V. Gounant

Randomized phase II trial of gefitinib or gemcitabine or docetaxel chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2 or 3 (IFCT-0301 study)

BACKGROUND To compare 3 treatment strategies in chemotherapy naive patients with advanced NSCLC and a PS 2-3. PATIENTS AND METHODS Patients were assigned to gefitinib 250mg daily (n=43) or to gemcitabine (1250mg/m(2) d 1, 8 q 21d) (n=42) or docetaxel (75mg/m(2) d 1 q 21d) (n=42). Treatments were taken until progression or toxicity. The primary endpoint was progression-free survival. Secondary end points were response and overall survival. RESULTS Disease control rates were 20.9%, 33.4% and 38.1%, respectively. Median PFS was 1.9 months in the gefitinib arm, 2.0 months in the gemcitabine arm and 2.0 months in the docetaxel arm (HR gemcitabine versus gefitinib: 0.74, 95%CI: [0.48; 1.16], HR docetaxel versus gefitinib: 0.67, 95%CI: [0.43; 1.05]). Median survival times were 2.2, 2.4 and 3.5 months, respectively (HR gemcitabine versus gefitinib: 0.76, 95%CI: [0.48; 1.20], HR docetaxel versus gefitinib: 0.69, 95%CI: [0.44; 1.09]). There were more grade 3-4 adverse events in the docetaxel arm when compared with either the gefitinib arm or the gemcitabine arm. CONCLUSION In unselected NSCLC patients with PS 2-3, gefitinib, gemcitabine and docetaxel achieved similar results. Docetaxel was associated with higher rates of adverse events.

Crizotinib Associated with Ground-Glass Opacity Predominant Pattern Interstitial Lung Disease: A Retrospective Observational Cohort Study with a Systematic Literature Review

Background: Crizotinib, an oral tyrosine kinase inhibitor that targets anaplastic lymphoma kinase, has proven to offer sustained progression-free survival in anaplastic lymphoma kinase–rearranged non–small-cell lung cancers. Occurrence of severe interstitial lung disease (ILD) was one of the crucial adverse events reported in randomized clinical trials and case reports. Methods: In September 2011, we observed a crizotinib-associated ILD case. Following this index case, we reviewed the clinical and computed tomographic scan features of all patients treated with crizotinib in our department, between October 2010 and July 2013, comparing patients with and without ILD. A systematic literature review was performed. Results: During this period, 29 patients were treated with crizotinib, five of whom developed ILD, in addition to the index case. Two types of adverse lung reactions may be observed in patients undergoing crizotinib therapy. The first is a severe, usually fatal, ILD that occurs during the first month of treatment (n = 1). The second is a less severe ILD, occurring later in time (n = 5). It occurs gradually with only few clinical symptoms, but predominant ground-glass opacities on computed tomography, along with an intensive lymphocytic alveolitis in bronchoalveolar lavage fluid. These cases had a longer response with a median progression-free survival duration at 19.9 months (17.9–23.5) compared with 6.2 months (1.2–13.6) for controls (p = 0.04). Conclusion: Forty-nine cases of crizotinib-associated ILD have been identified by the systematic review of the literature, including our six cases. Two types of adverse lung reactions may be observed with different presentation, prognosis, and treatment. Their potential mechanisms should be clarified. Nine patients with the less severe form of ILD were safely retreated.

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.

Nebulised liposomal amphotericin B for Aspergillus lung diseases: case series and literature review

Over the past 10 years the incidence of Aspergillus spp. has significantly increased, and it is now the most widespread air transmission fungal pathogen in developed countries. Whatever the clinical expression of the pulmonary disease and despite recent progress in antifungal drug therapy, morbidity and mortality related to aspergillosis lung disease still constitute a serious threat for immunosuppressed or mildly immunocompromised patients. Moreover, the treatments currently used have many limitations due to adverse effects and drug interactions. Finally, subjects exposed to azoles present an increased risk of Aspergillus‐resistant strain emergence. We have reported five cases with aspergillosis lung diseases that were either difficult to control or in which patients had a contra‐indication to triazole therapy, but which showed durable improvement following the administration of nebulised liposomal amphotericin B. Our alternative strategy could be of interest for patients with aspergillosis lung disease who otherwise cannot be conventionally treated by triazoles.

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.

Amélioration du pronostic des cancers bronchiques non à petites cellules : mythe ou réalité ?

Resume Un certain nombre d’arguments conduisent a penser que le pronostic des cancers bronchiques non a petites cellules a pu s’ameliorer pendant ces vingt dernieres annees. La comparaison des etudes historiques menees pendant des periodes differentes met en evidence un gain de survie mais expose a de nombreux biais lies a la selection des malades et a l’effet Will Rogers. Les etudes prospectives randomisees demontrent un certain nombre de progres : la chimiotherapie peri-operatoire dans les stades operables, la radio-chimiotherapie concomitante dans les IIIB, les drogues recentes dans les stades IV ameliorent le pronostic. Pourtant, l’analyse des registres jusqu’a 1997 n’objective pas d’amelioration significative de la survie. Cette discordance pourrait s’expliquer par les differences entre la population generale (stade avance, PS eleve) et la population selectionnee par les essais therapeutiques. De plus, les conclusions de ces essais ne sont pas toujours appliquees. Enfin, les progres les plus importants sont posterieurs a 1997. En conclusion, le pronostic des cancers bronchiques non a petites cellules s’est ameliore dans une population selectionnee de malades. Pour esperer retrouver cette amelioration dans la population generale, il faut que celle-ci soit traitee selon les recommandations issues de ces essais.

EGFR and KRAS mutation status in non-small-cell lung cancer occurring in HIV-infected patients

Non-small-cell lung cancer (NSCLC) is the most common non-acquired immune deficiency syndrome-related malignancy responsible for death. Mutational status is crucial for choosing treatment of advanced NSCLC, yet no data is available on the frequency of epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) mutations and their impact on NSCLC in human immunodeficiency virus (HIV)-infected patients (HIV-NSCLC). All consecutive HIV-NSCLC patients diagnosed between June 1996 and August 2013 at two Paris university hospitals were reviewed, with tumor samples analyzed for EGFR and KRAS mutational status. Overall, 63 tumor samples were analyzed out of 73 HIV-NSCLC cases, with 63% of advanced NSCLC. There were 60 non-squamous and nine squamous cell carcinomas, with EGFR and KRAS mutations identified in two (3.3%) and seven (11.5%) tumors, respectively. The proportion of KRAS mutations was 29% if solely the more sensitive molecular techniques were considered. The two patients with advanced adenocarcinoma harboring EGFR mutations exhibited lasting partial response to EGFR-tyrosine kinase inhibitors. Overall survival for patients with advanced NSCLC were >30 months for those with EGFR mutations, <3 months for KRAS mutations (n=2), and the median was 9 months [4.1-14.3] for wild-type (n=34). In multivariate analysis, KRAS mutation and CD4<200 cells/μL were associated with poor prognosis (hazard ratio (HR): 24 [4.1-140.2], p=0.0004; HR: 3.1 [1.3-7.5], p=0.01, respectively). EGFR mutation must be investigated in HIV-NSCLC cases due to its predictive and prognostic impact, whereas KRAS mutation is of poor prognostic value. Clinicians should search for drugs dedicated to this target population.

Association d'un lymphome thymique de type MALT et d'un syndrome de Gougerot-Sjögren.

INTRODUCTION Thymic mucosa-associated lymphoid tissue (MALT) lymphoma is a rare pathology, often associated with autoimmune diseases. The authors report the case of an Asian woman with Sjögrens syndrome. OBSERVATION A 48-year-old Chinese woman, without past medical history and a non-smoker, presented an alteration in her overall condition, dyspnoea at exercise, inflammatory polyarthralgia, and a dry eye and mouth syndrome over the last few months. Thoracic tomodensitometry detected an anterior heterogenic cystic mediastinal mass. A mediastinotomy was performed. The diagnosis of the surgical biopsy was thymic MALT lymphoma. The authors also diagnosed Sjögrens syndrome with the presence of four diagnostic criteria. Chemotherapy by rituximab, cyclophosphamide, vincristine, prednisone induced major tumoral regression. The patient declined surgery and will be monitored. CONCLUSION Thymic MALT lymphoma is a rare pathology. There is a high correlation with autoimmune diseases, like Sjögrens syndrome. Its appearance is that of an anterior mediastinal mass with a cystic component. The treatment is not well codified and is most often based on surgical resection, eventually followed by chemotherapy or radiotherapy. As far as the authors know, this is the second case of thymic MALT lymphoma treated by exclusive chemotherapy.

Le carcinome bronchiolo-alvéolaire

Resume Le carcinome bronchioloalveolaire est l’un des quatre sous-types histologiques des adenocarcinomes broncho-pulmonaires primitifs. Son incidence est en augmentation. Sa definition histologique tricte et restrictive necessite une exerese pulmonaire chirurgicale complete afin d’exclure tout signe d’invasion. Cette definition n’est applicable qu’aux formes nodulaires isolees operees. Le bilan d’extension pour rechercher la multiplicite des lesions necessite une tomodensitometrie en haute resolution afin de detecter des surdensites en verre depoli qui peuvent en etre un des premiers signes. La prise en charge therapeutique est globalement identique a celle des cancers non a petites cellules. Les formes nodulaires ou pneumoniques uniques traitees chirurgicalement sont de bon pronostic. Les formes nodulaires multiples sont parfois chirurgicales, alors que les formes pneumoniques multiples ou diffuses sont non chirurgicales et ont une mediocre sensibilite a la chimiotherapie et un pronostic sombre. Neanmoins, la decouverte recente de la sensibilite particuliere des carcinomes bronchioloalveolaires aux inhibiteurs des recepteurs a activite tyrosine kinase de l’EGF (Epidermal Growth Factor) ouvre de nouvelles perspectives de prise en charge therapeutique.

Mutation de l’EGFR, de l’étude du gène à la pratique clinique : exemplarité ou exception ?

Resume La decouverte des mutations de l’EGFR a l’occasion du developpement des inhibiteurs de tyrosine kinase de l’EGFR (ITK-EGFR) a revolutionne la prise en charge therapeutique des cancers bronchiques non a petites cellules metastatiques. En effet, cette decouverte a fait emerger le concept d’addiction oncogenique et a permis, par des methodes tres diverses, de decouvrir d’autres anomalies moleculaires cibles de nouvelles therapeutiques. Il peut s’agir comme pour l’EGFR de mutations sur d’autres recepteurs transmembranaires a tyrosine kinase (HER2, DDR2), mais aussi de kinases intracytoplasmiques (PI3K, BRaf). Il peut s’agir d’autres mecanismes comme les rearrangements (ALK, ROS1, RET) et les amplifications geniques (c-met, FGFR). Ces anomalies peuvent etre recherchees sur les plates-formes de l’INCa et permettre l’acces a de nouveaux traitements comme le crizotinib ou a des molecules utilisees dans d’autres pathologies ou en cours de developpement auxquels les malades peuvent acceder par des essais therapeutiques. Cette revue a pour objectif de mettre en avant les similarites et les differences entre l’EGFR et les autres addictions oncogeniques tant sur le plan moleculaire, de la demarche diagnostique ou de la prise en charge therapeutique.