Thierry Urban

Long-Term Outcome of Noninvasive Positive Pressure Ventilation for Obesity Hypoventilation Syndrome

BACKGROUND Few data are available on the long-term outcome of noninvasive positive pressure ventilation (NPPV) for obesity hypoventilation syndrome (OHS). This study was designed to determine long-term survival, treatment adherence, and prognostic factors in patients with OHS in whom NPPV was initiated in an acute setting vs under stable clinical conditions. METHODS One hundred thirty consecutive patients with OHS (56 women) who started NPPV between January 1995 and December 2006 either under stable conditions (stable group, n = 92) or during ICU management of acute hypercapnic exacerbation (acute group, n = 38) were retrospectively analyzed. RESULTS Arterial blood gases and the Epworth sleepiness scale were both significantly improved after 6 months of NPPV. With a mean follow-up of 4.1 +/- 2.9 years, 24 (18.5%) patients died and 24 (18.5%) discontinued NPPV. On Kaplan-Meier analysis, 1-, 2-, 3-, and 5-year survival probabilities were 97.5%, 93%, 88.3%, and 77.3%, respectively. Mortality was lower than that described in a previous series of patients with untreated OHS. Supplemental oxygen therapy was the only independent predictor of mortality. The probability of continuing NPPV was 80% at 3 years with a high rate of daily use ( > 7 h). Female sex was predictive of lower long-term adherence to NPPV. The acute and stable groups did not differ in terms of arterial blood gases and Epworth sleepiness scale at 6 months, long-term survival, and treatment adherence. CONCLUSIONS The results of this study support long-term NPPV as an effective and well-tolerated treatment of OHS whether initiated in the acute or chronic setting.

Lipid nanocapsules: Ready-to-use nanovectors for the aerosol delivery of paclitaxel

Aerosol drug delivery permits the development of dose-intensification strategies in severe, malignant lung diseases. The aim of the study was to demonstrate that the encapsulation of paclitaxel in lipid nanocapsules (LNCs), a novel drug nanocarrier for lipophilic components, allows one to provide pulmonary drug delivery of paclitaxel by nebulisation, thereby allowing preclinical and clinical studies. LNC dispersions are made into aerosols with commercial nebulisers. The structure, drug payload and cytotoxicity of nebulised LNCs were compared to fresh LNCs. The results demonstrated that LNC dispersions could be made into aerosols by using mesh nebulisers without altering the LNC structure. Only eFlow rapid-produced aerosols are compatible with human use: the mean duration to nebulise 3 ml of LNC dispersion is less than 9 min, with an aerosol mass median aerodynamic diameter equal to 2.7+/-0.1 microm and a fine-particle fraction (between 1.0 and 5.0 microm) of 81.5+/-3.1%. No modifications of drug payload or cytotoxicity effects of paclitaxel-loaded LNC (PTX-LNC) were observed. In order to carry out preclinical studies, a scaled-up LNC formulation protocol was used. Chemical parameters, such as acidity and osmolarity, were optimised, and a storage procedure for PTX-LNC batches was set-up. Animal studies are now needed to determine the tolerance and therapeutic potential of LNC dispersion aerosols.

Impact of Systematic EGFR and KRAS Mutation Evaluation on Progression-Free Survival and Overall Survival in Patients with Advanced Non–Small-Cell Lung Cancer Treated by Erlotinib in a French Prospective Cohort (ERMETIC Project—Part 2)

Background: Epidermal growth factor and v-Ki-ras2 Kirsten ras sarcoma (KRAS) mutation status, although associated with EGFR- tyrosine kinase inhibitor (TKI) efficacy, has not been used in clinical practice until recently. The prospective Evaluation of the EGFR Mutation status for the administration of EGFR-TKIs in non small cell lung Carcinoma (ERMETIC) study aimed to implement these biomarkers in France. Methods: Between March 2007 and April 2008, EGFR and KRAS were studied by sequencing DNA tumor specimens from 522 consecutive advanced non–small-cell lung cancer patients treated with EGFR-TKI, mostly in second- or third-line settings. Cox models were used to investigate the impact of patient characteristics and mutations on progression-free survival (PFS) and overall survival (OS). Added value from mutation status was evaluated using likelihood ratio (LR) tests. Classification and regression tree analysis aimed to identify homogeneous groups in terms of survival. Results: Among the 522 patients, 87% were white, 32% were women, and 18% were never-smokers, with 65% presenting with adenocarcinoma. Biological data were available for 307 patients, showing 44 EGFR mutations (14%) and 42 KRAS (14%) mutations. Median PFS was 2.4 months (interquartile range, 1.4–4.6) and median OS 5.6 months (interquartile range, 2.2–14.0). Factors independently associated with PFS were performance status 1 or 2 to 3 (hazards ratio [HR] = 1.5, 95% confidence interval [CI] 1.1–1.9; and HR = 2.3, CI 1.7–3.1, respectively; p < 0.001); former or current smoker status (HR = 1.8, CI 1.4–2.4 and 2.0,CI 1.4–2.8, respectively; p < 0.001); nonadenocarcinoma histology (squamous cell: HR = 0.9 CI 0.7–1.2]; others: HR = 1.6, 1.3–2.1; p < 0.001); at least two metastatic sites (HR = 1.3, CI 1.1–1.6 and 1.6, CI 1.3–2.1, respectively; p < 0.001); prior taxane-based chemotherapy (HR = 1.3, CI 1.0–1.3, p = 0.01); non-white (HR = 0.7, CI 0.5–0.9, p = 0.009). Similar results were found for OS. In addition, EGFR and KRAS mutations were significantly associated with PFS (HR = 0.5, CI 0.3–0.7 and HR = 1.2, CI 0.8–1.8, respectively, versus no mutation; LR p = 0.001). In the OS model, adjusted HR was 0.7 (0.4–1.0) for EGFR mutation and 1.7 (1.1–2.4) for KRAS (LR p = 0.004). Classification and regression tree analysis revealed EGFR mutation to be the primary factor for identifying homogeneous patient subgroups in terms of PFS. Conclusions: EGFR and KRAS status independently impacts outcomes in advanced non–small-cell lung cancer patients treated with EGFR-TKI. However, EGFR status impacts both PFS and OS whereas KRAS only impacts OS. These findings support the nationwide use of EGFR status for patient selection before EGFR-TKI therapy. The role of KRAS mutations remains to be elucidated.

Prognostic significance of serum p53 antibodies in patients with limited‐stage small cell lung cancer

p53 tumour suppressor gene alterations are one of the most frequent genetic events in lung cancer. A subset of patients with p53 mutation and cancer exhibited circulating serum anti‐p53 self‐antibodies (p53‐Ab). The prevalence of these antibodies in lung cancer is currently being analysed in a multicentric study. In a group of homogeneous SCLC patients, p53‐Ab were detected in 20/97 (20.6%) individuals. In this group of patients, Coxs multivariate analysis identified disease extent (p = 0.022), WHO initial performance status greater than 0 (p = 0.005), and the absence of a complete response after 6 months of treatment (p < 0.0001) as independent prognostic variables, with p53‐Ab being of borderline significance (p = 0.051). In the subset of limited‐stage SCLC patients, Coxs multivariate analysis found p53‐Ab (p = 0.033), WHO initial performance status greater than 0 (p = 0.028), and absence of a complete response (p < 0.001) to be independent prognostic variables. Thus, actuarial analysis showed that patients with limited‐stage SCLC and p53‐Ab had a median survival time of 10 months, whereas limited‐stage SCLC patients without p53‐Ab had a 17‐month median survival time (p = 0.014).Therefore, serum assay of p53‐Ab could help to identify a population of SCLC patients with an especially poor prognosis. This population could represent patients with tumours harboring aggressive p53 mutations. Int. J. Cancer (Pred. Oncol.) 89:81–86, 2000.

Randomized phase II trial of gefitinib or gemcitabine or docetaxel chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2 or 3 (IFCT-0301 study)

BACKGROUND To compare 3 treatment strategies in chemotherapy naive patients with advanced NSCLC and a PS 2-3. PATIENTS AND METHODS Patients were assigned to gefitinib 250mg daily (n=43) or to gemcitabine (1250mg/m(2) d 1, 8 q 21d) (n=42) or docetaxel (75mg/m(2) d 1 q 21d) (n=42). Treatments were taken until progression or toxicity. The primary endpoint was progression-free survival. Secondary end points were response and overall survival. RESULTS Disease control rates were 20.9%, 33.4% and 38.1%, respectively. Median PFS was 1.9 months in the gefitinib arm, 2.0 months in the gemcitabine arm and 2.0 months in the docetaxel arm (HR gemcitabine versus gefitinib: 0.74, 95%CI: [0.48; 1.16], HR docetaxel versus gefitinib: 0.67, 95%CI: [0.43; 1.05]). Median survival times were 2.2, 2.4 and 3.5 months, respectively (HR gemcitabine versus gefitinib: 0.76, 95%CI: [0.48; 1.20], HR docetaxel versus gefitinib: 0.69, 95%CI: [0.44; 1.09]). There were more grade 3-4 adverse events in the docetaxel arm when compared with either the gefitinib arm or the gemcitabine arm. CONCLUSION In unselected NSCLC patients with PS 2-3, gefitinib, gemcitabine and docetaxel achieved similar results. Docetaxel was associated with higher rates of adverse events.

The adaptation of lipid nanocapsule formulations for blood administration in animals.

In many cell-culture and animal models, the therapeutic effects of the entrapped drugs in lipid nanocapsules (LNCs) were preserved with low toxicity. These results allow foreseeing further preclinical efficiency and toxicity studies in animals. In this article, preliminary studies were performed to check the genetically modified organism (GMO) status of the LNCs components and to determine the effects of the acidity of the LNCs dispersions in acid-base balance in rats. Then, several freezing protocols to store paclitaxel-loaded LNCs dispersions for a 6-month period were compared. Results indicate that the Lipoïd S75-3 could not be certified GMO-free. The same soya bean lecithin certified to be GMO-free permitted to produce LNCs with expected characteristics. The blood administration of blank LNCs dispersions in rats induced no modifications of blood acidity, but a significant decrease of the base excess was observed. Injections of LNCs dispersions in animals might induce iatrogenic acidosis. We finally demonstrated that the best protocol to store LNCs dispersion for a 6-month period is by freezing in liquid nitrogen. This protocol minimized the characteristics modifications and interrupted the drug-release phenomenon. These original data are expected to prepare of LNCs dispersions well adapted for i.v. administration in animals.

A case report of subacute bronchial toxicity induced by an electronic cigarette

Jose Hureaux (JH): I would like to present the case of a 43-year-old patient who presented with bronchial syndrome associated with deterioration of pulmonary function tests (PFTs) after starting to use an electronic cigarette. He had a history of primary lung adenocarcinoma with a documented isolated brain metastasis (stage pT3N0M1b) treated by stereotactic brain radiotherapy, right upper lobectomy and chemotherapy. The patient had been under surveillance for 7 months. This patient, an active smoker (45 pack-years) undergoing smoking cessation with the assistance of his general practitioner based on a reduction strategy accompanied by nicotine replacement therapy (21 mg patch), continued to smoke about 20 cigarettes a day. In order to completely stop smoking, he decided to try an electronic cigarette on the advice of a friend. Thierry Urban (TU): Smoking cessation is useful in all patients operated for lung cancer, and must be encouraged. The e-cigarette provides nicotine via the inhaled route from which it is rapidly absorbed by a modality corresponding to the usual actions of smoking, while reducing the exposure of individuals to carcinogenic substances present in tobacco smoke. However, the real place of e-cigarettes in the therapeutic aid to smoking cessation is unknown. JH: He purchased an e-cigarette (‘La dynamique’ by CIGARTEX) and two …

Randomized multicenter phase II study of larotaxel (XRP9881) in combination with cisplatin or gemcitabine as first-line chemotherapy in nonirradiable stage IIIB or stage IV non-small cell lung cancer.

Introduction: This randomized phase II study investigated the efficacy and safety of a new taxane, larotaxel (XRP9881), in combination with either cisplatin or gemcitabine in the first-line treatment of patients with nonirradiable stage IIIB or stage IV non-small cell lung cancer to select the combination having the most promising antitumor activity. Methods: Patients received either larotaxel (50 mg/m2) as a 1-hour infusion, followed by a 1-hour infusion of cisplatin (75 mg/m2), every 3 weeks (arm A), or gemcitabine (800 mg/m2) as a 30 minute infusion, on days 1 and 8, and larotaxel (60 mg/m2) as a 1-hour infusion, on day 8 (following gemcitabine), every 3 weeks (arm B). The primary end point was the objective response rate (per-protocol population). Results: Thirty-two patients were randomized to arm A and 30 to arm B. The response rate was higher in arm A compared with arm B in both the per-protocol (26.7% versus 18.2%) and intention-to-treat (28.1% versus 13.3%) populations. In the intention-to-treat population, median progression-free survival for arm A versus arm B was 4.7 versus 3.3 months and median overall survival was 8.6 versus 7.3 months, respectively. Fifty percent of patients in arm A and 66.7% in arm B experienced at least one National Cancer Institute common toxicity criteria grade 3/4 adverse event and grade 3/4 neutropenia was observed in 46.9% and 41.4% of patients, respectively. Conclusions: Both larotaxel combinations were effective and manageable, however all measured efficacy parameters (response rate, progression free survival, and survival) seemed to favor the combination with cisplatin.

[18F]FDG Positron Emission Tomography within Two Weeks of Starting Erlotinib Therapy Can Predict Response in Non-Small Cell Lung Cancer Patients

Purpose The aim of this prospective study was to evaluate whether [18F]FDG-PET/CT, performed within two weeks of starting erlotinib therapy can predict tumor response defined by RECIST 1.1 criteria after 8 weeks of treatment in patients with inoperable (stage IIIA to IV) non-small cell lung cancer patients. Patients and Methods Three [18F]FDG-PET/CT scans were acquired in 12 patients before (5±4 days) and after 9±3 days (early PET) and 60±6 days (late PET) of erlotinib therapy. Conventional evaluation, including at least chest CT (baseline versus after 8 weeks of treatment), was performed according to RECIST 1.1 criteria. Change in [18F]FDG uptake was compared with conventional response, progression-free survival (PFS), and overall survival (OS). Results By using ROC analysis, the Area Under the Curve for prediction of metabolic non-progressive disease (mNP) by early PET was 0.86 (95% CI, 0.62 to 1.1; P = 0.04) at a cut-off of 21.6% reduction in maximum Standardized Uptake Value (SUVmax). This correctly classified 11/12 patients (7 with true progressive disease; 4 with true non-progressive disease; 1 with false progressive disease). Non-progressive disease after 8 weeks of treatment according to RECIST 1.1 criteria was significantly more frequent in patients classified mNP (P = 0.01, Fishers exact test). mNP patients showed prolonged PFS (HR = 0.27; 95% CI, 0.04 to 0.59; P<0.01) and OS (HR = 0.34; 95% CI, 0.06 to 0.84; P = 0.03). Late PET analysis provided concordant results. Conclusion Morphologic response, PFS and OS survival in non-small cell lung cancer patients can be predicted by [18F]FDG-PET/CT scan within 2 weeks after starting erlotinib therapy.

Development and in vitro evaluation of a novel lipid nanocapsule formulation of etoposide.

Small cell lung cancer (SCLC) is the most aggressive carcinoma in thoracic oncology, unfortunately, despite chemotherapy, relapse is constant. The effect of etoposide, a major drug used against SCLC, can potentially be enhanced after its encapsulation in nanocarriers. The aim of this study was to use the technology of lipid nanocapsules (LNCs) to obtain nanocarriers with drug loadings compatible with clinical use and with an industrial process. Solubility studies with different co-solvent were first performed, then several process were developed to obtain LNCs. LNCs were then characterized (size, zeta potential, and drug loading). The best formulation called Ω-LNCs had a size of 54.1±2.0 nm and a zeta potential of -5.8±3.5 mV and a etoposide drug loading of 5.7±0.3mg/g. The characteristics of this formulation were maintained after freeze drying and after a 15× scale-up. Release studies in a media mimicking plasma composition showed that 40% of the drug was released from the LNCs after 48 h. Moreover the activity of etoposide after encapsulation was enhanced on H209 cells, IC50 was 100 μM and 2.5 μM for etoposide and etoposide LNCs respectively. Unfortunately the formulation failed to be more cytotoxic than etoposide alone on H69AR cells that are resistant to etoposide. This study showed that is was possible to obtain a new etoposide nanocarrier without the use of organic solvent, that the process is suitable for scale-up and freeze drying and finally that etoposide activity is maintained which is very promising for future treatment of SCLC.