Potential lung cancer screening outcomes using different age and smoking thresholds in the ANRS-CO4 French Hospital Database on HIV cohort.

OBJECTIVES: In most lung screening programmes, only subjects ≥ 55 years old and smoking ≥ 30 pack-years are eligible to undergo chest low-dose computed tomography. Whether the same criteria should apply to people living with HIV (PLHIV) is uncertain, given the increased lung cancer risks associated with immunodeficiency and high rates of smoking. We assessed different outcomes obtained from simulating one round of lung cancer screening in PLHIV using different age and smoking thresholds for eligibility. METHODS: Data from the French Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS)-CO4 French Hospital Database on HIV (FHDH) cohort of PLHIV and a national representative survey of PLHIV in care in 2011 (the ANRS-VESPA2 [enquête sur les personnes atteintes] study) were used to estimate the maximum proportion of incident lung cancers occurring between 2012 and 2016 that would have potentially been detected by screening in 2011. Secondary outcomes were numbers of eligible subjects in the cohort and numbers of subjects needed to screen (NNS) to detect one lung cancer. RESULTS: Among 77819 PLHIV in 2011 (median age 46 years; 66% men), 285 subjects subsequently developed lung cancer. Adoption of the US Preventive Services Task Force (USPSTF) recommendations (55-80 years; ≥ 30 pack-years) would have detected 31% of lung cancers at most. Lowering the minimum age to 50 and 45 years would have detected 49% and 60% of cancers, respectively, but would have greatly increased the number of eligible subjects and the NNS to detect one case of lung cancer. CONCLUSIONS: Use of the USPSTF criteria would have detected only a minority of lung cancers in a large French cohort of PLHIV in 2011. Screening PLHIV at younger ages (45 or 50 years) and/or the use of lower smoking thresholds (20 pack-years) may be beneficial, despite the consequently higher numbers of eligible subjects and NNS to detect one case of lung cancer, and should be evaluated in future studies.

[IoNESCO trial: Immune neoajuvant therapy in early stage non-small cell lung cancer]. / Inhibiteurs du check-point immunitaire en néo-adjuvant dans les cancers bronchiques non à petites cellules localisés : essai IoNESCO.

BACKGROUND: Programmed cell death-ligand 1 (PD-L1) is a checkpoint receptor that facilitates immune evasion by tumor cells, through interaction with programmed cell death-1 (PD-1), a receptor expressed by T-cells. Durvalumab is an anti-PD-L1 monoclonal antibody that blocks PD-L1 interaction with PD-1 on T-cells, countering the tumor's immune-evading tactics. Phase I/II studies demonstrated durable responses and manageable tolerability in heavily pre-treated patients with non-small cell lung cancer (NSCLC). METHODS: This phase II study is designed to administrate three durvalumab IV infusions (10mg/kg at day 1, 15, 29) before surgery, to patients with pathologically confirmed NSCLC, clinical stage IB (>4cm) or stage II, ≥18 years of age, WHO performans status 0-1, without selection on PD-L1 expression. Preoperative chemotherapy and radiation therapy are not permitted. The primary objective is feasibility of complete surgical resection. Major pathological response on surgical tissue, defined as 10% or less remaining tumor cells, will be a secondary objective. Additional secondary objectives include tolerance, adverse effects, delay between start of treatment and surgery, response rate (RECIST 1.1), metabolic response rate, postoperative adverse events, disease-free survival and overall survival. A rate of complete resection<85% (P0) is considered unacceptable. P1 hypothesis is of 95%, and with a study power of 90% and an alpha risk of 5% (two-steps Fleming's procedure), 81 patients are required. EXPECTED RESULTS: To establish whether neoadjuvant immunotherapy is feasible and could improve the survival of patients with early-stage NSCLC.

[Current knowledge on perioperative treatments of non-small cell lung carcinomas]. / Traitements péri-opératoires des carcinomes bronchiques non à petites cellules.

Surgery is still the main treatment in early-stage of non-small cell lung cancer with 5-year survival of stage IA patients exceeding 80%, but 5-year survival of stage II patients rapidly decreasing with tumor size, N status, and visceral pleura invasion. The major metastatic risk in such patients has supported clinical research assessing systemic or loco-regional perioperative treatments. Modern phase 3 trials clearly validated adjuvant or neo-adjuvant platinum-based chemotherapy in resected stage I-III patients as a standard treatment of which value has been reassessed several independent meta-analyses, showing a 5% benefit in 5y-survival, and a decrease of the relative risk for death around from 12 to 25%. Conversely perioperative treatments were not validated for stage IA and IB patients. In more advanced stage patients, neo-adjuvant radio-chemotherapy has not been validated either. Adjuvant radiotherapy for N2 patients is currently tested in the large international phase 3 trial Lung-ART/IFCT-0503. The development of video-assisted thoracic surgery (VATS) has helped adjuvant chemotherapies for elderly patients. Perioperative targeted treatments in NSCLC with EGFR or ALK molecular alterations is currently assessed in the U.S. ALCHEMIST prospective trial. Finally, the role of immune check-points inhibitors is currently evaluated in a large international phase 3 trial testing adjuvant anti-PD-L1 monoclonal antibody, the BR31/IFCT-1401 trial, while a proof-of principle neo-adjuvant trial IONESCO/IFCT-1601, has just begun by the end of the 2016 year, with survival results of both trials expected in 5 to 7 years.

Pazopanib or placebo in completely resected stage I NSCLC patients: results of the phase II IFCT-0703 trial.

BACKGROUND: Adjuvant treatment in resected stage I non-small-cell lung cancer (NSCLC) is generally not recommended. Pazopanib is an oral tyrosine kinase inhibitor of VEGFR-1/2/3 and PDGFR-α/ß. We explored the feasibility and efficacy of adjuvant pazopanib in this population. PATIENTS AND METHODS: In this double-blind phase II/III trial, patients with resected stage I NSCLC were randomized to placebo or pazopanib 800 mg/day (P800) for 6 months with a two-step Fleming design. The primary endpoint was compliance (percentage of patients receiving ≥3 months pazopanib). From the interim analysis after 64 patients were included, the IDMC recommended reducing to pazopanib 400 mg/day (P400) due to insufficient compliance, with a one-step Fleming. Although unplanned, survival data were analyzed. RESULTS: A total of 71 patients were enrolled in each arm; 61% were male, 91% were smokers, median age was 60 years, 80% had pathological stage IA, and 16% had squamous cell carcinoma. Pazopanib compliance was 38% [95% confidence interval (CI) 23-55] with P800, increasing to 69% (95% CI 50-84; P = 0.027) with P400. Two patients had grade 4 toxicities with P800. The most common grade 3 toxicities were increased transaminases (16%), hypertension (13%), and diarrhea (9%) with P800, and gastrointestinal disorders (16%; 6% diarrhea) and hypertension (6%) with P400. Median follow-up was 47 months. Three-year recurrence-free survival was 76% (95% CI 65%-86%) with pazopanib and 83% (95% CI 74%-92%) with placebo [hazard ratio = 1.3 (95% CI 0.6-2.7), P = 0.53]. Five-year overall survival was 83% (95% CI 72-94) with pazopanib and 94% [95% CI 88-100] with placebo [hazard ratio = 1.8 (95% CI 0.6-5.5), P = 0.26]. CONCLUSIONS: In resected stage I NSCLC patients adjuvant 400 mg/day pazopanib but not 800 mg/day was feasible, although possibly infra-therapeutic and failed to improve relapse-free survival.

[Lung screening]. / Le dépistage du cancer du poumon.

The NLST study found in more than 53,000 (former-) heavy smokers that annual screening with low-dose CT-scan (LDCT) reduced lung cancer mortality and overall mortality by 20% and 6.7% respectively. However, several potential harms of such screening strategy were underlined: over-diagnosis bias, irradiation risk, and the high rate of false-positive results that could lead to futile invasive (and potentially harmful) exams, to impact quality of life, to increase patient's anxiety and costs. All these concerns were largely debated in several recent publications. Most of them concluded in a risk/benefit ratio favoring screening strategy by LDCT. Conversely, most of American academic societies currently recommend LDCT-based lung cancer screening. In France, a taskforce edited a common statement recommending screening smokers or ex-smokers, from 55 to 75years old who have smoked at least 30packs/year. The taskforce also underlined the need for clinical trials aiming to translate screening strategy to the French setting. However, the French Health Authority recently claimed that lung cancer screening was not relevant in the current setting.

[Economic impact of lung cancer screening in France: A modeling study]. / Modélisation de l'impact économique d'un dépistage organisé du cancer du poumon en France.

INTRODUCTION: The National Lung Screening Trial found that, in a selected population with a high risk of lung cancer, an annual low-dose CT-scan decreased lung cancer mortality by 20% and overall mortality by 7% compared to annual chest X-Ray. In France, a work group stated that individual screening should be considered in this setting. However, the economic impact of an organized and generalized (to all eligible individuals) screening in France was never reported. METHODS: This is a modeling study using French population demographic data and published data from randomized screening trials. We used the same selection criteria as NLST: 55-74-year-old smokers for at least 30 pack-years, current smoker or quit less than 15 years. We computed a second model including also 50-54-year-old individuals. Then, we used different participation rates: 65%, 45%, and 32%. RESULTS: According to the considered model, there would be 1,650,588 to 2,283,993 subjects eligible to screening in France. According to the model and participation rate, lung cancer screening would diagnose 3600 to 10,118 stages 1/2 lung cancer each year. There would be 5991 to 16,839 false-positives, of whom 1416 to 3981 would undergo unnecessary surgery. Screening policy would cost 105 to 215 € million per year. However, increasing the price of a cigarette pack by 0.05 to 0.10 € would fully cover the screening costs. CONCLUSION: Participation rate is a key point for screening impact. Screening could be easily funded by a small increase in cigarette prices.

[Script concordance test for knowledge assessment of lung cancer screening]. / Évaluation des connaissances sur le dépistage du cancer par test de concordance de script.

BACKGROUND: Annual screening for lung cancer using low-dose CT-scans is associated with decreased mortality. A survey conducted in Rhône-Alpes area in France found that clinicians need education and information on this topic. Script concordance tests (SCT) are a tool for assessing clinical reasoning in situations of uncertainty. They have not previously been used in France in the context of continuing medical education. METHOD: We created a questionnaire with 5 multiple-choice questions (MCQ) and two SCT scenarios. The questionnaire was sent to all clinicians and residents who are members of French-Speaking Respiratory Society or the French Young Pulmonologist Association. RESULTS: One hundred and ninety answers were analyzed. Seventy percent stated that decreasing mortality was the best criterion for assessing the effectiveness of a cancer screening policy, and 75% that low-dose CT scan was the best test to achieve this in lung cancer screening. Forty-five percent knew the eligibility criteria of the population, and 62% that low-dose CT scan should be performed annually. Participation in tumor boards and certification in oncology were significantly associated with a better score at MCQ and SCT. SCT and MCQ scores were significantly correlated (Spearman's Rho 0.339; P<0.0001). CONCLUSION: SCT are feasible by electronic survey and seem relevant. Improving knowledge of clinicians on lung cancer screening is still critical.

2014 update on non-small cell lung cancer (excluding diagnosis).

Lung cancer (LC) is a major public health issue because of its frequency, but especially because of the severity of this disease. The epidemiology has changed with an increased incidence in non-smokers and women. The ATS/ERS/IASLC classification of adenocarcinomas was modified in 2011, and they are now the most frequent histological subtype. More than half the cases of LC are diagnosed at the metastatic stage. Biopsies must provide tissue samples that are quantitatively large enough and of a good enough quality for diagnosis and to search for biomarkers. When the cancer seems to be localized, precise staging must be obtained. Treatment is based on the TNM classification. In localized stages, lobectomy associated with lymph node dissection is the standard therapy. Intraoperative chemotherapy improves survival in case of lymph node infiltration. Stereotactic radiation therapy and radiofrequency can be considered as specific cases. In cases with local progression, treatment is more controversial. In the presence of metastases, the goal is not a cure, but improving survival and quality of life. Numerous advances have been made with personalized treatment, (in particular in relation to the histological type and oncogenic addiction in tumors, access to new drugs, and improved management). Clinical research in thoracic cancer is very active. The fight against tobacco should remain a priority.

[Lung cancer in never smokers: a French national cohort (BioCAST/IFCT-1002)]. / BioCAST: le Bio-observatoire national du cancer bronchiques chez les patients non fumeurs (IFCT1002).

Around 5 to 25% of lung cancer worldwide occurs in lifelong non-smokers (less than 100 cigarettes in lifetime). Lung cancer in never smokers (LCINS) shows many clinical, epidemiological and molecular differences compared to those related to tobacco. It is therefore often considered as a separate entity. LCINS is also a good model for the study of lung cancer risk factors and tumoral mutation profiles (usually more common and specific). However, most data has come from retrospective studies and/or from Asian populations, although this disease shows high geographic lability. The BioCAST/IFCT-1002 is a national, multicentric, prospective study promoted by the French intergroup IFCT. The first objective is to describe the clinical and molecular epidemiology of LCINS in a French population. Detailed data (including exposure to many risk factors) are collected directly from the patient through a standardized questionnaire completed during a telephone interview. All patients also undergo blood sampling for the analysis of genomic polymorphisms and the characterization of epigenetic anomalies. BioCAST hopes to provide concrete answers for clinicians and patients about this entity.

Management strategy of pulmonary nodule in 2013.

Lung nodules are commonly found on computed tomography (CT) and need a standardized approach in order to avoid misdiagnosing lung cancer and delaying surgical excision whilst simultaneously avoiding unnecessary invasive procedures if the lesions prove to be benign. Great advances have been made in the last decade in various areas affecting the management of lung nodules: the understanding of the molecular mechanisms behind carcinogenesis, a new classification of lung adenocarcinoma, new data on lung cancer screening, widespread use of multi-detector row CT and development of volumetric analysis software for nodules. Recent decision-making algorithms are based on the size, density and follow-up of the nodule. The distinction between solid nodules, sub-solid nodules and pure ground glass nodules is fundamental, and has a strong correlation with the histologic spectrum of adenocarcinoma. In the absence of criteria suggesting benign disease, the radiologist's report should offer one of the following two options: follow-up based on the recommendations if the nodule is equivocal, or multidisciplinary discussion to consider invasive management if the nodule is highly suspicious of malignancy. Recent data from this statement are reviewed and practical guidelines are offered based on international expert consensus opinion.

From randomized trials to the clinic: is it time to implement individual lung-cancer screening in clinical practice? A multidisciplinary statement from French experts on behalf of the French intergroup (IFCT) and the groupe d'Oncologie de langue francaise (GOLF).

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.

Clinical and molecular features in patients with advanced non-small-cell lung carcinoma refractory to first-line platinum-based chemotherapy.

Most of the cases of non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage and are treated with platinum-doublet chemotherapy. However, some patients are refractory to this treatment. The aim of this study was to identify the clinical and molecular characteristics of patients with refractory disease. All consecutive patients between 2003 and 2006, who received a platinum-doublet chemotherapy as first-line treatment for stage IIIb-IV NSCLC, were included. Refractory patients were defined as early progressive disease (PD) at the first evaluation of chemotherapy according to WHO criteria. The clinical, histo-pathological, and molecular characteristics (EGFR: exon 19, 20, 21 and KRAS: exon 2 by PCR sequencing; ALK by immunohistochemistry) and survival of refractory patients with initial PD (r-patients) and controlled disease (c-patients) were compared by univariate analyses. Factors that differed between the two groups (p-value <0.25 in univariate analyses) were entered into multivariate analysis. In this study, 178 patients were included. The first tumor assessment was carried out after a median of three cycles (range 1-4). Forty-six (25.8%) patients were refractory. Clinical presentation was similar between r- and c-patients. The sarcomatoid histological subtype was more common in r-patients than c-patients (10.9% vs. 1.5%, respectively; p=0.057). The proportion of EGFR (5.2% vs. 9.6%, p=0.224) and KRAS mutations (11.1% vs. 5.7%, p=0.357), and the expression of ALK (6.3% vs. 2.5%, p=0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histological subtype was the only factor associated with early PD (OR=7.50; 95%CI: 1.02-55.45; p=0.048). r-Patients had significantly shorter survival than c-patients (median 5 months (IQR 3.2-9.9) vs. 15.4 months (IQR 9.9-22.5), respectively; p<0.0001). In conclusion, patients with early PD under platinum-doublet chemotherapy had shorter survival than c-patients. Sarcomatoid histological subtype was the only independent factor associated with early PD.

[Neurologic paraneoplastic syndrome with anti-CV2/CRMP5 antibodies revealing a small cell lung cancer. Effectiveness of the lung cancer treatment]. / Syndrome neurologique paranéoplasique à anticorps anti-CV2/CRMP5 révélateur d'un cancer bronchique à petites cellules. Efficacité du traitement du cancer bronchique.

INTRODUCTION: Paraneoplastic neurological syndrome associated with anti-CV2/CRMP5 antibodies are rare. Various clinical manifestations can occur, cerebellar ataxia, polyneuropathy, optic neuritis with NORB or uveitis. Small cell lung carcinoma is generally responsible. CASE REPORT: We report the case of a 64-year-old man who developed visual symptoms with papilledema, cerebellar signs, polyneuropathy confirmed with a neurophysiological studies. Anti-CV2/CRMP5 antibodies were present. A small cell lung carcinoma was responsible for this paraneoplastic syndrome revealing the cancer. The paraneoplastic syndrome improved with radio chemotherapy of the cancer alone. CONCLUSION: A paraneoplastic neurological syndrome must be evoked in case of an atypic neurological syndrome. This diagnostic can be confirmed by the presence of anti-neuronal antibodies. In this case, a small cells cancer of the lung must be research.

Coexisting pulmonary nodules in operable lung cancer: prevalence and probability of malignancy.

INTRODUCTION: Coexistence of pulmonary nodules in operable non small cell lung cancer (NSCLC) may influence the therapeutic indication. The aim of this study was to evaluate prospectively the prevalence and the probability of malignancy of pulmonary nodules in operable lung cancer. METHODS: From a prospective database, all surgically treated patients diagnosed with NSCLC from 1998 to 2003 were retrospectively reviewed. Patients presenting pulmonary nodule(s) were identified. RESULTS: Two hundred thirty nine patients had a complete resection for a NSCLC and 56 patients (24%) presented altogether 88 nodules on thoracic CT. Twenty-four of these nodules (27%) were malignant, 28 (32%) benign and 36 (41%) of undetermined nature. Five factors associated with nodule's malignancy were identified: tumour histology (non-squamous (non-SCC) 44% vs. SCC 7%, p=0.001), localization of the nodules in an upper lobe (vs. other lobe, p=0.004), co localization in the same lobe as the NSCLC (vs. another lobe, p=0.03), nodule size (p=0.05) and shape (speculated vs. non spiculated, p=0.02). From these factors, a probability score was assessed with a malignancy rate in SCC of 0% in nodules presenting ≤ 1 feature, 33% with 2 features and 100% with ≥ 3 features and in non-SCC of 40% with 1 feature, 82% with 2 features and 100% with 3 ≥ features. CONCLUSION: Diagnosis of satellite nodules associated with early stage NSCLC is common. We developed a predictive score to estimate the probability of malignancy which may be a precious aid in the management of pulmonary nodules associated to a NSCLC.