IMPORTANCE Many patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy show primary resistance. High-dose radiotherapy can lead to increased tumor antigen release, improved antigen presentation, and T-cell infiltration. This radiotherapy may enhance the effects of checkpoint inhibition.OBJECTIVE To assess whether stereotactic body radiotherapy on a single tumor site preceding pembrolizumab treatment enhances tumor response in patients with metastatic NSCLC. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized phase 2 study (PEMBRO-RT) of 92 patients with advanced NSCLC enrolled between July 1, 2015, and March 31, 2018, regardless of programmed death-ligand 1 (PD-L1) status. Data analysis was of the intention-to-treat population.INTERVENTIONS Pembrolizumab (200 mg/kg every 3 weeks) either alone (control arm) or after radiotherapy (3 doses of 8 Gy) (experimental arm) to a single tumor site until confirmed radiographic progression, unacceptable toxic effects, investigator decision, patient withdrawal of consent, or a maximum of 24 months. MAIN OUTCOMES AND MEASURESImprovement in overall response rate (ORR) at 12 weeks from 20% in the control arm to 50% in the experimental arm with P < .10. RESULTSOf the 92 patients enrolled, 76 were randomized to the control arm (n = 40) or the experimental arm (n = 36). Of those, the median age was 62 years (range, 35-78 years), and 44 (58%) were men. The ORR at 12 weeks was 18% in the control arm vs 36% in the experimental arm (P = .07). Median progression-free survival was 1.9 months (95% CI, 1.7-6.9 months) vs 6.6 months (95% CI, 4.0-14.6 months) (hazard ratio, 0.71; 95% CI, 0.42-1.18; P = .19), and median overall survival was 7.6 months (95% CI, 6.0-13.9 months) vs 15.9 months (95% CI, 7.1 months to not reached) (hazard ratio, 0.66; 95% CI, 0.37-1.18; P = .16). Subgroup analyses showed the largest benefit from the addition of radiotherapy in patients with PD-L1-negative tumors. No increase in treatment-related toxic effects was observed in the experimental arm.CONCLUSIONS AND RELEVANCE Stereotactic body radiotherapy prior to pembrolizumab was well tolerated. Although a doubling of ORR was observed, the results did not meet the study's prespecified end point criteria for meaningful clinical benefit. Positive results were largely influenced by the PD-L1-negative subgroup, which had significantly improved progression-free survival and overall survival. These results suggest that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC toward a more inflamed tumor microenvironment.

Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.

PurposeTo assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomorgraphy/computed tomography (PET/CT) studies.ProceduresEleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (n = 19) were delineated twice, once on PET and once on CT images.ResultsSixty-three features showed an intraclass correlation coefficient ≥ 0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively).ConclusionsThe majority of features in NSCLC [18F]FDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-0940-2) contains supplementary material, which is available to authorized users.

Unfit patients with ultracentral tumors who were treated using this scheme had a high local control and a median survival of 15.9 months. Despite manifestation of rates of a fatal lung bleeding comparable to those seen with conventional radiotherapy for endobronchial tumors, the overall rate of G5 toxicity is of potential concern. Additional work is needed to identify tumor and treatment factors related to hemorrhage.

PET with the glucose analog 18 F-FDG is increasingly used to monitor tumor response to therapy. To use quantitative measurements of tumor 18 F-FDG uptake for assessment of tumor response, the repeatability of this quantitative metabolic imaging method needs to be established. Therefore, we determined the repeatability of different standardized uptake value (SUV) measurements using the available data. Methods: A systematic literature search was performed to identify studies addressing 18 F-FDG repeatability in malignant tumors. The level of agreement between test and retest values of 2 PET uptake measures, maximum SUV (SUV max ) and mean SUV (SUV mean ), was assessed with the coefficient of repeatability using generalized linear mixed-effects models. In addition, the influence of tumor volume on repeatability was assessed. Principal component transformation was used to compare the reproducibility of the 2 different uptake measures. Results: Five cohorts were identified for this metaanalysis. For SUV max and SUV mean , datasets of 86 and 102 patients, respectively, were available. Percentage repeatability is a function of the level of uptake. SUV mean had the best repeatability characteristics; for serial PET scans, a threshold of a combination of 20% as well as 1.2 SUV mean units was most appropriate. After adjusting for uptake rate, tumor volume had minimal influence on repeatability. Conclusion: SUV mean had better repeatability performance than SUV max . Both measures showed poor repeatability for lesions with low 18 F-FDG uptake. We recommend the evaluation of biologic effects in PET by reporting a combination of minimal relative and absolute changes to account for test-retest variability.

In addition to tumor size measurements with CT, there is a need for quantitative measurements of metabolic active volumes, possibly adding to tracer uptake measurements in oncologic response evaluation with PET. The aim of this study was to evaluate the metabolic volume test-retest variability in 18 F-FDG and 39-deoxy-39-18 F-fluorothymidine ( 18 F-FLT) PET studies for various commonly used volumes of interest (VOIs) and the dependence of that variability on lesion size and relative radiotracer uptake. Methods: Twenty non-small cell lung cancer patients were scanned twice with 18 F-FDG (n 5 11) or 18 F-FLT (n 5 9). VOIs were defined on images reconstructed with normalization-and attenuation-weighted ordered-subset expectation maximization using 4 isocontours (A41%, A50%, and A70% thresholds, adapted for local background, and 50% threshold, uncorrected for background). Statistical analysis comprised intraclass correlation coefficients and BlandAltman analysis. Results: In the 18 F-FDG and 18 F-FLT groups, 34 and 20 lesions, respectively, were analyzed. Median volumes at the A50% threshold were 3.31 and 2.19 mL (interquartile range, 1.91-8.90 and 1.52-7.27 mL) for 18 F-FDG and 18 F-FLT, respectively. Intraclass correlation coefficients were greater than 0.9, with the exception of the A70%-based metabolic volumes for 18 F-FLT. For lesions greater than 4.2 mL, repeatability coefficients (RCs 5 1.96 · SD) of the percentage difference ranged from 22% to 37% for 18 F-FDG and from 39% to 73% for 18 F-FLT, depending on the VOI method being used. Repeatability was better for larger tumors, but there was no dependence on absolute uptake (standardized uptake value). Conclusion: Results indicate that changes of greater than 37% for 18 F-FDG and greater than 73% for 18 F-FLT (1.96 · SD) for lesions with A50% metabolic volumes greater than 4.2 mL represent a biologic effect. For smaller lesions (A50% VOI , 4.2 mL), an absolute change of 1.0 and 0.9 mL for 18 F-FDG and 18 F-FLT, respectively, is biologically relevant. Considering the balance between the success rate of automatic tumor delineation and repeatability of metabolic volume, a 50% threshold with correction for local background activity (A50%) seems optimal among the VOI methods evaluated.

With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non-small cell lung cancer. Methods: Patients were evaluated using an imaging protocol including CT, 18 F-FDG PET, H 2 15 O PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS). Results: Forty-four patients were included, and 40 underwent CT and 18 F-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P 5 0.01, and 12.5 vs. 2.9 mo, P 5 0.009, respectively). Whole-tumor K trans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor K trans values-that is, an increase in regions with low or high K trans values-after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P 5 0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P 5 0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and K trans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point. Conclusion: PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT.

Positron emission tomography with 18-fluorodeoxyglucose (FDG-PET) seems to be superior to computed tomography (CT) in staging the mediastinum in patients with non-small-cell lung cancer (NSCLC). However, recent results suggest that FDG-PET performance characteristics are conditional for nodal size as shown by CT: FDG-PET is more sensitive but less specific with lymph node enlargement on CT. The association between size and the probability of malignancy needs to be known to predict the post-test probabilities after PET, and finally, stratify patients for mediastinoscopy or thoracotomy depending on the PET and CT results. Therefore, we performed a meta-analysis of available studies reporting on the prevalence of metastatic involvement for different size categories of enlarged lymph nodes in patients with NSCLC and were able to include 14 studies. The prevalence of metastatic involvement and conditional test performance of CT and FDG-PET were calculated for lymph nodes measuring 10-15 mm, 16-20 mm and >20 mm. We found a post-test probability for N2 disease of 5% for lymph nodes measuring 10-15 mm on CT in patients with a negative FDG-PET result, suggesting that these patients should be planned for thoracotomy because the yield of mediastinoscopy will be extremely low. For patients with lymph nodes measuring > or =16 mm on CT and a negative FDG-PET result a post-test probability for N2 disease of 21% was found, suggesting that these patients should be planned for mediastinoscopy prior to possible thoracotomy to prevent too many unnecessary thoracotomies in this subset.