Dose-Response Relationship Between Radiation Therapy and Loss of Lung Perfusion Comparing Positron Emission Tomography and Dual-Energy Computed Tomography in Non-Small Cell Lung Cancer.

PURPOSE: Radiation therapy treatment for non-small cell lung cancer (NSCLC) may result in radiation damage to the perfused lung. The loss in perfusion may be measured from positron tomography emission (PET) perfusion imaging; however, this modality may not be widely available. Dual-energy computed tomography (DECT) with contrast may be an alternative to PET/CT. The purpose of this work is to investigate the equivalence of dose-response curves (DRCs) determined from PET and DECT in NSCLC. METHODS AND MATERIALS: PET and DECT data sets from the prospective clinical trial HI-FIVE (NTC03569072) were included in this preplanned trial analysis. Patients underwent 68Ga-macroaggregated albumin PET/CT examination and DECT with contrast on the same day at baseline and at 3 and 12 months after treatment. The perfused lung was defined from a threshold based on the maximum standardized uptake value (%SUVmax)/iodine concentration (%IoMax) in PET/DECT. The equivalence between PET and DECT DRC was established by comparing (1) the average of the normalized overlap of the 2 DRCs ranging from 0 (no overlap) to 1 (perfect overlap) and (2) the slope of a linear model applied to DRCs. RESULTS: Of the 19 patients enrolled in the clinical trial, 14/10 patients had a posttreatment imaging session at a median of 4.5/13.5 months, respectively. With 30%SUVmax/35%IoMax, the average normalized overlap was maximized, and the difference between PET and DECT slopes of the linear model was minimized at each time point (slope = 0.76%/Gy / 0.75%/Gy at 3 months and 0.86%/Gy / 0.87%/Gy at 12 months determined from PET/DECT). CONCLUSIONS: The dose-response relationship determined from DECT was comparable to that from PET at 3 and 12 months after treatment in patients with NSCLC.

The HI-FIVE Trial: A Prospective Trial Using 4-Dimensional 68Ga Ventilation-Perfusion Positron Emission Tomography-Computed Tomography for Functional Lung Avoidance in Locally Advanced Non-small Cell Lung Cancer.

PURPOSE: Functional lung avoidance (FLA) radiation therapy aims to spare regions of functional lung to reduce toxicity. We report the results of the first prospective trial of FLA using 4-dimensional gallium 68 ventilation-perfusion positron emission tomography-computed tomography (68Ga-4D-V/Q PET/CT). METHODS AND MATERIALS: Inclusion criteria required a diagnosis of stage III non-small cell lung cancer and the ability to undergo radical-intent chemoradiation therapy. Functional volumes were generated using planning 68Ga-4D-V/Q PET/CT. These volumes were used to generate a clinical FLA plan to 60 Gy in 30 fractions. The primary tumor was boosted to 69 Gy. A comparison anatomic plan was generated for each patient. Feasibility was met if FLA plans (compared with anatomic plans) allowed (1) a reduction in functional mean lung dose of ≥2% and a reduction in the functional lung volume receiving 20 Gy (fV20Gy) of ≥4%, and (2) a mean heart dose ≤30 Gy and relative heart volume receiving 50 Gy of <25%. RESULTS: In total, 19 patients were recruited; 1 withdrew consent. Eighteen patients underwent chemoradiation with FLA. Of the 18 patients, 15 met criteria for feasibility. All patients completed the entire course of chemoradiation therapy. Using FLA resulted in an average reduction of the functional mean lung dose of 12.4% (SD, ±12.8%) and a mean relative reduction of the fV20Gy of 22.9% (SD, ±11.9%). At 12 months, Kaplan-Meier estimates for overall survival were 83% (95% CI, 56%-94%) and estimates for progression-free survival were 50% (95% CI, 26%-70%). Quality-of-life scores were stable across all time points. CONCLUSIONS: Using 68Ga-4D-V/Q PET/CT to image and avoid functional lung is feasible.

Comparison of dual-energy CT with positron emission tomography for lung perfusion imaging in patients with non-small cell lung cancer.

Objective.Functional lung avoidance (FLA) radiotherapy treatment aims to spare lung regions identified as functional from imaging. Perfusion contributes to lung function and can be measured from the determination of pulmonary blood volume (PBV). An advantageous alternative to the current determination of PBV from positron emission tomography (PET) may be from dual energy CT (DECT), due to shorter examination time and widespread availability. This study aims to determine the correlation between PBV determined from DECT and PET in the context of FLA radiotherapy.Approach.DECT and PET acquisitions at baseline of patients enrolled in the HI-FIVE clinical trial (ID: NCT03569072) were reviewed. Determination of PBV from PET imaging (PBVPET), from DECT imaging generated from a commercial software (Syngo.via, Siemens Healthineers, Forchheim, Germany) with its lowest (PBVsyngoR=1) and highest (PBVsyngoR=10) smoothing level parameter value (R), and from a two-material decomposition (TMD) method (PBVTMDL) with variable median filter kernel size (L) were compared. Deformable image registration between DECT images and the CT component of the PET/CT was applied to PBV maps before resampling to the PET resolution. The Spearman correlation coefficient (rs) between PBV determinations was calculated voxel-wise in lung subvolumes.Main results.Of this cohort of 19 patients, 17 had a DECT acquisition at baseline. PBV maps determined from the commercial software and the TMD method were very strongly correlated [rs(PBVsyngoR=1,PBVTMDL=1) = 0.94 ± 0.01 andrs(PBVsyngoR=10,PBVTMDL=9) = 0.94 ± 0.02].PBVPETwas strongly correlated withPBVTMDL[rs(PBVPET,PBVTMDL=28) = 0.67 ± 0.11]. Perfusion patterns differed along the posterior-anterior direction [rs(PBVPET,PBVTMDL=28) = 0.77 ± 0.13/0.57 ± 0.16 in the anterior/posterior region].Significance. A strong correlation between DECT and PET determination of PBV was observed. Streak and smoothing effects in DECT and gravitational artefacts and misregistration in PET reduced the correlation posteriorly.

The impact of inter-observer variation in delineation on robustness of radiomics features in non-small cell lung cancer.

Artificial intelligence and radiomics have the potential to revolutionise cancer prognostication and personalised treatment. Manual outlining of the tumour volume for extraction of radiomics features (RF) is a subjective process. This study investigates robustness of RF to inter-observer variation (IOV) in contouring in lung cancer. We utilised two public imaging datasets: 'NSCLC-Radiomics' and 'NSCLC-Radiomics-Interobserver1' ('Interobserver'). For 'NSCLC-Radiomics', we created an additional set of manual contours for 92 patients, and for 'Interobserver', there were five manual and five semi-automated contours available for 20 patients. Dice coefficients (DC) were calculated for contours. 1113 RF were extracted including shape, first order and texture features. Intraclass correlation coefficient (ICC) was computed to assess robustness of RF to IOV. Cox regression analysis for overall survival (OS) was performed with a previously published radiomics signature. The median DC ranged from 0.81 ('NSCLC-Radiomics') to 0.85 ('Interobserver'-semi-automated). The median ICC for the 'NSCLC-Radiomics', 'Interobserver' (manual) and 'Interobserver' (semi-automated) were 0.90, 0.88 and 0.93 respectively. The ICC varied by feature type and was lower for first order and gray level co-occurrence matrix (GLCM) features. Shape features had a lower median ICC in the 'NSCLC-Radiomics' dataset compared to the 'Interobserver' dataset. Survival analysis showed similar separation of curves for three of four RF apart from 'original_shape_Compactness2', a feature with low ICC (0.61). The majority of RF are robust to IOV, with first order, GLCM and shape features being the least robust. Semi-automated contouring improves feature stability. Decreased robustness of a feature is significant as it may impact upon the features' prognostic capability.

Single-arm prospective interventional study assessing feasibility of using gallium-68 ventilation and perfusion PET/CT to avoid functional lung in patients with stage III non-small cell lung cancer.

BACKGROUND: In the curative-intent treatment of locally advanced lung cancer, significant morbidity and mortality can result from thoracic radiation therapy. Symptomatic radiation pneumonitis occurs in one in three patients and can lead to radiation-induced fibrosis. Local failure occurs in one in three patients due to the lungs being a dose-limiting organ, conventionally restricting tumour doses to around 60 Gy. Functional lung imaging using positron emission tomography (PET)/CT provides a geographic map of regional lung function and preclinical studies suggest this enables personalised lung radiotherapy. This map of lung function can be integrated into Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning systems, enabling conformal avoidance of highly functioning regions of lung, thereby facilitating increased doses to tumour while reducing normal tissue doses. METHODS AND ANALYSIS: This prospective interventional study will investigate the use of ventilation and perfusion PET/CT to identify highly functioning lung volumes and avoidance of these using VMAT planning. This single-arm trial will be conducted across two large public teaching hospitals in Australia. Twenty patients with stage III non-small cell lung cancer will be recruited. All patients enrolled will receive dose-escalated (69 Gy) functional avoidance radiation therapy. The primary endpoint is feasibility with this achieved if ≥15 out of 20 patients meet pre-defined feasibility criteria. Patients will be followed for 12 months post-treatment with serial imaging, biomarkers, toxicity assessment and quality of life assessment. DISCUSSION: Using advanced techniques such as VMAT functionally adapted radiation therapy may enable safe moderate dose escalation with an aim of improving local control and concurrently decreasing treatment related toxicity. If this technique is proven feasible, it will inform the design of a prospective randomised trial to assess the clinical benefits of functional lung avoidance radiation therapy. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee. All participants will provide written informed consent. Results will be disseminated via publications. TRIALS REGISTRATION NUMBER: NCT03569072; Pre-results.

Gallium-68 Ventilation/Perfusion PET-CT and CT Pulmonary Angiography for Pulmonary Embolism Diagnosis: An Interobserver Agreement Study.

Objectives: 68Ga Ventilation/Perfusion V/Q PET-CT is a promising imaging tool for pulmonary embolism diagnosis. However, no study has verified whether the interpretation is reproducible between different observers. The aim of this study was to assess the interobserver agreement in the interpretation of V/Q PET-CT for the diagnosis of acute PE, and to compare it to the interobserver agreement of CTPA interpretation. Methods: Twenty-four cancer patients with suspected acute PE underwent V/Q PET-CT and CTPA within 24 h as part of a prospective pilot study evaluating V/Q PET-CT for the management of patients with suspected PE. V/Q PET-CT and CTPA scans were reassessed independently by four nuclear medicine physicians and four radiologists, respectively. Physicians had different levels of expertise in reading V/Q scintigraphy and CTPA. Interpretation was blinded to the initial interpretation and any clinical information or imaging test result. For each modality, results were reported on a binary fashion. V/Q PET/CT scans were read as positive if there was at least one segmental or two subsegmental mismatched perfusion defects. CTPA scans were interpreted as positive if there was a constant intraluminal filling defect. Interobserver agreement was assessed by calculating kappa (κ) coefficients. Results: Out of the 24 V/Q PET-CT scans, the diagnostic conclusion was concordantly negative in 22 patients and concordantly positive in one patient. The remaining scan was interpreted as positive by one reader and negative by three readers. Out of the 24 CTPA scans, the diagnostic conclusion was concordantly negative in 16 and concordantly positive in one. Out of the seven remaining scans, PE was reported by one reader in four cases, by two readers in two cases, by three readers in one case. Most of discordant results on CTPA were related to clots reported on subsegmental arteries. Mean kappa coefficient was 0.79 for V/Q PET-CT interpretation and 0.39 for CTPA interpretation. Conclusions: Interobserver agreement in the interpretation of V/Q PET-CT for PE diagnosis was substantial (kappa 0.79) in a population with a low prevalence of significant PE. Agreement was lower with CTPA, mainly as a result of discrepancies at the level of the subsegmental arteries.