001), 3-yr survival was 75.1% and 79.5%, respectively (p=0.82). Survival did not differ with the CT regimen (GP versus TC, p=0.84). Three-yr survival increased from 68.1% in the PRE arms to 77.2% in the PERI arms in squamous cell carcinomas (SCC), and decreased from 67.7% to 61.6% in non SCC, respectively (Cox model interaction, p=0.35). Three-yr survival was 74.6% in the GP arms and 70.7% in the TC arms, in SCC, and was 64.2% and 65.4%, in non SCC, respectively (interaction, p=0.51). There was no interaction between CT strategy and stage. In stage II patients, 3-yr survival was 59.1% but 76.5% in responders, comparable to that of all stage I patients (72.9%). Conclusions: Despite an increased compliance of the all preoperative chemotherapy strategy, no difference was observed between the PRE and PERI arms. There might be an advantage for perioperative CT and for gemcitabine-based in SCC and for preoperative CT and for taxane-based in non SCC. No significant financial relationships to disclose.

Locally advanced non-small cell lung cancers (NSCLC) have a poor prognosis following surgery alone when this has been possible, because of a high rate of local and metastatic relapses [1-3]. Probability of 5 years survival for these patients ranges between 5 and 15 % [4–6]. Thus, locally advanced NSCLC for which resection is potentially possible but poorly curative are usually designated as marginally resectable [7]. Adjuvant post-operative chemotherapy or radiation therapy hardly seem to improve survival [8]. Therefore, other modality treatments might be proposed to improve survival.

Three cases of Pneumocystis carinii pneumonia occurring in adults with unexplained T-cell defects are reported. No HIV markers were found during the follow up, and neither was any immunosuppressive disease. The authors emphasize the possibility that Pneumocystis pneumonia may occur and may be treated successfully in previously healthy subjects.

8019 Background: Survival benefits can be predicted from progression-free survival in advanced colorectal cancer (Buyse et al, JCO 2007; 25:5218), but not in advanced breast cancer (Burzykowski et al, JCO 2007; in press). We investigated whether progression-free survival (PFS) could be considered a valid surrogate for overall survival (OS) in patients with advanced non small cell lung cancer (NSCLC). Methods: Individual patient data were collected from all trials comparing docetaxel to vinca alkaloids for the first-line treatment of patients with NSCLC (Douillard et al, J Thoracic Oncol 2007;2:939). Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. Treatment effects were estimated through hazard ratios in the 322 participating centers. Centers with less than 3 patients per treatment arm were grouped. Squared correlation coefficients were estimated along with their 95% confidence interval (CI). The surrogate threshold ...

7519 Background: Recent trials have shown a survival benefit of CT in resectable NSCLC. The primary objective was to define the best timing of CT (all before surgery versus perioperative). Another objective was to compare two regimens, gemcitabine-cisplatin (GP) and paclitaxel-carboplatin (TC). Methods: Between May 2001 and Dec 2005, 528 patients (pts) with a stage IA-II resectable NSCLC were randomized to 4 parallel arms: A: 2 GP + 2 GP in responders, then surgery, B: 2 GP - surgery + 2 GP in responders, C: 2 TC + 2 TC in responders then surgery, D: 2 TC - surgery + 2 TC in responders (GP: Gemcitabine 1250 mg/m2/d1, 8 and cisplatin 75 mg/m2/d1 q3 wk; TC: Paclitaxel 200 mg/m2/d1 and carboplatin AUC 6, q3 wk). Results: Pathological tumor volume and pathological complete response rate did not differ with the number of preoperative cycles. Proportions of pts receiving cycles 3 and 4 were higher when all CT was given before surgery. There were several significant differences in the main toxicities between GP and TC. Conclusions: 1- GP and TC were effective and safe. 2- Results of pathological response suggested that 2 cycles might be as effective as 4 cycles. 3- Dose intensity was higher when all chemotherapy was given before surgery compared to both before and after surgery. No significant financial relationships to disclose. [Table: see text]

7034 Background: Taxanes and vinca alkaloids are commonly used agents, in first-line therapy of advanced NSCLC. As some data in comparative studies have suggested possible differences in survival and safety, we performed a meta-analysis in order to assess the potential benefit of docetaxel-based regimens in comparison with vinca alkaloid-based regimens, in terms of overall survival (OS) and toxicity. Methods: MEDLINE, CANCERLIT and Cochrane Library searches were supplemented by information from clinical study reports and by manual searching of relevant meeting proceedings. Only randomized trials comparing docetaxel-based chemotherapy to vinorelbine- or vindesine-based chemotherapy were included. Outcomes recorded were OS and neutropenia. Fixed-effects and random-effects models were used to estimate the pooled hazard ratio (HR) of OS and the odds ratio (OR) of neutropenia. A HR or OR less than 1 indicates that docetaxel is superior to vinca alkaloids. Heterogeneity was assessed using the Cochran Q-test. Results: The seven selected trials (six using vinorelbine as vinca alkaloid) yielded a total of 2,867 patients (docetaxel regimens: 1,638; vinca alkaloid regimens: 1,229). Docetaxel was combined with a platinum compound in three trials, with gemcitabine in two trials and used as monotherapy in two trials. The vinca alkaloid was combined with a platinum compound in six trials, and used alone (vinorelbine) in one. The pooled estimate of the OS shows a significant improvement in favor of docetaxel (HR=0.89, 95%CI [0.82;0.96], p=0.03), this benefit persisting after exclusion of the vindesine study (HR=0.90 [0.83;0.98]) and also after excluding monotherapy regimens (HR=0.89 [0.82;0.97]. While neutropenia was common, it was significantly less frequent with docetaxel (OR=0.60 [0.39;0.92], p=0.019), as was febrile neutropenia (OR=0.60 [0.39;0.96], p=0.034). Conclusions: The results of this meta-analysis support the superior efficacy (OS) and safety (neutropenia and febrile neutropenia) of docetaxel in first-line therapy of advanced NSCLC as compared with vindesine or vinorelbine. Detailed results, as well as subgroup analyses, will be presented at the meeting. [Table: see text]

7057 Background: This study aimed at determining whether or not thalidomide prolongs survival of patients (pts) suffering from SCLC. Methods: Eligibility consisted of previously untreated ED-SCLC, age No significant financial relationships to disclose.

7097 Background: Gemcitabine-cisplatin is one of the reference doublets used in NSCLC. Oxaliplatin is a platin analog which offers a promising efficacy/tolerance profile in NSCLC. The combination of gemcitabine and oxaliplatin has been proven feasible and active in solid tumors. Methods: Patients with chemonaive, measurable, PS 0 or 1, stage IIIB/ IV NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 day 1 & 8 plus oxaliplatin 130 mg/m2 day 1 (GEMOX) or gemcitabine 1,250 mg/m2 day 1 & 8 plus cisplatin 80 mg/m2day 1 (GEMCIS). Cycles were given every 3 weeks. The primary endpoint of the study was the response rate according to the RECIST criteria. Secondary endpoints included tolerance, survival and quality of life. Results: Between October 2003 and December 2004, 130 patients (66 in GEMOX and 64 in GEMCIS) were accrued at 12 centres. Baseline patient characteristics were similar in the 2 groups. Mean age was 61. There were 96 males and 34 females; 27% of patients were PS 0 and 73% were PS 1; 15% had stage IIIB and 85% had stage IV. Median number of cycles was 5 in each group. Objective response rates were 36% in GEMOX (CI 95%: 25%-50%) and 39% in GEMCIS (CI 95%: 28%-54%) respectively. Time to progression was 173 days in the GEMOX group and 163 days in the GEMCIS group. Median survival was 10.8 months in the GEMOX group and 10.4 months in the GEMCIS group. Grade III/IV neutropenia was observed in 38% of patients after GEMOX and 41% after GEMCIS; thrombocytopenia was observed in 40% and 33% of cases respectively. Grade 2+ neurotoxicity was more frequent after GEMOX (18% vs 3%). Conclusions: GEMOX has an activity comparable to GEMCIS and may be an alternative for those patients with advanced NSCLC who have a contra-indication to cisplatin. [Table: see text]