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Purpose: Functional lung avoidance (FLA) radiation therapy is an evolving field. The aim of FLA planning is to reduce dose to areas of functioning lung, with comparable target coverage and dose to organs at risk. Multicriteria optimization (MCO) is a planning tool that may assist with FLA planning. This study assessed the feasibility of using MCO to adapt radiation therapy plans to avoid functional regions of lung that were identified using a 68 Ga-4D-V/Q positron emission tomography/computed tomography., Methods and Materials: A prospective clinical trial U1111-1138-4421 was performed in which patients had a 68 Ga-4D-V/Q positron emission tomography/computed tomography before radiation treatment. Of the 72 patients enrolled in this trial, 38 patients had stage III non-small cell lung cancer and were eligible for selection into this planning study. Functional lung target volumes HF lung (highly functioning lung) and F lung (functional lung) were defined using the ventilated and perfused lung. Using knowledge-based planning, a baseline anatomic plan was created, and then a functional adapted plan was generated using multicriteria optimization. The primary aim was to spare dose to HF lung. Using the MCO tools, a clinician selected the final FLA plan. Dose to functional lung, target volumes, organs at risk and measures of plan quality were compared using standard statistical methods., Results: The HF lung volume was successfully spared in all patients. The F lung volume was successfully spared in 36 of the 38 patients. There were no clinically significant differences in dose to anatomically defined organs at risk. There were differences in the planning target volume near maximum and minimum doses. Across the entire population, there was a statistically significant reduction in the functional mean lung dose but not in the functional volume receiving 20 Gy. All trade-off decisions were made by the clinician., Conclusions: Using MCO for FLA was achievable but did result in changes to planning target volume coverage. A distinct advantage in using MCO was that all decisions regarding the cost and benefits of FLA could be made in real time., Competing Interests: Disclosures Michael S. Hofman acknowledges grant support from AAA/Novartis, ANSTO, Bayer, and Isotopia; consulting fees for lectures or advisory boards from Astellas, AstraZeneca, Janssen, Merck/MSD, Mundipharma, and Point Biopharma. Nicholas Hardcastle, Shankar Siva, and Tomas Kron receives research grants from Varian Medical Systems and Reflexion Medical for unrelated work. Shankar Siva receives research grants from Merck-Sharp-Dohme and Bayer Pharmaceuticals. Shankar Siva acknowledges consulting fees for lectures or advisory boards from Astra Zeneca and Reflexion. Nicholas Bucknell acknowledges consulting fees for lectures or advisory boards from Astra Zeneca. The remaining authors declare there are no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

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 68 Ga-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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: The [18]F-fluoroethyl-l-tyrosine (FET) PET in Glioblastoma (FIG) study is an Australian prospective, multi-centre trial evaluating FET PET for newly diagnosed glioblastoma management. The Radiation Oncology credentialing program aimed to assess the feasibility in Radiation Oncologist (RO) derivation of standard-of-care target volumes (TV MR ) and hybrid target volumes (TV MR+FET ) incorporating pre-defined FET PET biological tumour volumes (BTVs)., Materials and Methods: Central review and analysis of TV MR and TV MR+FET was undertaken across three benchmarking cases. BTVs were pre-defined by a sole nuclear medicine expert. Intraclass correlation coefficient (ICC) confidence intervals (CIs) evaluated volume agreement. RO contour spatial and boundary agreement were evaluated (Dice similarity coefficient [DSC], Jaccard index [JAC], overlap volume [OV], Hausdorff distance [HD] and mean absolute surface distance [MASD]). Dose plan generation (one case per site) was assessed., Results: Data from 19 ROs across 10 trial sites (54 initial submissions, 8 resubmissions requested, 4 conditional passes) was assessed with an initial pass rate of 77.8 %; all resubmissions passed. TV MR+FET were significantly larger than TV MR (p < 0.001) for all cases. RO gross tumour volume (GTV) agreement was moderate-to-excellent for GTV MR (ICC = 0.910; 95 % CI, 0.708-0.997) and good-to-excellent for GTV MR+FET (ICC = 0.965; 95 % CI, 0.871-0.999). GTV MR+FET showed greater spatial overlap and boundary agreement compared to GTV MR . For the clinical target volume (CTV), CTV MR+FET showed lower average boundary agreement versus CTV MR (MASD: 1.73 mm vs. 1.61 mm, p = 0.042). All sites passed the planning exercise., Conclusions: The credentialing program demonstrated feasibility in successful credentialing of 19 ROs across 10 sites, increasing national expertise in TV MR+FET delineation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Objective . Clinical implementation of synthetic CT (sCT) from cone-beam CT (CBCT) for adaptive radiotherapy necessitates a high degree of anatomical integrity, Hounsfield unit (HU) accuracy, and image quality. To achieve these goals, a vision-transformer and anatomically sensitive loss functions are described. Better quantification of image quality is achieved using the alignment-invariant Fréchet inception distance (FID), and uncertainty estimation for sCT risk prediction is implemented in a scalable plug-and-play manner. Approach . Baseline U-Net, generative adversarial network (GAN), and CycleGAN models were trained to identify shortcomings in each approach. The proposed CycleGAN-Best model was empirically optimized based on a large ablation study and evaluated using classical image quality metrics, FID, gamma index, and a segmentation analysis. Two uncertainty estimation methods, Monte-Carlo Dropout (MCD) and test-time augmentation (TTA), were introduced to model epistemic and aleatoric uncertainty. Main results . FID was correlated to blind observer image quality scores with a Correlation Coefficient of -0.83, validating the metric as an accurate quantifier of perceived image quality. The FID and mean absolute error (MAE) of CycleGAN-Best was 42.11 ± 5.99 and 25.00 ± 1.97 HU, compared to 63.42 ± 15.45 and 31.80 HU for CycleGAN-Baseline, and 144.32 ± 20.91 and 68.00 ± 5.06 HU for the CBCT, respectively. Gamma 1%/1 mm pass rates were 98.66 ± 0.54% for CycleGAN-Best, compared to 86.72 ± 2.55% for the CBCT. TTA and MCD-based uncertainty maps were well spatially correlated with poor synthesis outputs. Significance . Anatomical accuracy was achieved by suppressing CycleGAN-related artefacts. FID better discriminated image quality, where alignment-based metrics such as MAE erroneously suggest poorer outputs perform better. Uncertainty estimation for sCT was shown to correlate with poor outputs and has clinical relevancy toward model risk assessment and quality assurance. The proposed model and accompanying evaluation and risk assessment tools are necessary additions to achieve clinically robust sCT generation models., (Creative Commons Attribution license.)

SBRT is an effective local treatment for patients with early-stage non-small cell lung cancer (NSCLC). This treatment is currently used in patients who have poor lung function or who decline surgery. As SBRT usually has small PTV margins, reducing the beam-on-time (BOT) is beneficial for accurate dose delivery by minimising intrafraction motion as well as improved patient comfort. Removal of the linear accelerator flattening filter can provide a higher dose rate which results in a faster treatment. In addition, the choice of photon energy can also affect the dose distribution to the target and the organs-at-risk (OAR). In this systematic review, studies analysing the choice of various photon beam energies, with a flattening filter or flattening filter free (FFF), were compared for their overall dosimetric benefit in the SBRT treatment for early-stage NSCLC. It was found that FFF treatment delivers a comparatively more conformal dose distribution, as well as a better homogeneity index and conformity index, and typically reduces BOT by between 30 and 50%. The trade-off may be a minor increase in monitor units for FFF treatment found in some studies but not others. Target conformity and OAR sparing, particularly lung doses appear better with 6MV FFF, but 10MV FFF was marginally more advantageous for skin sparing and BOT reduction. The favourable beam modality for clinical use would depend on the individual case, for which tumour size and depth, radiotherapy technique, as well as fractionation scheme need to be taken into account., (© 2023. The Author(s).)

Four-Dimensional Gallium 68 Ventilation-Perfusion Positron Emission Tomography ( 68 Ga-4D-V/Q PET/CT) allows for dynamic imaging of lung function. To date there has been no assessment of the feasibility of adapting radiation therapy plans to changes in lung function imaged at mid-treatment function using 68 Ga-4D-V/Q PET/CT. This study assessed the potential reductions of dose to the functional lung when radiation therapy plans were adapted to avoid functional lung at the mid-treatment timepoint using volumetric arc radiotherapy (VMAT)., Methods: A prospective clinical trial (U1111-1138-4421) was performed in patients undergoing conventionally fractionated radiation therapy for non-small cell lung cancer (NSCLC). A 68 Ga-4D-V/Q PET/CT was acquired at baseline and in the 4th week of treatment. Functional lung target volumes using the ventilated and perfused lung were created. Baseline functional volumes were compared to the week 4 V/Q functional volumes to describe the change in function over time. For each patient, 3 VMAT plans were created and optimised to spare ventilated, perfused or anatomical lung. All key dosimetry metrics were then compared including dose to target volumes, dose to organs at risk and dose to the anatomical and functional sub-units of lung., Results: 25 patients had both baseline and 4 week mid treatment 68 Ga-4D-V/Q PET/CT imaging. This resulted in a total of 75 adapted VMAT plans. The HPLung volume decreased in 16/25 patients with a mean of the change in volume (cc) -28 ± 515 cc [±SD, range -996 cc to 1496 cc]. The HVLung volume increased in 13/25 patients with mean of the change in volume (cc) + 112 ± 590 cc. [±SD, range -1424 cc to 950 cc]. The functional lung sparing technique was found to be feasible with no significant differences in dose to anatomically defined organs at risk. Most patients did derive a benefit with a reduction in functional volume receiving 20 Gy (fV20) and/or functional mean lung dose (fMLD) in either perfusion and/or ventilation. Patients with the most reduction in fV20 and fMLD were those with stage III NSCLC., Conclusion: Functional lung volumes change during treatment. Some patients benefit from using 68 Ga-4D-V/Q PET/CT in the 4th week of radiation therapy to adapt radiation plans. In these patients, the role of mid-treatment adaptation requires further prospective investigation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

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 ( r s ) 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 [ r s (PBVsyngoR=1,PBVTMDL=1) = 0.94 ± 0.01 and r s (PBVsyngoR=10,PBVTMDL=9) = 0.94 ± 0.02].PBVPETwas strongly correlated withPBVTMDL[ r s (PBVPET,PBVTMDL=28) = 0.67 ± 0.11]. Perfusion patterns differed along the posterior-anterior direction [ r s (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., (© 2023 Institute of Physics and Engineering in Medicine.)

Introduction: This study aims to investigate whether nodal metabolic tumour volume (nMTV) and nodal total lesion glycolysis (nTLG) on Fluorine-18 fluoro-deoxy-glucose positron emission tomography-computed tomography ( 18 F-FDG PET/CT) in inoperable node-positive stage II and III non-small cell lung cancer (NSCLC) are independent predictors of overall survival (OS) in patients undergoing curative-intent chemoradiotherapy/radiotherapy (CRT/RT)., Methods: Data from two prospective trials between 2004 and 2016 were analysed retrospectively. Primary, nodal and total metabolic tumour volume and total lesion glycolysis (pMTV, nMTV, tMTV, pTLG, nTLG and tTLG, respectively) were derived from baseline 18 F-FDG PET/CT. Cox regressions were used to model OS by 18 F-FDG PET/CT parameters adjusting for overall stage., Results: 89 patients with stage II (8%) and stage III (92%) were included. The median age at diagnosis was 67 years; 62% were male. The median follow-up was 6.9 years; the median OS was 2.2 years (95% CI 1.7-3.1). The median pMTV, nMTV and tMTV were 14 mL (range 0-360), 8 mL (range 0-250) and 34 mL (range 3-384), respectively. In 3 patients, the primary lesion could not be delineated from the central hilar mass. There was no association between nMTV (adjusted HR 1.04, 95% CI 0.95-1.15, P-value 0.43), pMTV (adjusted HR 1.0, 95% CI 0.96-1.04, P-value 0.92), tMTV (adjusted HR 1.0, 95% CI 0.97-1.04, P-value 0.88), nTLG, pTLG or tTLG and OS. Consistent results were noted when patients with central hilar lesions were excluded from analysis., Conclusion: In node-positive stage II and III NSCLC patients who underwent 18 F-FDG PET/CT-guided target delineation curative-intent concurrent CRT/RT, metabolic parameters did not appear to provide independent prognostication., (© 2021 The Royal Australian and New Zealand College of Radiologists.)

Background: Muscle wasting (Sarcopenia) is associated with poor outcomes in cancer patients. Early identification of sarcopenia can facilitate nutritional and exercise intervention. Cross-sectional skeletal muscle (SM) area at the third lumbar vertebra (L3) slice of a computed tomography (CT) image is increasingly used to assess body composition and calculate SM index (SMI), a validated surrogate marker for sarcopenia in cancer. Manual segmentation of SM requires multiple steps, which limits use in routine clinical practice. This project aims to develop an automatic method to segment L3 muscle in CT scans., Methods: Attenuation correction CTs from full body PET-CT scans from patients enrolled in two prospective trials were used. The training set consisted of 66 non-small cell lung cancer (NSCLC) patients who underwent curative intent radiotherapy. An additional 42 NSCLC patients prescribed curative intent chemo-radiotherapy from a second trial were used for testing. Each patient had multiple CT scans taken at different time points prior to and post- treatment (147 CTs in the training and validation set and 116 CTs in the independent testing set). Skeletal muscle at L3 vertebra was manually segmented by two observers, according to the Alberta protocol to serve as ground truth labels. This included 40 images segmented by both observers to measure inter-observer variation. An ensemble of 2.5D fully convolutional neural networks (U-Nets) was used to perform the segmentation. The final layer of U-Net produced the binary classification of the pixels into muscle and non-muscle area. The model performance was calculated using Dice score and absolute percentage error (APE) in skeletal muscle area between manual and automated contours., Results: We trained five 2.5D U-Nets using 5-fold cross validation and used them to predict the contours in the testing set. The model achieved a mean Dice score of 0.92 and an APE of 3.1% on the independent testing set. This was similar to inter-observer variation of 0.96 and 2.9% for mean Dice and APE respectively. We further quantified the performance of sarcopenia classification using computer generated skeletal muscle area. To meet a clinical diagnosis of sarcopenia based on Alberta protocol the model achieved a sensitivity of 84% and a specificity of 95%., Conclusions: This work demonstrates an automated method for accurate and reproducible segmentation of skeletal muscle area at L3. This is an efficient tool for large scale or routine computation of skeletal muscle area in cancer patients which may have applications on low quality CTs acquired as part of PET/CT studies for staging and surveillance of patients with cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Amarasinghe, Lopes, Beraldo, Kiss, Bucknell, Everitt, Jackson, Litchfield, Denehy, Blyth, Siva, MacManus, Ball, Li and Hardcastle.)

Purpose: Functional lung mapping from Ga 68 -ventilation/perfusion (V/Q) PET/CT, which has been shown to correlate with pulmonary function tests (PFTs), may be beneficial in a number of clinical applications where sparing regions of high lung function is of interest. Regions of clumping in the proximal airways in patients with airways disease can result in areas of focal intense activity and artefact in ventilation imaging. These artefacts may even shine through to subsequent perfusion images and create a challenge for quantitative analysis of PET imaging. We aimed to develop an automated algorithm that interprets the uptake histogram of PET images to calculate a peak uptake value more representative of the global lung volume., Methods: Sixty-six patients recruited from a prospective clinical trial underwent both V/Q PET/CT imaging and PFT analysis before treatment. PET images were normalised using an iterative histogram analysis technique to account for tracer hotspots prior to the threshold-based delineation of varying values. Pearson's correlation between fractional lung function and PFT score was calculated for ventilation, perfusion, and matched imaging volumes at varying threshold values., Results: For all functional imaging thresholds, only FEV1/FVC PFT yielded reasonable correlations to image-based functional volume. For ventilation, a range of 10-30% of adapted peak uptake value provided a reasonable threshold to define a volume that correlated with FEV1/FVC (r = 0.54-0.61). For perfusion imaging, a similar correlation was observed (r = 0.51-0.56) in the range of 20-60% adapted peak threshold. Matched volumes were closely linked to ventilation with a threshold range of 15-35% yielding a similar correlation (r = 0.55-0.58)., Conclusions: Histogram normalisation may be implemented to determine the presence of tracer clumping hotspots in Ga-68 V/Q PET imaging allowing for automated delineation of functional lung and standardisation of functional volume reporting.

Aims: At diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11-21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease., Materials and Methods: This retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan-Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors., Results: Forty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34-76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30-59). At 3 and 5 years, OS was 45% (95% confidence interval 32-63) and 30% (95% confidence interval 18-51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18-63). The 3- and 5-year PFS was 8% (95% confidence interval 3-22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11-0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15-0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13-2.15, P = 0.007) were associated with longer PFS., Conclusions: Definitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)