Functional Lung Avoidance Planning Using Multicriteria Optimization.

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 68Ga-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 68Ga-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.

[18]F-fluoroethyl-l-tyrosine positron emission tomography for radiotherapy target delineation: Results from a Radiation Oncology credentialing program.

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 (TVMR) and hybrid target volumes (TVMR+FET) incorporating pre-defined FET PET biological tumour volumes (BTVs). Materials and methods: Central review and analysis of TVMR and TVMR+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. TVMR+FET were significantly larger than TVMR (p < 0.001) for all cases. RO gross tumour volume (GTV) agreement was moderate-to-excellent for GTVMR (ICC = 0.910; 95 % CI, 0.708-0.997) and good-to-excellent for GTVMR+FET (ICC = 0.965; 95 % CI, 0.871-0.999). GTVMR+FET showed greater spatial overlap and boundary agreement compared to GTVMR. For the clinical target volume (CTV), CTVMR+FET showed lower average boundary agreement versus CTVMR (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 TVMR+FET delineation.

Transformer CycleGAN with uncertainty estimation for CBCT based synthetic CT in adaptive radiotherapy.

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.

Stereotactic body radiotherapy for early-stage lung cancer: a systematic review on the choice of photon energy and linac flattened/unflattened beams.

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.

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.

Impact on Pulmonary Function in a Randomized Trial of Single-Fraction and Multifraction Stereotactic Body Radiation Therapy for Pulmonary Oligometastatic Disease: An Analysis of TROG 13.01 (SAFRON II).

PURPOSE: The TROG 13.01 (SAFRON II) trial was a phase 2 multicenter trial comparing single-fraction (SF) and multifraction (MF) stereotactic body radiation therapy. Patients with 1 to 3 peripheral pulmonary oligometastases were randomized 1:1 between 28 Gy in 1 fraction and 48 Gy in 4 fractions. There were no differences between arms in efficacy or toxicity. We performed an analysis to assess changes in pulmonary function tests (PFTs) between arms over time and assessed the effect of the number and total volume of targets on PFT change over time. METHODS AND MATERIALS: A linear mixed model was used to describe the PFTs by treatment arm over time. The effect of number and volume of targets on PFTs at 6 and 12 months was assessed by a simple linear model. RESULTS: Ninety patients were randomized; 87 were treated for 133 pulmonary oligometastases. Forty-four were randomized to the SF arm and 43 to the MF arm. There were no differences in absolute or relative PFT measures of forced expiratory volume in 1 second (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), or forced vital capacity (FVC) between the 2 arms. At 12 months, there was a reduction in absolute DLCO from baseline (-1.7 mL/min/mm Hg [95% CI, -2.5 to -1.0]), relative DLCO (-5.5% [95% CI, -8.4% to -2.6%]), absolute FEV1 (-0.17 L [95% CI, -0.23 to -0.11]), and absolute FVC (-0.20 L [95% CI, -0.27 to -0.13]). In patients with multiple pulmonary targets, increase in target number (per lesion) was associated with a reduction in the absolute FEV1 at 6 months of -0.10 L (95% CI, -0.18 to -0.03; P = .007), FEV1 at 12 months of -0.10 L (95% CI, -0.20 to -0.01; P = .04), FVC at 6 months of -0.11 L (95% CI, -0.20 to -0.03; P = .014), and FVC at 24 months of -0.13 L (95% CI, -0.25 to -0.01; P = .036). Reduction in FEV1 was also seen per 10-mL increase in PTV at 12 months (-0.03 L [95% CI, -0.06 to -0.00], P = .036). The number of targets and PTV were not associated with DLCO. CONCLUSIONS: Treating multiple targets resulted in increased loss of FEV1 and FVC but not DLCO. There were no significant differences in PFT decline between SF and MF stereotactic body radiation therapy.

Comprehensive profiling identifies tumour and immune microenvironmental differences in clinical subsets of cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinomas (cSCCs) are the second most diagnosed skin cancer worldwide; however, little is known about the pathobiological factors that contribute to the diverse clinical outcomes seen. OBJECTIVES: To profile cSCCs comprehensively and identify the pathological processes that contribute to the disparities seen in their clinical behaviour. METHODS: We characterized the genomic, transcriptomic and immunohistochemical profiles of 211 cSCC tumours, including 37 cSCCs from immunocompromised patients. RESULTS: cSCCs from immunocompromised patients were characterized by a lack of B cells in the peritumoral stroma compared with immunocompetent patients. Further, an abundance of a memory B-cell-like population in the peritumoral stroma was associated with a better prognosis in all patients (immunocompetent and immunocompromised), as well as only immunocompetent patients. No differences in genetic -variants, tumour mutational burden or mutational signatures were observed between cSCCs from immunocompetent and immunocompromised patients. Thus, differences in survival between cSCCs from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but may be associated with differential host immune response. cSCC not from a primary head and neck site had lower tumour mutational burden and exhibited upregulation of the epithelial-mesenchymal transition programme compared with head and neck cSCC. Both factors were implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. CONCLUSIONS: We identified tumour and host immune factors that contribute to the disparate clinical behaviour of cSCC, with broad translational application, including prognostication, treatment prediction to current therapies and the identification of novel anticancer therapy approaches in cSCC.

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 Changes in Pulmonary Function After Stereotactic Body Radiation Therapy Versus Conventional 3-Dimensional Conformal Radiation Therapy for Stage I and IIA Non-Small Cell Lung Cancer: An Analysis of the TROG 09.02 (CHISEL) Phase 3 Trial.

PURPOSE: The TROG 09.02 CHISEL trial compared conventional radiation therapy (CRT) with stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage non-small cell lung cancer. Patients randomized to SBRT had less local failure and improved overall survival. This analysis reports differences in pulmonary function tests (PFTs) and the 6-minute walk test (SMWT) between patients who received SBRT and those who received CRT. METHODS AND MATERIALS: We analyzed the PFTs and SMWTs of all patients recruited to the CHISEL [trial. During this trial, patients underwent serial PFTs. Linear regression models were used to compare parameters between SBRT and CRT at 3 and 12 months after treatment. RESULTS: One hundred and one patients were enrolled; 33 patients were treated with CRT, 61 were treated with SBRT, and 7 did not receive treatment. Primary tumor size was similar between arms: SBRT 25 mm (standard deviation [SD], 9) and CRT 28 mm (SD, 9). On regression analysis, at 3 and 12 months, there was no evidence of a difference between arms in PFT decline or distance walked in the SMWT. Planning target volume size was significantly larger in the CRT arm, 142.79 cc (SD, 61.14), compared with the SBRT group, 46.15 cc (SD, 23.39). The mean biologically effective dose received by the target was significantly larger in the SBRT group, 125.92 Gy (SD, 21.58), compared with CRT, 65.49 Gy (SD, 6.32). Mean dose to the lungs minus the gross target volume incorporating motion was 8.9 Gy (SD, 2.34) in the CRT group and 4.37 Gy (SD, 1.42) in the SBRT group. CONCLUSIONS: Despite the considerably higher biologically effective doses delivered to the tumor in SBRT, there was no difference in decline in respiratory function observed between the 2 groups.

Mid-treatment adaptive planning during thoracic radiation using 68 Ventilation-Perfusion Positron emission tomography.

Four-Dimensional Gallium 68 Ventilation-Perfusion Positron Emission Tomography (68Ga-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 68Ga-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 68Ga-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 68Ga-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 68Ga-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.

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.

Avoiding Toxicity With Lung Radiation Therapy: An IASLC Perspective.

Toxicity concerns from thoracic radiation therapy in the treatment of lung cancers have changed substantially over the past few decades. Survival in the treatment of lung cancer has markedly improved and the introduction of advanced radiation and imaging techniques to treatment planning and delivery has made reducing toxicity possible. Phase 3 dose-escalation trials have revealed that excess dose to critical organs within the thorax can negatively impact overall survival. We summarize the existing literature on the known toxicities of thoracic radiation therapy, summarize the technological advances that have made toxicity reduction possible, and provide an overview of emerging technologies and biomarkers that are being evaluated to assess future toxicity reductions.

Stereotactic ablative radiation therapy for renal cell carcinoma with inferior vena cava tumor thrombus.

BACKGROUND: Inferior vena cava tumor thrombus (IVC-TT) is a rare yet deadly sequel of renal cell carcinoma (RCC) with limited treatment options. The standard treatment is extirpative surgery, which has high rates of morbidity and mortality. As a result, many patients are unfit or unwilling to undergo surgery and face poor prognosis. This stresses the need for alternative options for local disease control. Our study aims to assess the feasibility and oncological outcomes of stereotactic ablative radiation (SAbR) for IVC-TT. METHODS: A retrospective study reviewing six leading international institutions' experience in treating RCC with IVC-TT with SAbR. Primary end point was overall survival using Kaplan-Meier. RESULTS: Fifteen patients were included in the cohort. Over 50% of patients had high level IVC-TT (level III or IV), 66.7% had metastatic disease. Most eschewed surgery due to high surgical risk (7/15) or recurrent thrombus (3/15). All patients received SAbR to the IVC-TT with a median biologically equivalent dose (BED10) of 72 Gy (range: 37.5-100.8) delivered in a median of 5 fractions (range 1-5). Median overall survival was 34 months. Radiographic response was observed in 58% of patients. Symptom palliation was recorded in all patients receiving SAbR for this indication. Only grade 1 to 2 adverse events were noted. CONCLUSIONS: SAbR for IVC-TT appears feasible and safe. In patients who are not candidates for surgery, SAbR may palliate symptoms and improve outcomes. SAbR may be considered as part of a multimodal treatment approach for patients with RCC IVC-TT.

Cutaneous squamous cell carcinoma metastatic to the axilla and groin: Outcomes and prognostic factors.

PURPOSE: This study examined the clinical outcomes and prognostic factors of patients with metastatic cutaneous SCC metastatic to the axilla and groin when managed with curative-intent lymphadenectomy and received (neo)adjuvant treatment. METHODS AND MATERIALS: We conducted a single institution retrospective review. Patients who had nodal disease without distant spread were 18 years or older with no non-cutaneous primary identified. RESULTS: From January 2000 to July 2015, 78 patients were treated for axilla (64, 82%) or inguinal (14, 18%) involvement with cSCC. The median age was 75.5 years (range: 29-95), and 8 patients (11%) were immunosuppressed. The median size of the largest node was 45 mm (range: 8-135), and extracapsular extension was found in 63 (81%) cases. A majority of patients were treated with surgery alone (21, 26.9%) and surgery with adjuvant radiation therapy (54, 69%). The 2-year OS and PFS were 50% (95% CI: 40%-63%) and 43% (95% CI: 33%-56%), and 5-year OS and PFS were 33% (95% CI:23%-47%) and 32% (95% CI:22%-46%) respectively in the entire cohort. On univariable analysis, factors associated with longer OS were as follows: younger age (HR 1.1, 95% CI: 0.9-1.3 P = 0.021), improved performance status (HR 1.5, 95% CI:1.0-2.3 P = 0.026), lack of immunosuppression (HR 3.3, 95% CI: 1.5-7.3 P = 0.001), lower lymph node ratio (HR 1.2, 95% CI:1.0-1.3 P = 0.007), lower number of positive nodes (HR 1.1, 95% CI:1.0-1.2 P = 0.004) and the use of radiation therapy (HR 0.5, 95% CI:0.3-0.9 P = 0.012). CONCLUSION: Metastasis to the axilla and groin with cSCC has poor outcomes with standard treatment. The addition of immunotherapy warrants investigation.

A Deep Learning Model to Automate Skeletal Muscle Area Measurement on Computed Tomography Images.

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.

Automated assessment of functional lung imaging with 68Ga-ventilation/perfusion PET/CT using iterative histogram analysis.

PURPOSE: Functional lung mapping from Ga68-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.

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.

Monitoring DNA Damage and Repair in Peripheral Blood Mononuclear Cells of Lung Cancer Radiotherapy Patients.

Thoracic radiotherapy (RT) is required for the curative management of inoperable lung cancer, however, treatment delivery is limited by normal tissue toxicity. Prior studies suggest that using radiation-induced DNA damage response (DDR) in peripheral blood mononuclear cells (PBMC) has potential to predict RT-associated toxicities. We collected PBMC from 38 patients enrolled on a prospective clinical trial who received definitive fractionated RT for non-small cell lung cancer. DDR was measured by automated counting of nuclear γ-H2AX foci in immunofluorescence images. Analysis of samples collected before, during and after RT demonstrated the induction of DNA damage in PBMC collected shortly after RT commenced, however, this damage repaired later. Radiation dose to the tumour and lung contributed to the in vivo induction of γ-H2AX foci. Aliquots of PBMC collected before treatment were also irradiated ex vivo, and γ-H2AX kinetics were analyzed. A trend for increasing of fraction of irreparable DNA damage in patients with higher toxicity grades was revealed. Slow DNA repair in three patients was associated with a combined dysphagia/cough toxicity and was confirmed by elevated in vivo RT-generated irreparable DNA damage. These results warrant inclusion of an assessment of DDR in PBMC in a panel of predictive biomarkers that would identify patients at a higher risk of toxicity.