Present standards and future perspectives in the treatment of metastatic non-small cell lung cancer.

The development of novel effective immunotherapeutic agents and early clinical data hinting at significant activity in non-small cell lung cancer (NSCLC) has introduced yet another player in the field of management of advanced disease. At present, first-line cytotoxic chemotherapy is generally withheld pending results of molecular testing for any actionable genetic alteration that could lead to targeted treatment, and in their absence chemotherapy is prescribed as a default therapy. Phase III trials comparing head-to-head immune checkpoint inhibitors with standard platinum-based doublet chemotherapy are underway. Second-line chemotherapy is likewise being challenged in phase III trials, one of which having recently reported positive results in advanced squamous cell carcinoma. In tumors harboring actionable transforming genetic alterations such as EGFR mutations and ALK rearrangements, second- and third-generation inhibitors allow for multiple lines of targeted treatment beyond initial resistance, postponing the use of cytotoxic chemotherapy to very late lines of therapy. Chemotherapy as a longstanding but still present standard of care capable of prolonging survival, improving quality of life, and relieving symptoms sees its role increasingly restricted to clinical, immunological, and molecular subsets of patients where its activity and efficacy have never been tested prospectively.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.

BACKGROUND: One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS: We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS: From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION: Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING: Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

BRAF Alterations as Therapeutic Targets in Non-Small-Cell Lung Cancer.

BACKGROUND: Several subsets of non-small-cell lung cancer (NSCLC) are defined by molecular alterations acting as tumor drivers, some of them being currently therapeutically actionable. The rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway constitutes an attractive potential target, as v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations occur in 2-4% of NSCLC adenocarcinoma. METHODS: Here, we review the latest clinical data on BRAF serine/threonine kinase inhibitors in NSCLC. RESULTS: Treatment of V600E BRAF-mutated NSCLC with BRAF inhibitor monotherapy demonstrated encouraging antitumor activity. Combination of BRAF and MEK inhibitors using dabrafenib and trametinib is under evaluation. Preliminary data suggest superior efficacy compared with BRAF inhibitor monotherapy. CONCLUSION: Targeting BRAF alterations represents a promising new therapeutic approach for a restricted subset of oncogene-addicted NSCLC. Prospect ive trials refining this strategy are ongoing. A next step will probably aim at combining BRAF inhibitors and immunotherapy or alternatively improve a multilevel mitogen-activated protein kinase (MAPK) pathway blockade by combining with ERK inhibitors.

Eye-tracking of nodule detection in lung CT volumetric data.

PURPOSE: Signal detection on 3D medical images depends on many factors, such as foveal and peripheral vision, the type of signal, and background complexity, and the speed at which the frames are displayed. In this paper, the authors focus on the speed with which radiologists and naïve observers search through medical images. Prior to the study, the authors asked the radiologists to estimate the speed at which they scrolled through CT sets. They gave a subjective estimate of 5 frames per second (fps). The aim of this paper is to measure and analyze the speed with which humans scroll through image stacks, showing a method to visually display the behavior of observers as the search is made as well as measuring the accuracy of the decisions. This information will be useful in the development of model observers, mathematical algorithms that can be used to evaluate diagnostic imaging systems. METHODS: The authors performed a series of 3D 4-alternative forced-choice lung nodule detection tasks on volumetric stacks of chest CT images iteratively reconstructed in lung algorithm. The strategy used by three radiologists and three naïve observers was assessed using an eye-tracker in order to establish where their gaze was fixed during the experiment and to verify that when a decision was made, a correct answer was not due only to chance. In a first set of experiments, the observers were restricted to read the images at three fixed speeds of image scrolling and were allowed to see each alternative once. In the second set of experiments, the subjects were allowed to scroll through the image stacks at will with no time or gaze limits. In both static-speed and free-scrolling conditions, the four image stacks were displayed simultaneously. All trials were shown at two different image contrasts. RESULTS: The authors were able to determine a histogram of scrolling speeds in frames per second. The scrolling speed of the naïve observers and the radiologists at the moment the signal was detected was measured at 25-30 fps. For the task chosen, the performance of the observers was not affected by the contrast or experience of the observer. However, the naïve observers exhibited a different pattern of scrolling than the radiologists, which included a tendency toward higher number of direction changes and number of slices viewed. CONCLUSIONS: The authors have determined a distribution of speeds for volumetric detection tasks. The speed at detection was higher than that subjectively estimated by the radiologists before the experiment. The speed information that was measured will be useful in the development of 3D model observers, especially anthropomorphic model observers which try to mimic human behavior.

Available evidence on re-irradiation with stereotactic ablative radiotherapy following high-dose previous thoracic radiotherapy for lung malignancies.

Patients affected with intra-thoracic recurrences of primary or secondary lung malignancies after a first course of definitive radiotherapy have limited therapeutic options, and they are often treated with a palliative intent. Re-irradiation with stereotactic ablative radiotherapy (SABR) represents an appealing approach, due to the optimized dose distribution that allows for high-dose delivery with better sparing of organs at risk. This strategy has the goal of long-term control and even cure. Aim of this review is to report and discuss published data on re-irradiation with SABR in terms of efficacy and toxicity. Results indicate that thoracic re-irradiation may offer satisfactory disease control, however the data on outcome and toxicity are derived from low quality retrospective studies, and results should be cautiously interpreted. As SABR may be associated with serious toxicity, attention should be paid for an accurate patients' selection.

Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort.

INTRODUCTION: Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations, including V600E and other types. Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently tested in clinical trials, but access for patients is limited. The aim of this study was to document the clinical course of patients treated outside of clinical trials. METHODS: We conducted a retrospective multicenter cohort study in Europe of patients with advanced BRAF-mutant lung cancer treated with known BRAF inhibitors. Data were anonymized and centrally assessed for age, gender, smoking, histology, stage, local molecular diagnostic results, systemic therapies, and survival. Best response was assessed locally by RECIST1.1. RESULTS: We documented 35 patients treated in 17 centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63 years (range 42-85); gender was balanced; 14 (40%) were never smokers; all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other mutations; one of them had a concomitant KRAS mutation. Thirty (86%) patients had chemotherapy in the first line. Overall survival with first-line therapy was 25.3 months for V600E and 11.8 months for non-V600E. Thirty-one patients received one BRAF inhibitor, and four received a second inhibitor. Overall response rate with BRAF therapy was 53%, and disease control rate was 85%. Median progression-free survival with BRAF therapy was 5.0 months, and overall survival was 10.8 months. CONCLUSIONS: These results confirm the activity of targeted therapy in patients with BRAF-mutant lung adenocarcinoma. Further trials are warranted to study combination therapies and drug resistance mechanisms.

Chest CT at a dose below 0.3 mSv : impact of iterative reconstruction on image quality and lung analysis

Le nombre d'examens tomodensitométriques (Computed Tomography, CT) effectués chaque année étant en constante augmentation, différentes techniques d'optimisation, dont les algorithmes de reconstruction itérative permettant de réduire le bruit tout en maintenant la résolution spatiale, ont étés développées afin de réduire les doses délivrées. Le but de cette étude était d'évaluer l'impact des algorithmes de reconstruction itérative sur la qualité image à des doses effectives inférieures à 0.3 mSv, comparables à celle d'une radiographie thoracique. Vingt CT thoraciques effectués à cette dose effective ont été reconstruits en variant trois paramètres: l'algorithme de reconstruction, rétroprojection filtrée versus reconstruction itérative iDose4; la matrice, 5122 versus 7682; et le filtre de résolution en densité (mou) versus spatiale (dur). Ainsi, 8 séries ont été reconstruites pour chacun des 20 CT thoraciques. La qualité d'image de ces 8 séries a d'abord été évaluée qualitativement par deux radiologues expérimentés en aveugle en se basant sur la netteté des parois bronchiques et de l'interface entre le parenchyme pulmonaire et les vaisseaux, puis quantitativement en utilisant une formule de merit, fréquemment utilisée dans le développement de nouveaux algorithmes et filtres de reconstruction. La performance diagnostique de la meilleure série acquise à une dose effective inférieure à 0.3 mSv a été comparée à celle d'un CT de référence effectué à doses standards en relevant les anomalies du parenchyme pulmonaire. Les résultats montrent que la meilleure qualité d'image, tant qualitativement que quantitativement a été obtenue en utilisant iDose4, la matrice 5122 et le filtre mou, avec une concordance parfaite entre les classements quantitatif et qualitatif des 8 séries. D'autre part, la détection des nodules pulmonaires de plus de 4mm étaient similaire sur la meilleure série acquise à une dose effective inférieure à 0.3 mSv et le CT de référence. En conclusion, les CT thoraciques effectués à une dose effective inférieure à 0.3 mSv reconstruits avec iDose4, la matrice 5122 et le filtre mou peuvent être utilisés avec confiance pour diagnostiquer les nodules pulmonaires de plus de 4mm.

Why and how would we implement a lung cancer screening program?

For decades, lung cancer has been the most common cancer in terms of both incidence and mortality. There has been very little improvement in the prognosis of lung cancer. Early treatment following early diagnosis is considered to have potential for development. The National Lung Screening Trial (NLST), a large, well-designed randomized controlled trial, evaluated low-dose computed tomography (LDCT) as a screening tool for lung cancer. Compared with chest X-ray, annual LDCT screening reduced death from lung cancer and overall mortality by 20 and 6.7 %, respectively, in high-risk people aged 55-74 years. Several smaller trials of LDCT screening are under way, but none are sufficiently powered to detect a 20 % reduction in lung cancer death. Thus, it is very unlikely that the NLST results will be replicated. In addition, the NLST raises several issues related to screening, such as the high false-positive rate, overdiagnosis and cost. Healthcare providers and systems are now left with the question of whether the available findings should be translated into practice. We present the main reasons for implementing lung cancer screening in high-risk adults and discuss the main issues related to lung cancer screening. We stress the importance of eligibility criteria, smoking cessation programs, primary care physicians, and informed-decision making should lung cancer screening be implemented. Seven years ago, we were waiting for the results of trials. Such evidence is now available. Similar to almost all other cancer screens, uncertainties exist and persist even after recent scientific efforts and data. We believe that by staying within the characteristics of the original trial and appropriately sharing the evidence as well as the uncertainties, it is reasonable to implement a LDCT lung cancer screening program for smokers and former smokers.

Non-small cell lung cancer: the prevalence of oncogenic driver mutations in Switzerland

Background. Predictive molecular marker analyses are standard of care in order to select non-small cell lung cancer (NSCLC) patients for targeted therapies. The aim of this study was to determine the prevalence of targetable oncogenic driver mutations including EGFR, KRAS, BRAF, HER2, ALK and ROS1 in Switzerland. Methods. Eight Swiss pathology institutions provided retrospective and anonymized data on their predictive molecular marker results performed on NSCLC from January 2012 to December 2014. Clinico-pathological data were recorded including age, gender, histological NSCLC-subtype and specimen type (biopsy, conventional cytology and cell block, respectively) used for molecular analyses. The prevalence of oncogenic mutations were calculated and compared between the centres. Results. A total of 4187 NSCLC were included into the study. The median age was 67 years and 55% were male patients. The tumor specimens for molecular analysis were mostly derived from biopsies (69%), 26% were from conventional cytology specimens and only in 5% from cell blocks. The most prevalent gene mutation was KRAS with 30.6% (range: 27.3-33.9%), followed by EGFR, BRAF and HER2 mutations in 12.2% (range: 10.2-13.1%), 3.9% (range: 2.5-5.6%) and 1.1% (range: 0.9-4.0%), respectively, without significant differences between the eight centers. Concomitant EGFR and KRAS mutations were detected in only 3/2027 NSCLC. In contrast the prevalence of ALK (mean 6.5%, range: 2.8-11.7%) and ROS1 (mean 2.4%, range: 1.5-6.2%) rearrangements varied significantly between centers. Conclusions. The Prevalence of EGFR, KRAS, BRAF and HER2 mutations are well in line with data from other West European populations. Concomitant EGFR, KRAS, BRAF or HER2 mutations are exceptional. ALK FISH results vary significantly between the eight centres. Concomitant ALK FISH positive results in NSCLC harbouring other oncogenic driver mutation have only been observed in two smaller centres, highlighting the difficulty in ALK-FISH interpretation.

Clinical outcomes of lung transplant recipients with telomerase mutations.

BACKGROUND: Successful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations. METHODS: Subjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations. RESULTS: The median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive. CONCLUSIONS: The clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations.

Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy.

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging.

Cyclooxygenase-2 Expression in Non-Small Cell Lung Cancer Correlates With Hypertrophic Osteoarthropathy.

Hypertrophic osteoarthrpathy (HO) is a rare paraneoplasic syndrome associated with non-small cell lung cancer (NSCLC). The pathophysiology of HO is unknown but was recently related to enhanced levels of urine prostaglandin E2 (PGE2). Here, we report the case of a patient that presented HO in association with a resectable left upper lobe NSCLC. Following surgery and adjuvant chemotherapy, HO resolved and did not recur with development of a brain metastasis 1 year later. Interestingly, tumor cyclooxygenase-2, an enzyme responsible the synthesis of PGE2, was expressed in the primary tumor but not in the resected metastasis.

Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression.

An increased expression of nitric oxide synthase (NOS) has been observed in human colon carcinoma cell lines as well as in human gynecological, breast, and central nervous system tumors. This observation suggests a pathobiological role of tumor-associated NO production. Hence, we investigated NOS expression in human colon cancer in respect to tumor staging, NOS-expressing cell type(s), nitrotyrosine formation, inflammation, and vascular endothelial growth factor expression. Ca2+-dependent NOS activity was found in normal colon and in tumors but was significantly decreased in adenomas (P < 0.001) and carcinomas (Dukes' stages A-D: P < 0.002). Ca2+-independent NOS activity, indicating inducible NOS (NOS2), is markedly expressed in approximately 60% of human colon adenomas (P < 0.001 versus normal tissues) and in 20-25% of colon carcinomas (P < 0.01 versus normal tissues). Only low levels were found in the surrounding normal tissue. NOS2 activity decreased with increasing tumor stage (Dukes' A-D) and was lowest in colon metastases to liver and lung. NOS2 was detected in tissue mononuclear cells (TMCs), endothelium, and tumor epithelium. There was a statistically significant correlation between NOS2 enzymatic activity and the level of NOS2 protein detected by immunohistochemistry (P < 0.01). Western blot analysis of tumor extracts with Ca2+-independent NOS activity showed up to three distinct NOS2 protein bands at Mr 125,000-Mr 138,000. The same protein bands were heavily tyrosine-phosphorylated in some tumor tissues. TMCs, but not the tumor epithelium, were immunopositive using a polyclonal anti-nitrotyrosine antibody. However, only a subset of the NOS2-expressing TMCs stained positively for 3-nitrotyrosine, which is a marker for peroxynitrite formation. Furthermore, vascular endothelial growth factor expression was detected in adenomas expressing NOS2. These data are consistent with the hypothesis that excessive NO production by NOS2 may contribute to the pathogenesis of colon cancer progression at the transition of colon adenoma to carcinoma in situ.