IFCT-1502 CLINIVO: real-world evidence of long-term survival with nivolumab in a nationwide cohort of patients with advanced non-small-cell lung cancer.

BACKGROUND: Immunotherapy using inhibitors targeting immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) is currently the standard of care in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We carried out a nationwide cohort retrospective study of consecutive patients with advanced, refractory NSCLC who received nivolumab as second to later lines of treatment as part of the expanded access program. Key objectives were to assess the efficacy and safety of nivolumab and the efficacy of first post-nivolumab treatment. RESULTS: Nine hundred and two patients were enrolled: 317 (35%) with squamous cell carcinoma and 585 (65%) with non-squamous cell carcinoma. Median age was 64 years; there were 630 (70%) men, 795 (88%) smokers, 723 (81%) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0/1, 197 (22%) patients with brain metastases, and 212 (27%) with liver metastases. Best response was partial response for 16.2% and stable disease (SD) for 30.5%. Progression-free survival and overall survival (OS) rates at 2, 3, and 5 years were 8% and 25%, 6% and 16%, and 4% and 10%, respectively. At multivariate analysis, ECOG PS ≥2 [hazard ratio (HR) = 2.13, 95% confidence interval (95% CI) 1.78-2.55, P < 0.001], squamous histology (HR = 1.17, 95% CI 1.01-1.36, P = 0.04), and presence of central nervous system metastases (HR = 1.29, 95% CI 1.08-1.54, P = 0.005) were significantly associated with lower OS. Four hundred and ninety-two patients received at least one treatment after discontinuation of nivolumab, consisting of systemic therapies in 450 (91%). Radiation therapy was delivered to 118 (24%) patients. CONCLUSION: The CLINIVO cohort represents the largest real-world evidence cohort with the use of immune checkpoint inhibitor in advanced, metastatic NSCLC after failure of first-line chemotherapy, with long-term follow-up and analysis of subsequent therapies. Our data confirm the efficacy of nivolumab in a cohort larger than that reported in landmark clinical trials and identify prognostic factors, which reinforces the need for accurate selection of patients for treatment with immune checkpoint inhibitors. Our data indicate that oligoprogression is frequent after nivolumab exposure and provide a unique insight into the long-term survival.

[Feminization of the patient in thoracic oncology and experiences of caregivers: An exploratory study]. / Féminisation de la patientèle en oncologie thoracique et vécu des soignantes : recherche exploratoire.

INTRODUCTION: The epidemiology of lung cancer is evolving and caregivers need to address an emerging demographic, women, sometimes presenting at a young age. The effect of this ongoing change on thoracic oncology services and on the nursing population (registered nurses and auxiliary nurses) has not been evaluated. METHODS: A quantitative analysis can help to control the biases that may have an impact on nursing staff identification with female patients. A categorical and automated qualitative study (Tropes software) of speech productions related to "difficult situations" was carried out. RESULTS: Four contexts activating critical situations were identified: disagreement and conflict in care, a constraining situation of care, an overflow situation, particularly related to increased suffering of the patient and a feeling of being isolated in care delivery. Regarding the management of female patients, after the impact of disagreements in management, the feeling of care being constrained in the presence of a female patient with whom caregivers identify themselves is more significant than with regard to male patients. CONCLUSION: Support within the care team is essential, but not sufficient. Only a practice-based training context involving peers outside the team seems to help address the most impactful situations.

[Use of time of a nurse involved in breaking the diagnosis of lung cancer and navigating patients in the healthcare system: Experience of an academic thoracic oncology ward]. / Emploi du temps d'une infirmière d'annonce et de coordination du parcours de soins en cancérologie thoracique : expérience du CHU d'Angers.

The Plans cancer 1 and 2 created new nursing posts to improve the way that news about cancer was given to patients and to coordinate their care, helping them to navigate the system. We describe the way a nurse, assuming the role of assisting the doctor when a diagnosis of cancer is revealed and coordinating the care of patients in a teaching hospital, uses her time. One thousand and forty-one patients were supported by the nurse during 6515 procedures over 4.27 years. The median (interquartile range) number of interventions per patient was 3 (7). Helping to break news of cancer and the coordination of care represented approximately 20 and 80% of the working time of the nurse, respectively. The nurse spent 43% of her time without the doctor and more than half of this duration was dedicated to meetings with patients. The nurse timetable analysis shows that her role is very similar to a Canadian 'Pivot' nurse in oncology. In our experience, this combination of the announcement of cancer diagnosis and the coordination of subsequent care seems relevant, but the nurse is not replaced in the case of absence.

[Inhaled chemotherapy - Part 1: General concept and current technological challenges]. / La chimiothérapie inhalée ­ partie 1 : concept et challenges technologiques actuels.

Despite severe adverse effects, chemotherapy is still widely used in the treatment of lung tumors, including primary lung tumors and metastases. In order to reduce the risk of harm and to intensify treatment responses, several strategies have been described recently. These include the use of nanomedicine-based chemotherapies and pulmonary drug delivery. However, to treat lung tumors, inhalation cannot be effective and safe without an adaptation of current inhalation techniques, i.e. inhalation devices and drug formulations. This can be very challenging. This review presents recent preclinical developments that could address the limitations observed with aerosolized chemotherapy. The solutions involve the use of dry powder inhalers and advanced drug formulations, such as controlled and sustained release formulations and nanomedicine-based formulations.

[Inhaled chemotherapy - Part 2: Clinical practice and potential applications]. / La chimiothérapie inhalée ­ partie 2 : clinique et applications potentielles.

Lung tumours have a high incidence and cause many deaths worldwide. Despite progresses in treatment with targeted therapies and immunotherapies, the global 5-year survival rate remains low. In this context, inhaled chemotherapy could provide a means to intensify current therapeutic modalities. This review is based on clinical studies of inhaled chemotherapy against lung tumours. The advantages of this approach in terms of pharmacokinetic ratio and therapeutic index are presented as well as the limitations including contraindications and pulmonary side effects. Moreover, the challenges linked to technical aspects around administration are identified (inhalation device and facilities to limit aerosol propagation and exposure of healthcare professionals). The current developments proposed to overcome these challenges are described briefly. Also discussed are the potential applications for the distribution of the inhaled anticancer drug into tumour-bearing respiratory tracts and finally the potential indications for current therapeutic modalities.

Phase III study of the European Organisation for Research and Treatment of Cancer satisfaction with cancer care core questionnaire (EORTC PATSAT-C33) and specific complementary outpatient module (EORTC OUT-PATSAT7).

Advances in cancer care delivery require revision and further development of questionnaires assessing patients' perceived quality of care. This study pre-tested the revised EORTC satisfaction with cancer care core questionnaire applicable in both the cancer inpatient and outpatient settings, and its new, outpatient-specific complementary module. The process of revision, development of the extended application, and pre-testing of these questionnaires was based on phases I to III of the "EORTC Quality of Life Group Module Development Guidelines." In phase III, patients in 11 countries in four European regions, South America and Asia completed provisional versions of the questionnaires. Fifty-seven relevant issues selected from literature reviews and input from experts were operationalized into provisional items, and subsequently translated into ten languages. Assessment of understanding, acceptability, redundancy and relevance by patients (n = 151) from oncology inpatient wards, and outpatient chemotherapy, radiotherapy and consultation settings, led to retention of, deletion of and merging of 40, 14 and 6 items respectively. Cronbach's alpha coefficients for hypothesized questionnaire scales were above 0.80. Our results provide preliminary support for the 33-item EORTC Satisfaction with cancer care core questionnaire and the 7-item complementary module specific for the outpatient care setting. A large scale phase IV cross-cultural psychometric study is now underway.

[Unexpected adverse events of immunotherapies in non-small cell lung cancer: About 2 cases]. / Effets secondaires inhabituels des immunothérapies dans le cancer bronchique non à petites cellules : à propos de deux cas.

Programmed death receptor 1 (PD1) checkpoint inhibitors are known for immune mediated toxicities such as colitis, endocrinopathies and pneumonitis. However, other rare adverse effects are reported in the literature. Nivolumab is an anti-PD1 immunotherapy used in the second line of non-small cell lung cancer (NSCLC). We report two cases of rare toxicities occurring under nivolumab in patients without a history of dysimmunity. A 79-year-old patient with a large-cell carcinoma showed a muscle weakness after the second course, revealing myositis with a CPK grade IV elevation as well as symptoms of myasthenia. The diagnosis of myositis was confirmed by a muscle biopsy. An 82-year-old patient followed for bronchial adenocarcinoma with EGFR mutation, presented with nivolumab shoulder and hip pain with extreme fatigue. After further investigations, the diagnosis of systemic erythematosus lupus was retained. Investigations led to the diagnosis of systemic lupus erythematosus. For both patients treatment was interrupted and systemic corticosteroid therapy was initiated permitting resolution of symptoms. The occurrence of symptoms of dysimmunity should attract the attention of the clinician, leading to discontinuation of anti-PD1 therapy and corticosteroid therapy. Retreatment after symptoms resolution must be collegially discussed if no alternative therapeutic is available.

[Cannabis and lung. What we know and everything we don't know yet]. / Cannabis et poumon. Ce que l'on sait et tout ce que l'on ne sait pas.

Cannabis use increased sharply from 2010 to 2014 in France. Cannabis is often consumed with tobacco, although the use of marijuana is developing. Tobacco and cannabis smoke have many common characteristics in terms of irritants, carcinogens and carbon monoxide. They also differentiate by their dependence mechanisms, with nicotine and its receptors for tobacco and tetra-hydro-cannabinol (THC) and its specific receptors for cannabis. Chronic inhalation (700,000 daily users in France) over a long period most likely increases the relative risk of bronchial cancer. But long-term cohort studies targeting this group of strong cannabis users, especially over time, are lacking. Inhalation of cannabis smoke, despite an acute bronchodilator effect, is associated with the risk of chronic bronchitis in the case of regular use. However, the risk of developing COPD in the exclusive marijuana smoker group with no associated tobacco is not yet clear, with studies yielding discordant results. There is also a lack of long-term follow-up studies of respiratory investigations in large cannabis users. Finally, cannabis smoke contains various cannabinoids, for example cannabidiol which also have anti-inflammatory and antifibrotic properties, with the unconfirmed hypothesis that these properties can partially modulate the deleterious action of cannabis smoke.

[A bronchial mucous gland adenoma resected by endoscopic procedure]. / Un adénome des glandes muqueuses bronchiques réséqué par voie endoscopique.

INTRODUCTION: Surgical resection is usually performed for the treatment of endobronchial tumors. This case describes the use of endoscopic resection as an initial treatment, allowing to spare lung parenchyma. CASE REPORT: A patient was admitted to the emergency unit with right lower lobe pneumonia. A thoracic CT-scan and subsequent bronchoscopy revealed an intrabronchial tumor between the right main and intermediate bronchus. Biopsies were non-diagnostic and a PET-scanner did not find any abnormalities. Surgical resection was initially proposed but would have required a right upper lobectomy. The patient had stage 2 (moderate) chronic obstructive pulmonary disease (GOLD classification). Because of this, we decided to perform an endoscopic resection to obtain further histology and hopefully achieve total removal. Under conscious sedation, the resection by argon plasma coagulation with a flexible bronchoscope was realized without any complication. The histological diagnosis was a bronchial mucous gland adenoma. CONCLUSION: This case emphasizes the role of multidisciplinary discussion when considering suitability of local resection of tumors by an endobronchial procedure rather than a surgical resection.

Corneal graft rejection in a patient treated with nivolumab for primary lung cancer.

We report the case of a 58-year-old woman treated with nivolumab for an unresectable squamous non-small cell lung cancer, after first-line cisplatin and gemcitabine combination chemotherapy. This woman had a history of left corneal graft. After 9 cycles of nivolumab, the patient described decreased visual acuity in the left eye with watering and conjunctival erythema. Ophthalmological examination revealed chronic corneal graft rejection. The patient was then treated with an intravenous bolus of corticosteroids (500mg of methylprednisolone) for 3 days, followed by oral prednisone for 4 weeks and subconjunctival corticosteroid injections every 48h, while treatment with nivolumab was discontinued. No clinical benefit was observed 4 weeks later and the corneal graft became totally unfunctional despite of the therapy. We hypothesise that the treatment was started too late. To our knowledge, this is the first reported case of corneal graft rejection related to nivolumab.

[Can positron emission tomography assessment of response to treatment help to individualize use of erlotinib in non-small cell lung cancer?] / L'imagerie par émission de positons à la 3'-désoxy-3'-[18F]-fluorothymidine ([18F]FLT) peut-elle avoir un rôle théranostique lors du traitement par erlotinib dans le cancer bronchique non à petites cellules ?

Erlotinib can be prescribed in the treatment of locally advanced or metastatic non-small lung cancer cell (NSCLC) after failure of at least one prior chemotherapy regimen on the basis of the BR-21 study. Several publications have recently questioned these results. The metabolic imaging of solid tumours by positron emission tomography is a research field that could help customize the treatment of NSCLC and so complement the treatment approaches allowed by genetic analyses. This strategy is part of an innovative "early metabolic look" approach. The primary objective of this study is to determine if metabolic progression observed between the 7th and 14th day after initiation of treatment with erlotinib by 3'-Deoxy-3'-[18F]-Fluorothymidine PET in patients with EGFR naive NSCLC is predictive for morphological progression after 6 to 8 weeks of treatment. A health economic analysis will be conducted. This study is particularly innovative because it begins the exploration of the era of metabolic evaluation of therapeutic response in NSCLC.

[Simulation training in pulmonary medicine: Rationale, review of the literature and perspectives]. / La simulation en pneumologie: rationnel, données de la littérature et perspectives.

Training in pulmonary medicine requires the acquisition of a great deal of knowledge, but also technical know-how and interpersonal skills. The prevailing teaching pattern is mentorship. It implies a direct transmission of knowledge, but also entails some drawbacks such as disparity in learning opportunities, subjective evaluation of the trainee and potential risks for patients. There is growing interest in simulation training as a teaching technique, where students practice their skills in a secure environment, then analyse their performance in a debriefing session. It is complementary to other learning methods (abstraction, observation or mentorship) and forms part of an ethical approach: 'never practice on a real patient for the first time'. We have reviewed the literature related to simulation training in pulmonary medicine and in particular for physical examination, technical skills, pathologies, communication with patients and therapeutic education. In most of the studies, simulation training is a way of speeding up students' training - without necessarily yielding better results - and of respecting the procedures. We then present the French regulations and official guidelines regarding the use of this training method in the teaching of medicine. Finally, we shall consider some prospects of this approach for the community of pulmonologists.

[Simulation training: a pilot-study on reception of parents in a pediatric intensive care unit]. / Formation par la simulation : étude-pilote sur l'accueil des parents par une équipe de réanimation pédiatrique.

BACKGROUND: Simulation training is gradually being integrated into the curriculum for caregivers in intensive care units. There are few training programs on communication with families. GOAL: This pilot-study evaluated the impact of a training protocol on professional practices including a protocol for the reception of the parents of a child admitted to a pediatric intensive care unit. MATERIALS AND METHODS: The training program lasted 3 months and included three parts: a theoretical contribution, a simulation session with debriefing, and a focus group. During the simulation session, a multi-professional team of three healthcare providers (physician, nurse, assistant nurse) must apply a protocol for the reception of the parents of a child who had just been admitted. The protocol lasted 35 min and included three sequences: reception and dressing by the assistant nurse, medical meeting conducted by the physician and the nurse, support of the parents in the room by the nurse and the assistant nurse. The child was simulated by a manikin (SimBaby™, Laerdal) and the parents were prepared actors. The main objective of the pilot-study was to measure the rate of change in professional practices 1 year after the end of training. RESULTS: One year later, all healthcare providers (n=15) declared they had changed their professional practices and felt that half of these changes were due to the pilot-study. New practices such as receiving parents in pairs in a dedicated room or managing a short interview with the parents before supporting the child were applied "always" or "if possible". CONCLUSION: The pilot-study showed that the training program induced half of the changes of professional practices for welcoming the parents of a child admitted to pediatric intensive care unit 1 year later.

[Biological diagnosis of resistance to erlotinib in a malignant pleural effusion]. / Diagnostic biologique de résistance à l'erlotinib sur une pleurésie.

INTRODUCTION: The characterization of genetic abnormalities in non-small cell lung cancer (NSCLC) constitutes a theranostic revolution which is leading to rapid progress in the personalized management of this condition. CASE REPORT: We present the case of a patient with NSCLC harboring an activating mutation of the Epidermal Growth Factor Receptor (EGFR). After two years of treatment with a tyrosine kinase inhibitor (TKI), the development of a pleural effusion demonstrated that the NSCLC had progressed. The T790M mutation was identified in tumour cells from the pleural aspirate. This anomaly had not been observed in the initial lung biopsy sample. CONCLUSION: The genetic study of tumour cells contained in a biological fluid could be used to initiate molecular monitoring of the NSCLC tumour, without requiring repeated tissue biopsies and to customize the treatment in some patients with NSCLC.

[Postmarketing surveillance study on the use of topotecan in small-cell lung cancer. Use of topotecan in a pneumology university department]. / Étude post-autorisation de mise sur le marché sur le topotécan dans le cancer bronchique à petites cellules. Utilisation du topotécan dans un service de pneumologie universitaire.

BACKGROUND: Lung cancer is the leading cause of cancer related death in France and Europe. Small-cell lung carcinoma (SCLC) represents 15-20% of cases. International standards of care recommend the use of first-line chemotherapy, which has a high response rate. However, tumour recurrence occurs after a variable disease-free period. If the first-line treatment cannot be repeated during the relapse, intravenous topotecan may be used according to its market authorization (MA). METHODS: We report the first French postmarketing surveillance study on the use of topotecan in the SCLC. RESULTS: Between August 2005 to December 2009, 26 SCLC patients received at least one cycle of intravenous topotecan in our department. All patients were treated in accordance with MA. Seventeen patients received this treatment as second line, as in the MA study, while nine patients where treated beyond the second line. In the first group, we showed that the anti-tumour efficiency of topotecan is similar to that observed in the MA study (24% response) while grade 3 to 4 haematological toxicities were less frequent. In the second group of patients, who could not have been included in the MA study, the tumour response rate was equal to 11% without an increase in severe toxicity compared to the first group. Specific or overall survival was not different between the two groups. CONCLUSION: Our study provides original public health data on the target population, the anti-tumor efficiency and the toxicity of topotecan in the treatment of SCLC.

Multicenter observational study of erlotinib therapy (OBSTAR) for non small-cell lung cancer: a GFPC study.

CONTEXT: Erlotinib therapy for non small-cell lung cancer (NSCLC) has mainly been evaluated in randomized trials. METHOD: OBSTAR was a multicenter, retrospective, observational study involving all patients treated with erlotinib in 18 French centers between June 2005 and September 2007. The analyses focused on the patients' characteristics, previous treatments, and treatment efficacy during a three-year follow-up period. RESULTS: 534 patients were included in this study. The median survival times were respectively 5.2 [3.7-7.4] and 4.7 [4.1-5.7] months, depending to whether erlotinib was used as second- (n=190), or ≥ third-line treatment (n=305). The disease control rate were 39.1% [30.2-48.7] and 29.9% [29.6-36.9] according to the line of treatment. Factors predictive of an objective response were gender, age, and smoking status. Factors predictive of progression were age, sex, smoking status, the line of treatment, and the number of metastases. Treatment had to be interrupted for toxicity in 8.5% of cases. CONCLUSION: This study of erlotinib therapy in 2005-2007 confirms, in the general NSCLC patient population, the results of pivotal trials.

Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01).

BACKGROUND: Brain metastases (BM) occur in up to 40% of non-small-cell lung cancer (NSCLC) patients. This trial assessed the safety and efficacy of pemetrexed-cisplatin in this population. PATIENTS AND METHODS: Chemonaive NSCLC patients with BM ineligible for (radio)surgery, performance status (PS) of 0 to 2, were eligible for up to six cycles of cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) every 3 weeks. Whole -brain radiotherapy was given in case of disease progression or at chemotherapy completion. Primary end point was objective response rate (RR) on BM. Secondary end points included extracerebral and overall RR, safety profile and survival. RESULTS: Forty-three patients were enrolled. Initial characteristics were mean age 60.4 years; males 29; PS: 0 in 37.2%, 1 in 60.5% and 2 in 22.3% of patients; adenocarcinoma in 36 patients, large cell in 4 patients (nonsquamous, 93%) and squamous carcinoma in 3 patients. Functional classification of neurological status was stage I/II 86.0%, III 2.3% and IV 11.6%. Grade 3-4 hematological toxic effects were neutropenia, 11 patients (febrile neutropenia, 1 patient), and anemia, 6 patients. Non-hematological toxic effects were grade 2 urinary infection, one patient; grade 3 pneumonia, two patients; and grade 3 hypoacousia, one patient. Cerebral, extracerebral and overall RR by intent to treat analysis were 41.9%, 34.9% and 34.9%, respectively. Median survival time and time to progression were 7.4 and 4.0 months, respectively. CONCLUSION: Pemetrexed-cisplatin is an effective and well-tolerated regimen as first-line therapy for NSCLC patients with BM who always suffer a poor prognosis.

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

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

[Drug-induced pneumonitis in a patient treated with venlafaxine and propanolol]. / Pneumopathie médicamenteuse sous traitement par venlafaxine et propranolol.

INTRODUCTION: Venlafaxine and propranolol have rarely been identified as causes of pulmonary pathology. We describe a case of drug-induced pneumonitis occurring in a patient treated with these two medications. CASE REPORT: A 55 years old woman with liver cirrhosis treated with venlafaxine for 1 year and propranolol for 1 month was admitted to the intensive care unit because of acute respiratory failure. A Mycoplasma pneumoniae pneumonitis was diagnosed. After initial improvement under antibiotics, a new deterioration of respiratory status was observed 4 days after the reintroduction of venlafaxine and propranolol. Spontaneous recovery occurred after these treatments were withheld. Co administration of venlafaxine and propranolol, 2 drugs with affinity for the same cytochrome P450 isoenzyme (CYP2D6), may have contributed to drug accumulation and pulmonary toxicity. The liver cirrhosis of our patient may also have contributed to decreased cytochrome P450 enzymatic activity. CONCLUSIONS: Venlafaxine and propranolol share the same metabolic pathway and their co-administration may be complicated by drug induced pneumonitis.