Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial.

BACKGROUND: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). PATIENTS AND METHODS: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. RESULTS: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. CONCLUSIONS: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. CLINICAL TRIAL NUMBER: NCT02034981.

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.

EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib improves survival of lung cancer as second- or third-line therapy. However, after an initial response, most patients will recur, particularly within the central nervous system. The present study reports the case of a 27-yr-old nonsmoking male presenting with a metastatic lung adenocarcinoma with EGFR exon 19 deletion, associated with sensitivity to EGFR-TKI. Gefitinib, followed by chemotherapy and finally erlotinib resulted in prolonged disease control, until multiple liver metastases were detected. After stopping EGFR-TKI, brain metastases with carcinomatous meningitis were diagnosed. A secondary T790M mutation, associated with resistance to EGFR-TKI, was found on the liver biopsy but not in the cerebrospinal fluid. Erlotinib was reintroduced and allowed a quick neurological improvement, even though the extra-cranial disease remained resistant to erlotinib. The present report underscores the interest of molecular monitoring in lung cancer. Persistent cerebral tyrosine kinase inhibitor sensitivity should be considered in patients presenting with an early central nervous system relapse after stopping epidermal growth factor receptor tyrosine kinase inhibitor, even with a T790M-resistant mutation in noncerebral metastases. Questions remain concerning the selection of sub-clones during epidermal growth factor receptor tyrosine kinase inhibitor therapy, which could differ according to metastatic sites, especially in the central nervous system.

[Thyroid metastasis of lung cancer and abnormal thyroid function--a case report]. / Métastase thyroïdienne d'un cancer bronchique et dysthyroïdie--à propos d'un cas.

The thyroid gland is a very rare location of metastasis and the metastatic involvement of the thyroid is mostly asymptomatic. The authors report one of the first cases of pulmonary adenocarcinoma associated with painful metastatic involvement of the thyroid gland. Temporary hyperthyroidism was noted, followed, two months later, by clinically and biologically proven hypothyroidism with positive antithyroglobulin antibodies. The suspect goiter was detected by diffuse hyperfixation on 18-FDG PET Scan and the ultrasonography revealed two hypoechogenic nodules. The fine needle biopsy confirmed the metastatic origin of these nodules. The evolution after five cycles of chemotherapy by cisplatine and docetaxel was marked by a complete regression of the thyroid metastasis and an improvement in the thyroid function.

[First-line treatment with pemetrexed in association with cisplatin in patients with non-operable malignant pleural mesothelioma]. / Association pemetrexed-cisplatine en première ligne dans le mésothéliome pleural malin non opérable.

Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. The optimal treatment of MPM was not clearly defined, until the publication of the multicentre, controlled and randomized phase III trial by Vogelzang et al. in 2003, which made the pemetrexed-cisplatin association the gold standard for the non-operable stages. Eleven patients with histologically proven pleural mesothelioma, not candidates for curative surgery, were assessed for eligibility and treated in our hospital. The response rate was similar to the reference study and the toxicity was acceptable. The median survival time was 12.7 months with an objective response rate of 45.5%. The median time to progression was 7.7 months. Neutropenia (all grades included) was the most common haematological toxicity (42.1%) although only one grade 3/4 was noted. Grade 3/4 anaemia and thrombocytopenia were not reported. Nausea and vomiting were the most commonly reported clinical toxicities with 81.8% reported (all grades included). One cutaneous allergic reaction was reported. The combination of pemetrexed and cisplatin chemotherapy provided the best objectives responses, but new therapeutic regimens are still warranted for these patients with a poor prognosis. The results were similar to those obtained in the Vogelzang et al.'s trial despite a selection bias because they correspond to 36.7% of the total recruitment in the unit.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer.

BACKGROUND: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. PATIENTS AND METHODS: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m(2), day 1) and vinorelbine (25 mg/m(2) on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m(2), followed by 250 mg/m(2) weekly thereafter). RESULTS: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. CONCLUSION: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.

[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.

[The actual place of anti-angiogenesis in non-small cell lung cancer]. / Place actuelle des anti-angiogéniques dans le traitement des cancers bronchiques primitifs.

Since the early 90's, it seems that chemotherapy given alone in non-small cell lung cancer had reached a plateau. Many different pathways have been targeted, with or without chemotherapy, trying to improve the treatment efficacy. Angiogenesis plays an important role in the process of the tumour growth and in metastasis dissemination. Two main ways have been developed to block either directly the most important growth factor (vascular endothelial growth factor) using a humanized monoclonal antibody, or its receptors (using low-molecular-weight anti tyrosine kinases). Some of them are currently available in colorectal cancers or renal cell cancer. Many phase II or III trials have been published in non small cell lung cancer in the last years.

[Disseminated intravascular coagulation syndrome and thromboembolic complications of non-small-cell lung cancer. A case report]. / Coagulation intravasculaire disséminée et complications thromboemboliques dans le cancer bronchique non à petites cellules. A propos d'une observation.

Hemostatic disorders can be found in approximately 90% of cancer patients, but clinical expression in only 15%. Hemorrhagic complications are more frequent in acute leukaemia; solid tumors are often associated with deep venous thromboses (DVP). Disseminated intravascular coagulation syndrome (DICS) can be latent or acute, and has various clinical presentations, occurring in the course of many serious conditions including cancer. Patients have higher morbidity and mortality. Irrespective of the etiology, DICS can be revealed by a wide variety of clinical manifestations, from mild biological hemostasis disorders, to intravascular or extravascular microthromboses or lethal hemorrhagic events. We report the case of a 45-year-old female with non-small-cell lung cancer with metastases at diagnosis. The patient developed and finally died of numberous thromboembolic events subsequent to DICS. This case illustrates some rather rare complications of DICS and offers the opportunity to discuss the main therapeutic goal in this situation, i.e. to modulate the disproportionate production of thrombin, inducing thromboses and/or hemorrhages by consumption of the cellular and plasmatic coagulation factors. This means a symptomatic and mostly etiologic treatment, especially chemotherapy which can in itself provoke thromboembolic events.

[Pituitary metastases from lung cancer. Five cases]. / Métastases hypophysaires de cancers bronchiques. A propos de 5 cas.

Pituitary metastases are rare and generally asymptomatic. We studied 5 patients with pituitary metastases from lung cancer, illustrating the different clinical features. These metastases were in these cases symptomatic with the manifestation being diabetes insipidus or visual field defect. Histological subtypes from our five patients were as well small cell or non small cell lung cancer. After diagnosis of pituitary metastasis, prognosis seems to be linked to the histological subtype and the stage of lung cancer, rather than to the presence of such metastases.

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. / Réponse prolongée sous paclitaxel après immunothérapie par pembrolizumab dans le cancer bronchique.

INTRODUCTION: Pembrolizumab, a humanized monoclonal antibody IgG4 anti-PD-1, having offered promising results in patients suffering from non-small cell lung cancer metastatic and heavily pretreated. OBSERVATION: We report here the case of an unexpected good response after pembrolizumab failure obtained with paclitaxel in a 68-year-old patient with stage IV lung adenocarcinoma. Moreover, the response duration with paclitaxel was more than fourteen months. CONCLUSION: Our case suggests a mutual potentiation of chemotherapy and immunotherapy, and raises the issue of the treatment sequence to favor.

[Lung cancer in women]. / Le cancer bronchique chez la femme.

BACKGROUND: Since the end of the 1980's, there has been a significant increase in the incidence of lung cancer in women in France. This is largely due to an increase in women smoking since the end of the nineteen-sixties, some 20 years later than occurred in North America. STATE OF THE ART: Since 1995 lung cancer has been the third most common malignant cause of death in French women having become the most common in The United States in 1987. The epidemiology of the disease in women is different, with tobacco smoking explaining only 70% of the incidence. Moreover, even if smoking is the primary cause of lung cancer, the reported duration and amount smoked is generally speaking lower than in men with equivalent disease. Other risk factors such as higher expression of the gastrin-releasing peptide (GRP) receptor, hormonal factors, radon and passive smoking may also play a role. The distribution of histological types is also different in women, with a predominance of adenocarcinomas. Finally, prognosis appears to be better in women. PERSPECTIVES: Targeted therapies have introduced another gender distinction since women are more likely to respond to gefitinib and erlotinib than men. CONCLUSION: The massive increase in lung cancer in women is the most important epidemiological feature of recent years. Due to some differences in risk factors, histology distribution, prognosis and therapeutic response, specific studies devoted to female patients especially non-smokers are needed.

[Lung cancer in elderly patients]. / Le cancer bronchique chez le sujet âgé

Lung cancer occurring in elderly patients is an increasingly frequent clinical problem both because of an aging population and the general increase in incidence of the disease. The management of lung cancer in the elderly represents therefore a significant public health problem. The full range of therapeutic modalities may be used in these patients provided a comprehensive geriatric assessment is made, not limited to performance status assessment, but also taking into account comorbidities, which are frequent in elderly people, and functional capacities. Elderly patients are often managed in a sub-optimal fashion. With appropriate, equal treatment their prognosis is equivalent to that of younger patients.

[Duplication of the superior vena cava and other malformations discovered at insertion of a port-a-cath]. / Cathéter de chambre implantable: un curieux trajet.

We report a clinical case of a persistent left superior vena cava discovered in a 50-year-old female patient when a port-a-cath was inserted. This already seldom malformation was associated with an arteria lusoria and polysplenia with left inferior vena cava with hemiazygos continuation, right-sided stomach, short pancreas, preduodenal portal vein and intestinal malrotation, but without any cardiac abnormalities.

Concurrent cisplatin/etoposide chemotherapy plus twice daily thoracic radiotherapy in limited stage small cell lung cancer: a phase II study.

Thirty-one previously untreated patients with limited stage small-cell lung cancer (LSCLC) were included in a prospective study, to investigate the feasability and the efficacy of a combined modality treatment using concurrent hyperfractionated chest irradiation and cisplatin (P) plus etoposide (E) chemotherapy. All patients received intravenously P=75 mg/m(2) at day 1, plus E=120 mg/m(2) days 1-3, at 3-week intervals for six cycles. Irradiated patients received 45 Gy in two daily fractions, 5 days a week, from week 4 to week 6. During week 5, prophylactic cranial irradiation was initiated, in one daily fraction of 2.5 Gy for a total dose of 25 Gy. Twenty-nine patients were evaluable for response. Twenty-two (76%) achieved a complete response, five (17%) had a partial response. Five patients are currently alive. The overall response rate was 93% (CI 95% (83.7-100)). The median survival time was 14 months and the 2-year survival rate was 25%. Main toxicities were grade 3-4 esophagitis in half of the patients and myelosuppression. The results are not as optimistic as other studies using a similar regimen.

[Acute pleuro-pneumonitis resulting from leptospirosis]. / Une pleuro-pneumopathie sévère révélant une leptospirose.

We report a case of acute pneumonitis with pleural effusion and respiratory distress syndrome that was the inaugural sign of leptospirosis in a 37-year-old patient exposed to rat dejections at home. The patient was given penicillin and oxygen therapy with evacuation of the pleural effusion. Lung manifestations in leptospirosis usually occur as non-specific cough and hemoptysis. Pleural effusion is uncommon. Adult respiratory distress syndrome and profuse hemoptysis can also occur, requiring special care.

[Late manifestation of common variable immunodeficiency by Biermer's disease]. / Hypogammaglobulinémie commune variable révélée tardivement par une maladie de Biermer.

BACKGROUND: Common variable immunodeficiency (CVI) is a heterogeneous disorder characterized by decreased production of antibodies. Clinical presentation of CVI is generally that of recurrent pyogenic infections. Autoimmune diseases can also occur. The age of onset of symptoms shows two peaks at 1-5 and 16-20 years. CASE REPORT: A 77-year-old man was admitted in hospital for pernicious anemia. We discovered hypogammaglobulinemia with low levels of immunoglobulin G, A and M, but normal T-cell levels. We diagnosed common variable immunodeficiency. This patient had not had recurrent pyogenic infections. DISCUSSION: This case shows that common variable immunodeficiency can be revealed late by an autoimmune disease. The pathogenesis of autoimmune diseases in this immunodeficiency remains unknown despite several possible explanations.

[Lung cancer and pollution]. / Cancer du poumon et pollution.

Active smoking remains the main cause of lung cancer. However, one must not neglect the role of occupational exposure, mainly in males and also the role of pollution. In non-smoking females of countries like China, pollution due to the use of charcoal for cooking may represent the main cause for lung cancer. Outside pollution is mainly due to combustion of fossil fuels and to diesel exhaust. Inside pollution is mainly due to environmental tobacco exposure and radon in western countries whereas in developing countries it is mainly due to cooking methods.

[Paraneoplastic Cushing's syndrome and small cell bronchial carcinoma]. / Syndrome de Cushing paranéoplasique et carcinome bronchique à petites cellules.

Approximately 30% of small-cell bronchogenic cancers are associated with hypersecretion of ACTH. However, in most cases, there is no clinical expression. When a paraneoplastic Cushing syndrome occurs, it is an independent factor of poor prognosis. Management is extremely complex. Treatment must be based on high dose inhibitors prior to chemotherapy. Opportunistic infections, often fungal infections, are the main complications, even outside periods of aplasia, and cause significantly earlier mortality.

[Coagulation disorders and arterial thromboembolic events in non-small-cell lung cancer. A case report]. / Anomalies de la coagulation et événements thromboemboliques artériels dans le cancer bronchique non à petites cellules. A propos d'une observation.

Certain coagulation disorders can occur in patients with cancer and thromboembolic complications are frequent. We report the case of a 53-Year-old patient with metastatic adenocarcinoma of the lung treated with chemotherapy who presented several cerebral arterial thromboembolic events leading to death a few weeks after the initial diagnosis of cancer. This case illustrates the important role of certain satellite disorders related to coagulation activation: non-bacterial thrombotic endocarditis, disseminated intravascular coagulation, anti-phospholipid antibody syndrome. The role of anticancer chemotherapy as a favoring factor for thromboembolic events is also emphasized in patients with non-small-cell lung cancer.