[EGFR molecular characterization in non-small cell bronchic cancer: comparative prospective study by NGS and Idylla platform technologies]. / Caractérisation moléculaire de l'EGFR dans les cancers bronchiques non à petites cellules : étude prospective comparative des technologies NGS et automate Idylla.

INTRODUCTION: Detection of genetic alterations in the EGFR tyrosine kinase domain is a major concern in the management of non-small cell lung cancer because it conditions access to tyrosine kinase inhibitors. In practice, it is possible to characterize only well-documented mutations or to sequence all relevant EGFR exons and also other targets of theranostic interest. This prospective study compares the targeted EGFR characterization on Idylla platform (Biocartis) and a more extensive one by next generation sequencing using Ion Torrent technology. MATERIAL AND METHODS: A total of 100 formalin-fixed paraffin-embedded tumour samples were tested simultaneously by both techniques under the conditions recommended by the suppliers. The comparison covered all technical and practical aspects of the laboratory. RESULTS: At least one EGFR mutation of interest for tyrosine kinase inhibitors for 9 and 7 samples was detected respectively by sequencing and by the Idylla system. For three samples, EGFR sensitive mutations to tyrosine kinase inhibitors were detected only by next-generation sequencing. In addition, for 37 samples, mutations of clinical interest outside EGFR were characterized by sequencing and communicated to the prescriber. CONCLUSION: Idylla technology allows the rapid characterization of a majority of EGFR variants. The result can be optimized by careful analysis of the amplification curves with the Idylla Explore tool or by increasing the amount of initial material. A complementary new generation sequencing analysis for non-contributory results by Idylla should also be recommended.

[News about targeted therapies in non-small-cell lung cancer in 2015 (except immuno-therapy)]. / Actualités sur les thérapies ciblées dans les cancers bronchiques non à petites cellules, hors immunothérapie.

Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSé program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSé program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC.

Radiotherapy in the management of synchronous metastatic lung cancer.

Metastatic lung cancer classically portends a poor prognosis. The management of metastatic lung cancer has dramatically changed with the emergence of immune checkpoint inhibitors, targeted therapy and due to a better understanding of the oligometastatic process. In metastatic lung cancers, radiation therapy which was only used with palliative intent for decades, represents today a promising way to treat primary and oligometastatic sites with a curative intent. Herein we present through a literature review the role of radiotherapy in the management of synchronous metastatic lung cancers.

[First-line immunotherapy in non-small cell lung cancer diagnosed with brain metastases]. / CBNPC sans addictions oncogéniques métastatique cérébral d'emblée : place de l'immunothérapie.

INTRODUCTION: Up to 30% patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) present with brain metastases. In the absence of oncogenic addiction, first-line immunotherapy, alone or in combination with chemotherapy, is the current standard of care. This review aims to synthesize the available data regarding the efficacy of immunotherapy in these patients, and to discuss the possibility of its being coordinated with local treatments such as radiotherapy. STATE OF THE ART: NSCLC patients with brain metastases appear to have survival benefits with immunotherapy similar to those of NSCLC patients without brain metastases. However, this finding is based on mainly prospective studies having included highly selected patients with pre-treated and stable brain metastases. Several retrospective studies and two prospective single-arm studies have confirmed the intracranial efficacy of immunotherapy, either alone or in combination with chemotherapy. PERSPECTIVES: The indications and optimal timing for cerebral radiotherapy remain subjects of debate. To date, there exists no randomized study assessing the addition of brain radiotherapy to first-line immunotherapy. That said, a recent meta-analysis showed increased intracerebral response when radiotherapy complemented immunotherapy. CONCLUSIONS: For NSCLC patients with brain metastases, the available data suggest a clear benefit of first-line immunotherapy, whether alone or combined with chemotherapy. However, most of these data are drawn from retrospective, non-randomized studies with small sample sizes.

[Stereotactic Body Radiation Therapy for less than 3cm (stage I) and 5cm (stage II) inoperable lung tumors: 10 years experience of Montpellier Cancer Institute]. / Radiothérapie stéréotaxique (RTST) pulmonaire des tumeurs de moins de 3cm (stade I) et 5cm (stade II) non opérées : 10 ans d'expérience de l'Institut du Cancer de Montpellier (ICM).

PURPOSE: Search for predictive factors on survival and local control for less than 3 centimeters (cm) (stage I) and 5cm (stage II) inoperable lung tumors treated by Stereotactic Body Radiation Therapy (SBRT) in a retrospective monocentric study from Montpellier Cancer Institute (ICM) PATIENTS AND METHOD: Every patients treated at ICM for a stage I or II inoperable lung tumors from 2009 to 2019 were analyzed. RESULTS: One hundred and seventy nine lesions were treated in 176 patients, with a major part (82,7%) in operated due to chronic obstructive pulmonary disease. Median overall survival for all patients was 71,7 months with a 35 months follow-up and the 2 years loco-regional free survival was 94,0 months. Better associated outcomes were stage I (median overall survival 71,7 versus 29,0 months P=0,004 ; HR=2,37 P=0,005), BED≥150Gy (median time-to-progression not reached versus 76,7 months P=0,025), small size of Planning Target Volume (PTV) (HR=0,42 P=0,032 when PTV<15,6 cc). 7,3% of all patients developed radiation pneumonitis. CONCLUSION: SBRT is associated with an excellent overall survival and a high rate of local control for less than 3cm (stage I) and 5cm (stage II) lung tumors but a low rate of toxicities. For these patients with many comorbidities, BED over 150Gy seems to be associated with a better loco-regional free survival, while cause of death is often other than lung cancer.

[Stereotactic radiotherapy for operable stage I non-small cell lung cancer]. / Place de la radiothérapie stéréotaxique pour les cancers bronchiques non à petites cellules de stade I opérables.

Standard treatment stage of non-small cell lung cancer is currently surgery. For inoperable patients, stereotactic body radiotherapy is the reference treatment. This non-invasive technique has developed considerably and its excellent results in terms of carcinological control and tolerance raise the question of its indication for operable patients, especially for old patients and/or with comorbidities. This article reviews the available data in the literature of the place of stereotactic body radiotherapy for medically operable patients with stage I non-small cell lung cancer.

[Olimetastatic disease: Current status and perspectives in non-small cell lung cancer]. / Les maladies oligométastatiques : état actuel et perspectives dans les cancers bronchiques non à petites cellules.

The concept of oligometastatic disease was first introduced in the late 1990s to describe an situation more or less midway between locally advanced tumours and multifocal metastatic cancer. Four concepts are currently used: synchronous oligometastatic disease, metachronous oligometastatic disease (or oligo-recurrence), oligo-persistence and oligo-progression. Some phase II studies, randomised or not, have validated this concept in non-small cell lung cancer (NSCLC) and suggest the interest of adding local ablative therapy to systemic treatment. That said, numerous questions remain, and the impact of this therapeutic approach in the framework of immunotherapies and targeted therapies has yet to be assessed. Which of these new treatments offer hope of significantly improved long-term survival in stage IV NSCLC? This article appraises current knowledge and therapeutic regarding oligometastatic NSCLC.

[Interest of focal radiotherapy in case of oligoprogression under immunotherapy in the treatment of metastatic non-small cell lung cancer]. / Oligroprogression sous nivolumab du cancer bronchique non à petites cellules métastatiques traitées par radiothérapie.

INTRODUCTION: The prognosis of metastatic non-small cell lung cancer (NSCLC) has been improved by the use of immune checkpoint inhibitors (ICI). Unfortunately, in some cases, cancer cells will develop resistance mechanisms. In case of progression in a limited number of lesions (oligoprogression), focal treatment with radiotherapy is proposed while continuing the ICI therapy. METHODS: A cohort of 37 patients with metastatic NSCLC treated with nivolumab (anti-PD-1) in second or subsequent line and who received focal radiotherapy for oligoprogression with continuation of nivolumab was compared with a control cohort of 87 patients no oligoprogressor treated par immunotherapy. RESULTS: After a median follow-up of 37 months [18; 62], the median progression free survival (PFS) in the radiotherapy-treated cohort was 15.04 versus 5.04 months in the control cohort, with a statistically significant difference (P=0.048). The median PFS following focal radiotherapy in the oligoprogressor group was 7.5 months. In univariate analysis, the presence of lung metastasis was associated with increased PFS, in contrast to the presence of brain metastases, which were associated with decreased PFS in the radiotherapy group. The median overall survival was not reached in both groups, with no significant difference between the two cohorts. CONCLUSION: The combination of focal radiotherapy in case of oligoprogression and continued treatment with nivolumab in the treatment of metastatic NSCLC in the second or subsequent line of treatment seems to be with an increase in PFS.

[Impact of immunotherapy on the therapeutic strategy for the management of stage I non-small cell lung cancer: The radiation oncologist's point of view]. / Influence de l'immunothérapie sur le choix du traitement des cancers bronchiques non à petites cellules de stade I : point de vue de l'oncologue radiothérapeute.

Surgery is the standard treatment for operable patients with stage I non-small cell lung cancer (NSCLC) (T1-T2aN0M0). Stereotactic body radiotherapy (SBRT) is the treatment of choice for non-operable patients, and its positioning for operable patients remains to be clarified. The pattern of recurrence after management of stage I NSCLC is dominated by the risk of distant recurrence, this constituting the rationale for the adjunction of systemic treatment, and especially check point inhibitor (CPI), in combination with surgery or SBRT for patients with high risk features. While the benefit of postoperative CPI on the micro-metastatic disease is logically considered within the framework of a simply additive effect of both therapeutic modalities, it is reasonable to consider a synergistic effect of both CPI and SBRT. Given the role of tumor draining nodes in the development of an anti-tumor immune response, a "tumor-draining node sparing" strategy enabled by SBRT could therefore be of major interest in combination with CPI. Pending confirmation of the role of CPI in combination with RTS for the management of stage I NSCLC, we thus discuss in this review the theoretical advantages that this therapeutic strategy could have compared to a surgical strategy.

[Drug-drug interactions of tyrosine kinase inhibitors in treatment of non-small-cell lung carcinoma]. / Interactions médicamenteuses des inhibiteurs de tyrosine kinase dans le traitement du cancer bronchique non à petites cellules.

The development of tyrosine kinase inhibitors has revolutionized the treatment strategy in patients with non-small cell lung cancer with activating EGFR mutations, ALK or ROS-1 gene rearrangements. The Food and Drug Administration and European Medicines Agency have approved several inhibitors for the treatment of non-small cell lung cancer : five tyrosine kinase inhibitors targeting EGFR (erlotinib, gefitinib, afatinib, osimertinib and dacomitinib) and six tyrosine kinase inhibitors targeting ALK (crizotinib, céritinib, alectinib, brigatinib, lorlatinib and entrectinib). Interestingly, these tyrosine kinase inhibitor treatments are administered orally. While this route of administration improves the treatment flexibility and provides a comfortable and preferable option for patients, it also increases the risk of drug-drug interactions. The latter may result in changes in pharmacokinetics or pharmacodynamics of the tyrosine kinase inhibitors or their concomitant treatments, with subsequent risks of increasing their toxicity and/or reducing their effectiveness. This review provides an overview of drug-drug interactions with tyrosine kinase inhibitors targeting EGFR and ALK, as well as practical recommendations to guide oncologists and clinical pharmacists in the process of managing drug-drug interactions during the treatment of non-small cell lung cancer with tyrosine kinase inhibitors.

[The role of the intensive care unit after thoracic surgery]. / Place de la réanimation après chirurgie thoracique.

Lung (bronchial) cancer is the leading cause of cancer-related death in Western countries today. Thoracic surgery represents a major therapeutic strategy and the various advances made in recent years have made it possible to develop less and less invasive techniques. That said, the postoperative period may be lengthy, post-surgical approaches need to be more precisely codified, and it matters that the different interventions involved be supported by sound scientific evidence. To date, however, there exists no evidence that preventive postoperative admission to intensive care is beneficial for patients having undergone lung resection surgery without immediate complications. A stratification of the risk of complications taking into consideration the patient's general state of health (e.g., nutritional status, degree of autonomy, etc.), comorbidities and type of surgery could be a useful predictive tool regarding the need for postoperative intensive care. However, serious post-operative complications remain relatively frequent and post-operative management of these intensive care patients is liable to become complex and long-lasting. In the aftermath of the validation of "enhanced recovery after surgery" (ERAS) in thoracic surgery, new protocols are needed to optimize management of patients having undergone pulmonary resection. This article focuses on the main postoperative complications and more broadly on intensive care patient management following thoracic surgery.

[Pulmonary manifestations induced by osimertinib]. / Toxicité pulmonaire induite par l'osimertinib.

INTRODUCTION: The third-generation tyrosine kinase inhibitor (TKI) osimertinib is recommended as a first-line treatment in advanced non-small cell lung cancer harboring an activating mutation of Epidermal Growth Factor Receptor (EGFR). Adverse pulmonary events related to osimertinib exposure have been reported, primarily in Japanese patients. They rarely occur in the Caucasian population. OBSERVATION: Herein we report two clinical cases of osimertinib-induced lung toxicities in patients diagnosed with advanced lung adenocarcinoma harboring an EGFR mutation. In the first case, interstitial pneumonia was asymptomatic and evolved favorably after osimertinib discontinuation. The second patient presented a more extensive form of lung injuries and despite systemic corticosteroid therapy, the evolution was fatal. CONCLUSION: Osimertinib-related lung toxicities remain exceptional. While most forms are mild, consideration of TKI treatment discontinuation may be necessitated. Introduction of another TKI or rechallenge with osimertinib might be considered along with corticosteroid therapy if necessary. Diffuse alveolar damage is a pejorative prognostic factor.

Impact of radiotherapy schedule on survival of patients treated with immune-checkpoint inhibitors for advanced melanoma and non-small cell lung cancer.

PURPOSE: Preclinical and clinical data suggest a potential benefit in the addition of radiotherapy (RT) to immune-checkpoint inhibitors (ICI) during the treatment of advanced cancers. Nevertheless, the ideal patients for this approach and the optimal RT regimen is still debated. MATERIAL AND METHODS: The aim of this study was to determine the effect RT schedule has on survival for advanced non-small cell lung cancer and melanoma patients (pts) treated with ICI (anti-PD1 or anti-CTLA4) and concomitant RT. RESULTS: A total of 58 pts were identified, of which 26 received RT concomitantly with ICI while the remaining 32 pts were treated with RT at the time of progression under ICI. The RT parameters associated with outcome include dose per fraction, biological effective dose, RT to all targets and lung irradiation. Independent predictors of improved progression-free survival were lung irradiation, melanoma histology, oligometastatic status (<6 metastasis), presence of liver metastasis, PNN<7000/mm3 and normal LDH. Independent predictors of improved overall survival were melanoma histology and normal LDH. Among pts who were irradiated at progression, 68.7% had an overall clinical benefit and had a median extension of ICI use by 2.3 months (range: 0-29.1), among which 2 presented with an abscopal effect. CONCLUSIONS: The irradiation of lung metastases may increase survival in patients under ICI. RT at progression could prolong the use of ICI, and neutrophilia and LDH should be considered during patient selection of this combined RT/ICI approach.

[Management of EGFR mutated non-small cell lung carcinoma patients]. / Analyse de la prise en charge des cancers bronchiques avec mutation du gène de l'EGFR.

INTRODUCTION: Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC). Over the past decade, the management of NSCLC-carrying EGFR mutation has evolved considerably with the use of tyrosine kinase inhibitors (TKIs). The main objective of this retrospective study was to analyze the evolution of therapeutic strategies in a cohort of patients with metastatic or locally advanced EGFR- mutated NSCLC. METHODS: Data on patients with EGFR-mutated NSCLC, eligible for TKIs, and treated between 2010 to 2019 were collected. The main therapeutic strategies adopted following progression under TKIs and the prognostic factors for survival were analyzed. RESULTS: The median age of the 177 patients was included in the cohort was 70years. The majority of patients (77.4%) received TKIs as first-line treatment, while 16.4% received chemotherapy. Osimertinib initiation as second-line treatment was a factor for better prognosis (OR=0.5). Finally, change of chemotherapy line was the main therapeutic strategy adopted for 41.3% of the patients having relapsed under TKIs. DISCUSSION: Therapeutic management of EGFR-mutated NSCLC patients was in accordance with regional, national and international recommendations. The characterization of progression under TKI therapy has become systematic, allowing better adaption of therapeutic strategies.

[Perioperative treatment for resected non-small cell lung cancer: Which option in 2020?] / Les traitements périopératoires des cancers bronchiques non à petites cellules : quelles options en 2020 ?

Surgery is the ultimate curative treatment for resectable non-small cell lung cancer (NSCLC). However, the prognosis for operated patients remains disappointing. Multiple randomized studies have shown that administering perioperative chemotherapy improves the prognosis and increases the cure rate by around 3-5%. The purpose of this article is to take stock of the role of perioperative treatments for NSCLC, which can be completely resected. Six questions were evaluated: 1) What is the place of (neo) adjuvant chemotherapy in 2020, among others in the early stages (IB)? 2) Can new chemotherapy agents be combined with a platinum derivative? 3) What is the place of radiochemotherapy for resectable NSCLC? 4) Is there a place for postoperative radiotherapy (PORT)? 5) Is there a place for targeted therapies for resectable NSCLC? 6) What is the place of immunotherapies in the perioperative period?

[The role of prophylactic cranial irradiation in small cell lung cancer]. / Quel rôle pour l'irradiation cérébrale prophylactique dans le cancer à petites cellules ? Une étude rétrospective unicentrique.

INTRODUCTION: Prophylactic cranial irradiation (PCI) is considered standard therapeutic management in small cell lung cancer (SCLC). This is based on old randomised trials with methodological limitations, namely the absence of magnetic resonance imaging (MRI) of the brain. The aim of this study is to assess the risk not administering PCI when systematic brain imaging is applied. METHODS: Retrospective study including untreated SCLC, without PCI and receiving brain imaging at the time of diagnosis. Kaplan-Meier and log-rank statistics were used for survival analyses. RESULTS: Among 150 patients, 75 were possibly eligible for PCI. Thirteen patients presented with an isolated brain recurrence as the first site of progression with no other metastatic sites apparent, and in 6 patients, the brain was the only recurrent site during the whole follow-up. In the group of patients eligible for PCI, there was no statistically significant survival difference according to the brain progression status (P=0.11). CONCLUSIONS: The expected impact of PCI seems limited in terms of overall survival and prevention of isolated brain metastases in patients having systematic brain imaging during SCLC work-up.

[Early-stage lung cancer: Is there still a role for surgery?] / Tumeurs de petits stades. La chirurgie a-t-elle encore sa place ?

For a patient with stage I or II non-small cell lung cancer (NSCLC) surgical resection remains the treatment of choice on condition that the patient is functionally operable. A complete resection should be obtained. Often lobectomy is feasible by a minimally invasive approach. For patients with compromised cardiopulmonary function stereotactic radiotherapy is an alternative treatment. For patients who are functionally operable, no definite recommendation can be made as no large, randomised studies have been performed with a sufficient number of patients and long-term follow-up. For this reason, it is important to discuss every patient within a multidisciplinary team with participation of thoracic surgeons and radiation oncologists. To provide personalised advice, the primary tumour, its extension, the patient's comorbidities and his respiratory and cardiac function have to be considered.

[Evolution of the costs and management of lung cancer between 2004 and 2014]. / Évolution des coûts et de la prise en charge du cancer pulmonaire entre 2004 et 2014.

BACKGROUND: Given its morbidity and mortality, lung cancer is a major public health issue. In recent years, it has benefited from several therapeutic innovations. The objective of this study was to compare, over two distinct periods of ten years, the impact on survival and the costs of lung cancer management. METHODS: The monocentric study assessed survival and the direct costs of lung cancer management of patients diagnosed in Brest University hospital in 2004 and in 2014. RESULTS: The analysis included 142 patients in 2004 and 156 in 2014. Most patients were smokers (72%), metastatic at diagnosis (60%) both in 2004 and in 2014. Median survival was not significantly improved between the 2 periods (9.7 versus 10.9 months), but there was a significant increase in the average cost of care per patient (€ 17,063 vs. € 29,264, P=<0.0001) between 2004 and 2014. CONCLUSION: The significant increase in treatment costs did not translate into an improvement in the survival of patients with lung cancer between 2004 and 2014.

[Predictive factors for skeletal-related events in lung cancer]. / Facteurs prédictifs de survenue d'évènements osseux dans le cancer bronchique.

INTRODUCTION: Skeletal-related events (SRE) are common in patients with bone metastatic lung cancer and have a negative impact on quality of life and survival. The objective of this study is to identify predictive factors for SRE occurrence among this population. METHODS: We conducted a 3-year retrospective study including 100 lung cancer patients with bone metastasis. RESULTS: Eighty-two patients presented at least one SRE (69.5% at baseline). The median occurrence for SRE was 4.5 months and severe bone pain was the most common SRE (56%). The alkaline phosphatase serum level>120IU/L (hazard ratio [sHR]=2.8; 95% confidence interval (CI) [1.5-5.4]; P=0.002) and calcemia>2.6mmol/L ([sHR]=9.7; 95% CI [5.1-18.4]; P<0.001) were identified as risk factors for SRE occurrence while the presence of an initial SRE was associated with a decrease of this risk ([sHR]=0.2; 95% CI [0.1-0.4]; P<0.001). CONCLUSION: The elevated alkaline phosphatase serum level and hypercalcemia are risk factors for SRE occurrence in bone metastatic lung cancer patients and should be used as biomarkers to adapt current medical practice for these patients.

[Approaches to the pre-operative functional assessment of patients with lung cancer and preoperative rehabilitation]. / Bilan fonctionnel préopératoire du cancer bronchique et réhabilitation préopératoire.

Surgery is the best treatment for early lung cancer but requires a preoperative functional evaluation to identify patients who may be at a high risk of complications or death. Guideline algorithms include a cardiological evaluation, a cardiopulmonary assessment to calculate the predicted residual lung function, and identify patients needing exercise testing to complete the evaluation. According to most expert opinion, exercise tests have a very high predictive value of complications. However, since the publication of these guidelines, minimally-invasive surgery, sublobar resections, prehabilitation and enhanced recovery after surgery (ERAS) programmes have been developed. Implementation of these techniques and programs is associated with a decrease in postoperative mortality and complications. In addition, the current guidelines and the cut-off values they identified are based on early series of patients, and are designed to select patients before major lung resection (lobectomy-pneumonectomy) performed by thoracotomy. Therefore, after a review of the current guidelines and a brief update on prehabilitation (smoking cessation, exercise training and nutritional aspects), we will discuss the need to redefine functional criteria to select patients who will benefit from lung surgery.