Safety and Patient-Reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab in stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies (GFPC 06-2018 study).

BACKGROUND: In an open-label multicenter non-randomized non-comparative phase II study in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC), oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine-kinase inhibitor and no prior chemotherapy (NCT04042558), atezolizumab, carboplatin, pemetrexed with or without bevacizumab showed some promising result. Beyond the clinical evaluation, we assessed safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in this population. MATERIALS: Patients received platinum-pemetrexed-atezolizumab-bevacizumab (PPAB cohort) or, if not eligible, platinum-pemetrexed-atezolizumab (PPA cohort). The incidence, nature, and severity of adverse events (AEs) were assessed. PROs were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-Core 30 and EORTC QLQ-Lung Cancer 13). RESULT: Overall, 68 (PPAB) and 72 (PPA) patients were evaluable for safety. Grade 3-4 AEs occurred in 83.8% (PPAB) and 63.9% (PPA). Grade 3-4 atezolizumab-related AEs occurred in 29.4% and 19.4%, respectively. Grade 3-4 bevacizumab-related AEs occurred in 36.8% (PPAB). Most frequent grade 3-4 AEs were neutropenia (19.1% in PPAB; 23.6% in PPA) and asthenia (16.2% in PPAB; 9.7% in PPA). In PPAB, we observed a global stability in global health security (GHS) score, fatigue and dyspnea with a constant tendency of improvement, and a significant improvement in cough. In PPA, we observed a significant improvement in GHS score with a significant improvement in fatigue, dyspnea and cough. At week 54, we observed an improvement from baseline in GHS score for 49.2% of patients. In both cohorts, patients reported on average no clinically significant worsening in their overall health or physical functioning scores. CONCLUSION: PPAB and PPA combinations seem tolerable and manageable in patients with stage IIIB/IV non-squamous NSCLC with oncogenic addiction (EGFR mutation or ALK/ROS1 fusion) after targeted therapies.

Routine EGFR molecular analysis in non-small-cell lung cancer patients is feasible: exons 18-21 sequencing results of 753 patients and subsequent clinical outcomes.

BACKGROUND: Epidermal growth factor receptor (EGFR)-targeting therapies dramatically modified the prognosis of stage 4 non-small-cell lung cancer. Sensitizing EGFR mutations are the best efficacy factor of these treatments. In 2006, the French National Cancer Institute launched a network of 28 centers for EGFR molecular analysis in routine practice. The aim of this retrospective study was to describe the results of routine EGFR analysis in one of these centers (Lyon University Hospital) and to assess outcomes in patients with the mutation. METHODS: EGFR mutations were analyzed for exons 18-21 by direct sequencing. The characteristics of each sample were retrospectively collected from the lab archives. Subsequent outcomes for patients harboring at least one mutation were retrospectively collected from each referring physician. RESULTS: During 1 year, 792 samples were analyzed, corresponding to 753 patients. A total of 133 mutations were diagnosed in 124 samples (15.7 %), corresponding to 121 patients. Most of them (77.4 %) were sensitizing mutations and were located in exons 19 and 21. Others were resistance mutations (8.3 %) or rare mutations (14.3 %) for which effects on tyrosine kinase inhibitor (TKI) sensitivity are unknown. The rate of indeterminate results (i.e., no sequencing of the entire exon 19 or 21) was 6.3 % (n = 50 samples). The only factor statistically associated with a risk of failure was sample from bone tissue: 13.7 % gave incomplete results (i.e., no whole sequencing of exons 18-21). CONCLUSIONS: Eighty-five of the 121 patients with EGFR mutations were treated with TKI. There were no differences in progression free survival (PFS) according to the type of molecule (erlotinib or gefitinib) or to the line of prescription of TKI. By contrast, exon 18 sensitizing mutations showed a worse PFS than exon 19 or 21 mutations. Finally, dose reduction was significantly more frequent in the erlotinib group than in the gefitinib group.

PD-L1-expression patterns in large-cell neuroendocrine carcinoma of the lung: potential implications for use of immunotherapy in these patients: the GFPC 03-2017 "EPNEC" study.

BACKGROUND: Few data are available on programmed cell-death-protein-1-ligand-1 (PD-L1) expression on large-cell neuroendocrine carcinomas of the lung (LCNECs). We analyzed PD-L1 expression on tumor (TCs) and inflammatory cells (ICs) from LCNEC patients to assess relationships between this expression, clinical characteristics, and disease outcomes. METHODS: PD-L1 expression was determined by immunohistochemistry with monoclonal antibody 22C3 in consecutive LCNEC patients managed in 17 French centers between January 2014 and December 2016. RESULTS: After centralized review, only 68 out of 105 (64%) patients had confirmed LCNEC diagnoses. Median overall survival (OS) (95% CI) was 11 (7-16) months for all patients, 7 (5-10), 21 (10-not reached) and not reached months for metastatic, stage III and localized forms (p = 0.0001). Respectively, 11% and 75% of the tumor samples were TC+ and IC+, and 66% had a TC-/IC+ profile. Comparing IC+ versus IC- metastatic LCNEC, the former had significantly longer progression-free survival [9 (4-13) versus 4 (1-8) months; p = 0.03], with a trend towards better median OS [12 (7-18) versus 9.5 (4-14) months; p = 0.21]. Compared to patients with TC- tumors, those with TC+ LCNECs tended to have non-significantly shorter median OS [4 (1-6.2) versus 11 (8-18) months, respectively]. Median OS was significantly shorter for patients with TC+/IC- metastatic LCNECs than those with TC-IC+ lesions (2 versus 8 months, respectively; p = 0.04). CONCLUSION: TC-/IC+ was the most frequent PD-L1-expression profile for LCNECs, a pattern quite specific compared with non-small-cell lung cancer and small-cell lung cancer. IC PD-L1 expression seems to have a prognostic role.

Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis.

PURPOSE: To investigate variations of circulating serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and interleukin-10 (IL-10) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non-small-cell lung cancer and correlate these variations with the occurrence of radiation pneumonitis. PATIENTS AND METHODS: Ninety-six patients receiving 3D-CRT for stage I to III disease were evaluated prospectively. Circulating cytokine levels were determined before, every 2 weeks during, and at the end of treatment. Radiation pneumonitis was evaluated prospectively between 6 and 8 weeks after 3D-CRT. The predictive value of clinical, dosimetric, and biologic (cytokine levels) factors was evaluated both in univariate and multivariate analyses. RESULTS: Forty patients (44%) experienced score 1 or more radiation pneumonitis. No association was found between baseline cytokine levels and the risk of radiation pneumonitis. In the whole population, mean levels of TNFalpha, IL-6, and IL-10 remained stable during radiotherapy. IL-6 levels were significantly higher (P = .047) during 3D-CRT in patients with radiation pneumonitis. In the multivariate analysis, covariations of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were evidenced as independently predictive of radiation pneumonitis in this series (P = .011). CONCLUSION: Early variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.

A prospective study on radiation pneumonitis following conformal radiation therapy in non-small-cell lung cancer: clinical and dosimetric factors analysis.

BACKGROUND AND PURPOSE: Clinical and dosimetric prognostic factors for radiation pneumonitis (RP) have been reported after three-dimensional conformal radiotherapy (3D-CRT) in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Ninety-six patients who received 3D-CRT for stage IA to IIIB NSCLC were evaluated prospectively. Surgery was performed before radiation in 51% of the patients (n = 49). RP was diagnosed six-eight weeks after 3D-CRT using the Lent-Soma classification. Factors evaluated included treatment factors such as total mean lung dose (MLD), and dose-volume histogram (DVH) thresholds for several radiation dose steps. These thresholds were originally determined from the median of the irradiated lung volume at each step. RESULTS: Six patients could not be evaluated for RP six weeks after 3D-CRT. Of the 90 remaining patients, 40 (44%) had RP (i.e. grade > or =1) at 6 weeks, including 7 patients (7.8%) with severe RP (grade > or =2). Regarding the whole toxicity (grade > or =1), age (> or =60 years), MLD, V20 and V30 were significantly related to RP. DVH thresholds determined for radiation doses from 20 to 40 Gy were also predictive of RP. Considering only severe RP (grade > or =2), only MLD, V20 and V30 remained associated with increased acute pulmonary toxicity. CONCLUSIONS: In this study, dosimetric factors (MLD, V20, V30) and age (> or =60 years) were predictive of RP regarding the whole pulmonary toxicity (grade > or =1). In addition, thresholds from 20 to 40 Gy, based on a stratification according to the median of the percentage of irradiated lung volume, were also predictive factors. They may, therefore, help discriminate patients at high and low risk for RP. However, only MLD, V20 and V30 remained associated with severe RP (grade > or =2), probably due to the small number of severe events in our series.

[Maintenance therapy in advanced non-small cell lung cancer: A new paradigm?]. / Traitement de maintenance dans les cancers bronchiques non à petites cellules métastatiques : une révolution conceptuelle ?

Standard treatment of advanced non-small cell lung cancer is based on several lines of therapy separated by treatment-free intervals in which each new line is started when tumour progression is detected. The maintenance strategy consists of pursuing an appropriate, well-tolerated treatment after the end of first-line chemotherapy in order to maintain the initial therapeutic benefit and to avoid rapid clinical deterioration that would rule out further treatment. Two kinds of maintenance therapy have been investigated: continuation maintenance which consists in continuing a targeted agent or a chemotherapy agent that was part of initial induction therapy and switch maintenance defined by initiating a new agent immediately after the end of induction chemotherapy. Clinical trials show that maintenance strategy provides a significant benefit in terms of disease control and improves overall survival for switch maintenance with pemetrexed or erlotinib. Survival benefit appears to be due mainly to the progression-free survival gain and to the increase in the proportion of patients who can receive several lines of treatment. Maintenance therapy is an important option for patients receiving first-line treatment, particularly for those with rapid disease progression. The choice of continuation or switch maintenance will depend on drug used in combination to platinum for induction treatment, response to first-line, histology and patient's preference.

The role of pemetrexed in lung adenocarcinoma, mixed subtype with bronchioloalveolar carcinoma features.

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (ADC-WBF) belong to the same anatomo-clinical entity and show very similar epidemiologic, clinical and biological characteristics. However there is a lack of consensus for the treatment of unresectable forms. Although epidermal growth factor receptor tyrosine kinase inhibitors and paclitaxel do have some efficacy, the aim of this review is to assess the role that pemetrexed, a new generation antifolate, could play in this context. Pemetrexed has proved to be particularly effective in advanced lung adenocarcinomas and unresectable mesotheliomas, and cases of major and sustained responses of ADC-WBF to pemetrexed have been reported. The preclinical rationale explaining this efficacy is that it inhibits the growth of BAC cell lines in vitro. BAC tumors overexpress FR-alpha, a protein involved in pemetrexed intracellular transport, at rates higher than those observed in lung adenocarcinomas and mesotheliomas and it would seem that pemetrexed efficacy is correlated to FR-alpha expression. The role played by thymidylate synthase expression level in sensitivity to pemetrexed also needs to be specifically explored in ADC-WBF. The results of two phase II trials, SWOG 0526 and IFCT 05-04, will hopefully provide decisive information on the relevance of pemetrexed in ADC-WBF management and the molecular predictors of response.

Predictive factors of late radiation fibrosis: a prospective study in non-small cell lung cancer.

PURPOSE: To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Ninety-six patients with Stage IA-IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor alpha, tumor growth factor beta1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF. RESULTS: Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade >or=1), including six severe RF (Grades 2-3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p < 0.05). Dosimetric factors (mean lung dose, percentage of lung volume receiving more than 10, 20, 30, 40, and 50 Gy) were highly correlated with RF (p < 0.001). In multivariate analysis, previous acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT. CONCLUSIONS: This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT.

Major and prolonged response to pemetrexed in two cases of lung adenocarcinoma with bronchioloalveolar carcinoma features.

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma mixed subtype with bronchioloalveolar features (ADC-WBF) represent a unique anatomo-clinical entity accounting for some 20% of non-small cell lung cancers (NSCLC). These tumors seem less sensitive to chemotherapy than other NSCLC. We report two cases of advanced ADC-WBF treated with second-line and fourth-line pemetrexed. Major and durable radiological response associated with clinical and functional improvement was achieved in both patients, without important drug toxicity. After treatment arrest, the two patients experienced progressive disease but responded to retreatment with pemetrexed. Recent data suggest that paclitaxel-based chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors could be an acceptable therapeutic strategy in unresectable CBA and ADC-WBF. The cases reported here and preclinical findings suggest a therapeutic efficacy of pemetrexed in these tumors. Prospective studies are required to evaluate this hypothesis.

[A difficult end of life]. / Une fin de vie difficile.

The law specifies how a doctor may write a medical certifcate and how a patient or his beneficiaries can obtain his medical records. It's important for a doctor to know this rules. A 56 years old patient was referred to our hospital for pulmonary adenocarcinoma cT2N2M1, the clinical stage was IV. The patient underwent radiotherapy and chemotherapy. During the treatment, the relations with the family were difficult. The patient refuse to accept the doctors tell his son any information and get married with his companion in secret. After patient's death, the son and the wife asked for many medical certificates. The doctors turned down so the son asked for the patient medical records. This observation asks the question of the medical certificates: how and when write them, which are obligatories? Moreover, how should a patient or his beneficiaries obtain medical records?

[Confidentiality in medical practice: tell no one]. / Le secret médical à tout prix?...

Medical confidentiality is sometimes difficult to impose on patient's families, especially in the field of oncology. Here, we describe the case of a 54-years-old woman with a T1N0M0 lung adenocarcinoma. After the diagnosis was made, she advised the medical team not to inform her family about her disease. Although the patient was aware of the high-risk of relapse, she was lost of follow-up after first-line treatment. Five years later, she presented with multi-metastatic recurrence and had to be admitted in an intensive-care unit for severe respiratory failure due to tumor progression. She kept refusing to inform her family, which in the end was contacted by the patient's sister, a few hours before her death. This observation highlights the absolute inviolability of medical confidentiality and led the French Association of Young Pneumologist to initiate a multi-disciplinary symposium on ethical problems raised by the management of patients with lung cancer.

[Angiogenesis and lung cancer]. / Angiogenèse et cancer bronchique.

Inhibition of specific processes essential for tumour vascular development is actually one of the key strategies for treatment of lung cancer, for which angiogenesis is consistently predictive of a poor prognosis. The most promising agents target the vascular endothelial growth factor (VEGF) pathway, either by preventing VEGF-receptor binding as bevacizumab or inhibiting downstream receptor signaling in endothelial cells. Combination of bevacizumab with standard first-line chemotherapy in non-small cell lung cancer demonstrates a significant survival advantage comparing to chemotherapy alone, which provides the "proof of concept" for inhibition of angiogenesis in lung cancer. Development of small molecules inhibiting tyrosine kinase activity of VEGF-receptors is ongoing; many of them showed a single-agent activity but their most likely use will be in combination with chemotherapy or biological agents. Toxicity issues are of concern with the occurrence of fatal pulmonary hemorrhage after cavitation and necrosis of primary tumour, which requires appropriate selection of patients before treatment. A better understanding of the complex process of angiogenesis and of surrogate markers of treatment effect will improve our ability to design more effective therapies.