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Background: The link between organizing pneumonia (OP) and gastroesophageal reflux disease (GERD) is not well known. There is little evidence in the literature to establish a causal link between GERD and OP. Objectives: The aim of the study was to assess the hypothesis that OP is more severe when it is associated with GERD and that it leads to more frequent relapses. Methods: In a retrospective study on 44 patients suffering from OP, we compared the clinical, radiological and histological characteristics of 2 groups, 1 composed of patients with GERD (n = 20) and the other of patients without GERD (n = 24). Results: The GERD group was distinguished by a higher number of patients with migratory alveolar opacities on chest radiography and thoracic computerized tomography (14/20 vs. 9/24; p = 0.03 and 18/20 vs. 13/24; p = 0.01), greater hypoxemia [60 (42-80) vs. 70 (51-112) mm Hg; p = 0.03], greater bronchoalveolar lavage cellularity [0.255 (0.1-1.8) vs. 0.150 (0.05-0.4) g/l; p = 0.035] and more frequent relapses (14/20 vs. 9/24; p = 0.03). Conclusions: OP associated with GERD is more severe and results in more frequent relapses. Microinhalation of gastric secretions might induce lung inflammation leading to OP and relapse. We suggest that typical symptoms of GERD such as pyrosis should be investigated in OP.

Resume Contexte Le colloque singulier entre le medecin referent et le patient en cancerologie integre, depuis leur mise en place par le Plan cancer, les elements decisionnels issus de la reunion de concertation pluridisciplinaire (RCP). Methodes Afin d’evaluer l’impact de la RCP sur la relation medecin-patient, une etude a ete menee au centre hospitalier universitaire (CHU) de Tours entre janvier 2005 et mai 2006. Trois outils methodologiques complementaires ont ete elabores : un questionnaire patients, une etude de dossiers portant sur la mise en application des decisions de la RCP et un questionnaire aux medecins referents participant aux RCP. Resultats Cent quarante-cinq questionnaires ont ete recueillis aupres de patients dont le dossier a ete discute en RCP, 40 questionnaires recueillis aupres des medecins participant aux reunions et une analyse de 324 dossiers a ete realisee. Quatre-vingt pour cent des patients reconnaissaient l’avis de la RCP comme rassurant, 73 % exprimaient que le plus important pour eux etait la relation avec le medecin referent et 96 % avaient une totale ou grande confiance dans le medecin referent. La confiance semblait liee a la qualite de la communication, a la liberte de dialogue et a la competence reconnue du medecin en particulier dans le choix du traitement. L’etude des dossiers a montre que dans 91 % des cas, l’avis de la RCP etait applique et que, dans 69 % des cas, c’est le medecin referent qui delivrait l’information au patient apres la RCP. Du point de vue des medecins, 33/40 disaient que la RCP ne modifiait pas leur relation avec le patient. On note que 35/40 exprimaient que la consultation apres RCP facilitait la presentation de la decision et 37/40 que la decision appliquee etait toujours ou souvent en accord avec l’avis de la RCP. Conclusion La RCP apparait le plus souvent ne pas modifier le colloque singulier. De par la confiance que le patient lui accorde, le role du medecin referent est essentiel dans l’integration de l’avis collegial de la RCP et il s’agit de veiller au risque d’un desengagement de celui-ci dans le choix decisionnel.

Lung cancer is the leading cause of cancer-related deaths in industrialized countries and non small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Cisplatin doublet based chemotherapy, which is the recommended regimen in first line therapy in advanced or metastatic NSCLC, improves survival but in low proportion. Monoclonal antibodies (mAbs) are a novel promising therapeutic class used with great results in inflammatory diseases such as rheumatoid arthritis. Antibodies are natural proteins with modular structure, specific pharmacodynamics and pharmacokinetics and possibly produced against any antigens, thus giving them several advantages over small drug therapeutics. In solid tumors, therapeutic mAbs improved progression free survival (PFS) and overall survival (OS) of patients with breast and colon cancers and had considerably changed the treatment in clinical practice. In NSCLC, bevacizumab, an anti-VEGF mAb, and cetuximab, an anti-EGFR mAb, are the most studied antibodies. Bevacizumab acts on angiognenesis and improved PFS of non squamous NSCLC but in low proportion as shown in two large phase III trials. It was approved by European Medicines Agency (EMEA) and Food and Drug administration (FDA) as a first line therapy in combination with cisplatin doublet chemotherapy. Cetuximab slightly enhanced OS but did not improve PFS in two large phase III trials. These results added to high adverse effect lead to cetuximab refusal by EMEA and FDA in NSCLC. At first glance, the results of mAbs in NSCLC are somewhat disappointing, in contrast to the benefits obtained with mAb treatments in other solid tumors. However, many other mAbs directed against novel targets, such as IGF1-R or CTLA-4, and new mAbs targeting VEGFR and EGFR pathways with different pharmacodymamical and pharmacokinetic properties are under evaluation and may change our vision of taking care of patients with NSCLC. In conclusion, it seems that mAbs therapy in NSCLC clearly marks the start of a new era in NSCLC treatment, with promises in improving patient survival and quality of life.

Introduction Vinflunine (Javlor) has shown significant antitumour activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose of vinflunine in combination with gemcitabine for treatment of advanced NSCLC in chemonaive patients. Methods A phase I and pharmacokinetic study was conducted to determine the maximum tolerated dose and to establish the recommended dose of vinflunine (VFL) administered on day 1 every 21 days combined with gemcitabine given on days 1 and 8 every 3 weeks. Results Nineteen patients were included in this study. Three patients experienced a dose limiting toxicity, with constipation in one patient, hypertension in one patient, and constipation and febrile neutropenia in one patient. The combination of VFL 320 mg/m 2 and gemcitabine 1250 mg/m 2 was defined as the maximum tolerated dose. The recommended dose was established at the dose of VFL 320 mg/m 2 combined with gemcitabine 1000 mg/m 2 . Neither VFL nor gemcitabine seemed to be influencing the pharmacokinetics of each other. All patients were evaluable for tumor response. Seven presented a partial response and eight experienced a stable disease. Conclusions The combination of VFL 320 mg/m 2 administered on day 1 combined with gemcitabine 1000 mg/m 2 given on days 1 and 8 every 3 weeks is established as the RD and was shown to be active in these chemonaive NSCLC patients.

Multidisciplinary meeting (MDM) in oncology has been institutionalised in France by the Cancer Plan. This study aims to determine the place of MDM in the decision process. From November 2004 to July 2005, we observed 29 meetings at the Tours Hospital and 324 case presentations, 80 in orthopaedics, 151 in gastroenterology and 93 in chest medicine. Forty physicians attending the meetings answered a questionnaire exploring their opinions on MDM and the collegial decision. We found that MDM is mostly the place for technical discussions and that patients' wishes are rarely addressed. The different medical specialities are well represented but we observed that only physicians attend MDM. Decisions for straightforward cases are rapidly validated. For more complex clinical situations (25 to 40% of case presentations), the multidisciplinary approach allows to adapt guidelines or to choose alternative treatments. All the physicians interviewed express that MDM legitimates the medical decision. It occurs that they disagree with the RCP decision. We discuss how MDM impacts on the medical decision as well as the shift from the individual decision to the collective one, particularly in term of responsibility.

Background: Tissue factor (TF), the main initiator of blood coagulation, is also a signaling protein that regulates cancer progression. TF synthesis was recently shown to be affected by tumor suppressor genes (TSGs) in tumor cell lines. We therefore studied TF gene (F3) expression and the status of genes coding for tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and serine/threonine kinase 11 (STK11) in non–small cell lung cancer (NSCLC). Heparanase (HPSE) gene expression was also measured because this endo-β-D-glucuronidase was recently shown to enhance TF gene expression. Methods: TF and heparanase mRNA expression was measured by real-time PCR in 53 NSCLC tumors. Exons 5–8 of TP53 were sequenced from genomic DNA. Mutations of PTEN and STK11 were screened by multiplex ligation-dependent probe amplification. Results: TF mRNA levels were significantly higher in T3–T4 tumors (P = 0.04) and in stages III–IV of NSCLC (P = 0.03). Mutations of TP53, STK11, and PTEN were identified in 20 (37.7%), 21 (39%), and 20 (37.7%) of tumors, respectively. TF expression was higher in mutated TP53 (TP53Mut) (P = 0.02) and PTENMut (P = 0.03) samples. Moreover, TF mRNA increased from 2700 copies (no mutation) to 11 6415 when 3 TSG were mutated. Heparanase gene expression did not differ according to TF gene (F3) expression or TSG mutation. The median survival time was shorter in patients with tumor TF mRNA levels above median values (relative risk 2.2; P = 0.03, multivariate analysis) and when TP53 was mutated (relative risk 1.8; P = 0.02). Conclusions: These results provide clear evidence that combined oncogene events affecting TSG dramatically increase TF gene expression in lung tumors. Moreover, this study suggests that TF gene expression could be used as a prognostic marker in NSCLC. .

Despite an increasing interest in the use of inhalation for local delivery of molecules for respiratory diseases and systemic disorders, methods to deliver therapy through airways has received little attention for lung cancer treatment. However, inhalation of anticancer drugs is an attractive alternative route to systemic administration which results in limited concentration of the medication in the lungs, and triggers whole-body toxicity. In this study, we investigated the feasibility of nebulization for therapeutic antibodies, a new class of fully-approved anticancer drugs in oncology medicine. Cetuximab, a chimeric IgG1 targeting the epidermal growth factor receptor (EGFR), was nebulized using three types of delivery devices: a jet nebulizer PARI LC+®, a mesh nebulizer AeronebPro® and an ultrasonic nebulizer SYST’AM® LS290. Aerosol size distribution was measured using a cascade impactor and aerosol droplets were observed under optical microscopy. The immunological and pharmacological properties of cetuximab were evaluated following nebulization using A431 cells. The aerosol particle clouds generated with the three nebulizers displayed similar aerodynamical characteristics, but the IgG formed aggregates in liquid phase following nebulization with both the jet and ultrasonic devices. Flow cytometry analyses and assays of EGFR-phosphorylation and cell growth inhibitions on A431 demonstrated that both the mesh and the jet nebulizers preserved the binding affinity to EGFR and the inhibitory activities of cetuximab. Altogether, our results indicate that cetuximab resists the physical constraints of nebulization. Thus, airway delivery represents a promising alternative to systemic administration for local delivery of therapeutic antibodies in lung cancer treatment.

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.

International audience; Tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type serine proteinase inhibitor that inhibits plasmin-dependent activation of several metalloproteinases. Downregulation of TFPI-2 could thus enhance the invasive potential of neoplastic cells in several cancers, including lung cancer. In this study, TFPI-2 mRNA was measured using a real-time PCR method in tumours of 59 patients with non-small-cell lung cancer (NSCLC). Tumour TFPI-2 mRNA levels appeared well correlated with protein expression evaluated by immunohistochemistry and were 4-120 times lower compared to those of nonaffected lung tissue in 22 cases (37%). Hypermethylation of the TFPI-2 gene promoter was demonstrated by restriction enzyme-polymerase chain reaction in 12 of 40 cases of NSCLC (30%), including nine of 17 for whom tumour TFPI-2 gene expression was lower than in noncancerous tissue. In contrast, this epigenetic modification was shown in only three of 23 tumours in which no decrease in TFPI-2 synthesis was found (P ¼ 0.016). Decreased TFPI-2 gene expression and hypermethylation were more frequently associated with stages III or IV NSCLC (eight out of 10, P ¼ 0.02) and the TFPI-2 gene promoter was more frequently hypermethylated in patients with lymph node metastases (eight out of 16, P ¼ 0.02). These results suggest that silencing of the TFPI-2 gene by hypermethylation might contribute to tumour progression in NSCLC.

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.

Aims: A case–control study was carried out between 1998 and 2000 to investigate the relation between systemic sclerosis and occupational exposure. Methods: Eighty cases of systemic sclerosis admitted consecutively to the Department of Internal Medicine at the University Hospital of Tours from 1998 to 2000 were included. For each case, two age, gender, and smoking habits matched controls hospitalised during the same period in the same department were selected. A committee of experts was set up retrospectively to assess occupational exposure. Exposure to silica dust and organic solvents (such as trichlorethylene and other chlorinated solvents, and benzene and other aromatic solvents) was investigated using semiquantitative estimates of exposure. An exposure score was calculated for each subject based on probability, intensity, daily frequency, and duration of exposure for each period of employment. The final cumulative exposure score was obtained, taking into account all periods of employment. Results: Significant associations with SS were observed for crystalline silica, trichlorethylene, chlorinated solvents, toluene, aromatic solvents, ketones, white spirit, epoxy resins, and welding fumes. Risk of SS was significantly associated with a high final cumulative exposure score of occupational exposure to crystalline silica, trichlorethylene, chlorinated solvents, welding fumes, and any types of solvents. Conclusion: Results confirm the influence of occupational risk factors in the occurrence of SS in both men and women. The link is not only with silica but also with other compounds such as solvents.

A randomized phase II trial of oral vs. intravenous (i.v.) vinorelbine was designed to determine the efficacy and safety of oral vinorelbine with an intrapatient dose escalation in previously untreated patients with advanced non-small-cell lung cancer (NSCLC).Between December 1997 and April 1999, 115 patients with stage IIIB or IV NSCLC were randomized (2 to 1) to receive either oral vinorelbine at a dose of 60 mg/m2/week for the first three administrations and then increased to 80 mg/m2/week in the absence of severe neutropenia, or i.v. vinorelbine at 30 mg/m2/week.One hundred and fourteen patients (76 in the oral arm and 38 in the i.v. arm) were treated. Ninety-eight patients (86%) were eligible and assessable. The two treatment arms were well-balanced for demographic and prognostic features. After external panel review, the response rates in evaluable patients were 14%, in the oral arm and 12% in the i.v. arm. The median progression-free survival with oral and i.v. vinorelbine was 3.2 months and 2.1 months, respectively, and the median survival 9.3 and 7.9 months, respectively. The most common hematological toxicity was neutropenia, which was severe (grade 3-4) in 46% of patients and for 7% of administrations in the oral arm, and in 62% of patients and for 25% of administrations in the i.v. arm. Non-hematological toxicities including nausea, vomiting, anorexia, weight loss, diarrhea .and constipation were generally mild to moderate.The activity of oral and i.v. vinorelbine in advanced NSCLC appears to be comparable. The safety profiles of both formulations look qualitatively similar. Oral vinorelbine can therefore be considered a good alternative to i.v. administration.

Using nebulization to deliver aminoglycosides may be of benefit in cystic fibrosis (CF) patients colonized byPseudomonas aeruginosa. However, one problem with this route is the absence of clinical parameters allowing estimation of the mass of drug deposited in the lungs (MDL). The aim of this study was to assess whether aminoglycoside excretion in the urine reflects the MDL.Fourteen studies were performed in seven CF patients. Amikacin was mixed with albumin labelled with99mTc and nebulized with an ultrasonic nebulizer. The MDL was determined by the mass-balance technique. Urine was collected during the 24 h following inhalation and was assayed for amikacin by fluorescence polorization immunoassay (FPIA).The mean±sem MDL was 14.0±2.2% of the nebulizer charge. The mean±sem amount of amikacin excreted in the urine was 20.9±4.5 mg and correlated with the MDL (r=0.93; p=0.0001). There was, however, wide intersubject variability in both deposition and excretion in the urine.Monitoring excretion of aminoglycosides in the urine allows noninvasive estimation of the mass of drug deposited in the lung in cystic fibrosis patients, which might be useful to assess the dose-response relationship in groups of patients, but intersubject variability prevents its use for individual follow-up.

Background: The combination of etoposide plus cisplatin (EP) is considered to be standard therapy for small-cell lung cancer (SCLC). To determine whether drug intensification improves survival of patients with extensive SCLC, we compared this treatment with a four-drug regimen containing EP plus cyclophosphamide and 4'-epidoxorubicin (PCDE). Methods: In a phase III clinical trial organized by the French Federation of Cancer Institutes, patients were randomly assigned to receive either EP (n = 109; etoposide at a dose of 100 mg/m 2 on days 1-3 plus cisplatin at 100 mg/m 2 on day 2) or PCDE (n = 117; etoposide and cisplatin given as in EP plus cyclophosphamide at 400 mg/m 2 on days 1-3 and 4'-epidoxorubicin at 40 mg/m 2 on day 1) every 4 weeks. Both groups received a total of six cycles. Survival differences were analyzed by Wilcoxon and log-rank tests. Associations of treatment group and putative prognostic variables with survival were tested in the Cox proportional hazards model. Quality of life was assessed from the responses to the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (C30, health status and lung cancer module 13). All statistical tests were two-sided. Results: Patients in the PCDE arm had a statistically significant higher frequency of combined complete plus partial responses compared with those in the EP arm (21% plus 55% versus 13% plus 48%, respectively; P = .02 for difference in combined objective responses). Patients in the PCDE arm survived longer than those in the EP arm (1-year survival rate: 40% and 29%, respectively; median survival: 10.5 and 9.3 months, respectively; log-rank P = .0067). In the Cox model, the relative risk of death for patients in the PCDE arm compared with those in the EP arm was 0.70 (95% confidence interval = 0.51 to 0.95); the disease also progressed more slowly in patients in the PCDE arm. Hematologic toxicity was higher in the PCDE arm (22% with documented infections compared with 8% in the EP arm; P = .0038), and the toxicity-related death rate was 9% in the PCDE arm versus 5.5% in the EP arm (P = .22). The global health status showed similar improvement in both arms during treatment. Conclusion: Compared with the EP regimen, the PCDE regimen yielded higher response rates and better survival rates in patients with extensive SCLC without affecting the quality of life of the patients during chemotherapy.

Colistin aerosols are frequently administered to patients with cystic fibrosis. However, questions arise concerning the effect of both jet and ultrasonic nebulizers on the properties of the drug. The aim of this study was to characterize the anti-Pseudomonas aeruginosa (PA) activity of colistin after jet (Pari LL) and ultrasonic (DP100) nebulization. A bench study was performed by capturing the aerosols, determining the drug mass, and assessing its anti-PA activity. Because the inhaled mass of colistin had to be entirely recovered for the bacteriological study, it was assessed by isotopic methods, mixing the drug with a 99mTc-labelled tracer and demonstrating that 99mTc activity accurately predicted the mass of colistin. Colistin was extracted from the filters and its antibiotic activity was determined using the method employed for the study of the bacteriostatic and bactericidal power of serum on the ATCC 27853 PA strain. The postnebulization minimum inhibitory concentrations (MIC) were 1.9 micrograms.mL-1 with DP100 and 0.5 microgram.mL-1 with Pari LL. These values were less than two dilutions different from the 1 microgram.mL-1 MIC of non-nebulized colistin. We conclude that neither jet nebulization nor ultrasonic nebulization alter the antibiotic properties of colistin and that both systems can be used to nebulize colistin.

The aim of the present study was to characterize amphotericin B aerosols nebulized by ultrasonic and jet nebulizers and to study their deposition and pharmacokinetics in patients with pulmonary mycetoma. The aerodynamic behaviour and pulmonary deposition of amphotericin B particles were measured using a direct isotopic method based on stable labelling of the drug with 99mTc. Each nebulizer was bench tested for inhaled mass and particle size distribution. Three patients suffering from pulmonary aspergilloma were enrolled for a 4 week clinical study. They received 5 mg of amphotericin B daily delivered by either Fisoneb or DP100 (ultrasonic) or Respirgard II (jet) nebulizers. Deposition of radiolabelled amphotericin B was measured once with each nebulizer using a gamma-camera. In two patients, amphotericin B serum concentration was monitored over a 330 min period after the nebulization had been completed. Inhaled masses of the three nebulizers, assessed as % of labelled drug caught in inspiratory filter in duplicate experiments, were: 5.8 and 3.6% for Respirgard II; 26.5 and 28.3% with Fisoneb; 5.9 and 6.3% for DP100. Mass median aerodynamic diameter (mean +/- SD) results were: 0.28 +/- 0.04 micron with Respirgard II; 4.82 +/- 0.78 microns with Fisoneb; and 2.27 +/- 1.14 microns with DP100. Because of larger particles and significantly greater inhaled mass, Fisoneb delivered more amphotericin B to the central airways, the lung periphery and in the mycetoma lung regions. Amphotericin B serum concentrations correlated with pulmonary deposition and remained below 25 ng.mL-1. No untoward effects were reported by the patients during the 4 week trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Despite advances in cancer therapy, mortality is still high except in early-stage tumors, and screening remains a challenge. The randomized National Lung Screening Trial (NLST), comparing annual low-dose computed tomography (LDCT) and chest X-rays, revealed a 20% decrease in lung-cancer-specific mortality. These results raised numerous questions. The French intergroup for thoracic oncology and the French-speaking oncology group convened an expert group to provide a coherent outlook on screening modalities in France. Methods A literature review was carried out and transmitted to the expert group, which was divided into three workshops to tackle specific questions, with responses presented in a plenary session. A writing committee drafted this article. Results The multidisciplinary group favored individual screening in France, when carried out as outlined in this article and after informing subjects of the benefits and risks. The target population involves subjects aged 55–74 years, who are smokers or have a 30 pack-year smoking history. Subjects should be informed about the benefits of quitting. Screening should involve LDCT scanning with specific modalities. Criteria for CT positivity and management algorithms for positive examinations are given. Conclusions Individual screening requires rigorous assessment and precise research in order to potentially develop a lung-cancer screening policy.

International audience; CONTEXT: The setting of multidisciplinary meeting (MDM) by the French Cancer Plan has introduced new decisional elements in the patient-physician relationship in oncology. METHODS: To assess the potential impact of MDM on this relationship, a study was conducted at the Tours Hospital: 145 questionnaires were collected from patients whose files have been discussed in MDM, 40 questionnaires were collected from physicians attending these meetings and an analysis of 324 files was performed. RESULTS: Patients recognize the decisional process of MDM as reassuring for 80% of them. However, a majority (73%) expressed that the most important for them is the relationship with the referring physician, almost all (96%) having a total or great confidence in him. The results emphasize that trust appears to be related to the quality of communication, open dialogue and the competence of the doctor in particular in the choice of treatment. A review of files shows that in 91% of cases, the opinion of the RCP is applied and that, in 69% of cases, the referring doctor delivers the information to the patient after MDM. From the physicians' perspective, 33/40 report that the MDM do not alter their relationship with the patient. We note that 35/40 express that the consultation after MDM facilitates the presentation of the decision and 37/40 that the decision is always or often applied in accordance with the opinion of the MDM. CONCLUSION: MDM appears in most cases in this study not to modify the patient-physician relationship. Due to the patient confidence into the referring physician, the role of this one is essential in integrating the decisional multidisciplinary opinion of MDM and it is important to ensure from his/her disengagement in the decisional process.

BACKGROUND--J001X is an acylated poly-galactoside isolated from the membrane of Klebsiella and able to interact with macrophages, mainly in their activated state. The aim of the present study was to determine the ability of 99m-labelled technetium (99mTc)-J001X scintigraphy to image pulmonary disease, defined by high resolution computed tomographic scanning and pulmonary function tests, in patients suffering from scleroderma. METHODS--Patients were considered to have pulmonary disease when they had at least two positive signs on high resolution computed tomography, or a decrease in lung volume and single breath carbon monoxide transfer, or both, with no disease process other than scleroderma in their medical history. Positive J001X scintigraphic imaging was defined by symmetrical bilateral pulmonary fixation three and five hours after inhalation of 99mTc-J001X. J001X scintigraphic results were compared with disease activity as indicated by bronchoalveolar lavage (BAL) fluid lymphocytosis. RESULTS--Seventeen patients were studied, in 12 of whom J001X scintigraphy was positive. There was no correlation between BAL lymphocytosis and J001X scintigraphic findings, nor between BAL and pulmonary scleroderma. This was not surprising because of the high specificity of macrophage targeting by J001X. CONCLUSIONS--Follow up of a larger population over a longer period is needed to establish whether there is a prognostic value for positive J001X scintigraphic findings in scleroderma.

Summary Purpose The purpose of the study was to assess the possible benefit of the combination vinorelbine (NVB)-cisplatin (DDP) in comparison with NVB alone in advanced non- small cell lung cancer (NSCLC), not treated previously. It also involved confirmation of the efficacy of vinorelbine as monotherapy. Patients and methods In this phase 111 trial, 231 eligible patients were stratified by centre and randomized to receive either NVB alone, 30 mg/m2/week or the combination of NVB 30 mg/m2/week and DDP 80 mg/m2/3 weeks. Patients were to be treated for a minimum of 6 weeks, with the first response assessment performed 9 weeks after the beginning of treatment. Results The two groups differed in terms of objective response rates (16% and 43%, respectively, p = 0.0001) and median time to progression (10 weeks and 20 weeks, p = 0.0001). However, the difference was not significant for median survival time (32 weeks, 33 weeks, p = 0.48). The addition of DDP resulted in an increase in toxicity, in particular renal, hematologic, neurologic and emetic. This toxicity led to treatment discontinuation in 8% and 21% of patients, respectively. Respectively 3% and 13% of patients stopped treatment early during objective response (toxicity or refusal). Conclusions The NVB-DDP combination increased objective response rates and time to progression in comparison with NVB alone, but did not influence the survival of patients. The activity of NVB in the treatment of advanced NSCLC was confirmed.

A glycolipid (J001X) isolated from the membrane proteoglycans of a non-pathogenic strain of Klebsiella pneumoniae was developed to bind selectively to macrophages. A scintigraphic technique could thus be developed and applied to an experimental model of lung berylliosis. Six baboons were injected intratracheally with a beryllium metal suspension. Three to 24 months later, they were submitted to both an anatomical and a functional respiratory evaluation. Two baboons were explored at the early stage of alveolitis and four baboons at a more advanced stage characterised by a granulomatous disorder. Scintigraphy was performed using J001X labelled with 99mtechnetium administered as an aerosol. In the six baboons, conventional imaging techniques (chest x ray film, computed tomography scan, gallium scintigraphy), failed to show either any lung abnormality or mediastinal lymph nodes consistent with beryllium disease. In the two recently contaminated baboons, J001X scintigraphy showed a well defined parenchymal fixation facing the contaminated lobe. In the four baboons who were at a more advanced stage of berylliosis, J001X fixation was always focused paratracheally without any significant involvement of the lung parenchyma. The subcarinal and laterotracheal lymph nodes seen at necropsy corresponded to J001X scintigraphic fixations. In conclusion, when compared with conventional techniques such as chest x ray film, computed tomography scan, magnetic resonance imaging, and gallium scintigraphy, J001X scintigraphy has proved its ability to detect occult lesions in experimental berylliosis in baboons. By comparison with gallium scintigraphy, scintigraphy with J001X appears to have superior sensitivity and can be performed in four hours.

Introduction: Although airways route is an attractive alternative route to systemic administration, increasing concentration of the drug in the lungs while reducing whole-body toxicity, it is not often exploited in lung cancer treatment. After checking that cetuximab, an anti-cancer antibody binding to EGFR, resists the physical constraints of nebulization, we established an animal model of lung tumour sensitive to the antibody. Then, we used the animal model to evaluate cetuximab antitumor efficiency, biodistribution and pharmacokinetic following delivery through airways. Methods: Cetuximab was nebulized with the IA-1C MicroSprayer™ (PennCentury Inc., USA) connected to a FMJ-250 high pressure syringe, a device used to administrate, directly inside the trachea, aerosol in mice. The effect of nebulization on cetuximab was assessed in terms of its affinity for membrane EGFR (using flow cytometry), inhibition of cell growth and inhibition of EGFR phosphorylation. To ensure that airways delivery of cetuximab did not lead to additional toxicity, we compared tolerance to cetuximab delivered through systemic and pulmonary routes in mice without tumors. An animal model of lung cancer sensitive to cetuximab was established and consists in the instillation of human epidermoid carcinoma cells endotracheally in nude mice. The model was exploited to study cetuximab biodistribution and pharmacokinetic following delivery through systemic and pulmonary routes. Therapeutic efficiency of nebulized cetuximab was determined in tumor- bearing animals. Results: Firstly, our results showed that MicroSprayer™ did not alter cetuximab integrity, immunological and pharmacological properties. Secondly, airways administration of cetuximab in mice seemed to be well-tolerated and did not induced additional toxicity in lungs, kidney, colon, skin, liver or spleen. Finally, higher, more rapid and prolonged lung uptake was observed in animals receiving cetuximab through the pulmonary route. Antitumor efficiency of nebulized cetuximab is currently under investigation. Conclusion: These results highlight the potential of the pulmonary route for delivery of anticancer antibody in lung cancer.

The aim of this study was to evaluate the effect on tumour growth of gemcitabine delivered by aerosol in an orthotopic model of lung carcinoma. Large cell carcinoma (NCI-H460) cells were implanted intrabronchially in 24 male BALB/c nude mice on day (d) 0. Aerosols were delivered once a week from d1 to d29 using an endotracheal sprayer. Altogether, 16 animals received gemcitabine at 8 (n = 8) and 12 mg·kg −1 (n = 8), and eight received a vehicle aerosol. Animals were sacrificed on d36 for histological examination. All animals in the vehicle group developed a large infiltrating carcinoma. Comparatively, four of 13 (31%) animals treated with gemcitabine had no visible tumour and nine of 13 (69%) had a smaller carcinoma with a mean±sem largest tumour diameter of 2.05±0.7 versus 5±0.3 mm in the vehicle group. Gemcitabine was well tolerated at 8 mg·kg −1 . At 12 mg·kg −1 , three cases of fatal pulmonary oedema were observed, prompting a dose reduction to 8 mg·kg −1 in the remaining animals. A dose effect was observed, with more marked tumour growth inhibition in the animals treated at 12 mg·kg −1 on d1 and d8. In conclusion, in this study, an animal model of aerosolised chemotherapy in lung cancer was developed and demonstrated inhibition of orthotopic tumour growth by aerosol delivery of gemcitabine.

Summary Background: Patient preference as well as concerns and difficulties with intravenous access and pharmaco-economic issues have driven the development of oral vinorelbine. Patients and methods: Four phase II studies were conducted in chemotherapy- naive non-small-cell lung cancer (NSCLC) and as first-line chemotherapy of advanced breast cancer (ABC). As recommended in the phase I dose-finding study, the first step used a weekly dose of 80 mg/m2. This regimen was associated with an excessive rate of early deaths (10%) due to complicated neutropenia and led to discontinuati on of the first two studies. In a second step, the dose of 60 mg/m2/week was given for the first three courses and subsequently increased to 80 mg/m2/week, in the absence of severe neutropenia. Results: One hundred and thirty eight patients (76 with NSCLC and 62 with ABC) received this regimen, of whom only five were unable to undergo dose escalation. The incidence of febrile neutropenia and neutropenic sepsis were low (2.9 and 3.6%, respectively). Although severe events were uncommon, nausea/vomiting and diarrhoea were frequent and primary prophylaxis with antiemetics should be recommended. Conclusions: Overall, the safety profile of oral vinorelbine at 60 mg/m"/week for the first three courses with escalation to 80 mg/m2 is qualitatively comparable to that of i.v. vinorelbine at standard doses. Similarly to i.v. chemotherapy, close haematological monitoring is necessary. Background Vinorelbine is a semi-synthetic vinca-alkaloid which has demonstrated broad clinical antitumour activity in a weekly intravenous (i.v.) schedule. Intravenous vinorelbine has been established as one of the most active agents in the treatment of non-small-cell lung cancer (NSCLC) [1-3] and advanced breast cancer (ABC) [4]. The development of oral chemotherapy may allow improvement of patient comfort and reduction of the constraints and overall cost of the treatment [5, 6]. A soft gelatin capsule was formulated and shown to be stable for at least 24 months. In a phase I dose-finding study in patients with ABC, the maximum tolerated dose was 100 mg/m2 on a weekly schedule, and the recommended dose for further clinical investigations was 80 mg/m 2 [7], Dose-limiting toxicities included neutropenia, nausea/vomiting and constipation. Preliminary evidence of activity was obtained in first and second-line treatment for ABC. An absolute bioavailability study compared an i.v. infusion of vinorelbine 25 mg/m2 with an oral administration of 80 mg/m 2 [8]. The bioavailability of the oral form was 43% ± 14. Based on the linearity of vinorelbine pharmacokinetics whatever the route of administration [9-11], it was established that the oral dose of 80 mg/m2 corresponded to an i.v. dose of 30 mg/m2 and the oral dose of 60 mg/m2 to an i.v. dose of 25 mg/m2. Interestingly, the pharmacokinetic behaviour of capsules was compared in fed and fasting conditions and was found to be similar [10]. Phase II studies were conducted in NSCLC and ABC to assess the efficacy of oral vinorelbine as a single agent. As recommended in the phase I dose-finding study, we initially studied the toxicity profile of a weekly dose of 80 mg/m2. Due to safety concerns, the study regimen had to be modified, and the starting dose of oral vinorelbine was reduced to 60 mg/m2. We will hereby report the safety profiles of oral vinorelbine in these two consecutive steps of the clinical investigation.

Summary Background Although the average age of lung cancer patients is increasing, many elderly patients remain undertreated, mainly because of the fear of higher treatment toxicity in this category of patients. We conducted a study to evaluate the efficacy and tolerability of a combination therapy with carboplatin (C) and etoposide phosphate (EP) in elderly patients with Small-Cell Lung Cancer (SCLC). Patients and methods Previously untreated patients older than 70 years with stage IIIB/IV SCLC received a combination of EP (100 mg/m2 D1, D2, D3) and C (Dl, dose calculated according to the Calvert formula). Response rate, survival and toxicity were assessed. Results Thirty-eight patients (mean age 76 years, range 70–88 years) received a total of 162 cycles. Eighteen patients (47%) received the six scheduled cycles. Thirty patients were evaluable for efficacy (2 CR and 20 PR). The median survival was 237 days and the one-year probability of survival was 26%. The most common adverse effect was transient grade 3 or 4 neutropenia, observed during 57% of evaluable cycles, while five episodes of febrile neutropenia also occurred, with one fatal (bactaeriemia). It is noteworthy that no renal or liver toxicity was observed, and no mucitis was noted. Unfortunately, a relatively high proportion of patients died shortly after the start of the study. Although most deaths seemed unrelated to the treatment, the possibility of its exacerbatory effect on comorbidities, especially cardiovascular, cannot be excluded. Conclusion The two-drug regimen of carboplatin and etoposide phosphate is feasible in most elderly patients with an acceptable toxicity, and the overall results suggest that patients even older than 70 years may benefit from full treatment. Therefore, consideration should be given to offering active treatment to most patients with SCLC, regardless of age but with special attention paid to comorbidities.