Publications by authors named "Thierry Urban"

35 Publications

Sputum versus nasopharyngeal samples for the molecular diagnosis of respiratory viral infection in cystic fibrosis: A pilot study.

J Cyst Fibros 2020 Sep 14. Epub 2020 Sep 14.

Univ Brest, Inserm, EFS, UMR 1078, GGB Génétique, Génomique Fonctionnelle et Biotechnologies, F-29200 Brest, France; Unité de Virologie, Département de Bactériologie-Virologie-Parasitologie-Mycologie-Hygiène, Pôle de Biologie-Pathologie, Centre Hospitalier Régional et Universitaire, 29609 Brest cedex, France. Electronic address:

Viruses are important agents in lung function deterioration in Cystic Fibrosis (CF). To date, no standard operating procedures (SOPs) have been established to determine which sampling method is the most effective for an optimal virological diagnosis of respiratory viral infections in CF. Here we investigated the performances of two sampling sites, sputum samples versus nasopharyngeal (NP) swabs, for thirty participants from three CF centres presenting an acute respiratory infection. Sputum and NP samples were simultaneously collected and multiplex PCR targeting 16 to 18 viruses were performed. Viruses were detected for 18/30 patients (60%). A high concordance between the sputum and NP samples was observed in 25 (83%) paired samples of which 13 tested positive and 12 tested negative. These results highlighted the relevance of sputum sampling for diagnostic of respiratory viruses in CF, which is less invasive and better accepted by CF patients than NP, and allows accurate bacterial detection.
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http://dx.doi.org/10.1016/j.jcf.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489228PMC
September 2020

Association Between Nocturnal Hypoxemia and Cancer Incidence in Patients Investigated for OSA: Data From a Large Multicenter French Cohort.

Chest 2020 Dec 3;158(6):2610-2620. Epub 2020 Jul 3.

Department of Respiratory and Sleep Medicine, Angers University Hospital, Angers; INSERM Unit 1063, Angers. Electronic address:

Background: Previous studies have yielded inconsistent findings regarding the association between OSA and cancer in humans.

Research Question: Is there an association between indexes of sleep-disordered breathing severity and cancer incidence in patients investigated for suspected OSA?

Study Design And Methods: Data from a large multicenter cohort of cancer-free patients investigated for OSA were linked to health administrative data to identify new-onset cancer. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the association of cancer incidence with OSA severity and nocturnal hypoxemia.

Results: After a median follow-up period of 5.8 years (interquartile range, 3.8-7.8), 718 of 8,748 patients (8.2%) had received a diagnosis of cancer. On unadjusted Kaplan-Meier survival analyses, cancer incidence was associated with increasing severity of OSA (log-rank test, P < .0005) and nocturnal hypoxemia (log-rank test, P < .0001 for both oxygen desaturation index and percent night time with oxygen saturation < 90% [T90]). After adjustment for anthropomorphic data, smoking and alcohol consumption, comorbid cardiac, metabolic, and respiratory diseases, marital status, type of sleep study, and study site, only T90 was associated with cancer incidence (adjusted hazard ratio, 1.33; 95% CI, 1.05-1.68 for T90 ≥ 13% vs < 0.01%; P = .02). On stratified analyses, the association between T90 and cancer appeared stronger in older patients with obesity and no adequate OSA therapy. Among the most frequent cancer sites, nocturnal hypoxemia was associated with lung and breast malignancies.

Interpretation: Nocturnal hypoxemia was associated with all-cancer incidence in patients investigated for OSA. Whether OSA therapy might reduce the risk of cancer needs further evaluation.
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http://dx.doi.org/10.1016/j.chest.2020.06.055DOI Listing
December 2020

Phase II Study Evaluating the Mechanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR-mutated Non-pretreated Advanced Lung Cancer Receiving Osimertinib Until and Beyond Radiologic Progression: The MELROSE Trial.

Clin Lung Cancer 2020 01 1;21(1):e10-e14. Epub 2019 Oct 1.

Department of Biochemistry, Centre Hospitalier Universitaire Nantes, Nantes, France.

Background: Osimertinib, a third-generation tyrosine kinase inhibitor, is a new therapeutic option in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non-small-cell lung cancer (NSCLC). The tumor escape mechanisms after first-line treatment with osimertinib are partially known; most of the data being obtained by analysis of circulating tumor DNA (ctDNA) from the FLAURA phase III trial.

Study Design: The MELROSE study, a French multicentric, open label, phase II trial (ClinicalTrials.govNCT03865511) plans to enroll 150 patients with treatment-naive advanced EGFR-mutated (L858R or exon 19 deletion) NSCLC, age ≥ 18 years, with an Eastern Cooperative Oncology Group performance status 0 or 1. All patients will receive osimertinib at the dose of 80 mg/d. Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria will be performed every 3 months, with brain and thoracoabdominal computed tomographic scan. The continuation of osimertinib is at the discretion of the referring physician, particularly if clinical benefit is observed. The primary objective is the genetic tumor profile, both on tissue biopsy and ctDNA analyses, at the time of disease progression. Other endpoints include kinetic studies of ctDNA, biological progression-free survival (bPFS) (time from first study dose to first biological event on ctDNA), median PFS according to RECIST criteria 1.1 (called radiological [r] PFS), and median clinical (c) PFS (time from the first study dose to off-osimertinib). This study started in April 2019, and 18 centers in France are participants.
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http://dx.doi.org/10.1016/j.cllc.2019.09.007DOI Listing
January 2020

Cost-Effectiveness of Web-Based Patient-Reported Outcome Surveillance in Patients With Lung Cancer.

J Thorac Oncol 2019 06 15;14(6):1012-1020. Epub 2019 Feb 15.

Department of Radiation Oncology, Jean Bernard Center, Inter-Regional Institute of Oncology, Le Mans, France.

Introduction: A multicenter randomized clinical trial in France found an overall survival benefit of web-based patient-reported outcome (PRO)-based surveillance after initial treatment for lung cancer compared with conventional surveillance. The aim of this study was to assess the cost-effectiveness of this PRO-based surveillance in lung cancer patients.

Methods: This medico-economic analysis used data from the clinical trial, augmented by abstracted chart data and costs of consultations, imaging, transportations, information technology, and treatments. Costs were calculated based on actual reimbursement rates in France, and health utilities were estimated based on scientific literature review. Willingness-to-pay thresholds of €30,000 per quality-adjusted life year (QALY) and €90,000 per QALY were used to define a very cost-effective and cost-effective strategy, respectively. Average annual costs of experimental and control surveillance approaches were calculated. The incremental cost-effectiveness ratio was expressed as cost per life-year gained and QALY gained, from the health insurance payer perspective. One-way and multivariate probabilistic sensitivity analyses were performed.

Results: Average annual cost of surveillance follow-up was €362 lower per patient in the PRO arm (€941/year/patient) compared to control (€1,304/year/patient). The PRO approach presented an incremental cost-effectiveness ratio of €12,127 per life-year gained and €20,912 per QALY gained. The probabilities that the experimental strategy is very cost-effective and cost-effective were 97% and 100%, respectively.

Conclusions: Surveillance of lung cancer patients using web-based PRO reduced the follow-up costs. Compared to conventional monitoring, this surveillance modality represents a cost-effective strategy and should be considered in cancer care delivery.
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http://dx.doi.org/10.1016/j.jtho.2019.02.005DOI Listing
June 2019

Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.

Lancet Oncol 2019 02 16;20(2):239-253. Epub 2019 Jan 16.

University Hospital Bichat Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris-Diderot University Paris, Paris, France.

Background: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma.

Methods: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272.

Findings: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure).

Interpretation: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials.

Funding: French Cooperative Thoracic Intergroup.
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http://dx.doi.org/10.1016/S1470-2045(18)30765-4DOI Listing
February 2019

Thoracic and cutaneous sarcoid-like reaction associated with anti-PD-1 therapy: longitudinal monitoring of PD-1 and PD-L1 expression after stopping treatment.

J Immunother Cancer 2018 06 13;6(1):52. Epub 2018 Jun 13.

Service de Pneumologie, Centre Hospitalier Universitaire, 4 rue Larrey, 49000, Angers, France.

Background: Immune checkpoint inhibitors (ICI) target T cell inhibitory pathways that are responsible for cancer tolerance by down-modulating immune functions. ICI have revolutionized patients care with lung cancer. Nevertheless, restoring endogenous antitumor T-cell responses can induce immune related adverse events, such as sarcoidosis.

Case Presentation: We report here the first case of a thoracic and cutaneous sarcoid-like reaction in a patient with a relapsing unresectable non-small cell lung cancer (NSCLC) treated with nivolumab, an anti-PD-1 mAb. The expression of PD-1 and its ligands, PD-L1 and PD-L2, was assessed by flow cytometry on peripheral blood mononuclear cells (PBMC) and compared to patients who had discontinued nivolumab therapy without having developed any immune related adverse events. PD-L1 expression was transiently increased on B cells, T cells and monocytes, whereas PD-L2 expression was not modulated. PD-1 was transiently undetectable when PD-L1 was maximal, before returning to basal level. Sarcoidosis spontaneously resolved, without corticotherapy.

Conclusion: This case sheds the light on a complex regulation of PD-L1 expression in vivo on PBMC after nivolumab arrest and triggers the question of monitoring the expression of immune checkpoint on immune cells during and after treatment with ICI.
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http://dx.doi.org/10.1186/s40425-018-0372-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001149PMC
June 2018

Absence of lung fibrosis after a single pulmonary delivery of lipid nanocapsules in rats.

Int J Nanomedicine 2017 8;12:8159-8170. Epub 2017 Nov 8.

Unité Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire.

Lipid nanocapsules (LNCs) are potential drug carriers for pulmonary delivery since they can be nebulized without any structural or functional changes, and the aerosols produced are highly compatible with pulmonary drug delivery in human beings. The alveolar surface tension, in vitro cytotoxicity, biodistribution and pulmonary toxicity in rats of a single endotracheal spray of LNCs or paclitaxel-loaded LNCs were studied. In vitro cytotoxicity of LNCs after a spray remained unchanged. Biodistribution study showed a homogeneous repartition in the lungs in rats with an improvement in lung retention of the radiolabeled tracer loaded in LNCs compared to the absence of LNCs with a lung half-time of 8.8±0.7 hours. Bronchoalveolar fluid analysis revealed transient 7-day alveolar inflammation, reaching a maximum between days 2 and 4, characterized by a peak of granulocytes at day 1 followed by a peak of lymphocytes at day 3. Alveolar protein levels were increased at days 3 and 7. Acute inflammation was increased with paclitaxel-loaded LNCs in comparison with blank LNCs but dropped out at day 7. No histological pulmonary lesion was observed at day 60. LNCs lowered surface tension to a greater degree than Curosurf in a physicochemical model of the pulmonary alveolus. A single pulmonary delivery of LNCs induces a short-term alveolar inflammation with no residual lesions in rats at day 60. These data permit to start the study of LNCs in surfactant replacement therapy.
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http://dx.doi.org/10.2147/IJN.S146740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687496PMC
March 2018

Primary and secondary lung tumors

Rev Prat 2017 Sep;67(7):e355-e363

Service pneumologie, oncologie thoracique et allergologie, CRCM Angers, centre de coordination de cancérologie, Inserm UMR S 1066 micro- et nano-médecines biomimétiques (MINT), CHU 49933 Angers Cedex 9, France.

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September 2017

Advances in primary bronchial cancer

Rev Prat 2017 Sep;67(7):e354

Service pneumologie, oncologie thoracique et allergologie, CRCM Angers, centre de coordination de cancérologie, Inserm UMR S 1066 micro- et nano-médecines biomimétiques (MINT), CHU 49933 Angers Cedex 9, France.

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September 2017

Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists.

Cancer Med 2017 Aug 18;6(8):1923-1929. Epub 2017 Jul 18.

Department of Endocrinology, Diabetes and Nutrition, Reference Centre of Rare Thyroid Disease, Hospital of Angers, Angers Cedex 09, F-49933, France.

Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T-lymphocyte antigen-4 and those that target programmed cell death-protein 1, have been approved for use in melanoma, non-small-cell lung cancer, and renal cell carcinoma as first-line or second-line therapy. Their adverse events are primarily regarded as immune-related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action.
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http://dx.doi.org/10.1002/cam4.1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548876PMC
August 2017

Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients.

J Natl Cancer Inst 2017 09;109(9)

CORIA UMR 6614-Normandie Université, CNRS Université et INSA de Rouen, Campus Universitaire du Madrillet, Saint-Etienne du Rouvray, France.

Background: The use of web-based monitoring for lung cancer patients is growing in interest because of promising recent results suggesting improvement in cancer and resource utilization outcomes. It remains an open question whether the overall survival (OS) in these patients could be improved by using a web-mediated follow-up rather than classical scheduled follow-up and imaging.

Methods: Advanced-stage lung cancer patients without evidence of disease progression after or during initial treatment were randomly assigned in a multicenter phase III trial to compare a web-mediated follow-up algorithm (experimental arm), based on weekly self-scored patient symptoms, with routine follow-up with CT scans scheduled every three to six months according to the disease stage (control arm). In the experimental arm, an alert email was automatically sent to the oncologist when self-scored symptoms matched predefined criteria. The primary outcome was OS.

Results: From June 2014 to January 2016, 133 patients were enrolled and 121 were retained in the intent-to-treat analysis; 12 deemed ineligible after random assignment were not subsequently followed. Most of the patients (95.1%) had stage III or IV disease. The median follow-up was nine months. The median OS was 19.0 months (95% confidence interval [CI] = 12.5 to noncalculable) in the experimental and 12.0 months (95% CI = 8.6 to 16.4) in the control arm (one-sided P = .001) (hazard ratio = 0.32, 95% CI = 0.15 to 0.67, one-sided P = .002). The performance status at first detected relapse was 0 to 1 for 75.9% of the patients in the experimental arm and for 32.5% of those in the control arm (two-sided P < .001). Optimal treatment was initiated in 72.4% of the patients in the experimental arm and in 32.5% of those in the control arm (two-sided P < .001).

Conclusions: A web-mediated follow-up algorithm based on self-reported symptoms improved OS due to early relapse detection and better performance status at relapse.
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http://dx.doi.org/10.1093/jnci/djx029DOI Listing
September 2017

Maintenance Treatment by Erlotinib and Toxic Cardiomyopathy: A Case Report.

Oncology 2016 18;90(3):176-7. Epub 2016 Feb 18.

Pulmonology Department, University Hospital of Angers, Angers, France.

Erlotinib maintenance treatment improves progression-free survival compared with observation after first-line chemotherapy in unselected advanced non-small cell lung cancer (NSCLC). Very few cardiac adverse effects have been observed in phase III studies on tyrosine kinase inhibitors (TKI). We report the case of a 71-year-old woman with metastatic NSCLC treated with cisplatin/pemetrexed and then erlotinib maintenance therapy. After 26 months of TKI therapy, she developed dilated cardiomyopathy. Despite symptomatic treatment, left ventricular ejection fraction decreased to 25%. Ischemic heart disease was excluded by coronary angiography and cardiac magnetic resonance imaging, and no other cause was found. Erlotinib was stopped, and cardiac resynchronization therapy by pacemaker was initiated. This case report highlights the possible cardiotoxic effects of long-term erlotinib and suggests the need for close clinical and echocardiographic follow-up of patients receiving long-term TKI therapy.
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http://dx.doi.org/10.1159/000444186DOI Listing
July 2016

Use of Simulation to Validate Questionnaires on a Sensitive Subject.

Simul Healthc 2016 Feb;11(1):65-6

LUNAM Université 40 rue de Rennes, 49000 Angers France Centre de coordination en cancérologie Centre Hospitalier Universitaire 4 rue Larrey, 49933 ANGERS Cedex 9 France Angers PLateforme Hospitalo-Universitaire de Simulation en Santé Centre Hospitalier Universitaire 4 rue Larrey, 49933 ANGERS Cedex 9 France LUNAM Université 40 rue de Rennes, 49000 Angers France Centre de coordination en cancérologie Centre Hospitalier Universitaire 4 rue Larrey, 49933 ANGERS Cedex 9 France Départment d'Onco-hématologie Centre Jean Bernard, 72000 Le Mans France Faculté des Lettres et Sciences Humaines Victor-Segalen de Brest Université de Bretagne Occidentale 29000 Brest Pôle Biologie Pharmacie et Santé Publique Centre Hospitalier Universitaire de Poitiers Université de Poitiers, 49000 Poitiers France Département d'Hématologie de l'Université de Tours, 37044 Tours France LUNAM Université 40 rue de Rennes, 49000 Angers France Centre de coordination en cancérologie Centre Hospitalier Universitaire 4 rue Larrey, 49933 ANGERS Cedex 9 France.

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http://dx.doi.org/10.1097/SIH.0000000000000145DOI Listing
February 2016

Similar survival rates with first-line gefitinib, gemcitabine, or docetaxel in a randomized phase II trial in elderly patients with advanced non-small cell lung cancer and a poor performance status (IFCT-0301).

J Geriatr Oncol 2015 May 16;6(3):233-40. Epub 2015 Feb 16.

Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France.

Objectives: We evaluated the impact of age in a randomized phase II trial that compared three first-line drugs in elderly patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status (PS).

Materials And Methods: Patients with advanced NSCLC with a PS of 2 or 3 were enrolled into a multicenter randomized trial: arm A, gefitinib; arm B, gemcitabine; and arm C, docetaxel. We performed subgroup analyses according to age.

Results: Between December 2004 and June 2007, 127 patients were enrolled. Analyses were performed between the two subgroups aged <70years (younger, n=56) and ≥70years (older, n=71). Patients mainly had adenocarcinoma (46% young vs. 51%: elderly), of which 62% vs. 75% had a PS of 2, respectively. Significantly more elderly patients were women and non-smokers, and there was a non-significant trend towards more PS-2 among the elderly. Progression-free survival (PFS) was 1.4months (95% CI: 1.1-1.9) for younger compared to 2.3months (95% CI: 2.1-2.9) for elderly patients. Overall survival (OS) was 2.0months (95% CI: 1.5-2.4) and 3.7months (95% CI: 2.4-4.8), respectively. Toxicity did not differ between younger and older patients. NSCLC was better controlled in elderly patients after three cycles of monotherapy compared to younger patients (p=0.034). When adjusted for stratification criteria, age was the main prognostic factor for PFS. Adjusted HRs for PFS was 0.57 (95% CI: 0.38-0.85) for the elderly compared to patients aged <70years (p=0.004).

Conclusions: Older patients had a decreased risk of progression/death compared to younger patients. Single-agent chemotherapy can be considered for patients aged ≥70years with a PS of 2.
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http://dx.doi.org/10.1016/j.jgo.2015.02.002DOI Listing
May 2015

Lung cancer in combined pulmonary fibrosis and emphysema: a series of 47 Western patients.

J Thorac Oncol 2014 Aug;9(8):1162-70

*Department of Respiratory Medicine, National Reference Center for rare pulmonary diseases, Hôpital Louis Pradel, Hospices Civils de Lyon; Université Claude Bernard Lyon 1, Lyon; †Department of Respiratory Medicine, CHRU Tours, Université François Rabelais, INSERM UMR 1100, Tours; ‡Chest Department, Expert Center of Thoracic Oncology, Regional Reference Center for rare pulmonary diseases, Hôpital Tenon, Assistance Publique Hôpitaux de Paris; Université Pierre et Marie Curie; §Department of Respiratory Medicine, Competence Center for Rare Pulmonary Diseases, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Paris; ‖Department of Respiratory Medicine, CHU Angers, Angers; ¶Department of Respiratory Medicine, Competence Center for rare pulmonary diseases, Hôpital Pontchaillou, IRSET UMR 1085, Université de Rennes 1, Rennes, France; #Department of Respiratory Medicine, CHU Mont-Godine, Université Catholique de Louvain, Yvoir, Belgium; and **Pulmonology Service, Hôpital de Bourgoin-Jallieu, Bourgoin-Jallieu, France.

Introduction: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is characterized by imaging features consisting of the association of centrilobular and/or paraseptal emphysema and pulmonary fibrosis. Virtually all patients are smokers and thus at high risk of developing lung cancer.

Methods: This retrospective multicentre study was conducted by the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P).

Results: A total of 47 patients presenting with lung cancer and CPFE syndrome were identified. All patients were smokers, with a mean of 47 pack-years. A pathological diagnosis of lung cancer was obtained for 38 (81%) patients. Histological type was squamous cell carcinoma in 17 (36%) patients, adenocarcinoma in 14 (30%), non-small-cell lung cancer not otherwise specified in three (6%), small-cell lung cancer in three (6%), and sarcomatoid carcinoma in one (2%). Overall, 20 of the 47 patients could not receive standard-of-care treatment for lung cancer, as per international recommendations or guidelines; this limitation was considered to be directly related to the CPFE syndrome in eight (40%) cases.

Conclusion: Lung cancer in patients with CPFE syndrome represents a specific entity with a poor prognosis, that further represents the most characteristic and severe model of tobacco-related disease.
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http://dx.doi.org/10.1097/JTO.0000000000000209DOI Listing
August 2014

[¹⁸F]FDG positron emission tomography within two weeks of starting erlotinib therapy can predict response in non-small cell lung cancer patients.

PLoS One 2014 5;9(2):e87629. Epub 2014 Feb 5.

LUNAM Université, 49 000, Angers, France ; INSERM UMR_S 1066 Micro et Nanomédecines Biomimétiques, Angers, France ; Université d'Angers, CHU Angers, Pôle des Spécialités Médicales et Chirurgicales Intégrées, Département de Pneumologie, Angers, France ; Université d'Angers, Equipe Pyver, Angers, France.

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, Fisher's 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914822PMC
November 2014

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

Thorax 2014 Jun 16;69(6):596-7. Epub 2014 Jan 16.

LUNAM Université, Angers, France CHU Angers, Département de Pneumologie, Oncologie et Allergologie, Angers, France INSERM UMR_S 1066 Micro et Nanomédecines Biomimétiques, Angers, France Université d'Angers, Equipe Pyver, Angers, France.

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http://dx.doi.org/10.1136/thoraxjnl-2013-204767DOI Listing
June 2014

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

Eur J Pharm Sci 2013 Oct 4;50(2):172-80. Epub 2013 Jul 4.

Lunam Université, INSERM U1066, Micro et Nanomédecines Biomimétiques-MINT, Angers, France.

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.
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http://dx.doi.org/10.1016/j.ejps.2013.06.013DOI Listing
October 2013

Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.

J Clin Oncol 2013 Jun 22;31(16):1997-2003. Epub 2013 Apr 22.

Centre Hospitalier Universitaire de Toulouse, Université de Toulouse III, Toulouse Cedex, France.

Purpose: HER2 mutations are identified in approximately 2%of non-small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC.

Patients And Methods: We retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments.

Results: HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti-human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate [DCR], 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively.

Conclusion: This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.
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http://dx.doi.org/10.1200/JCO.2012.45.6095DOI Listing
June 2013

Proteolytic cleavage of the long pentraxin PTX3 in the airways of cystic fibrosis patients.

Innate Immun 2013 Dec 8;19(6):611-22. Epub 2013 Mar 8.

1LUNAM Université, Université d'Angers, Angers, France.

The prototypic long pentraxin PTX3, a soluble pattern recognition receptor, plays an important role in innate defense against selected pathogens by favoring their elimination and the initiation of protective responses. PTX3 has notably beneficial effects in mice infected with Aspergillus fumigatus and Pseudomonas aeruginosa. Cystic fibrosis (CF), a severe inherited autosomal recessive disease, is characterized by recurrent lung infections, especially by these two pathogens. We thus hypothesized that the status of PTX3 may be altered in CF patients. Level and integrity of PTX3 were analyzed in the sputum samples from 51 CF patients and 7 patients with chronic obstructive pulmonary disease (COPD). The levels of PTX3 were increased in serums from CF patients, but low in their respiratory secretions. PTX3 concentrations in sputum samples were dramatically lower in CF patients than in COPD patients. The low concentration of PTX3 resulted from a proteolysis cleavage by elastase and A. fumigatus proteases. Interestingly, the N-ter domain of PTX3, involved in protection against A. fumigatus, is preferentially degraded by these proteases. These results indicate that the selective proteolysis of PTX3 in the CF lung may explain, in part, the recurrent lung infections by PTX3-sensitive pathogens in CF patients.
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http://dx.doi.org/10.1177/1753425913476741DOI Listing
December 2013

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).

J Thorac Oncol 2012 Oct;7(10):1490-502

Service de Pneumologie-AH-HP Hôpital Tenon, Faculté de Médecine P&M Curie, université Paris 6 Paris, France.

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.
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http://dx.doi.org/10.1097/JTO.0b013e318265b2b5DOI Listing
October 2012

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).

Lung Cancer 2010 Dec 18;70(3):301-7. Epub 2010 Apr 18.

Service d'Oncologie Médicale, AP-HP Hôpital Avicenne, Université Paris XIII, Bobigny, France.

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.
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http://dx.doi.org/10.1016/j.lungcan.2010.03.003DOI Listing
December 2010

Long-term outcome of noninvasive positive pressure ventilation for obesity hypoventilation syndrome.

Chest 2010 Jul 26;138(1):84-90. Epub 2010 Mar 26.

Département de Pneumologie, Centre Hospitalier Universitaire, Angers, France.

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.
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http://dx.doi.org/10.1378/chest.09-2472DOI Listing
July 2010

Toxicological study and efficacy of blank and paclitaxel-loaded lipid nanocapsules after i.v. administration in mice.

Pharm Res 2010 Mar;27(3):421-30

Pulmonology Department, Academic Hospital, Angers, 49933, France.

Purpose: Lipid nanocapsules (LNCs) are solvent-free drug nanocarriers permitting entrapment of paclitaxel and increasing its antitumoural effect in animal models after i.v. injection. The tolerance and efficacy of LNCs after repeated dose i.v. administration were assessed in mice. The maximum tolerated dose (MTD) and 50 percent lethal dose (LD50) were studied.

Methods: Paclitaxel-loaded LNC formulation was given i.v. at the dose of 12 mg/kg per day for 5 consecutive days in comparison with blank LNCs and saline. Histological examination, complete blood counts and biochemical quantification were performed after a recovery of 7 days. Growth of NCI-H460 subcutaneous xenografts in nude mice receiving one of the aforementioned schedules was assessed. MTD and LD50 were determined by Irwin test.

Results: No mortality was observed in repeated injections studies. Histological studies revealed no lesions and no accumulation of lipids. Blood studies were normal. The tumoural growth was significantly reduced in the group treated by paclitaxel-loaded LNCs. The MTDs/LD50s of Taxol, paclitaxel-loaded LNCs and blank LNCs were 12/19.5, 96/216 and above 288/288 mg/kg, respectively.

Conclusions: This study demonstrates that a five-day i.v. injection schedule of paclitaxel-loaded LNC dispersions induces no histological or biochemical abnormalities in mice and improves paclitaxel efficacy and therapeutic index in comparison with Taxol.
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http://dx.doi.org/10.1007/s11095-009-0024-yDOI Listing
March 2010

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

Eur J Pharm Biopharm 2009 Oct 26;73(2):239-46. Epub 2009 Jun 26.

Pulmonology Department, Academic Hospital, Angers, France.

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.
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http://dx.doi.org/10.1016/j.ejpb.2009.06.013DOI Listing
October 2009

[An unusual pulmonary tumor].

Ann Pathol 2009 Apr 20;29(2):158-60. Epub 2009 Mar 20.

Département de pathologie cellulaire et tissulaire, CHU d'Angers, 4, rue Larrey, 49933 Angers cedex 09, France.

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http://dx.doi.org/10.1016/j.annpat.2008.09.055DOI Listing
April 2009

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.

J Thorac Oncol 2008 Aug;3(8):894-901

Department of Pneumology and Thoracic Surgery, 3rd Faculty of Medicine, Charles University, Faculty Hospital Bulovka and Postgraduate Medical School, Praha, Czech Republic.

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/m) as a 1-hour infusion, followed by a 1-hour infusion of cisplatin (75 mg/m), every 3 weeks (arm A), or gemcitabine (800 mg/m) as a 30 minute infusion, on days 1 and 8, and larotaxel (60 mg/m) 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.
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http://dx.doi.org/10.1097/JTO.0b013e31817e6669DOI Listing
August 2008

Aerosolized chemotherapy.

J Aerosol Med Pulm Drug Deliv 2008 Mar;21(1):61-70

Département de Pneumologie, CHU, Angers, France.

Regional chemotherapy has been proposed as a treatment modality in a number of cancer settings. In primary or metastatic lung cancer, administration of chemotherapy via inhalation could increase exposure of lung tumor to the drug, while minimizing systemic side effects. Several proof of concept studies in animal models of metastatic or primary lung cancer have demonstrated the safety, pharmacokinetic advantage, and antitumor effect of aerosol administration of several chemotherapeutic agents including doxorubicin, gemcitabine and liposome-encapsulated formulations of paclitaxel and 9-nitrocamptothecin (9-NC). Recent phase I studies have demonstrated the feasibility of aerosol delivery of doxorubicin and liposomal formulations of 9-NC and cisplatin in patients with primary and metastatic lung cancer with a limited pharmacokinetic profile consistent with the observed low systemic toxicity. Further studies integrating safety, pharmacokinetic, and efficacy considerations are required to determine whether there is a place for local administration of chemotherapy via inhalation in lung cancer.
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http://dx.doi.org/10.1089/jamp.2007.0656DOI Listing
March 2008