Armelle Lavole

Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial.

BACKGROUND Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

Effect of highly active antiretroviral therapy on survival of HIV infected patients with non-small-cell lung cancer

OBJECTIVE To evaluate the impact of highly active antiretroviral therapy (HAART) on survival in HIV infected patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS All consecutive HIV infected patients with NSCLC diagnosed between 06/1996 and 03/2007 at two University hospitals in Paris (France) were prospectively followed until death. The association between survival and clinical and biological factors was analyzed by univariate and multivariate models. Survival analysis was performed by Kaplan-Meier estimates and the Cox proportional hazards regression model. RESULTS During the study period, NSCLC was diagnosed in 49 consecutive HIV infected patients (median age 46 years); 84% had advanced disease. Median survival was 8.1 months (range 5-10 months). In multivariate analysis, baseline parameters with significant positive impact on survival included performance status (PS) < or =1 (HR=0.2, 95%CI [0.09, 0.46], p=0.0001), stage I-II disease (HR=0.15, 95%CI [0.04, 0.53], p=0.003), and use of HAART (HR=0.4, 95%CI [0.2, 0.9], p=0.027). CONCLUSION HAART is a good prognostic factor for survival in HIV infected patients with NSCLC. Stage of disease and PS are two other valid survival prognostic factors.

High-resolution computed tomographic imaging of airways in sarcoidosis patients with airflow obstruction.

Objective: To investigate airway involvement in patients with pulmonary sarcoidosis and airflow obstruction (AO) using high-resolution computed tomography. Methods: Forty-two sarcoidosis patients with AO and 42 matched sarcoidosis patients without AO were retrospectively analyzed. High-resolution computed tomographic patterns of airway involvement were bronchial distortion, peribronchovascular thickening, small airway obstruction, and bronchial compression by enlarged lymph nodes. Results: Interobserver agreement was good (&kgr; > 0.8). High-resolution computed tomographic patterns of airway involvement were found more frequently, scored higher, and were more often multiple (P < 0.05) in patients with AO than those without. Functional improvement under treatment was observed more frequently in patients with predominant peribronchovascular thickening compared with patients with predominant bronchial distortion (P < 0.03). Conclusions: In pulmonary sarcoidosis patients with AO, high-resolution computed tomography is a reliable tool to identify underlying airways involvements, which are often multiple, and enables prediction of the therapeutic response.

Factors associated with long‐term survival of patients with advanced non‐small cell lung cancer

Background and objective:  Only a small proportion of patients with advanced non‐small cell lung cancer (NSCLC) have a life expectancy greater than 2 years. The aim of this study was to identify the factors associated with long‐term survival of patients with advanced NSCLC.

Neutrophils Promote Aerogenous Spread of Lung Adenocarcinoma with Bronchioloalveolar Carcinoma Features

Purpose: Adenocarcinoma with bronchioloalveolar carcinoma (BAC) features is a subtype of non–small cell lung cancers characterized by an intense inflammatory reaction composed of macrophages and neutrophils and by a distinct natural history with intrapulmonary spread leading to death due to respiratory failure. We hypothesized that neutrophils could promote aerogenous spread of lung adenocarcinoma with BAC features. Experimental Design: We examined the effect of neutrophils on A549 cell line detachment in vitro and we quantified desquamation of tumor cells on tumor tissue (n = 25) and on matched bronchioloalveolar lavage (n = 17) in vivo in a series of patients with adenocarcinoma with BAC features. Results: Neutrophils induced A549 detachment mediated by signals through cell-to-cell contact. Detached A549 cells were still viable and able to proliferate in vitro. Neutralization studies identified several membrane-bound molecules involved in detachment (i.e., intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, tumor necrosis factor α/tumor necrosis factor α receptor inhibitor, interleukin-1α /interleukin-1α receptor, and neutrophil elastase). In tumor tissue, shedding was detected in all samples, with a median shedding score of 42% (range, 4-95%). Micropapillary clusters were detected in 23 of the 25 tumor tissue samples, with a median micropapillary score of 1.40 (range, 0-2.1), and tumor cells were detected in 7 of 17 lavages. The micropapillary score was associated with a high neutrophil count in bronchioloalveolar lavage (P = 0.051). The shedding cell percentage was a significant factor in shorter survival (P = 0.034, univariate Cox analysis). Conclusions: Tumor shedding is induced by neutrophils. It is a significant factor of shorter survival and may be an important event in adenocarcinoma progression.

Blood vessel invasion is a major feature and a factor of poor prognosis in sarcomatoid carcinoma of the lung

OBJECTIVES Pulmonary sarcomatoid carcinomas (SC) are highly disseminated types of non-small-cell lung carcinoma. Their prognosis is poor. New therapeutic targets are needed to improve disease management. MATERIALS AND METHODS From 1995 to 2013, clinical and survival data from all consecutive patients with surgically treated SC were collected. Pathological and biomarker analyses were performed: TTF1, P63, c-MET and ALK expression (immunohistochemistry), PAS staining, ALK rearrangement (FISH), and EGFR, KRAS, HER2, BRAF, PIK3CA, and MET genes mutations (PCR). RESULTS Seventy-seven patients were included. Median age was 61 years (53-69). Histological subtypes were pleomorphic carcinoma (78%), carcinosarcoma (12%), and giant-cell and/or spindle-cell carcinoma (10%). Blood vessel invasion (BVI) was present in 90% of cases. Morphology and immunohistochemistry were indicative of an adenocarcinoma, squamous, and adenosquamous origin in 41.5%, 17% and 11.5%, respectively, 30% remained not-otherwise-specified. KRAS, PIK3CA, EGFR, and MET mutations were found in 31%, 8%, 3%, and 3%, respectively. No tumors had HER2 or BRAF mutations, or ALK rearrangement, whereas 34% had a c-MET positive score. Five-year overall survival (OS) was 29% for the whole population. At multivariate analysis, tumor size <50mm (HR=1.96 [1.04-3.73], p=0.011), no lymph-node metastasis (HR=3.25 [1.68-6.31], p<0.0001), no parietal pleural invasion (HR=1.16 [1.06-1.28], p=0.002), no BVI (HR=1.22 [1.06-1.40], p=0.005), and no squamous component (HR=3.17 [1.48-6.79], p=0.01) were associated with longer OS. Biomarkers did not influence OS. CONCLUSION Dedifferentiation in NSCLC could lead to SC and an epithelial subtype component could influence outcome. BVI was present in almost all SCs and was an independent factor of poor prognosis.

Skin Toxicities Compromise Prolonged Pemetrexed Treatment

Introduction: Pemetrexed is approved to treat non-small cell lung cancer and has an overall favorable toxicity profile. A case of pemetrexed-induced cutaneous adverse events (CAE), i.e., periorbital edema with conjunctivitis and edema of the limbs, leading to severe fluid retention, was diagnosed in our unit. The aim of this study was to evaluate the incidence and risk factors for CAEs. Methods: Patients treated with pemetrexed were identified from a prospective cohort. To detect pemetrexed-associated CAEs, questionnaires were answered by patients and the referring oncologist. Results: Included were 107 patients treated with four cycles or more of pemetrexed. Pemetrexed-induced CAEs were observed in 37 of 107 (35%) total patients (TPs) and 25 of 47 (53%) alive patients (APs). Conjunctivitis was the most frequent CAE: 27 of 107 (25%) in TPs and 21 of 47 (44%) in APs. Periorbital edema occurred in 16 of 107 (15%) TPs and 14 of 47 (30%) APs. Limb edema was present in 14 of 107 (13%) TPs and 12 of 47 (25%) APs. Only two cases of CAE influenced pemetrexed treatment. No significant differences in age, body surface area, smoking status, and performance status were detected. Patients with CAE had more cycles of pemetrexed (7 versus 5.5; p = 0.028). In univariate and multivariate analyses, gender ratio was statistically different (p = 0.031): 48% (12/25) of women in the CAE group versus only 18% (4/18) in the control group. Conclusion: Pemetrexed induces frequent conjunctivitis, peripheral edema, and edema of the limbs. Female gender seems to be an independent risk for CAE. CAEs are frequently disabling and symptomatic treatment should be proposed.

Changes in the Pattern of Respiratory Diseases Necessitating Hospitalization of HIV-infectedPatients Since the Advent of Highly Active Antiretroviral Therapy

The incidence rates of opportunistic diseases, hospital admission and death have fallen markedly since the advent of highly active antiretroviral therapy (HAART). We examined the impact of HAART on the pattern of HIV-related respiratory diseases necessitating hospitalization. We retrospectively compared the numbers and etiologies of respiratory diseases diagnosed in HIV-infected patients hospitalized in the chest department of a Paris university hospital during the three years preceding widespread prescription of HAART in France (era 1, starting in July 1993) and the first three years of widespread HAART prescription (era 2, starting in July 1996). Respectively, 207 and 119 HIV-infected patients were admitted for respiratory disease in era 1 and era 2. Only 31.1% of patients admitted during era 2 were receiving HAART. Pulmonary opportunistic infections other than Pneumocystis carinii pneumonia (PCP) (p = 0.0008) and exacerbations of chronic bronchial disease due to gram-negative bacilli (p = 0.04) virtually disappeared in era 2. In contrast, PCP, bacterial pneumonia, tuberculosis, pulmonary Kaposi’s sarcoma and pulmonary non-Hodgkin lymphoma showed only a twofold decrease in era 2, while lung cancer was more frequent (p = 0.004). The frequency of severe respiratory diseases necessitating hospitalization of HIV-infected patients has fallen since the advent of HAART, and their etiologic distribution has changed.

Trends in survival after cancer diagnosis among HIV-infected individuals between 1992 and 2009. Results from the FHDH-ANRS CO4 cohort

Although the decline in cancer mortality rates with the advent of combination antiretroviral therapy (cART) in HIV‐infected individuals can be mostly explained by a decrease in cancers incidence, we looked here if improved survival after cancer diagnosis could also contribute to this decline. Survival trends were analyzed for most frequent cancers in the HIV‐infected population followed in the French Hospital Database on HIV: 979 and 2,760 cases of visceral and non‐visceral Kaposis sarcoma (KS), 2,339 and 461 cases of non‐Hodgkin lymphoma (NHL) and Hodgkins lymphoma (HL), 446 lung, 312 liver and 257 anal cancers. Five‐year Kaplan–Meier survival rates were estimated for four periods: 1992–1996, 1997–2000, 2001–2004 and 2005–2009. Cox proportional hazard models were used to compare survival across the periods, after adjustment for confounding factors. For 2001–2004, survival was compared to the general population after standardization on age and sex. Between the pre‐cART (1992–1996) and early‐cART (1997–2000) periods, survival improved after KS, NHL, HL and anal cancer and remained stable after lung and liver cancers. During the cART era, 5‐year survival improved after visceral and non‐visceral KS, NHL, HL and liver cancer, being 83, 92, 65, 87 and 19% in 2005–2009, respectively, and remained stable after lung and anal cancers, being 16 and 65%, respectively. Compared with the general population, survival in HIV‐infected individuals in 2001–2004 was poorer for hematological malignancies and similar for solid tumors. For hematological malignancies, survival continues to improve after 2004, suggesting that the gap between the HIV‐infected and general populations will close in the future.

Infections aspergillaires broncho-pulmonaires du sujet non immunodéprimé

Resume La definition des infections aspergillaires broncho-pulmonaires chez les patients non immunodeprimes reste vague et de nombreuses entites cliniques, radiologiques et anatomo-pathologiques ont ete decrites avec une varietes de denominations, i.e. aspergillome simple, aspergillome complexe, aspergillose semi-invasive, aspergillose pulmonaire chronique necrosante, aspergillose chronique cavitaire, fibrosante ou pleurale, tracheobronchite aspergillaire pseudo-membraneuse et aspergillose invasive. Neanmoins, ces entites partagent des caracteristiques communes, suggerant qu’elles appartiennent au meme groupe d’infections aspergillaires : 1- alteration locale ou systemique des defenses anti-infectieuses (alcool, tabac, diabete) ; 2- maladie broncho-pulmonaire sous-jacente responsable ou non de cavites pleurales ou broncho-pulmonaires residuelles (tuberculose active ou sequelles tuberculeuses, dilatation des bronches, sarcoidose, BPCO) ; 3 utilisation frequente d’une corticotherapie prolongee orale ou systemique a faible dose ; 4- absence de ou faible invasion vasculaire, presence d’une reaction granulomateuse et faible tendance metastatique. A l’exception de l’aspergillose invasive, il n’y a pas de recommandations sur le traitement des infections aspergillaires broncho-pulmonaires du patient non immunodeprime. L’embolisation bronchique peut stopper une hemoptysie dans certains cas. La chirurgie qui s’accompagne d’une morbi-mortalite elevee, est generalement impossible du fait de l’alteration de la fonction respiratoire ou de la severite des co-morbidites. Beaucoup de cas cliniques ou de petites etudes retrospectives ont rapporte l’efficacite de nombreux agents anti-fongiques. Les triazoles per os, i.e. l’itraconazole et, en particulier, le voriconazole apparaissent appropries pour le traitement des infections aspergillaires broncho-pulmonaires du patient non immuno-deprime.