PTEN Depletion Increases Radiosensitivity in Response to Ataxia Telangiectasia-Related-3 (ATR) Inhibition in Non-Small Cell Lung Cancer (NSCLC).

Radiotherapy (RT) treatment is an important strategy for the management of non-small cell lung cancer (NSCLC). Local recurrence amongst patients with late-stage NSCLC remains a challenge. The loss of PTEN has been associated with radio-resistance. This study aimed to examine the efficacy of RT combined with ataxia telangiectasia-mutated Rad3-related (ATR) inhibition using Ceralasertib in phosphatase and tensin homolog (PTEN)-depleted NSCLC cells and to assess early inflammatory responses indicative of radiation pneumonitis (RP) after combined-modality treatment. Small hairpin RNA (shRNA) transfections were used to generate H460 and A549 PTEN-depleted models. Ceralasertib was evaluated as a single agent and in combination with RT in vitro and in vivo. Histological staining was used to assess immune cell infiltration in pneumonitis-prone C3H/NeJ mice. Here, we report that the inhibition of ATR in combination with RT caused a significant reduction in PTEN-depleted NSCLC cells, with delayed DNA repair and reduced cell viability, as shown by an increase in cells in Sub G1. Combination treatment in vivo significantly inhibited H460 PTEN-depleted tumour growth in comparison to H460 non-targeting PTEN-expressing (NT) cell-line-derived xenografts (CDXs). Additionally, there was no significant increase in infiltrating macrophages or neutrophils except at 4 weeks, whereby combination treatment significantly increased macrophage levels relative to RT alone. Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations.

Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients. METHODS: This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450. FINDINGS: Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group. INTERPRETATION: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. FUNDING: Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.

Stereotactic radiotherapy for oligoprogressive ER-positive breast cancer (AVATAR).

BACKGROUND: The enhanced knowledge of cancer biology has led to considerable advancement in systemic therapy for advanced breast cancer. Recently, studies showed that cyclin-dependent kinase (CDK) 4/6 inhibitor, when added to endocrine therapy, had improved the outcomes of patients with advanced ER-positive HER2-negative breast cancer. However, the disease often progresses following a period of treatment response. In a subset of patients, disease progression may occur at limited sites, i.e., oligoprogressive disease (OPD). In the past few years, stereotactic radiotherapy (SRT) has emerged as a safe and effective treatment for advanced cancer when delivered to limited metastatic sites. Hence, it is worth investigating the role of SRT in the setting of oligoprogressive breast cancer. METHOD: AVATAR is a multicentre phase II registry trial of SRT with endocrine therapy and CDK 4/6 inhibitor for the management of advanced ER-positive HER2-negative breast cancer. The study aims to enrol 32 patients with OPD limited to 5 lesions. The primary endpoint of the study is time to change systemic therapy measured from the commencement of SRT to change in systemic therapy. Secondary objectives include overall survival, progression free survival and treatment related toxicity. The exploratory objective is to describe the time to change in systemic therapy by the site (bone only vs. non-bone lesions) and number (1 vs. > 1) of OPD. DISCUSSION: This study aims to explore the effect of SRT in maximising the benefit of systemic therapy in patients with oligoprogressive ER-positive HER2-negative breast cancer. This approach might help reduce the burden of disease and improve the life quality in these patients. TRIAL REGISTRATION: ACTRN, ACTRN12620001212943 . Date of registration 16 November 2020- Retrospectively registered.

Practical implications to contemplate when considering radical therapy for stage III non-small-cell lung cancer.

The type of patients with stage III non-small-cell lung cancer (NSCLC) selected for concurrent chemoradiotherapy (cCRT) varies between and within countries, with higher-volume centres treating patients with more co-morbidities and higher-stage disease. However, in spite of these disease characteristics, these patients have improved overall survival, suggesting that there are additional approaches that should be optimised and potentially standardised. This paper aims to review the current knowledge and best practices surrounding treatment for patients eligible for cCRT. Initially, this includes timely acquisition of the full diagnostic workup for the multidisciplinary team to comprehensively assess a patient for treatment, as well as imaging scans, patient history, lung function and genetic tests. Such information can provide prognostic information on how a patient will tolerate their cCRT regimen, and to perhaps limit the use of additional supportive care, such as steroids, which could impact on further treatments, such as immunotherapy. Furthermore, knowledge of the safety profile of individual double-platinum chemotherapy regimens and the technological advances in radiotherapy could aid in optimising patients for cCRT treatment, improving its efficacy whilst minimising its toxicities. Finally, providing patients with preparatory and ongoing support with input from dieticians, palliative care professionals, respiratory and care-of-the-elderly physicians during treatment may also help in more effective treatment delivery, allowing patients to achieve the maximum potential from their treatments.

Learning radiotherapy: the state of the art.

BACKGROUND: The last two decades have seen revolutionary developments in both radiotherapy technology and postgraduate medical training. Trainees are expected to attain competencies using a mix of experiential learning, formal postgraduate teaching, self-directed learning and peer education. Radiation (Clinical) Oncology is a recognised 'craft specialty' where the apprenticeship model of training is applicable. This scoping review examines the evidence in relation to how medical trainees learn radiotherapy. METHODS: A systematic search of MEDINE and EMBASE was undertaken to identify studies of trainee and/or trainer experience of radiotherapy learning published 1999-2018. Results pertaining to Medical Oncology, workforce trends, undergraduate radiotherapy exposure, academic training, global health, non-medical staff, health service infrastructure and recruitment to training programmes were not included. RESULTS: A total of 146 publications were included in the synthesis. Five themes were apparent through careful iterative analysis representing broadly inter-related issues. Most articles studied radiotherapy training from the perspective of the trainee doctor. Most literature reports results of observational, local or national surveys with a tightly defined scope. Considerable variation exists within hospitals, within countries, over time and between different curricular areas. CONCLUSIONS: Medical education has not kept pace with changes in the field of radiotherapy and large differences are demonstrated in experience between trainees in different hospitals, countries and training stages. Interpersonal relationships, departmental organisation, and national curricula impact on training quality. Qualitative and quantitative research examining modern radiotherapy learning has been uncommon and uncoordinated, until recently. To date no single study has been designed to comprehensively assess a department's training scheme.

Pulmonary vein dose and risk of atrial fibrillation in patients with non-small cell lung cancer following definitive radiotherapy: An NI-HEART analysis.

BACKGROUND AND PURPOSE: Symptomatic arrhythmia is common following radiotherapy for non-small cell lung cancer (NSCLC), frequently resulting in morbidity and hospitalization. Modern treatment planning technology theoretically allows sparing of cardiac substructures. Atrial fibrillation (AF) comprises the majority of post-radiotherapy arrhythmias, but efforts to prevent this cardiotoxicity have been limited as the causative cardiac substructure is not known. In this study we investigated if incidental radiation dose to the pulmonary veins (PVs) is associated with AF. MATERIAL AND METHODS: A single-centre study of patients completing contemporary (chemo)radiation for NSCLC, with modern planning techniques. Oncology, cardiology and death records were examined, and AF events were verified by a cardiologist. Cardiac substructures were contoured on planning scans for retrospective dose analysis. RESULTS: In 420 eligible patients with NSCLC treated with intensity-modulated (70%) or 3D-conformal (30%) radiotherapy with a median OS of 21.8 months (IQR 10.8-35.1), there were 26 cases of new AF (6%). All cases were grade 3 except two cases of grade 4. Dose metrics for both the left (V55) and right (V10) PVs were associated with the incidence of new AF. Metrics remained statistically significant after accounting for the competing risk of death and cardiovascular covariables for both the left (HR 1.02, 95%CI 1.00-1.03, p = 0.005) and right (HR 1.01 (95%CI 1.00-1.02, p = 0.033) PVs. CONCLUSION: Radiation dose to the PVs during treatment of NSCLC was associated with the onset of AF. Actively sparing the PVs during treatment planning could reduce the incidence of AF during follow-up, and screening for AF may be warranted for select cases.

Baseline Cardiac Parameters as Biomarkers of Radiation Cardiotoxicity in Lung Cancer: An NI-HEART Analysis.

Background: Radiation-induced cardiotoxicity poses a significant challenge in lung cancer management because of the close anatomical proximity of the heart to the lungs, compounded by a high prevalence of cardiovascular risk factors among patients. Objectives: The aim of this study was to assess the predictive value of routinely available clinical and imaging-based cardiac parameters in identifying "high risk" patients for major adverse cardiac events (MACE) and mortality following radiation therapy (RT). Methods: The medical records of patients who underwent definitive RT for non-small cell lung cancer using modern planning techniques at a single center between 2015 and 2020 were retrospectively reviewed. Cardiac events were verified by cardiologists, and mortality data were confirmed with the national registry. Cardiac substructures were autosegmented on RT planning scans for retrospective structure and dose analysis, and their correlation with clinical factors was examined. Fine-Gray models were used to analyze relationships while considering the competing risk for death. Results: Among 478 patients included in the study, 77 (16%) developed 88 MACE, with a median time to event of 16.3 months. A higher burden of pre-existing cardiac diseases was associated with an increased cumulative incidence of MACE (55% [95% CI: 12%-20%] vs 16% [95% CI: 35%-71%]; P < 0.001). Left atrial and left ventricular enlargement on RT planning scans was associated with cumulative incidence of atrial arrhythmia (14% [95% CI: 9%-20%] vs 4% [95% CI: 2%-8%]; P = 0.001) and heart failure (13% [95% CI: 8%-18%] vs 6% [95% CI: 3%-10%]; P = 0.007) at 5 years, respectively. However, myocardial infarction was not associated with the presence of coronary calcium (4.2% [95% CI: 2%-7%] vs 0% [95% CI: 0%-0%]; P = 0.094). No cardiac imaging metrics were found to be both clinically and statistically associated with survival. Conclusions: The present findings suggest that cardiac history and RT planning scan parameters may offer potential utility in prospectively evaluating cardiotoxicity risk following RT for patients with lung cancer.

Re-challenge chemotherapy with gemcitabine plus carboplatin in patients with non-small cell lung cancer.

Despite recent improvements to current therapies and the emergence of novel agents to manage advanced non-small cell lung cancer (NSCLC), the patients' overall survival remains poor. Re-challenging with first-line chemotherapy upon relapse is common in the management of small cell lung cancer but is not well reported for advanced NSCLC. NSCLC relapse has been attributed to acquired drug resistance, but the repopulation of sensitive clones may also play a role, in which case re-challenge may be appropriate. Here, we report the results of re-challenge with gemcitabine plus carboplatin in 22 patients from a single institution who had previously received gemcitabine plus platinum in the first-line setting and had either partial response or a progression-free interval of longer than 6 months. In this retrospective study, the charts of patients who underwent second-line chemotherapy for NSCLC in our cancer center between January 2005 and April 2010 were reviewed. All the patients who received a combination of gemcitabine and carboplatin for re-challenge were included in the study. These patients were offered second-line treatment on confirmation of clear radiological disease progression. The overall response rate was 15% and disease control rate was 75%. The median survival time was 10.4 months, with 46% of patients alive at 1 year. These results suggest that re-challenge chemotherapy should be considered in selected patients with radiological partial response or a progression-free survival of longer than 6 months to the initial therapy.

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.

Clinicoradiological outcomes after radical radiotherapy for lung cancer in patients with interstitial lung disease.

Objective: Interstitial lung disease (ILD) is relatively common in patients with lung cancer with an incidence of 7.5%. Historically pre-existing ILD was a contraindication to radical radiotherapy owing to increased radiation pneumonitis rates, worsened fibrosis and poorer survival compared with non-ILD cohorts. Herein, the clinical and radiological toxicity outcomes of a contemporaneous cohort are described. Methods: Patients with ILD treated with radical radiotherapy for lung cancer at a regional cancer centre were collected prospectively. Radiotherapy planning, tumour characteristics, and pre- and post-treatment functional and radiological parameters were recorded. Cross-sectional images were independently assessed by two Consultant Thoracic Radiologists. Results: Twenty-seven patients with co-existing ILD received radical radiotherapy from February 2009 to April 2019, with predominance of usual interstitial pneumonia subtype (52%). According to ILD-GAP scores, most patients were Stage I. After radiotherapy, localised (41%) or extensive (41%) progressive interstitial changes were noted for most patients yet dyspnoea scores (n = 15 available) and spirometry (n = 10 available) were stable. One-third of patients with ILD went on to receive long-term oxygen therapy, which was significantly more than the non-ILD cohort. Median survival trended towards being worse compared with non-ILD cases (17.8 vs 24.0 months, p = 0.834). Conclusion: Radiological progression of ILD and reduced survival were observed post-radiotherapy in this small cohort receiving lung cancer radiotherapy, although a matched functional decline was frequently absent. Although there is an excess of early deaths, long-term disease control is achievable. Advances in knowledge: For selected patients with ILD, long-term lung cancer control without severely impacting respiratory function may be possible with radical radiotherapy, albeit with a slightly higher risk of death.

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.

Association between statin therapy dose intensity and radiation cardiotoxicity in non-small cell lung cancer: Results from the NI-HEART study.

INTRODUCTION: Radiation cardiotoxicity is a dose-limiting toxicity and major survivorship issue for patients with non-small cell lung cancer (NSCLC) completing curative-intent radiotherapy, however patients' cardiovascular baseline is not routinely optimised prior to treatment. In this study we examined the impact of statin therapy on overall survival and post-radiotherapy cardiac events. METHODS: Patients treated between 2015-2020 at a regional center were identified. Clinical notes were interrogated for baseline patient, tumor and cardiac details, and both follow-up cancer control and cardiac events. Three cardiologists verified cardiac events. Radiotherapy planning scans were retrieved for application of validated deep learning-based autosegmentation. Pre-specified Cox regression analyses were generated with varying degrees of adjustment for overall survival. Fine and Gray regression for the risk of cardiac events, accounting for the competing risk of death and cardiac covariables was undertaken. RESULTS: Statin therapy was prescribed to 59% of the 478 included patients. The majority (88%) of patients not prescribed a statin had at least one indication for statin therapy according to cardiovascular guidelines. In total, 340 patients (71%) died and 79 patients (17%) experienced a cardiac event. High-intensity (HR 0.68, 95%CI 0.50-0.91, p = 0.012) and medium-intensity (HR 0.70, 95%CI 0.51-0.97, p = 0.033) statin therapy were associated with improved overall survival after adjustment for patient, cancer, treatment, response and cardiovascular clinical factors. There were no consistent differences in the rate or grade of cardiac events according to statin intensity. CONCLUSIONS: Statin therapy is associated with improved overall survival in patients receiving curative-intent radiotherapy for NSCLC, and there is evidence of a dose-response relationship. This study highlights the importance of a pre-treatment cardiovascular risk assessment in this cohort. Further studies are needed to examine if statin therapy is cardioprotective in patients undergoing treatment for NSCLC with considerable incidental cardiac radiation dose and a low baseline cardiac risk.

A pulmonary vein atlas for radiotherapy planning.

BACKGROUND AND PURPOSE: Cardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated. MATERIALS AND METHODS: The gross and radiological anatomy relevant to atrial fibrillation was derived from cardiology and radiology literature by a multidisciplinary team. A region of interest and contouring instructions for radiotherapy computed tomography scans were iteratively developed and subsequently evaluated. Radiation oncologists (n = 5) and radiation technologists (n = 2) contoured the PVs on the four-dimensional planning datasets of five patients with locally advanced lung cancer treated with 1.8-2.75 Gy fractions. Contours were compared to reference contours agreed by the researchers using geometric and dosimetric parameters. RESULTS: The mean dose to the PVs was 35% prescription dose. Geometric and dosimetric similarity of the observer contours with reference contours was fair, with an overall mean Dice of 0.80 ± 0.02. The right superior PV (mean DSC 0.83 ± 0.02) had better overlap than the left (mean DSC 0.80 ± 0.03), but the inferior PVs were equivalent (mean DSC of 0.78). The mean difference in mean dose was 0.79 Gy ± 0.71 (1.46% ± 1.25). CONCLUSION: A PV atlas with multidisciplinary approval led to reproducible delineation for radiotherapy planning, supporting the utility of the atlas in future clinical radiotherapy cardiotoxicity research encompassing arrhythmia endpoints.

Treatment Time Optimization in Single Fraction Stereotactic Ablative Radiation Therapy: A 10-Year Institutional Experience.

Purpose: Stereotactic ablative radiation therapy (SABR) delivered in a single fraction (SF) can be considered to have higher uncertainty given that the error probability is concentrated in a single session. This study aims to report the variation in technology and technique used and its effect on intrafraction motion based on a 10 years of experience in SF SABR. Methods and Materials: Records of patients receiving SF SABR delivered at our instruction between 2010 and 2019 were included. Treatment parameters were extracted from the patient management database by using an in-house script. Treatment time was defined as the time difference between the first image acquisition to the last beam off of a single session. The intrafraction variation was measured from the 3-dimensional couch displacement measured after the first cone beam computed tomography (CBCT) acquired during a treatment. Results: The number of SF SABR increased continuously from 2010 to 2019 and were mainly lung treatments. Treatment time was minimized by using volumetric modulated arc therapy, flattening filter-free dose rate, and coplanar field (24 ± 9 min). Treatment time increased as the number of CBCTs per session increased. The most common scenario involved both 2 and 3 CBCTs per session. On the average, a CBCT acquisition added 6 minutes to the treatment time. All treatments considered, the average intrafraction variation was 1.7 ± 1.6 mm. Conclusions: SF SABR usage increased with time in our institution. The intrafraction motion was acceptable and therefore a single fraction is an efficacious treatment option when considering SABR.

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.

Utility of Biology-Guided Radiotherapy to De Novo Metastases Diagnosed During Staging of High-Risk Biopsy-Proven Prostate Cancer.

Background: Biology-guided radiotherapy (BgRT) uses real-time functional imaging to guide radiation therapy treatment. Positron emission tomography (PET) tracers targeting prostate-specific membrane antigen (PSMA) are superior for prostate cancer detection than conventional imaging. This study aims at describing nodal and distant metastasis distribution from prostate cancer and at determining the proportion of metastatic lesions suitable for BgRT. Methods: A single-institution patient subset from the ProPSMA trial (ID ACTRN12617000005358) was analysed. Gross tumour volumes (GTV) were delineated on the CT component of a PSMA PET/CT scan. To determine the suitability of BgRT tracking zones, the normalized SUV (nSUV) was calculated as the ratio of SUVmax inside the GTV to the SUVmean of adjacent three-dimensional shells of thickness 5 mm/10 mm/20 mm as a measure of signal to background contrast. Targets were suitable for BgRT if (1) nSUV was larger than an nSUV threshold and (2) non-tumour tissue inside adjacent shell was free of PET-avid uptake. Results: Of this cohort of 84 patients, 24 had at least one pelvic node or metastatic site disease, 1 to 13 lesions per patient, with a total of 98 lesions (60 pelvic nodes/38 extra-pelvic nodal diseases and haematogenous metastases). Target volumes ranged from 0.08 to 9.6 cm3 while SUVmax ranged from 2.1 to 55.0. nSUV ranged from 1.9 to 15.7/2.4 to 25.7/2.5 to 34.5 for the 5 mm/10 mm/20 mm shell expansion. Furthermore, 74%/68%/34% of the lesions had nSUV ≥ 3 and were free of PSMA PET uptake inside the GTV outer shell margin expansion of 5 mm/10 mm/20 mm. Adjacent avid organs were another lesion, bladder, bowel, ureter, prostate, and liver. Conclusions: The majority of PSMA PET/CT-defined radiotherapy targets would be suitable for BgRT by using a 10-mm tracking zone in prostate cancer. A subset of lesions had adjacent non-tumour uptake, mainly due to the proximity of ureter or bladder, and may require exclusion from emission tracking during BgRT.

A Systematic Review Into the Radiologic Features Predicting Local Recurrence After Stereotactic Ablative Body Radiotherapy (SABR) in Patients With Non-Small Cell Lung Cancer (NSCLC).

PURPOSE: Posttreatment surveillance for local recurrence (LR) after stereotactic ablative body radiotherapy (SABR) can include both fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). Radiation-induced lung injury shares a similar appearance to LR after treatment, making the detection of LR on imaging difficult for clinicians. We aimed to summarize radiologic features of CT and FDG-PET predicting LR and to evaluate radiomics as another tool for detecting LR. METHODS AND MATERIALS: We searched MEDLINE, EMBASE, and PubMed databases for published studies and Web of Science, Wiley Online, and Science Direct databases for conference abstracts that had patient populations with non-small cell lung cancer and reported post-SABR radiologic features of FDG-PET or CT and radiomics from either FDG-PET or CT. Studies for inclusion were independently reviewed by 2 authors. RESULTS: Across 32 relevant studies, the incidence of LR was 13% (222/1726). On CT, certain gross radiologic appearances and kinetic features of changes in size, diameter, volume, or 3 consecutive rises in volume of masslike consolidation are suggestive of LR. **Particular regard should be made for the presence of any ≥3 high-risk features on CT or the individual high-risk features of enlarging opacity at ≥12 month's post-SABR as being highly suspicious of LR. On FDG-PET a relative reduction of <5% of maximum standardised uptake value (SUVmax) from baseline in the first 12 months or cut-offs of SUVmax >5 and SUVmean >3.44 after 12 months can indicate LR. There is limited evidence available to corroborate radiomic features suggestive of LR. CONCLUSIONS: This research has identified common features of LR compared with radiation-induced lung injury, which may aid in early and accurate detection of LR post-SABR; further research is required to validate these findings.