Incidental Pulmonary Nodules - What Do We Know in 2022.

Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, and early LC diagnosis can significantly improve outcomes and survival rates in affected patients. Implementation of LC screening programs using low-dose computed tomography CT in high-risk subjects aims to detect LC as early as possible, but so far, adoption of screening programs into routine clinical care has been very slow. In recent years, the use of CT has significantly increased the rate of incidentally detected pulmonary nodules. Although most of those incidental pulmonary nodules (IPNs) are benign, some of them represent early-stage LC. Given the large number of IPNs detected in the range of several millions each year, this represents an additional, maybe even larger, opportunity to drive stage shift in LC diagnosis, next to LC screening programs. Comprehensive evaluation and targeted work-up of IPNs are mandatory to identify the malignant nodules from the crowd, and several guidelines provide radiologists and physicians' guidance on IPN assessment and management. However, IPNs still seem to be inadequately processed due to various reasons including insufficient reporting in the radiological report, missing communication between stakeholders, absence of patient tracking systems, and uncertainty regarding responsibilities for the IPN management. In recent years, several approaches such as lung nodule programs, patient tracking software, artificial intelligence, and communication software were introduced into clinical practice to address those shortcomings. This review evaluates the current situation of IPN management and highlights recent developments in process improvement to achieve first steps toward stage shift in LC diagnosis.

Protocol of a Randomized Controlled Study of the PneumRx Endobronchial Coil System versus Standard-of-Care Medical Management in the Treatment of Subjects with Severe Emphysema (ELEVATE).

BACKGROUND: The PneumRx endobronchial coil system for patients with severe emphysema has been shown to improve quality of life, exercise capacity, and pulmonary function in patients with emphysema. A post hoc analysis of the RENEW trial has identified patient characteristics and lobar selection methods associated with improved outcomes, which have to be confirmed prospectively. METHODS: The ELEVATE trial is a prospective, multicenter, open label, randomized (2:1), controlled trial comparing outcomes in patients treated with endobronchial coils (treatment) to a medically managed control group (control). The trial aims to enroll 210 patients (140 in the treatment group and 70 in the control group) with severe emphysema. Control patients will be eligible to crossover to coil treatment after 6 months of follow-up. The co-primary effectiveness endpoints are percent change in forced expiratory volume in 1 s and quality of life measured by change in St. George's Respiratory Questionnaire from baseline to 6 months. Secondary objectives are determination of responder rates of clinical endpoints and mean change in other functional and physiologic endpoints. All patients will be followed for 24 months after initial treatment. Adverse events will be collected on an ongoing basis throughout the trial. DISCUSSION: The primary objective of the ELEVATE trial is to prospectively confirm the safety and effectiveness profile of the coil system for the treatment of severe emphysema in consideration of the findings of previous randomized controlled trials. Secondary objectives are the determination of responder rates in all clinical endpoints and mean change in physiologic endpoints.

Epithelial phenotype as a predictive marker for response to EGFR-TKIs in non-small cell lung cancer patients with wild-type EGFR.

Epithelial-to-mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Nowadays, there is still no predictive biomarker identified for the use of EGFR-TKIs in non-small cell lung cancer (NSCLC) patients with wild-type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR-TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from June 2008 to September 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E-cadherin, fibronectin, N-cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (p = 0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5 vs. 11.1 vs. 0.0 vs. 2.4%, p = 0.011), longer progression-free survival (4.4 vs. 1.9 vs. 1.7 vs. 1.0 months, p < 0.001) and longer overall survival (11.5 vs. 8.9 vs. 4.5 vs. 4.9 months, p < 0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild-type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild-type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR-TKI therapy in this population.

Quantitative lung perfusion evaluation using Fourier decomposition perfusion MRI.

PURPOSE: To quantitatively evaluate lung perfusion using Fourier decomposition perfusion MRI. The Fourier decomposition (FD) method is a noninvasive method for assessing ventilation- and perfusion-related information in the lungs, where the perfusion maps in particular have shown promise for clinical use. However, the perfusion maps are nonquantitative and dimensionless, making follow-ups and direct comparisons between patients difficult. We present an approach to obtain physically meaningful and quantifiable perfusion maps using the FD method. METHODS: The standard FD perfusion images are quantified by comparing the partially blood-filled pixels in the lung parenchyma with the fully blood-filled pixels in the aorta. The percentage of blood in a pixel is then combined with the temporal information, yielding quantitative blood flow values. The values of 10 healthy volunteers are compared with SEEPAGE measurements which have shown high consistency with dynamic contrast enhanced-MRI. RESULTS: All pulmonary blood flow (PBF) values are within the expected range. The two methods are in good agreement (mean difference = 0.2 mL/min/100 mL, mean absolute difference = 11 mL/min/100 mL, mean PBF-FD = 150 mL/min/100 mL, mean PBF-SEEPAGE = 151 mL/min/100 mL). The Bland-Altman plot shows a good spread of values, indicating no systematic bias between the methods. CONCLUSION: Quantitative lung perfusion can be obtained using the Fourier Decomposition method combined with a small amount of postprocessing.

Quantitative lung ventilation using Fourier decomposition MRI; comparison and initial study.

OBJECTIVE: The Fourier decomposition (FD) method is a noninvasive method for assessing ventilation and perfusion-related information in the lungs, but the lack of quantifiable values is a drawback. We demonstrate a novel technique for quantification of the FD ventilation maps, compare it to two published methods, and show results from both healthy volunteers and patients diagnosed with lung cancer. MATERIALS AND METHODS: We quantified the standard FD ventilation images by utilizing additional information, i.e., the zero-frequency component image, which is also obtained from the Fourier analysis. This image acts as a baseline for the changes recorded in the FD ventilation image and can therefore be used to calculate the ventilation. Using this technique, we compared the ventilation values from ten healthy volunteers and ten patients to two previously published methods for quantitative ventilation assessment. RESULTS: All methods showed good overall agreement (mean difference between the methods was 14-38 ml/min). The mean minute ventilation for the FD method was calculated to be 693 ml/min for a 2D slice, which is in the expected range. CONCLUSION: The zero-frequency component image can be used as a baseline to quantify the FD ventilation maps. Our initial study showed good agreement with published methods in healthy volunteers, but less so in patients with lung cancer.

Is arterial pulse contour analysis using Nexfin a new option in the noninvasive measurement of cardiac output?--A pilot study.

OBJECTIVES: A growing interest in monitoring cardiac output (CO) noninvasively has emerged; however, its determination has been difficult using the standard approaches. The aim of this study was to evaluate the accuracy and precision of pulse contour analysis (PCA) compared with cardiac magnetic resonance imaging (CMR). DESIGN: A single-center prospective study. SETTING: A university hospital. PARTICIPANTS: Thirty-nine consecutive stable patients undergoing CMR. INTERVENTIONS: CO was determined twice by PCA using the Nexfin monitoring system (BMEYE BV, Amsterdam, The Netherlands). Measurements were performed after 10 minutes of rest in a stable supine position immediately before or after the CMR examination. MEASUREMENTS AND MAIN RESULTS: There was a mean bias of 0.2 ± 1.9 L/min between CMR and PCA and a reproducibility of 0.2 ± 0.6 L/min for PCA. Between 4.8 and 6.3 L/min (second quartile of COCMR), there was a good agreement (mean bias = -0.2 ± 1.3 L/min). Comparing quartile 1 (-1.3 ± 2.0 L/min) overestimating and quartiles 3 (1.4 ± 0.9 L/min) and 4 (0.9 ± 2.0 L/min) underestimating CO, a statistically significant difference was found. The reproducibility was not affected by the quartile (p = 0.23, analysis of variance), whereas there was a significant difference between the nonoutlier and outlier group when using the Mann-Whitney U test (p = 0.02). CONCLUSIONS: Noninvasive PCA allows the safe and economic measurement of CO, yet it still has major limitations. Although the agreement with CMR was acceptable, there was a clinically unacceptable variation; absolute values should not be used interchangeably. These results suggest that therapeutic interventions and clinical decisions should not be based on noninvasive PCA measurements at the present time.

Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement may predict the outcome of targeted drug therapy and also are associated with the efficacy of chemotherapy in patients with nonsmall cell lung cancer (NSCLC). The authors of this report investigated the relation of EGFR mutation or ALK rearrangement status and the expression of DNA repair or synthesis genes, including excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS), and breast cancer-early onset (BRCA1), as a potential explanation for these observations. METHODS: In total, 104 resected lung adenocarcinomas from women who were nonsmokers were analyzed concurrently for EGFR mutations, ALK rearrangements, and mRNA expression of the ERCC1, RRM1, TS, and BRCA1 genes. EGFR mutations were detected with a proprietary detection kit, ALK rearrangements were detected by polymerase chain reaction analysis, and genetic mRNA expression was detected by real-time polymerase chain reaction analysis. RESULTS: Of 104 patients, 73 (70.2%) had EGFR mutations, and 10 (9.6%) had ALK rearrangements. ERCC1 mRNA levels in patients who had EGFR mutations were 3.44 ± 1.94 × 10(-3) , which were significantly lower than the levels in patients who were positive for ALK rearrangements and in patients who were negative for both biomarkers (4.60 ± 1.95 × 10(-3) and 4.95 ± 2.33 × 10(-3) , respectively; P = .010). However, TS mRNA levels were significantly lower in patients who had EGFR mutations (1.15 ± 1.38 × 10(-3) vs 2.69 ± 3.97 × 10(-3) ; P = .006) or ALK rearrangements (1.21 ± 0.78 × 10(-3) vs 2.69 ± 3.97 × 10(-3) ; P = .020) than in patients who were negative for both biomarkers. CONCLUSIONS: NSCLC specimens that harbored activating EGFR mutations were more likely to express low ERCC1 and TS mRNA levels, whereas patients with NSCLC who had ALK rearrangement were more likely to express low TS mRNA levels.

Predicting malignancy in mediastinal lymph nodes by endobronchial ultrasound: a new ultrasound scoring system.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound (EBUS) is now widely used in patients with resectable non-small-cell lung cancer to sample mediastinal lymph nodes (LN) for preoperative staging. The aim of this study was to investigate prospectively the utility of six ultrasound criteria to predict malignancy in mediastinal LN. METHODS: EBUS was performed in patients with mediastinal lymphadenopathy irrespective of the underlying disease. The following criteria were expected to predict malignancy: short axis >1 cm, heterogeneous pattern, round shape, distinct margin, absence of a central hilar structure and high blood flow in a LN. A sum score prediction model for malignancy was built. If more than two criteria were present, LN was classified as high risk for malignancy. Moreover, interrater variability of two blinded investigators was evaluated. RESULTS: Two hundred eighty-one LN in 145 patients were analysed. Forty-four percent of LN were found malignant, 10% revealed sarcoidosis, and 10% revealed tuberculosis. Interobserver agreement was very good. Positive predictive value was best for heterogeneity (73%), with a negative predictive value of more than 80%. The sum score resulted in an odds ratio of 15.5 if more than two criteria were positive (P < 0.00001). CONCLUSIONS: The assessment of ultrasound criteria during routine EBUS examinations is feasible and reproducible with very good interrater agreement. If less than three of the described criteria are present, a LN has a very low chance of being malignant. The best single criterion to predict malignancy is heterogeneity. The introduction of the sum score of ultrasound criteria could potentially increase diagnostic accuracy.

Design and Rationale of the HANSE Study: A Holistic German Lung Cancer Screening Trial Using Low-Dose Computed Tomography.

Despite the high prevalence and mortality of lung cancer and proven effectiveness of low-dose computed tomography (LDCT) to reduce mortality, Germany still lacks a national screening program. The German Institute for Quality and Efficiency in Health Care (IQWiG) and the Federal Office for Radiation Protection (BfS) both published positive scientific evaluations recommending a quality-controlled national screening program. IQWiG underlined the importance of a clear risk definition, integrated smoking cessation programs, and quality assurance, highlighting the necessity of procedural optimization.In the HANSE study, former and current smokers aged 55-79 years are assessed for their lung cancer risk by the NELSON and PLCOM2012 risk scores. 5000 high-risk participants, defined as PLCOM2012 6-year risk ≥ 1.58 % or fulfilling NELSON risk inclusion criteria, will be screened by LDCT at baseline and after 12 months. Lung nodules are analyzed by a modified Lung-RADS 1.1 score of the HANSE study, and values of emphysema and coronary calcium are determined and randomly reported to the participants. 7100 low-risk participants serve as a control. All patients are followed-up for up to 10 years. The sensitivity and specificity of the two risk assessments and LDCT screening, effects of the randomized LDCT reporting, efficiency of lung nodule management, and several other factors are assessed to analyze the success and quality of the holistic screening program.The HANSE study is designed as a holistic lung cancer screening study in northern Germany to answer pressing questions for a successful implementation of an effective German lung cancer screening program. · HANSE is designed to address pressing questions for the implementation of lung cancer screening in Germany.. · HANSE compares NELSON and PLCOM2012 risk assessments for optimal definition of the high-risk group. . · HANSE integrates cardiac calcium and pulmonary emphysema scoring in a holistic screening approach.. CITATION FORMAT: · Vogel-Claussen J, Lasch F, Bollmann B et al. Design and Rationale of the HANSE Study: A Holistic German Lung Cancer Screening Trial Using Low-Dose Computed Tomography. Fortschr Röntgenstr 2022; 194: 1333 - 1345.

A randomized, multicenter phase II study comparing efficacy, safety and tolerability of two dosing regimens of cisplatin and pemetrexed in patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor-chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule. METHODS: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 (arm A), or pemetrexed 500 mg/m2 (day 1) and cisplatin 40 mg/m2 (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life. RESULTS: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1-6) and five (1-6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34-1.62), p = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68-1.68), p = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17-2.38); p = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B. CONCLUSION: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT) number 2011-001963-37.

Predictors of Response to Endobronchial Coil Therapy in Patients With Advanced Emphysema.

BACKGROUND: The Lung Volume Reduction Coil Treatment in Patients With Emphysema (RENEW) trial reported improvements in quality of life, pulmonary function, and exercise performance following endobronchial coil treatment. OBJECTIVES: The purpose of this post hoc analysis was to identify baseline predictors, including quantitative CT measures, that identify patients most likely to significantly benefit from endobronchial coil therapy. METHODS: Quantitative CT analysis by an independent radiology laboratory and a qualitative evaluation by five blinded experts of the baseline thoracic CT imaging were performed. Univariate and multivariate logistic regression analyses were performed to elucidate characteristics associated with clinical response. RESULTS: In total, 125 patients underwent coil treatment and had evaluable 12-month follow-up results. Of these, 78 patients received treatment of lobes with the highest emphysematous destruction determined by quantitative CT analysis (quantitative visual match [QVM]+), and 47 received treatment in at least one lobe that was not the most destroyed (QVM-). From the 78 patients with QVM+ treatment, a subgroup of 50 patients (64%) was identified with baseline residual volume > 200% predicted, emphysema score > 20% low attenuation area, and absence of airway disease. In this subgroup, greater lobar residual volume reduction in the treated lobes was achieved, which was associated with significant mean ± SE improvement in FEV1 (15.2 ± 3.1%), St. George's Respiratory Questionnaire (-12 ± 2 points), and residual volume (-0.57 ± 0.13 L). DISCUSSION: This post hoc analysis found that both significant hyperinflation (residual volume ≥ 200% predicted) and CT analysis are critical for patient selection and treatment planning for endobronchial coil therapy. Quantitative CT analysis is important to identify optimal lobar treatment and to exclude patients with insufficient emphysema (< 20% low attenuation area), whereas visual assessment identifies patients with signs of airway disease associated with worse outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01608490; URL: www.clinicaltrials.gov.

KRAS-Mutant non-small cell lung cancer: From biology to therapy.

In patients with non-small cell lung cancer (NSCLC), the most frequent oncogene driver mutation in Western countries is Kirsten rat sarcoma viral oncogene homolog (KRAS), and KRAS-mutant NSCLC is associated with smoking. There are various sources of biological heterogeneity of KRAS-mutant NSCLC, including different genotypes that may be associated with specific clinical outcomes, the presence of other co-mutations that exhibit different biological features and drug sensitivity patterns, and mutant allelic content. The efficacy of chemotherapy in patients with KRAS-mutant NSCLC is generally poor and numerous novel therapeutic strategies have been developed. These approaches include targeting KRAS membrane associations, targeting downstream signalling pathways, the use of KRAS synthetic lethality, direct targeting of KRAS, and immunotherapy. Of these, immunotherapy may be one of the most promising treatment approaches for patients with KRAS-mutant NSCLC. Recent data also suggest the potential for distinct efficacy of immunotherapy according to the presence of other co-mutations. In view of the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualised and, in future, may require the use of rational combinations of treatment, many of which are currently under investigation.

Dynamic volume perfusion computed tomography parameters versus RECIST for the prediction of outcome in lung cancer patients treated with conventional chemotherapy.

INTRODUCTION: To compare dynamic volume perfusion computed tomography (dVPCT) parameters with Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for prediction of therapy response and overall survival (OS) in non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients treated with conventional chemotherapy. METHODS: A total of 173 lung cancer patients (131 men; 61 ± 10 years) undergoing dVPCT before (T1) and after chemotherapy (T2) and follow-up were prospectively included. dVPCT-derived blood flow, blood volume, mean transit time, and permeability (PERM) were assessed, compared between NSCLC and SCLC and patients' response to therapy was determined according to RECIST 1.1. RESULTS: One hundred of one hundred and seventy-three patients underwent dVPCT at T1 and T2 within a median of 44 (range, 31-108) days. dVPCT values were differing in NSCLC and SCLC, but were not significantly differing between patients with partial response, stable, or progressive disease. Eighty-five patients (NSCLC = 72 and SCLC = 13) with a follow-up for greater than or equal to 6 months were analyzed for OS. Fifty-six of eighty-five patients died during follow-up. Receiver operating characteristic analysis determined T1/T2 with highest predictive values regarding OS for blood flow, blood volume, mean transit time, and permeability (area under the curve: 0.53, 0.61, 0.54, and 0.53, respectively, all p > 0.05). Kaplan-Meier statistics revealed OS of patient groups assigned according to dVPCT T1/T2 cutoff values was not differing for neither dVPCT parameter, whereas RECIST groups significantly differed in OS (p = 0.02). Cox proportional hazards regression determined progressive disease status to independently predict OS (p = 0.004), while none of the dVPCT parameters did so. CONCLUSIONS: dVPCT values, differ between NSCLC and SCLC, are not related to RECIST 1.1 classification and do not improve OS prediction in lung cancer patients treated with conventional chemotherapy.

Non-invasive quantitative pulmonary V/Q imaging using Fourier decomposition MRI at 1.5T.

OBJECTIVES: Techniques for quantitative pulmonary perfusion and ventilation using the Fourier Decomposition method were recently demonstrated. We combine these two techniques and show that ventilation-perfusion (V/Q) imaging is possible using only a single MR acquisition of less than thirty seconds. METHODS: The Fourier Decomposition method is used in combination with two quantification techniques, which extract baselines from within the images themselves and thus allows quantification. For the perfusion, a region assumed to consist of 100% blood is utilized, while for the ventilation the zero-frequency component is used. V/Q-imaging is then done by dividing the quantified ventilation map with the quantified perfusion map. The techniques were used on ten healthy volunteers and fifteen patients diagnosed with lung cancer. RESULTS: A mean V/Q-ratio of 1.15 ± 0.22 was found for the healthy volunteers and a mean V/Q-ratio of 1.93 ± 0.83 for the non-afflicted lung in the patients. Mean V/Q-ratio in the afflicted (tumor-bearing) lung was found to be 1.61 ± 1.06. Functional defects were clearly visible in many of the patient images, but 5 of 15 patient images had to be excluded due to artifacts or low SNR, indicating a lack of robustness. CONCLUSION: Non-invasive, quantitative V/Q-imaging is possible using Fourier Decomposition MRI. The method requires only a single acquisition of less than 30 seconds, but robustness in patients remains an issue.

Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: A double blind randomised phase III study of the lung cancer group, EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064).

BACKGROUND: Switch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC. METHODS: Patients with non-progressive disease after 4-6 cycles of chemotherapy were randomised to receive either pazopanib 800mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety. RESULTS: A total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n=50) or placebo (n=52). Median age was 64years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40-1.28]; p=0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43-1.03], p=0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1-2. Grade 3-4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE. CONCLUSIONS: Switch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis.

A randomized Phase 2 study of pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in patients with completely resected stage IB or II Non-Small-Cell Lung Cancer.

OBJECTIVES: We investigated the feasibility of cisplatin or carboplatin combined with pemetrexed as adjuvant treatment in patients with completely resected Stage IB/II Non-Small-Cell Lung Cancer (NSCLC). MATERIALS AND METHODS: Patients in this multicenter, open-label, parallel-group, non-comparative Phase 2 study were randomized (1:1) to pemetrexed (500 mg/m(2)) with either cisplatin (75 mg/m(2)) or carboplatin (AUC5) for 4 cycles of 21 days. The primary endpoint was treatment feasibility (defined as 4 cycles completed with no cycle delay >42 days and ≤2 dose reductions, with a median relative dose intensity (RDI) ≥95% [overall]; and no Grade ≥3 toxicities at the follow-up visit 30 days after last drug administration). Secondary objectives included overall survival (OS) and safety. RESULTS: We randomized 122 patients and treated 118. 71.9% (46/64) of patients in pemetrexed+cisplatin and 88.9% (48/54) in pemetrexed+carboplatin completed 4 cycles (median RDI >97% for all compounds). Neither treatment met the pre-defined feasibility level >60% of patients: 59.4% (95% confidence interval [CI]: 46.4;71.5) pemetrexed+cisplatin; 50.0% (95%CI: 36.1;63.9) in pemetrexed+carboplatin. In a post-hoc analysis considering only safety, both regimens were feasible with 81.3% (95%CI: 69.5;89.9) in pemetrexed+cisplatin and 90.7% (95%CI: 79.7;96.9) in pemetrexed+carboplatin. OS rates for both groups were 82-83% after 3 years and 80-83% after 5 years. Treatment-related Grade ≥3 adverse events (mostly hematological) were experienced by approximately 30% of patients in each group. CONCLUSION: Although the study did not meet the primary objective, both treatment groups demonstrated good safety-related feasibility and tolerability as adjuvant treatment in patients with completely resected Stage IB/II NSCLC.

High Discrepancy of Driver Mutations in Patients with NSCLC and Synchronous Multiple Lung Ground-Glass Nodules.

BACKGROUND: The aim of this study was to investigate the discordance rates of eight known driver mutations among multiple matched intrapulmonary ground-glass nodules (GGNs) in non-small-cell lung cancer (NSCLC) patients. METHODS: Tumors from 35 patients with multiple lesions resected, including confirmed NSCLC and at least one GGN, were analyzed for mutations in EGFR, KRAS, HER2, BRAF, and PIK3CA together with fusions in ALK, ROS1, and RET. RESULTS: From 35 patients, a total of 72 lesions (60 were GGNs) were analyzed. These included nine adenocarcinoma in situ, nine minimal invasive adenocarcinoma, and 54 invasive adenocarcinoma. Among them, 33 tumor lesions (45.8 %) were found harboring EGFR mutations: 13 tumors with exon 19 deletion, 18 with L858R on exon 21, and two with both exon 19 del and L858R mutation. There were 5 tumors (6.9 %) harboring EML4-ALK fusion, four HER2 mutations (5.6%), three KRAS mutations (4.2%), one ROS1 fusion and one BRAF mutation. When we used the matched tumors to determine the intertumor discrepancy, only six out of 30 patients harbored identical mutations. The discordance rate of driver mutations was 80% (24 of 30) in those patients harboring at least one of the detected driver mutations. The median disease-free survival was 41.2 months (95% confidence interval: 35.8-52.6 months) and the median overall survival was "still not reached" in this cohort. CONCLUSIONS: We found a high discrepancy of driver mutations among NSCLC patients with GGNs and a favorable prognosis after multiple lesions resection, which support surgical resection in this situation as a reasonable approach.

Perspectives of novel imaging techniques for staging, therapy response assessment, and monitoring of surveillance in lung cancer: summary of the Dresden 2013 Post WCLC-IASLC State-of-the-Art Imaging Workshop.

Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fact that conventional approaches for therapy response assessment such as Response Evaluation Criteria in Solid Tumors or World Health Organization criteria-that exclusively focus on the change in tumor size-are of less value for response assessment in modern thoracic oncology. The aim of this article comprises two parts: a short review of the most promising state-of-the-art imaging techniques that have the potential to play a larger role in thoracic oncology within the near future followed by a meeting report including recommendations of an interdisciplinary expert panel that discussed the potential of the different techniques during the Dresden 2013 Post World Congress of Lung Cancer (WCLC)--International Association for the Study of Lung Cancer (IASLC) meeting. It is intended to provide a comprehensive summary about ongoing trends and future perspectives on functional imaging in thoracic oncology.

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.

T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients.

BACKGROUND AND PURPOSE: Continuous EGFR-TKI treatment beyond progression has shown promising benefit for some patients with acquired resistance to EGFR-TKIs. The aim of this study was to investigate the association of secondary T790M mutation at the time of progression with the efficacy of EGFR-TKI treatment beyond progression. METHODS: From March 2011 to March 2013, patients with advanced NSCLC who developed acquired resistance to EGFR-TKI and where a re-biopsy was performed at Tongji University Cancer Institute were included into this study. Scorpion ARMS was used to detect EGFR mutation status. RESULTS: A total of 54 patients were enrolled in this study with a median progression-free survival time (PFS1) of 10.9 months according to RECIST criteria. In all, 53.7% (29/54) had T790M mutation after the failure of EGFR-TKIs; PFS1 was not statistically significantly different between patients with T790M mutation and without (13.0 vs. 10.5 months, p = 0.894). In all, 41 patients received TKI treatment beyond progression, including 22 with local progression to receive additional local therapy and 19 with gradual progression to receive additional chemotherapy. The median progression-free survival time (PFS2) of patients who received EGFR-TKI beyond progression treatment was 3.5 months (95% CI, 2.689-4.311). Patients with T790M mutation had significantly longer PFS2 (6.3 vs. 2.6 months, p = 0.002) and overall survival (39.8 vs. 23.2 months, p = 0.044) than those without. CONCLUSION: Patients with secondary T790M mutation at the time of progression having gradual or local progression after acquired resistance to EGFR-TKI benefit more from EGFR-TKI treatment beyond progression compared to those without T790M mutation.