Christelle Clément-Duchêne

Bevacizumab in Patients with Nonsquamous Non–Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study

Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-naïve or pretreated patients with non–small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup. Experimental Design: Patients with stage IV nonsquamous NSCLC, Eastern Cooperative Oncology Group performance status 0–1, and untreated, asymptomatic brain metastases received first-line bevacizumab (15 mg/kg) plus carboplatin (area under the curve ×6) and paclitaxel (200 mg/m2) every 3 weeks (B + CP), or second-line bevacizumab plus erlotinib (150 mg/d; B + E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B + CP) or more than two (B + E) intracranial hemorrhages. Results: In first-line B + CP cohort (n = 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (CI), 5.7–7.1] and median overall survival (OS) of 16.0 months. Investigator-assessed overall response rate (ORR) was 62.7%: 61.2% in intracranial lesions and 64.2% in extracranial lesions. Because of low enrolment (n = 24), efficacy results for the second-line B + E cohort were exploratory only; 6-month PFS rate was 57.2%, median PFS was 6.3 months (95% CI, 3.0–8.4), median OS was 12.0 months, and ORR was 12.5%. Adverse events were comparable with previous trials of bevacizumab. One grade 1 intracranial hemorrhage occurred and resolved without sequelae. Conclusions: The BRAIN study demonstrates encouraging efficacy and acceptable safety of bevacizumab with first-line paclitaxel and carboplatin in patients with NSCLC and asymptomatic, untreated brain metastases. Clin Cancer Res; 21(8); 1896–903. ©2015 AACR.

Characteristics of never smoker lung cancer including environmental and occupational risk factors.

INTRODUCTION Clinical characteristics and risk factors of nonsmoker patients with lung cancer are still debated. AIM AND METHODS The aim of this work is to describe the characteristics of never smoker patients with lung cancer, focusing on occupational and environmental exposures, Data collected were: age, gender, histological types, methods of diagnosis, TNM staging, smoking, and occupational data. Statistical analysis included descriptive analyses, Pearsons chi-square or nonparametric tests, and logistic regressions. RESULTS All lung cancers diagnosed between January 1, 1997 and December 31, 2006, representing 1493 cases were included. Lung adenocarcinoma (ADC) [Odds Ratio (OR)=2.5 (1.5-4.3), p<0.0001] as well as clinical stage I cases at diagnosis [OR=2.4 (1.3-4.3)] were most frequent in nonsmokers relative to ever smokers. Comparison of clinical features among male and female nonsmoker patients did not reveal significant differences. Conversely, strong differences appeared when comparing environmental tobacco smoke (ETS) and occupational exposures in nonsmoker women vs men: ETS exposure (78.6% nonsmoker women vs 21.4% nonsmoker men, p<0.0001), occupational exposure (9.4% vs 48.6%, p<0.0005). Noteworthy, a sizeable number of nonsmoker male (40.0%), and nonsmoker female (31.2%) patients had no known exposure to major lung carcinogens. CONCLUSIONS Main risk factors (ETS and occupational exposure) may only explain some cases.

Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): A phase II trial

The synergistic activity of pemetrexed with platinum agents in non-small cell lung cancer (NSCLC) and the renal safety of carboplatin suggest a balanced benefit/risk profile for this combination in elderly patients. This multicenter, single-arm, phase II study included 62 patients (≥70 years) with chemonaïve advanced NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and assigned to receive 6 cycles of 3-weekly pemetrexed 500 mg/m(2) and carboplatin AUC 5. The primary endpoint was objective tumor response rate (ORR). Sixty-two patients received at least one dose of chemotherapy. Median age was 76.4 years [70.2-86] and all patients had PS 0 (16.1%) or PS 1 (83.9%). Stage IIIb disease in 21% patients and stage IV in 79% patients. Non-squamous cell carcinoma in 66.1% patients (adenocarcinoma 51.6%, large cell carcinoma 8.1%, other 6.5%) and squamous cell carcinoma in 33.9% patients. ORR was 28.6% (95% confidence interval [CI], 16.58-43.26), all were partial responses. Stable disease rate was 42.9%. Grade 3/4 toxicities related to study drugs were: asthenia 16.1%, anorexia 4.8%, diarrhea 3.2%, neutropenia 51.6%, leucopenia 30.7%, thrombocytopenia 29%, anemia 19.4%. One related fatal septic shock occurred. In advanced NSCLC, pemetrexed use is restricted to non-squamous histology. The combination pemetrexed-carboplatin could be a valuable treatment option in elderly patients. Neutropenia was the most common toxicity. The ORR is within the range of data reported for pemetrexed-carboplatin in the general NSCLC population (24-31%).

Relationships between lung adenocarcinoma and gender, age, smoking and occupational risk factors: A case–case study

BACKGROUND The hypothesis that some risk factors for lung cancer may have more specific associations with particular histologic types remains controversial. The aim of this study was to investigate possible associations between adenocarcinoma and gender, age, smoking characteristics and selected occupational carcinogens in relation to other histologic types. METHODS This study included all histologically confirmed lung cancer cases diagnosed consecutively in two French University hospitals from 1997 to 2006. All medical data were obtained by face-to-face patient interviews. Occupational carcinogen exposures of each patient were assessed by an industrial hygienist. Relationships between risk factors and adenocarcinoma were analyzed by case-case comparisons using unconditional logistic regressions (ULRs). RESULTS A total of 1493 subjects were enrolled in this study, comprising 1303 men (87.3%), 67 nonsmokers (4.5%) and 489 adenocarcinomas (32.7%). Using ULR, no associations were observed between adenocarcinoma and age, gender or smoking characteristics except for a negative relationship with smoking duration (p<0.0001). Significant associations were observed between ADC and exposure to welding fumes and silica in the whole population and with polycyclic aromatic hydrocarbons in ever smokers. CONCLUSION This study demonstrated that some risk factors, such as duration of smoking and certain occupational exposures but not gender or age, have a more important influence on the incidence of lung ADC than on other histologic types. As the distribution of histologic types may reflect underlying biological mechanisms, these findings also suggest that lung carcinogenesis pathways should be studied in relation to smoking duration and other lung cancer risk factors.

A Phase II First-Line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Nonsquamous Non-small Cell Lung Cancer

Background: Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab. Methods: Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m2 on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity. Results: From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1–42) with 37 patients (78.7%) completing ≥4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8–7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0–16.5). The OS is 57% at 1 year and 10% at 2 years. Conclusions: Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.

Antiangiogenic Agents and Vascular Disrupting Agents for the Treatment of Lung Cancer: A Review

Although lung cancer therapy has slowly improved with standard cytotoxic chemotherapy drugs, we have reached an efficacy plateau. The addition of targeted agents, such as those with antiangiogenesis activity, to chemotherapy can improve response and survival outcomes. The first of these agents to gain approval in lung cancer in October 2006 was the antivascular endothelial growth factor antibody, bevacizumab. Small molecule tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor also have proven activity and are under active investigation. Vascular disrupting agents target existing tumor vasculature leading to tumor necrosis, and are being studied in solid tumors, including lung cancer, both as single agents and in combination with chemotherapy. This article will review these new targeted antiangiogenic and antivascular agents with a focus on their use as lung cancer therapeutics.

Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and Non-Hispanic white women who have never smoked.

Background: Lung cancer is the leading cause of cancer death among U.S. Asian/Pacific Islander (API) and Latina women despite low smoking prevalence. This study examined survival patterns following non–small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS). Methods: Women diagnosed with lung cancer from 1998 to 2003 and 2005 to 2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic (NH) white, 23 U.S.-born Latina, 32 foreign-born Latina, 30 U.S.-born API, and 190 foreign-born API never-smokers diagnosed with lung cancer and followed through 2008. Results: All-cause survival was poorer among APIs [HR = 1.7 (95% CI: 1.0–2.8) among U.S.-born APIs and HR = 1.2 (95% CI: 0.9–1.5) among foreign-born APIs] and Latinas [HR = 2.1 (95% CI: 1.2–3.6) among U.S.-born Latinas; HR = 1.4 (95% CI: 0.9–2.3) among foreign-born Latinas] relative to NH whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors. Conclusions: Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations as possible explanations for these striking racial/ethnic differences. Impact: Latina and API female never-smokers diagnosed with lung cancer were up to two times more likely to die than NH whites, highlighting the need for additional research to identify the underlying reasons for the disparities and heightened clinical awareness. Cancer Epidemiol Biomarkers Prev; 20(3); 545–54. ©2011 AACR.

Smoking, Occupational Risk Factors, and Bronchial Tumor Location A Possible Impact for Lung Cancer Computed Tomography Scan Screening

Introduction: The aim of this study was to describe associations between lung tumor location and smoking as well as selected occupational exposures. In the context of lung cancer screening by computed tomography scan, tumor location may have an interest. Computed tomography scan is known to better detect more peripheral tumors. Methods: Lung cancer cases diagnosed in two French University hospitals between 1997 and 2009 were included. Tumors visible on white-light bronchoscopy were defined as central. Occupational exposures were assessed by the same expert. Data were analyzed by case-case comparisons using unconditional logistic regressions. Results: A total of 1701 cases were included, comprising mainly men (86.3%), current smokers (52.8%), or former smokers (42.8%). Main histological subtypes of cancer were adenocarcinomas (33.8%) and squamous cell carcinomas (32.6%). The tumor location was found to be central in 61% of cases, and never smokers and women had more often peripheral tumors. Exposure to asbestos was significantly associated with central location with dose-response relationship (odds ratio [OR] for peripheral tumors = 0.45, 95% confidence interval [CI] 0.29–0.70) for the highest level of exposure. Exposure to silica dust was significantly associated with peripheral tumor (OR for peripheral tumors = 3.28, 95%CI 1.50–7.17) for the highest level of exposure. Exposure to welding fumes was associated with central location (OR for peripheral tumors = 0.51, 95% CI 0.26–0.96) for the first level of exposure). Conclusions: Smoking characteristics and occupational exposures have to be considered to define more accurately high-risk populations suitable for lung cancer screening or early detection programs.

Prognostic value of health-related quality of life for overall survival in elderly non-small-cell lung cancer patients

BACKGROUND We investigated whether the health-related quality of life (HRQoL) score is a prognostic factor for overall survival (OS) in elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS We included 451 NSCLC patients aged 70-89 years enrolled in the Intergroupe Francophone de Cancérologie Thoracique 0501 trial, using scores of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 at baseline to investigate the prognostic value of HRQoL for OS, in addition to conventional factors. Cox regression model was used for both univariate and multivariate analyses of OS. RESULTS Global health status (GH) dimension score at baseline was associated with favourable OS when adjusted for clinical, functional, and histological factors (hazard ratio [HR]: 0.986; 95% confidence interval [CI]: 0.980-0.992). We distinguished three groups according to GH score: high (GH <46), intermediate (46 ≤ GH ≤ 67), and low (GH >67) mortality risk. The median OS values were 14.5, 8.2, and 5.3 months in the low-, intermediate-, and high-risk categories, respectively (log-rank P <0.0001). In the high-risk group, doublet chemotherapy was not associated with favourable OS (HR: 0.70; 95% CI: 0.49-1.003; P=0.052), whereas in the intermediate- and low-risk groups, doublet chemotherapy was associated with favourable OS (HR: 0.72; 95% CI: 0.54-0.96; P=0.023 and HR: 0.50; 95% CI: 0.30-0.84; P=0.0089, respectively). CONCLUSION This study supports the additional prognostic value of HRQoL data at diagnosis to identify vulnerable subpopulations in elderly NSCLC patients. HRQoL could thus be valuable in selecting patients who will benefit from doublet chemotherapy.

A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer

INTRODUCTION Regardless of epidermal growth factor receptor (EGFR) mutation status, erlotinib improves survival for patients with advanced non-small cell lung cancer (NSCLC) after one or more chemotherapy regimens. Enzastaurin is an oral serine/threonine kinase inhibitor. This phase II study was designed to evaluate the efficacy and safety of erlotinib and enzastaurin in NSCLC, a combination with promise to overcome EGFR resistance based on preclinical models. METHODS Eligible patients with advanced NSCLC (IIIB or IV) who had failed one or two prior systemic treatment regimen(s) were enrolled and received erlotinib 150 mg/day and enzastaurin 500 mg/day (after a 1125-mg loading dose on day 1, cycle 1), both orally in 28-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS From January 2008 to July 2009, 49 patients were enrolled: 29 (59%) men and 20 (41%) women; 8 (16%) were non-smokers. The median PFS was 1.7 months (one-sided 90% CI: 1.5-NA) and median overall survival (OS) was 8.3 months (95% CI: 5.3-14.3). Five patients had partial response, for an overall response rate of 10.2%; the disease control rate was 30.6% (responders+10 patients with stable disease). Grade 3-4 drug-related adverse events in ≥5% of patients were diarrhea, acne, and nausea. One possibly drug-related death due to interstitial lung disease occurred during the study. CONCLUSIONS In previously treated, unselected, advanced NSCLC patients, the addition of enzastaurin to erlotinib did not improve PFS, response, or OS compared with historical data of single-agent erlotinib, but was well tolerated.