Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

Real world data of efficacy and safety of erlotinib as first-line TKI treatment in EGFR mutation-positive advanced non-small cell lung cancer: Results from the EGFR-2013-CPHG study.

BACKGROUND: Phase III clinical trials have demonstrated the merits of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in the treatment of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. Using a cohort of unselected patients treated with erlotinib, we sought to further describe patient and tumour characteristics, and to evaluate their progression-free survival (PFS) and overall survival (OS). METHODS: Overall, 44 pulmonologists included patients with the required characteristics as follows: Stage IIIB-IV NSCLC, EGFR-activating mutation, age≥18 years, and having to start erlotinib therapy or receiving erlotinib therapy as the first-line TKI, regardless of treatment-line. The analyses were performed using R software, with survival rates calculated according to the Kaplan-Meier method. RESULTS: A total of 177 patients, aged 72 years on average, were enrolled over a 2-year period. The cohort included 123 women (69.5%), 158 Caucasians (89.3%), 112 non-smokers (63.2%), and 167 adenocarcinomas (94.3%), at either stage IIIB (21) or IV (156), with a good performance status (PS 0-1, 127). Overall, 40 exhibited brain metastases at baseline (22.6%), while 75 had undergone earlier treatment (42.4%). Median PFS was 11.7 months and OS 25.8 months, with respectively a 1-year rate of 48.6% and 74%. The risk of death correlated with ECOG status (PS=2, HR=4.48, P<0.001) but not with brain metastasis (HR=1.67, P=0.278). CONCLUSIONS: This study has confirmed erlotinib's efficacy and safety for unselected patients, with PFS and OS comparable to those obtained in phase III trials.

Patients with atherosclerotic peripheral arterial disease have a high risk of lung cancer: Systematic review and meta-analysis of literature.

PURPOSE: Lung cancer and atherosclerosis share common risk factors. Literature data suggest that the prevalence of lung malignancy in patients with peripheral arterial disease (PAD) is higher than in the general population. Our goal was to determine, through a systematic literature review, the prevalence of lung cancer in patients with PAD. METHODS: We consulted available publications in the Cochrane library, MEDLINE, PUBMED, EMBASE, and ClinicalTrials.gov. We included all articles, written in English or French, published between 1990 and 2020 reporting the prevalence of lung cancer in patients with PAD (atherosclerotic aortic aneurysm or peripheral occlusive diseases). Patients with coronary artery disease, cardiac valvulopathy or carotid stenosis were not included. We did not include case reports. We performed a critical analysis of each article. Data were collected from two independent readers. A fixed effect model meta-analysis allowed to estimate a summary prevalence rate. RESULTS: We identified 303 articles, and selected 19 articles according to selection criteria. A total of 16849 patients were included (mean age 68.3 years, 75.1% of males). Aortic aneurysms were found in 29% of patients and atherosclerotic occlusive disease in 66% of patients. Lung cancer was identified in 538 patients, representing a prevalence of 3%. DISCUSSION: Lung cancer is found in 3% of patients with atherosclerotic PAD. This prevalence is higher than that found in lung cancer screening programs performed in the general population of smokers and former smokers. These patients should be screened for lung cancer. Their selection may dramatically increase the benefit of lung cancer screening.

Chemoradiotherapy efficacy is predicted by intra-tumour CD8+/FoxP3+ double positive T cell density in locally advanced N2 non-small-cell lung carcinoma.

BACKGROUND: Radiotherapy is a standard of care for locally advanced stage III N2 non-small-cell lung carcinoma (NSCLC) combined with surgery/chemotherapy. Radiotherapy is hypothesised to induce tumour immunogenic cell death, to release neoantigen resulting in intra-tumoural immune infiltration and abscopal effect. Conversely, it has not been demonstrated if immune cells are necessary to drive radiotherapy efficacy and predict patient's survival. PATIENTS AND METHODS: We retrospectively analysed tumour samples and clinical data from 113 patients, 89 resected (PORT) and 24 non-resected (DRC) N2-NSCLC treated with chemotherapy and radiotherapy (same radiotherapy department from 2002 to 2015). The immune environment was characterised with in situ multiplex staining (CD8, FoxP3, PD-L1 and cytokeratin) and correlated with clinical data and survival. RESULTS: High density of CD8+ T cells was associated with OS (p = 0.04, HR = 1.93 [0.99-3.78]) and DFS (p = 0.003, HR = 2.42 [1.31-4.47]) in the PORT. High density of CD8+/FoxP3+ double positive cells was associated with OS (p = 0.01, HR = 1.97 [1.11-3.48]) in the whole population, with OS (p = 0.05, HR = 1.92 [0.98-3.74]) and PFS (p = 0.03, HR = 1.83 [1.03-3.23]) in the PORT without reaching significance for the DRC. Intermediate PD-L1 expression in tumour cells (TPS = 1-49%) was associated with a higher survival in the PORT. CONCLUSIONS: Intra-tumoural CD8+ T cell and particularly CD8+/FoxP3+ double positive T cell densities predict survival in stage III N2-NSCLC suggesting the need for a pre-existing intra-tumour immunity to mediate the action of radiotherapy. Density of CD8+/FoxP3+ cells was the best predictor of patient's survival in multivariate analysis and could represent a biomarker of radiotherapy efficacy.

Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations.

BACKGROUND: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. PATIENTS AND METHODS: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications. CONCLUSION: Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02304809.

Nivolumab-refractory patients with advanced non-small-cell lung cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity. METHODS: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015. RESULTS: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p < 0.0001), shorter duration of treatment before nivolumab (p = 0.028) and had dramatically shorter nivolumab overall survival (p < 0.0001) than patients who did not present with refractory disease. CONCLUSION: Nivolumab-refractory disease can affect up to 20% of patients treated with nivolumab for advanced NSCLC with dramatically shortened survival rates. Further studies are needed to understand the precise mechanisms leading to refractory disease as well as its management.

[Analysis of immune microenvironment by multiplex immunohistochemistry in locally advanced non-small cell lung cancer: Principles and perspectives]. / Analyse du microenvironnement immunitaire par immunohistochimie multiplex dans le cancer bronchopulmonaire non à petites cellules localement évolué : principes et perspectives.

Recent therapeutic advances in non-small cell lung cancer allow a better understanding of the interactions between the tumour and its direct immune environment. The identification of new immune biomarkers integrating both cell subpopulations and their interactions is a real issue in oncology. New techniques of tissue analysis, particularly multiplex immunohistochemistry, consisting of a labelling of several antigens of interest by immunofluorescence on the same slide, provide a better understanding of the tumour environment. Integration of these modalities of analysis to the therapeutic decision is promising, because it allows an increased characterization of each tumour, particularly interesting with radiotherapy and immunotherapy. This article describes the potential of these assays in locally advanced non-small cell lung cancer.

[Why screen for lung cancer in patients with arterial disease?]. / Pourquoi dépister le cancer du poumon chez les artériopathes ?

Lung cancer remains the leading cause of cancer death in France. Such a prognosis is explained by late diagnosis at a metastatic stage for half of the patients. Tobacco is the main risk factor for lung cancer, as it is for peripheral arterial disease. A review of literature shows that between 2.3% and 19% of patients with arterial disease also have lung cancer. When lung cancer is detected after treatment of arterial disease, it is at an advanced stage. But it can be diagnosed at an early stage when it is searched simultaneously with arterial disease treatment. There is no recommendation for lung cancer screening specifically for patients with arterial disease. However individual screening based on an annual low-dose chest scan is proposed for smokers meeting the criteria defined by the study of the National Lung Screening Trial (NLST). Such screening has two disadvantages : the high number of false positives and the irradiation induced by the accumulation of examinations. The ISET method would alternatively help to identify circulating tumor cells on a simple blood test for subjects not yet at solid tumor stage, provided this method be subject to multicentric validation. Thus one could consider that the management of a patient with arterial disease meeting NLST criteria should be accompanied with screening for lung cancer by searching for tumor cells associated with low-dose scanner.

Diagnosis and standardized report for non-small cell lung cancer.

In the assessment of lung cancer, computed tomography guides the use of bronchoscopy and establishes whether local treatment may be appropriate for the NSCLC or whether it is at an advanced stage. Percutaneous biopsy of a lesion suspected to be a metastasis can provide histological confirmation, allowing staging to be carried out at the same time. The initial presentation depends on the staging and histological type, ranging from an isolated nodule or mass to atelectasis or obstructive pneumonia, isolated lymph node disease or isolated pleural effusion to miliary metastasis in tumors showing EGFR mutation. Tumor (T) status depends on tumor size, distance from the carina, and invasion of the chest wall and mediastinal organs. PET-CT is superior to CT in identifying lymph node invasion (N2 for ipsilateral mediastinal disease and N3 for contralateral or supraclavicular disease). As a general rule, all contraindications for surgery should be confirmed via histological examination, with the exception of cerebral metastases.

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.

[Targeted agents in the treatment of lung cancer]. / Place des traitements ciblés dans la prise en charge des cancers broncho-pulmonaires.

Lung cancer is in France, the leading cause of cancer death. Despite the dramatic advances that have allowed in a few years to go, for metastatic cancer, from a median survival without specific treatment of 4.5 months and now almost always more than one year, survival remains disappointing and further improvements are needed. Progress in the accumulated knowledge of the inner workings of normal and tumoral cells have paved the way for the development of targeted therapeutics called biological or simply targeted therapies. Two biological processes are already the target of marketed drugs, this is the way the receptor of epidermal growth factor (EGFR) and the path of neo-angiogenesis. It is almost assumed that, in the very near future, the inhibition of EML4-ALK will also be the subject of new drugs. In the medium term, it is conceivable that the molecular dissection of the tumors actually lead to the prescription of treatments tailored to mutations and other abnormalities that direct the growth of cancers.

[A phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non squamous, non-small cell lung cancer (NSCLC)]. / Protocole IFCT 0803--Étude de phase II évaluant l'association de cétuximab à une radiothérapie et chimiothérapie concomitante par cisplatine et pémétrexed dans le traitement des cancers bronchiques non à petites cellules non épidermoïdes de stade III, inopérables.

BACKGROUND: Cisplatin-based chemotherapy and concurrent radiotherapy are the standard treatments for locally advanced unresectable NSCLC. New therapeutic combinations using molecular targeted drugs are needed. METHODS: Eligible patients with previously untreated stage III non squamous, NSCLC will receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m(2)) and pemetrexed (500 mg/m(2)) on day 1 administered intravenously every 21 days for four cycles; weekly cetuximab will be added from the first week of therapy. The primary objective of this phase II study (IFCT 0803) is to assess the disease control rate at the 16th week, one month after the completion of the treatment. Based on a two-stage Simon approach, a total of 106 patients are required with an interim analysis of the first 34 planned. EXPECTED RESULTS: This trial will provide information on the feasibility, efficacy and tolerability of this new therapeutic combination. Should the primary objective be achieved, a phase III randomised study testing the position of cetuximab could be considered.

[PET-CT for evaluation of the solitary pulmonary nodule: an update]. / TEP-TDM pour l'exploration du nodule pulmonaire solitaire: acquis et perspectives.

INTRODUCTION: Positron emission tomography (PET) with 18F-FDG has become an important tool for the characterization of solitary pulmonary nodules (SPN). BACKGROUND: The results of the main meta-analyses show that the sensitivity and specificity of 18F-FDG PET for determining malignancy of SPN are close to 95% and 80% respectively. The limits of the technology are now well known. False negative results are mainly due to certain histological types with low metabolic activity (such as bronchiolo-alveolar carcinoma and typical carcinoid), or small size (nodules less than 8 mm). False positives are mainly represented by granulomatous and infectious processes. VIEWPOINTS: A gain in accuracy occurred with the advent of hybrid PET/CT machines that combine the functional data from 18FDG-PET and the morphological data of computed tomography. Improved imaging protocols (eg. injection of iodinated contrast media) could further enhance the performance of PET-CT. Further improvements will rely on respiratory synchronization protocols and on the advent of new PET tracers. CONCLUSION: 18F-FDG PET-CT should be performed for any nodule over 8 mm in size when the pre-test probability of malignancy is not deemed negligible.

[Atmospheric air pollution and lung cancer: epidemiologic data]. / Pollution atmosphérique et cancer bronchique: données épidémiologiques.

INTRODUCTION: Much has been written about the short term effects of air pollution on health. In contrast, long term effects, which may be highly significant such as lung cancer, have been addressed in only a few cohort studies. STATE OF THE ART: Long term effects of air pollution on mortality have been evaluated in three American and three European prospective cohort studies. These studies consistently demonstrate associations between ambient fine particulate air pollution and elevated risks of both cardiopulmonary and lung cancer mortality. They indicate that diesel exhaust especially contributes to the human lung cancer burden. PERSPECTIVES AND CONCLUSIONS: Although long-term health effects of air pollution are of relatively small magnitude at the individual level when compared to that of tobacco smoking, their consequences are considerable in terms of public health.

The NER proteins are differentially expressed in ever smokers and in never smokers with lung adenocarcinoma.

BACKGROUND: The expression levels of excision repair cross-complementation group 1 (ERCC1), replication protein A (RPA) and xeroderma pigmentosum group F (XPF) nucleotide excision repair proteins may be important in the response to platin-based therapy in lung cancer patients. It is not known whether ERCC1, RPA and XPF expression levels differ between ever smokers (ES) and never smokers (NS). PATIENTS AND METHODS: ERCC1, RPA and XPF expression levels were immunohistochemically evaluated in 125 patients with resected lung adenocarcinoma (AC) and carefully reviewed smoking status. RESULTS: ERCC1 was correlated with XPF (P = 0.001), but not with RPA (P = 0.11). In the univariate analysis, ERCC1 and XPF levels were higher in NS compared with ES (P = 0.004 and P = 0.003, respectively). In the multivariate analysis, the smoking status was predictive of the ERCC1 level [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.03-6.2] after adjustment for variables linked to the smoking status, including age and the presence of bronchioloalveolar (BAC) features. The smoking status was also predictive of both RPA (OR 6.7, 95% CI 1.5-33.3) and XPF levels (OR 12.5, 95% CI 2.9-50) after adjusting for age, sex and BAC features. CONCLUSION: In patients with resected lung AC, ERCC1, RPA and XPF expression levels are higher in NS compared with ES.

An open phase II trial of gemcitabine, oxaliplatin and vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients.

The purpose of this multicentric Phase II study was to evaluate the safety and efficacy of a gemcitabine/oxaliplatin/vinorelbine combination as first-line therapy in advanced non-small cell lung cancer patients. Patients followed a fortnightly drug schedule, receiving on day 1, vinorelbine 25mg/m(2) (20-min infusion); gemcitabine 700 mg/m(2) (70-min infusion, fixed 10mg/m(2)/min); and on day 2, oxaliplatin 85 mg/m(2) (2-h infusion). Thirty-nine patients with a median age of 58 years received a total of 306 cycles (median 8 cycles); 67% were males. Most had adenocarcinoma (51%), large-cell (23%) and squamous cell carcinoma (21%); 15% had stage IIIB and 85% stage IV. There was one complete response (3%; 95% CI: 0.1-13%), 15 partial responses (PR) (38%; 95% CI: 23-55%), and 13 patients with stable disease (33%; 95% CI: 19-50%) of at least 2 months duration, for an overall non-progression rate of 74%. Median progression-free survival (PFS) was 4.1 months (95% CI: 3.1-8.7) and overall survival was 11.7 months (95% CI: 7.7-19.4). No treatment-related deaths occurred and very few grade 3-4 events were observed. Overall, the regimen was well tolerated and the planned recommended dose intensity was safely delivered to more than 95% of patients. This triple combination therapy study yielded favourable efficacy and toxicity results, which merit further evaluation in prospective randomised trials.

[Abdominal pain during the course of lung cancer]. / Douleur abdominale au cours de l'évolution d'un cancer bronchique.

INTRODUCTION: Metastatic involvement of the peritoneum from a lung cancer is infrequently encountered. METHODS: We present the case report of a patient with bronchial adenocarcinoma whose course is complicated by the occurrence of a peritoneal carcinomatosis, as documented by FDG-PET. CONCLUSION: Unexplained abdominal pain in a lung cancer patient may be a peritoneal carcinomatosis. The diagnosis can be helped by PET-scan. However, the therapeutic opportunities are very limited.

[IFCT-0302 trial: randomised study comparing two follow-up schedules in completely resected non-small cell lung cancer]. / Protocole IFCT-0302: essai randomisé de deux schémas de surveillance dans les cancers bronchiques non à petites cellules complètement réséqués.

BACKGROUND: The authorities advocate a minimalist attitude towards the follow-up of resected bronchial carcinoma (clinical examination and chest x-ray). A survey showed that 70% of French respiratory physicians have chosen to use the CT scanner and often endoscopy. The published data are equivocal and are often based on retrospective studies. Lung cancer is a good model for a study of post-operative surveillance. Recurrences often occur in easily observed areas, they may be detected while still asymptomatic and are sometimes potentially curable. Second primary tumours may develop at the same site. METHODS: The Intergroupe Francophone de Cancerologie Thoracique (IFCT) has initiated a trial comparing simple follow-up (clinical examination, chest x-ray) with a more intensive follow-up (CT scan, fibreoptic bronchoscopy). The surveillance will take place every 6 months for 2 years and then annually until 5 years. EXPECTED RESULTS: The main aim is to determine whether intensive follow-up improves patient survival. The opposite question is equally important. If an expensive and demanding follow-up does not affect the chances of cure these results will influence our practice.

[The consequences of passive smoking in adults]. / Conséquences du tabagisme passif chez l'adulte.

INTRODUCTION: Passive smoking is the involuntary inhalation by a non-smoker of smoke generated in his neighbourhood by one or more smokers. BACKGROUND: The effect of this exposure is already generally recognised in children. In adults the induction of chronic obstructive lung disease has not been demonstrated. This is no longer the case for ischaemic heart disease and lung cancer where the effect of passive exposure of non-smokers to cigarette smoke is recognised. The biological plausibility together with the concordance of results obtained over successive years, as well as the large numbers of patients included in the studies, lead to a confident conclusion that the risks in adult non-smokers are increased by the order of 25%. CONCLUSIONS: There is no evidence that bias affects the conclusions reached and the World Health Organisation has recently classified passive smoking as being carcinogenic in man. As a result of these data prevention of passive exposure to cigarette smoke should be part of a larger framework of smoking prevention, especially among the young.