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Background and Purpose: Stereotactic ablative body radiotherapy (SABR) is increasingly used for early-stage lung cancer, however the impact of dose to the heart and cardiac substructures remains largely unknown. The study investigated doses received by cardiac substructures in SABR patients and impact on survival., Materials and Methods: SSBROC is an Australian multi-centre phase II prospective study of SABR for stage I non-small cell lung cancer. Patients were treated between 2013 and 2019 across 9 centres. In this secondary analysis of the dataset, a previously published and locally developed open-source hybrid deep learning cardiac substructure automatic segmentation tool was deployed on the planning CTs of 117 trial patients. Physical doses to 18 cardiac structures and EQD2 converted doses (α/β = 3) were calculated. Endpoints evaluated include pericardial effusion and overall survival. Associations between cardiac doses and survival were analysed with the Kaplan-Meier method and Cox proportional hazards models., Results: Cardiac structures that received the highest physical mean doses were superior vena cava (22.5 Gy) and sinoatrial node (18.3 Gy). The highest physical maximum dose was received by the heart (51.7 Gy) and right atrium (45.3 Gy). Three patients developed grade 2, and one grade 3 pericardial effusion. The cohort receiving higher than median mean heart dose (MHD) had poorer survival compared to those who received below median MHD (p = 0.00004). On multivariable Cox analysis, male gender and maximum dose to ascending aorta were significant for worse survival., Conclusions: Patients treated with lung SABR may receive high doses to cardiac substructures. Dichotomising the patients according to median mean heart dose showed a clear difference in survival. On multivariable analyses gender and dose to ascending aorta were significant for survival, however cardiac substructure dosimetry and outcomes should be further explored in larger studies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: ERCC1 rs11615 and ERCC2 rs238406 single nuclear polymorphism (SNPs) are known for their association with treatment outcome, likely related to radiosensitivity of both tumor and normal tissue in patients with non-small-cell lung cancer. This study aimed to review the effect of 1) these ERCC1/2 SNPs and 2) other SNPs of DNA repair genes on radiation pneumonitis (RP) in patients with lung cancer., Materials and Methods: SNPs of our interest included ERCC1 rs11615 and ERCC2 rs238406 and other genes of DNA repair pathways that are functional and biologically active. DNA repair SNPs reported by at least two independent studies were pooled for meta-analysis. The study endpoint was radiation pneumonitis (RP) after radiotherapy. Recessive, dominant, homozygous, heterozygous, and allelic genotype models were used where appropriate., Results: A total of 16 studies (3080 patients) were identified from the systematic review and 12 studies (2090 patients) on 11 SNPs were included in the meta-analysis. The SNPs were ATM rs189037, ATM rs373759, NEIL1 rs4462560, NEIL1 rs7402844, APE1 rs1130409, XRCC3 rs861539, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, ERCC2 rs13181, and XRCC1 rs25487. ERCC1 rs11615 (236 patients) and ERCC2 rs238406 (254 patients) were not significantly associated with RP. Using the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001)., Conclusion: Genetic variation in the DNA repair pathway genes may play a significant role in the risk of developing radiation pneumonitis in patients with lung cancer. Further studies are needed on genotypic features of DNA repair pathway genes and their association with treatment sensitivity, as such knowledge may guide personalized radiation dose prescription., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: The objective of this study was to develop a two-year overall survival model for inoperable stage I-III non-small cell lung cancer (NSCLC) patients using routine radiation oncology data over a federated (distributed) learning network and evaluate the potential of decision support for curative versus palliative radiotherapy., Methods: A federated infrastructure of data extraction, de-identification, standardisation, image analysis, and modelling was installed for seven clinics to obtain clinical and imaging features and survival information for patients treated in 2011-2019. A logistic regression model was trained for the 2011-2016 curative patient cohort and validated for the 2017-2019 cohort. Features were selected with univariate and model-based analysis and optimised using bootstrapping. System performance was assessed by the receiver operating characteristic (ROC) and corresponding area under curve (AUC), C-index, calibration metrics and Kaplan-Meier survival curves, with risk groups defined by model probability quartiles. Decision support was evaluated using a case-control analysis using propensity matching between treatment groups., Results: 1655 patient datasets were included. The overall model AUC was 0.68. Fifty-eight percent of patients treated with palliative radiotherapy had a low-to-moderate risk prediction according to the model, with survival times not significantly different (p = 0.87 and 0.061) from patients treated with curative radiotherapy classified as high-risk by the model. When survival was simulated by risk group and model-indicated treatment, there was an estimated 11% increase in survival rate at two years (p < 0.01)., Conclusion: Federated learning over multiple institution data can be used to develop and validate decision support systems for lung cancer while quantifying the potential impact of their use in practice. This paves the way for personalised medicine, where decisions can be based more closely on individual patient details from routine care., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: The Royal College of Radiologists (RCR) audit of radical radiotherapy (RR) for patients with non-small cell lung cancer (NSCLC) in 2013 concluded that there was under-treatment compared to international comparators and marked variability between cancer networks. Elderly patients were less likely to receive guideline recommended treatments. Access to technological developments was low. Various national and local interventions have since taken place. This study aims to re-assess national practice., Materials and Methods: Radiotherapy departments completed one questionnaire for each patient started on RR for 4 weeks in January 2023., Results: Ninety-three percent of centres returned data on 295 patients. RR has increased 70% since 2013 but patients on average wait 20% longer to start treatment (p = 0.02). Staging investigations were often outside a desirable timeframe (79% of PET/CT scans). Advanced planning techniques are used more frequently: 4-dimensional planning increased from 33% to 90% (P < 0.001), cone beam imaging from 67% to 97% (p < 0.001) and colleague led peer review increased from 41% to 73% (P < 0.001)., Conclusion: There have been significant improvements in care. There has been a considerable increase in clinical oncology workload with evidence of stress on the system that requires additional resourcing., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The landscape of lung radiotherapy (RT) has rapidly evolved over the past decade with modern RT and surgical techniques, systemic therapies, and expanding indications for RT. To date, 2 MRI-guided RT (MRgRT) units, 1 using a 0.35T magnet and 1 using a 1.5T magnet, are available for commercial use with more systems in the pipeline. MRgRT offers distinct advantages such as real-time target tracking, margin reduction, and on-table treatment adaptation, which may help overcome many of the common challenges associated with thoracic RT. Nonetheless, the use of MRI for image guidance and the current MRgRT units also have intrinsic limitations. In this review article, we will discuss clinical experiences to date, advantages, challenges, and future directions of MRgRT to the lung., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Pneumonitis is a common and potentially deadly complication of combined chemoradiation and immune checkpoint inhibition (CRT-ICI) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study we sought to identify the risk factors for pneumonitis with CRT-ICI therapy in LA-NSCLC cases and determine its impact on survival., Materials and Methods: We conducted a retrospective chart review of 140 patients with LA-NSCLC who underwent curative-intent CRT-ICI with durvalumab between 2018 and 2021. Pneumonitis was diagnosed by a multidisciplinary team of clinical experts. We used multivariable cause-specific hazard models to identify risk factors associated with grade ≥2 pneumonitis. We constructed multivariable Cox proportional hazard models to investigate the impact of pneumonitis on all-cause mortality., Results: The median age of the cohort was 67 years; most patients were current or former smokers (86%). The cumulative incidence of grade ≥2 pneumonitis was 23%. Among survivors, 25/28 patients had persistent parenchymal scarring. In multivariable analyses, the mean lung dose (hazard ratio 1.14 per Gy, 95% confidence interval 1.03-1.25) and interstitial lung disease (hazard ratio 3.8, 95% confidence interval 1.3-11.0) increased the risk for pneumonitis. In adjusted models, grade ≥2 pneumonitis (hazard ratio 2.5, 95% confidence interval 1.0-6.2, P = 0.049) and high-grade (≥3) pneumonitis (hazard ratio 8.3, 95% confidence interval 3.0-23.0, P < 0.001) were associated with higher all-cause mortality., Conclusions: Risk factors for pneumonitis in LA-NSCLC patients undergoing CRT-ICI include the mean radiation dose to the lung and pre-treatment interstitial lung disease. Although most cases are not fatal, pneumonitis in this setting is associated with markedly increased mortality., (Copyright © 2023. Published by Elsevier Ltd.)

Aims: Previous work found that during the first wave of the COVID-19 pandemic, 34% of patients with lung cancer treated with curative-intent radiotherapy in the UK had a change to their centre's usual standard of care treatment (Banfill et al. Clin Oncol 2022;34:19-27). We present the impact of these changes on patient outcomes., Materials and Methods: The COVID-RT Lung database was a prospective multicentre UK cohort study including patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between April and October 2020. Data were collected on patient demographics, radiotherapy and systemic treatments, toxicity, relapse and death. Multivariable Cox and logistic regression were used to assess the impact of having a change to radiotherapy on survival, distant relapse and grade ≥3 acute toxicity. The impact of omitting chemotherapy on survival and relapse was assessed using multivariable Cox regression., Results: Patient and follow-up forms were available for 1280 patients. Seven hundred and sixty-five (59.8%) patients were aged over 70 years and 603 (47.1%) were female. The median follow-up was 213 days (119, 376). Patients with stage I-II non-small cell lung cancer (NSCLC) who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.859) or death (P = 0.884); however, they did have increased odds of grade ≥3 acute toxicity (P = 0.0348). Patients with stage III NSCLC who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.216) or death (P = 0.789); however, they did have increased odds of grade ≥3 acute toxicity (P < 0.001). Patients with stage III NSCLC who had their chemotherapy omitted had no significant increase in distant relapse (P = 0.0827) or death (P = 0.0661)., Conclusion: This study suggests that changes to radiotherapy and chemotherapy made in response to the COVID-19 pandemic did not significantly affect distant relapse or survival. Changes to radiotherapy, namely increased hypofractionation, led to increased odds of grade ≥3 acute toxicity. These results are important, as hypofractionated treatments can help to reduce hospital attendances in the context of potential future emergency situations., (Copyright © 2023. Published by Elsevier Ltd.)

Aims: Clinical equipoise exists regarding early-stage lung cancer treatment among patients as trials comparing stereotactic body radiation therapy (SBRT) and surgical resection are unavailable. Given the potential differences in treatment effectiveness and side-effects, we sought to determine the associations between treatment type, decision regret and depression., Materials and Methods: A multicentre, prospective study of patients with stage IA-IIA non-small cell lung cancer (NSCLC) with planned treatment with SBRT or surgical resection was conducted. Decision regret and depression were measured using the Decision Regret Scale (DRS) and Patient Health Questionnaire-4 (PHQ-4) at 3, 6 and 12 months post-treatment, respectively. Mixed linear regression modelling examined associations between treatment and decision regret adjusting for patient sociodemographics., Results: Among 211 study participants with early-stage lung cancer, 128 (61%) patients received SBRT and 83 (39%) received surgical resection. The mean age was 73 years (standard deviation = 8); 57% were female; 79% were White non-Hispanic. In the entire cohort at 3 months post-treatment, 72 (34%) and 57 (27%) patients had mild and severe decision regret, respectively. Among patients who received SBRT or surgery, 71% and 46% of patients experienced at least mild decision regret at 3 months, respectively. DRS scores increased at 6 months and decreased slightly at 12 months of follow-up in both groups. Higher DRS scores were associated with SBRT treatment (adjusted mean difference = 4.18, 95% confidence interval 0.82 to 7.54) and depression (adjusted mean difference = 3.49, 95% confidence interval 0.52 to 6.47). Neither patient satisfaction with their provider nor decision-making role concordance was associated with DRS scores., Conclusions: Most early-stage lung cancer patients experienced at least mild decision regret, which was associated with SBRT treatment and depression symptoms. Findings suggest patients with early-stage lung cancer may not be receiving optimal treatment decision-making support. Therefore, opportunities for improved patient-clinician communication probably exist., (Copyright © 2023. Published by Elsevier Ltd.)

Aims: Accelerated hypofractionated radiotherapy is used at our institution for non-small cell lung cancer (NSCLC) patients not eligible for stereotactic body radiotherapy or chemoradiotherapy. The purpose of this study was to report clinical outcomes of delivering 60 Gy in 15 fractions for these patients., Materials and Methods: All NSCLC patients who received 60 Gy in 15 fractions were reviewed. Outcomes of interest were local failure, regional failure, distant progression, overall survival and treatment-associated toxicities., Results: In total, 111 patients were included. The median age was 78.8 years and most tumours were adenocarcinoma (n = 55, 49.6%). Sixty-five patients (58.6%) were N0. The cumulative incidence of local failure at 12 and 24 months in the N0 cohort was 5.2% and 14.2%, respectively, compared with 11.5% and 14.8% for N+ patients. Tumour size >35 mm predicted for local failure (hazard ratio 2.706, 95% confidence interval 1.002-7.307, P = 0.0494). Distant progression at 12 and 24 months in N0 patients was 13.7% and 24.3% compared with 24.6% and 33.5% in N+ patients. In N0 patients, larger tumour size was associated with increased risk of distant progression. The median overall survival was 38.1 months in N0 patients versus 31.7 months in N+ patients. The most common toxicity was radiation pneumonitis (n = 6, 6.4%). The incidence of any grade 3 toxicity was 10.3% at ≥1 year. There were no deaths or hospitalisations attributed to treatment., Conclusions: Accelerated hypofractionated radiotherapy is well tolerated and resulted in favourable clinical outcomes in various stages of NSCLC patients., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: To assess the risk of cardiac toxicity following radical radiotherapy in advanced lung cancer patients., Materials and Methods: Patients with a diagnosis of stage III non-small cell lung cancer (NSCLC) receiving chemoradiotherapy were extracted from a population-based cohort in Ontario, Canada. The primary outcome of cardiac toxicity, defined as cardiac events or congestive heart failure, was assessed at 1 and 5 years following chemoradiotherapy. Secondary outcomes included overall survival, survival in relationship to post-treatment cardiac events and the effect of radiotherapy technique on cardiac toxicity., Results: In total, 2031 NSCLC patients were included. The cumulative incidence of cardiac toxicity at 5 years was 20.3% (18.4-22.3). The median survival was 13.7 months in NSCLC patients who had a cardiac event post-chemoradiotherapy compared with 23.4 months in those who did not (P = 0.012). There was a trend towards increased cumulative cardiac toxicity (hazard ratio 3.37, P = 0.14) with three-dimensional conformal radiotherapy compared with intensity-modulated or volumetric arc radiotherapy techniques., Conclusion: The risk of cardiac events and congestive heart failure 5 years after radical thoracic radiotherapy appears high and survival is inferior at 1 year in those patients who experience a cardiac event post-treatment. More conformal radiotherapy techniques may help reduce cardiac toxicity. Further studies should investigate adaptive treatment planning and close monitoring and intervention in this high-risk group after chemoradiotherapy., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

There have been significant advances in the systemic treatment of stage IV lung cancer, which is now recommended first line in patients with adequate fitness. This includes some patients with brain metastases due to the increased understanding of the central nervous system penetration of targeted therapies. The trials evidence base for palliative radiotherapy pre-dated this routine use of systemic therapy in our practice, which means that the sequence and role of palliative radiotherapy are not currently well defined in the first-line treatment setting. However, due to its efficacy in symptom control, radiotherapy remains a core component in the palliative management of lung cancer, particularly in the second-line setting and those unsuited to primary systemic treatment. This overview focuses on the evidence behind palliative radiotherapy to the thorax and brain for non-small cell and small cell lung cancer and the potential for future studies, including the TOURIST Trial Platform, to guide the future direction of these treatments., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Background: Lung cancer outcomes in the UK are worse than those in many similar countries. The RCR developed a series of 43 consensus statements (CS) to facilitate improvements in care for patients treated with radiotherapy., Methods: We asked all 61 UK radiotherapy centres to self-assess the implementation of the CS and to describe their departmental key strengths and weaknesses in September 2021., Results: 87% of centres returned their assessments. Whilst developmental activity was seen in most areas for most centres, 24 of the statements were felt to be difficult to implement within the next 2 years by at least one centre. The most frequently reported strengths were in the implementation of SABR (stereotactic body radiotherapy), concurrent chemoradiation for non-small cell lung cancer and technological aspects of treatment planning. The most frequently described departmental weaknesses were in pre-habilitation, timeliness of PET/CT scans and prophylaxis for Pneumocystis jiroveci Pneumonia (PJP). Barriers to implementation were often due to insufficient resource, a requirement for organisations to work together, and a perceived lack of evidence base. Strengths were often attributed to good team working, a local champion and being an early adopter., Conclusions: This work confirms the commitment of lung cancer radiotherapy teams across the UK to improve outcomes for their patients. Most of the statements have been implemented at least partially. Themes have been identified to aid further progress, one of which is a requirement for significant investment., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Oligometastatic non-small cell lung cancer encompasses a number of distinct clinical scenarios with a pattern of limited tumour burden on imaging. Delivering local ablative therapy to individual metastatic lesions may assist in disease modification and contribute to improved outcomes. We review the published randomised clinical trials that support the implementation of stereotactic ablative radiotherapy as a standard of care in certain oligometastatic non-small cell lung cancer clinical scenarios, and highlight the current knowledge gaps and areas of ongoing research., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Stereotactic ablative radiotherapy (SABR) is an important curative-intent treatment option for early-stage non-small cell lung cancer. It offers good cancer control without invasive surgery and has become the standard of care for medically inoperable patients. The literature on SABR for early-stage non-small cell lung cancer is substantial and continues to grow. However, there remain areas of controversy where data are limited - notably the use of SABR in medically operable patients. Other areas of some debate include the treatment of central/ultra-central and large (>5 cm) lesions, as well as treatment with co-existing interstitial lung disease. This review article provides an overview of the current literature together with a discussion of future directions., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: With interest in normal tissue sparing and dose-escalated radiotherapy in the treatment of inoperable locally advanced non-small cell lung cancer, this study investigated the impact of motion-managed moderate deep inspiration breath hold (mDIBH) on normal tissue sparing and dose-escalation potential and compared this to planning with a four-dimensional motion-encompassing internal target volume or motion-compensating mid-ventilation approach., Materials and Methods: Twenty-one patients underwent four-dimensional and mDIBH planning computed tomography scans. Internal and mid-ventilation target volumes were generated on the four-dimensional scan, with mDIBH target volumes generated on the mDIBH scan. Isotoxic target dose-escalation guidelines were used to generate six plans per patient: three with a target dose cap and three without. Target dose-escalation potential, normal tissue complication probability and differences in pre-specified dose-volume metrics were evaluated for the three motion-management techniques., Results: The mean total lung volume was significantly greater with mDIBH compared with four-dimensional scans. Lung dose (mean and V 21 Gy ) and mean heart dose were significantly reduced with mDIBH in comparison with four-dimensional-based approaches, and this translated to a significant reduction in heart and lung normal tissue complication probability with mDIBH. In 20/21 patients, the trial target prescription dose cap of 79.2 Gy was achievable with all motion-management techniques., Conclusion: mDIBH aids lung and heart dose sparing in isotoxic dose-escalated radiotherapy compared with four-dimensional planning techniques. Given concerns about lung and cardiac toxicity, particularly in an era of consolidation immunotherapy, reduced normal tissue doses may be advantageous for treatment tolerance and outcome., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Aims: So far, the impact of intra-thoracic anatomical changes (ITACs) on patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer is unknown. Studying these is important, as ITACs have the potential to impact the workflow and reduce treatment quality. The aim of this study was to assess and categorise ITACs, as detected on cone beam computed tomography scans (CBCT), and their subsequent impact upon treatment in lung cancer patients treated with SABR., Materials and Methods: CBCTs from 100 patients treated with SABR for early non-small cell lung cancer were retrospectively reviewed. The presence of the following ITACs was assessed: atelectasis, infiltrative change, pleural effusion, baseline shift and gross tumour volume (GTV) increase and decrease. ITACs were graded using a traffic light protocol. This was adapted from a tool previously developed to assesses potential target undercoverage or organ at risk overdose. The frequency of physics or clinician review was noted. A linear mixed effects model was used to assess the relationship between ITAC grade and set-up time (time from first CBCT to beam delivery)., Results: ITACs were observed in 22% of patients. Twenty-one per cent of these were categorised as 'red', implying a risk of underdosage to the GTV. Most were 'yellow' (51%), indicating little impact upon planning target volume coverage of the GTV. Physics or clinician review was required in 10% of all treatment fractions overall. Three patients needed their treatment replanned. The mixed effect model analysis showed that ITACs cause a significant prolongation of set-up time (Χ 2 (3) = 9.22, P = 0.02)., Conclusion: Most ITACs were minor, but associated with unplanned physics or clinician review, representing a potentially significant resource burden. ITACs also had a significant impact upon set-up time, with consequences for the wider workflow and intra-fraction motion. Detailed guidance on the management of ITACs is needed to provide support for therapeutic radiographers delivering lung SABR., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Aims: To report late toxicity and long-term outcomes of intensity-modulated radiotherapy (IMRT)-based stereotactic ablative body radiotherapy (SABR) in patients with ultra-central lung tumours., Materials and Methods: This is a single-institution retrospective analysis of patients treated with SABR for ultra-central tumours between May 2008 and April 2016. Ultra-central location was defined as tumour (GTV) abutting or involving trachea, main or lobar bronchi. Respiratory motion management and static-field dynamic-IMRT were used, with dose prescribed homogeneously (maximum <120%). Descriptive analysis, Kaplan-Meier method, log-rank test and Cox regression were used to assess outcomes., Results: Sixty-five per cent of patients had inoperable primary non-small cell lung cancer and 35% had lung oligometastases. The median age was 72 (range 34-85) years. The median gross tumour volume and planning target volume (PTV) were 19.6 (range 1.7-203.3) cm 3 and 57.4 (range 7.7-426.6) cm 3 , respectively. The most commonly used dose fractionation was 60 Gy in eight fractions (n = 51, 87.8%). Median BED 10 for D98%PTV and D2%PTV were 102.6 Gy and 115.06 Gy, respectively. With a median follow-up of 26.5 (range 3.2-100.5) months, fatal haemoptysis occurred in five patients (8.7%), of which two were directly attributable to SABR. A statistically significant difference was identified between median BED 3 for 4 cm 3 of airway, for patients who developed haemoptysis versus those who did not (147.4 versus 47.2 Gy, P = 0.005). At the last known follow-up, 50 patients (87.7%) were without local recurrence. Freedom from local progression at 2 and 4 years was 92 and 79.8%, respectively. The median overall survival was 34.3 (95% confidence interval 6.1-61.6) months. Overall survival at 2 and 4 years was 55.1 and 41.2%, respectively., Conclusion: In patients with high-risk ultra-central lung tumours, IMRT-based SABR with homogenous dose prescription achieves high local control, similar to that reported for peripheral tumours. Although fatal haemoptysis occurred in 8.7% of patients, a direct causality with SABR was evident in only 3%. Larger studies are warranted to ascertain factors associated with outcomes, especially toxicity, and identify patients who would probably benefit from this treatment., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: The neutrophil-lymphocyte ratio (NLR) and the absolute lymphocyte count (ALC) have been proposed as prognostic markers in non-small cell lung cancer (NSCLC). The objective of this study was to examine the association of NLR/ALC before and after curative-intent radiotherapy for NSCLC on disease recurrence and overall survival., Materials and Methods: A retrospective study of consecutive patients who underwent curative-intent radiotherapy for NSCLC across nine sites in the UK from 1 October 2014 to 1 October 2016. A multivariate analysis was carried out to assess the ability of pre-treatment NLR/ALC, post-treatment NLR/ALC and change in NLR/ALC, adjusted for confounding factors using the Cox proportional hazards model, to predict disease recurrence and overall survival within 2 years of treatment., Results: In total, 425 patients were identified with complete blood parameter values. None of the NLR/ALC parameters were independent predictors of disease recurrence. Higher pre-NLR, post-NLR and change in NLR plus lower post-ALC were all independent predictors of worse survival. Receiver operator curve analysis found a pre-NLR > 2.5 (odds ratio 1.71, 95% confidence interval 1.06-2.79, P < 0.05), a post-NLR > 5.5 (odds ratio 2.36, 95% confidence interval 1.49-3.76, P < 0.001), a change in NLR >3.6 (odds ratio 2.41, 95% confidence interval 1.5-3.91, P < 0.001) and a post-ALC < 0.8 (odds ratio 2.86, 95% confidence interval 1.76-4.69, P < 0.001) optimally predicted poor overall survival on both univariate and multivariate analysis when adjusted for confounding factors. Median overall survival for the high-versus low-risk groups were: pre-NLR 770 versus 1009 days (P = 0.34), post-NLR 596 versus 1287 days (P ≤ 0.001), change in NLR 553 versus 1214 days (P ≤ 0.001) and post-ALC 594 versus 1287 days (P ≤ 0.001)., Conclusion: NLR and ALC, surrogate markers for systemic inflammation, have prognostic value in NSCLC patients treated with curative-intent radiotherapy. These simple and readily available parameters may have a future role in risk stratification post-treatment to inform the intensity of surveillance protocols., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Oligometastatic non-small cell lung cancer (NSCLC) has been recognized as a unique, yet common, clinical entity over the past 2-3 decades. Numerous retrospective series and early phase single arm trials have demonstrated the efficacy and safety of aggressive approaches in select patients. In addition, results from recent randomized trials have demonstrated potential benefits of radiation therapy and surgery as a form of local ablative therapy (LAT) in prolonging disease-free survival and overall survival. However, more questions remain given the limitation of existing clinical evidence and the lack of well validated biomarkers. Advances in late stage randomized trials with biological correlatives may further clarify the role of LAT to assist with clinical decision making in treating patients with oligometastatic NSCLC. In this review, we discuss the clinical and biologic data surrounding patient selection for LAT in oligometastatic NSCLC, as well as future directions in prospective and translational studies., (Copyright © 2021. Published by Elsevier Inc.)

Aims: Stereotactic ablative radiation therapy (SABR) is a standard of care for medically inoperable early stage non-small cell lung carcinoma. Tumours greater than 5 cm have been excluded from randomised trials using SABR and, hence, it is not used as a standard for larger lung tumours. However, improvements in radiation therapy techniques and the success of SABR in treatment of early stage disease may allow safe delivery of ablative doses to larger tumours. We analysed our experience with tumours ≥5 cm to determine the efficacy and toxicity profile of SABR in this setting., Materials and Methods: We evaluated survival, control rates, patterns of failure and toxicity in patients with a tumour diameter larger than 5 cm that had no nodal or distant metastases treated with SABR technology. Patients had been treated in two centres since 2009 and were retrospectively analysed. All patients had positron emission tomography staging, were discussed at a tumour board and were documented to have no nodal or distant metastatic disease. Treatment outcomes were analysed using Kaplan-Meier estimates and compared using the Log-rank test. Cox regression was used to investigate the association between the survival outcomes and predictor variables., Results: In total, 86 patients were identified. Six patients had no follow-up imaging. Therefore, 80 patients were available for analysis. All patients were reclassified according to the updated AJCC eighth edition. The median follow-up was 19.6 months. No patients received neoadjuvant or concurrent systemic therapy. One patient received adjuvant systemic therapy. The median age at treatment was 77 years (range 58-91). Eighty-four per cent were stage T3N0M0 and 16% were staged T4N0M0. The median tumour diameter was 5.8 cm (range 5.0-9.3 cm). The median gross tumour volume, measured on a single phase of the respiratory cycle, was 45.7 cm 3 (range 12.1-203.3 cm 3 ). The median overall survival was 20.9 months (95% confidence interval 12.6-29.1 months). One-, 2- and 3-year overall survival was 71%, 48% and 32%, respectively. The median local failure-free survival was 19.5 months (95% confidence interval 14.4-24.6). The median disease-free survival was 15.1 months (95% confidence interval 9.9-20.4 months). Local control at 1, 2 and 3 years was 85% (95% confidence interval 76-94%), 71% (95% confidence interval 58-84%) and 57% (95% confidence interval 40-74%), respectively. Forty-four patients (55%) had any treatment failure (local, mediastinal, intrapulmonary or distant metastases). Out-of-field intrapulmonary disease progression was the most common mode of failure, occurring in 21 patients (26%). Local failure occurred in 19 patients (24%) - alone or in combination with other progression. Distant metastases occurred in 20 patients (25%). Neither histological subtype, tumour size nor gross tumour volume had a statistically significant effect on local failure-free survival. Two patients experienced grade 3 late dyspnoea. There were no other reported grade 3 or higher acute or late toxicities., Conclusion: SABR for larger lung tumours ≥5 cm results in high local control and acceptable survival in patients with medically inoperable large non-small cell lung carcinoma treated with radiation alone. Such patients should be considered for SABR owing to fewer treatment fractions and acceptable toxicity. Local control analysis reveals a sustained pattern of local failure emphasising the need for long-term follow-up. Improvements in technical strategies are required to further improve local control., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The best survival for patients with unresectable, locally advanced NSCLC is currently achieved through concurrent chemoradiation followed by durvalumab for a year. Despite the best standard of care treatment, the majority of patients still develop disease recurrence, which could be distant and/or local. Trials continue to try and improve outcomes for patients with unresectable NSCLC, typically through treatment intensification, with the addition of more systemic agents, or more radiation dose to the tumor. Although RTOG 0617 showed that uniform dose escalation across an unselected population of patients undergoing chemoradiation is not beneficial, efforts continue to select patients and tumor subsets that are likely to benefit from dose escalation. This review describes some of the ongoing therapeutic trials in unresectable NSCLC, with an emphasis on quantitative imaging and precision radiation dose escalation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Radiation therapy plays an integral role in the treatment of all stages of non-small cell lung cancer. Survival outcomes are improving, but radiation therapy remains associated with long-term toxicity. Recently, it has become evident that the heart is an important organ at risk for treatment-related morbidity. In this review, we discuss the hypothesis that particle radiation therapy offers superior dosimetry compared with photon-based treatment, and that this comparative advantage translates into clinically meaningful cardiac toxicity reduction with similar local tumor control. We discuss the evidence in non-small cell lung cancer to date, the ongoing prospective trials that may provide additional insight, and the opportunities to optimally integrate particle therapy into future prospective investigation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Radiation treatment of early stage nonsmall cell lung cancer has evolved over the past 2 decades to progressively more hypofractionated treatment courses. Results comparable to surgical resection are seen with stereotactic body radiotherapy, which is now the standard of care for medically inoperable patients, and a treatment option for operable patients as well. Understanding of the optimal radiation dose and fractionation are evolving, especially for central tumors which have higher treatment toxicity than peripheral tumors., (Copyright © 2020. Published by Elsevier Inc.)

Locoregional recurrence occurs in 10%-30% of non-small cell lung cancer (NSCLC) after treatment with definitive (chemo)radiotherapy. Re-irradiation is the main curative-intent treatment option for these patients; however, it represents a therapeutic challenge for thoracic radiation oncologists. Re-irradiation practices are variable worldwide with lack of agreement on the optimal dose or the cumulative maximum dose acceptable for critical organs. The role of re-irradiation in NSCLC is also not clearly defined in the era of immunotherapy. In this review, we will present published and on-going re-irradiation studies for recurrent NSCLC. We will appraise available evidence for critical organ dose constraints and provide a framework for future therapeutic approaches and trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The dosimetric advantages of particle therapy lead to significantly reduced integral dose to normal tissues, making it an attractive treatment option for body sites such as the thorax. With reduced normal tissue dose comes the potential for dose escalation, toxicity reduction, or hypofractionation. While proton and heavy ion therapy have been used extensively for NSCLC, there are challenges in planning and delivery compared with X-ray-based radiation therapy. Particularly, range uncertainties compounded by breathing motion have to be considered. This article summarizes the current state of particle therapy for NSCLC with a specific focus on the impact of dosimetric uncertainties in planning and delivery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The concept of oligometastatic disease has evolved substantially over the past decade. During this time, there has been a transition from retrospective and single-arm prospective studies to randomized evidence suggesting a benefit of local consolidative therapy (LCT) in the setting of limited metastatic non-small cell lung cancer. These trials had constraints and were thus limited in the strength of their conclusions, but led to several other ongoing randomized trials examining the role of LCT. These studies span various disease states (synchronous oligometastatic vs oligoprogressive), the scope of histologies included, and in how they define oligometastases. In addition, parallel biologic work is attempting to integrate relevant biomarkers and molecular classifications, with the ultimate goal of more precisely defining oligometastases and triaging patients to appropriate care. Finally, consensus guidelines have been initiated that provide a framework for designing future studies and for maintaining consistency across analyses that will facilitate the interpretation of results. This review describes the prior randomized data, the limitations therein, and future directions of clinical and preclinical studies that highlight the emerging paradigms for treatment of this select patient cohort., (Copyright © 2020. Published by Elsevier Inc.)

Lung cancer is the leading cause of cancer deaths worldwide, and patients with nonsmall cell lung cancer have traditionally had a poor prognosis. An improved understanding of targetable oncogenic molecular alterations has led to a growing number of effective and first-line therapies in targeted patient populations. This review provides an overview of systemic therapy options available for patients with mutation-driven nonsmall cell lung cancer, as well as a discussion of data regarding safety when combined with radiation therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors are approved for a variety of indications for locally advanced and metastatic non-small cell lung cancer (NSCLC), and trials are ongoing in the early-stage setting. There is an unmet need to understand which patients may derive benefit from immunotherapies and how to harness combined modality therapies to improve overall response rates and durability. Here, we review studies from the bench-to-bedside to examine the role of radiation therapy (RT) on the tumor immune microenvironment in NSCLC with an eye toward augmenting antitumor immunity. Together, these data provide a foundation for developing future clinical trials harnessing RT to augment antitumor immunity and highlight the need for correlative translational studies to directly characterize the impact of RT on the human NSCLC tumor immune microenvironment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recent treatment advances have improved outcomes for patients with non-small cell lung cancer (NSCLC), often utilizing tumor molecular characterization to identify targetable mutations. This is further enhanced by advancements in "liquid biopsies", using peripheral blood for noninvasive, serial sampling of tumor biology. While tumor genomic alterations have established therapeutic implications in metastatic NSCLC, research is also ongoing to develop applications for tissue and liquid biomarkers in earlier stage disease, such as patients treated with radiation for early stage or locoregional NSCLC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Twenty per cent of patients with non-small cell lung cancer present with stage III locally advanced disease. Precision radiotherapy with pencil beam scanning (PBS) protons may improve outcomes. However, stage III is a heterogeneous group and accounting for complex tumour motion is challenging. As yet, it remains unclear as to whom will benefit. In our retrospective planning study, we explored if patients with superior sulcus tumours (SSTs) are a select cohort who might benefit from this treatment., Materials and Methods: Patients with SSTs treated with radical radiotherapy using four-dimensional planning computed tomography between 2010 and 2015 were identified. Tumour motion was assessed and excluded if greater than 5 mm. Photon volumetric-modulated arc therapy (VMAT) and PBS proton single-field optimisation plans, with and without inhomogeneity corrections, were generated retrospectively. Robustness analysis was assessed for VMAT and PBS plans involving: (i) 5 mm geometric uncertainty, with an additional 3.5% range uncertainty for proton plans; (ii) verification plans at maximal inhalation and exhalation. Comparative dosimetric and robustness analyses were carried out., Results: Ten patients were suitable. The mean clinical target volume D95 was 98.1% ± 0.4 (97.5-98.8) and 98.4% ± 0.2 (98.1-98.9) for PBS and VMAT plans, respectively. All normal tissue tolerances were achieved. The same four PBS and VMAT plans failed robustness assessment. Inhomogeneity corrections minimally impacted proton plan robustness and made it worse in one case. The most important factor affecting target coverage and robustness was the clinical target volume entering the spinal canal. Proton plans significantly reduced the mean lung dose (by 21.9%), lung V5, V10, V20 (by 47.9%, 36.4%, 12.1%, respectively), mean heart dose (by 21.4%) and thoracic vertebra dose (by 29.2%) (P < 0.05)., Conclusions: In this planning study, robust PBS plans were achievable in carefully selected patients. Considerable dose reductions to the lung, heart and thoracic vertebra were possible without compromising target coverage. Sparing these lymphopenia-related organs may be particularly important in this era of immunotherapy., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: To quantify the reliability of a commercially available auto-segmentation tool in locally advanced non-small cell lung cancer using serial four-dimensional computed tomography (4DCT) scans during conventionally fractionated radiotherapy., Materials and Methods: Eight patients with serial 4DCT scans (n = 44) acquired over the course of radiotherapy were assessed. Each 4DCT had a physician-defined primary tumour manual contour (MC). An auto-contour (AC) and a user-adjusted auto-contour (UA-AC) were created for each scan. Geometric agreement of the AC and the UA-AC to the MC was assessed using the dice similarity coefficient (DSC), the centre of mass (COM) shift from the MC and the structure volume difference from the MC. Bland Altman analysis was carried out to assess agreement between contouring methods. Dosimetric reliability was assessed by comparison of planning target volume dose coverage on the MC and UA-AC. The time trend analysis of the geometric accuracy measures from the initial planning scan through to the final scan for each patient was evaluated using a Wilcoxon signed ranks test to assess the reliability of the UA-AC over the duration of radiotherapy., Results: User adjustment significantly improved all geometric comparison metrics over the AC alone. Improved agreement was observed in smaller tumours not abutting normal soft tissue and median values for geometric comparisons to the MC for DSC, tumour volume difference and COM offset were 0.80 (range 0.49-0.89), 0.8 cm 3 (range 0.0-5.9 cm 3 ) and 0.16 cm (range 0.09-0.69 cm), respectively. There were no significant differences in dose metrics measured from the MC and the UA-AC after Bonferroni correction. Variation in geometric agreement between the MC and the UA-AC were observed over the course of radiotherapy with both DSC (P = 0.035) and COM shift from the MC (ns) worsening. The median tumour volume difference from the MC improved at the later time point., Conclusions: These findings suggest that the UA-AC can produce geometrically and dosimetrically acceptable contours for appropriately selected patients with non-small cell lung cancer. Larger studies are required to confirm the findings., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: There is a paucity of evidence on which to produce recommendations on neither the clinical nor the imaging follow-up of lung cancer patients after curative-intent radiotherapy. In the 2019 National Institute for Health and Care Excellence lung cancer guidelines, further research into risk-stratification models to inform follow-up protocols was recommended., Materials and Methods: A retrospective study of consecutive patients undergoing curative-intent radiotherapy for non-small cell lung cancer from 1 October 2014 to 1 October 2016 across nine UK trusts was carried out. Twenty-two demographic, clinical and treatment-related variables were collected and multivariable logistic regression was used to develop and validate two risk-stratification models to determine the risk of disease recurrence and death., Results: In total, 898 patients were included in the study. The mean age was 72 years, 63% (562/898) had a good performance status (0-1) and 43% (388/898), 15% (134/898) and 42% (376/898) were clinical stage I, II and III, respectively. Thirty-six per cent (322/898) suffered disease recurrence and 41% (369/898) died in the first 2 years after radiotherapy. The ASSENT score (age, performance status, smoking status, staging endobronchial ultrasound, N-stage, T-stage) was developed, which stratifies the risk for disease recurrence within 2 years, with an area under the receiver operating characteristic curve (AUROC) for the total score of 0.712 (0.671-0.753) and 0.72 (0.65-0.789) in the derivation and validation sets, respectively. The STEPS score (sex, performance status, staging endobronchial ultrasound, T-stage, N-stage) was developed, which stratifies the risk of death within 2 years, with an AUROC for the total score of 0.625 (0.581-0.669) and 0.607 (0.53-0.684) in the derivation and validation sets, respectively., Conclusions: These validated risk-stratification models could be used to inform follow-up protocols after curative-intent radiotherapy for lung cancer. The modest performance highlights the need for more advanced risk prediction tools., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: Choosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients., Materials and Methods: A retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated., Results: Univariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), 'lifelong never' smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively., Conclusion: In this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status., (Copyright © 2020 The Royal College of Radiologists. All rights reserved.)

Patients treated with curative-intent lung radiotherapy are in the group at highest risk of severe complications and death from COVID-19. There is therefore an urgent need to reduce the risks associated with multiple hospital visits and their anti-cancer treatment. One recommendation is to consider alternative dose-fractionation schedules or radiotherapy techniques. This would also increase radiotherapy service capacity for operable patients with stage I-III lung cancer, who might be unable to have surgery during the pandemic. Here we identify reduced-fractionation for curative-intent radiotherapy regimes in lung cancer, from a literature search carried out between 20/03/2020 and 30/03/2020 as well as published and unpublished audits of hypofractionated regimes from UK centres. Evidence, practical considerations and limitations are discussed for early-stage NSCLC, stage III NSCLC, early-stage and locally advanced SCLC. We recommend discussion of this guidance document with other specialist lung MDT members to disseminate the potential changes to radiotherapy practices that could be made to reduce pressure on other departments such as thoracic surgery. It is also a crucial part of the consent process to ensure that the risks and benefits of undergoing cancer treatment during the COVID-19 pandemic and the uncertainties surrounding toxicity from reduced fractionation have been adequately discussed with patients. Furthermore, centres should document all deviations from standard protocols, and we urge all colleagues, where possible, to join national/international data collection initiatives (such as COVID-RT Lung) aimed at recording the impact of the COVID-19 pandemic on lung cancer treatment and outcomes., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Treatment of locally recurrent non-small lung cancer (NSCLC) after definitive chemoradiation therapy is challenging as patients are often inoperable and systemic therapy alone frequently results in suboptimal outcomes. Re-irradiation of NSCLC may be the best strategy for treating locoregional failures with the goal of durable long-term control and potentially cure. Repeat irradiation is technically challenging for fear of life-threatening toxicities to previously irradiated organs at risk while also delivering definitive doses of radiation to recurrent disease. No standard guidelines exist with regards to re-irradiation technique and re-treatment dose constraints to organs at risks. We herein describe a case of locoregional recurrence after definitive chemoradiation therapy for NSCLC with expert opinions for subsequent management. As described and guided by our experts, we review the various techniques for repeat radiation therapy, treatment planning goals, and reported toxicities and outcomes in the re-irradiation setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: To evaluate the impact of peer review and contouring workshops on reducing uncertainty in target volume delineation for lung cancer radiotherapy., Materials and Methods: Data from two lung cancer target volume delineation courses were analysed. In total, 22 trainees in clinical oncology working across different UK centres attended these courses with priori experience in lung cancer radiotherapy. The courses were made up of short presentations and contouring practice sessions. The participants were divided into two groups and asked to first individually delineate (IND) and then individually peer review (IPR) the contours of another participant. The contours were discussed with an expert panel consisting of two consultant clinical oncologists and a consultant radiologist. Contours were analysed quantitatively by measuring the volume and local distance standard deviation (localSD) from the reference expert consensus contour and qualitatively through visual analysis. Feedback from the participants was obtained using a questionnaire., Results: All participants applied minor editing to the contours during IPR, leading to a non-statistically significant reduction in the mean delineated volume (IND = 140.92 cm 3 , IPR = 125.26 cm 3 , P = 0.211). The overall interobserver variation was similar, with a localSD of 0.33 cm and 0.38 cm for the IND and IPR, respectively (P = 0.848). Six participants (29%) carried out correct major changes by either including tumour or excluding healthy tissue. One participant (5%) carried out an incorrect edit by excluding parts of the tumour, while another observer failed to identify a major contour error. The participants' level of confidence in target volume delineation increased following the course and identified the discussions with the radiologist and colleagues as the most important highlights of the course., Conclusion: IPR could improve target volume delineation quality among trainee oncologists by identifying most major contour errors. However, errors were also introduced after IPR, suggesting the need to further discuss major changes with a multidisciplinary team., (Copyright © 2020 The Royal College of Radiologists. All rights reserved.)

Aims: Stereotactic ablative body radiotherapy doses for peripheral lung lesions caused high toxicity when used for central non-small cell lung cancer (NSCLC). To determine a safe stereotactic ablative body radiotherapy dose for central tumours, the phase I/II Radiation Therapy Oncology Group RTOG 0813 trial used 50 Gy/five fractions as a baseline. From 2013, 50 Gy/five fractions was adopted at the Beatson West of Scotland Cancer Centre for inoperable early stage central NSCLC. We report our prospectively collected toxicity and efficacy data., Materials and Methods: Patient and treatment characteristics were obtained from electronic medical records. Tumours were classed as moderately central or ultra-central tumours using published definitions. Toxicity was assessed in a centralised follow-up clinic at 2 weeks, 6 weeks, 3 months, 6 months, 1 year and 2 years after treatment., Results: Fifty patients (31 women, 19 men, median age 75.1 years) were identified with T1-2N0M0 moderately central NSCLC; one patient had both an ultra-central and a moderately central tumour. Eighty-four per cent were medically unfit for surgery. Forty per cent had biopsy-proven NSCLC and 60% were diagnosed radiologically using 18-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Fifty-six per cent of patients were Eastern Cooperative Oncology Group (ECOG) performance status 2 or worse. All patients received 50 Gy/five fractions on alternate days on schedule. Two patients died within 90 days of treatment, one from a chest infection, the other cause of death was unknown. There was one episode of early grade 3 oesophagitis and one grade 3 late dyspnoea. There was no grade 4 toxicity. Over a median follow-up of 25.2 months (range 1-70 months), there were 34 deaths: 18 unrelated to cancer and 16 due to cancer recurrence. The median overall survival was 27.0 months (95% confidence interval 20.6-35.9) and cancer-specific survival was 39.8 months (95% confidence interval 28.6, not reached)., Conclusion: This study has shown that 50 Gy/five fractions is a safe dose and fractionation for early stage inoperable moderately central NSCLC, with outcomes comparable with other series, even with patients with a poor performance status., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: Stereotactic ablative body radiotherapy (SABR) is now considered the standard of care for medically inoperable stage I non-small cell lung cancer (NSCLC). The English National Cancer Registration and Analysis Service (NCRAS) collects data on all patients diagnosed with lung cancer, including information on treatment. We wanted to compare outcomes for patients with stage I NSCLC treated with radical radiotherapy with either SABR or fractionated radiotherapy., Materials and Methods: All patients diagnosed with stage I NSCLC in 2015 and 2016 were identified from the NCRAS dataset, validated by the National Lung Cancer Audit, and their treatment data were collated. For patients who received radiotherapy, those receiving radical dose fractionations, including SABR, were identified through linkage to the national Radiotherapy Dataset. Clinical outcomes for those receiving SABR or more fractionated radical radiotherapy were compared using univariate and fully adjusted Cox proportional hazards models., Results: In total, 12 384 patients with stage I NSCLC were identified during the study period; 53.5% underwent surgical resection, 24.3% received no documented treatment, 18.6% received radical radiotherapy and 3.5% received other non-curative-intent treatments. For those receiving radical radiotherapy, 69% received SABR and 31% received fractionated treatment. The hazard ratio of death for the 1587 patients who received SABR was 0.69 (95% confidence interval 0.61-0.79) compared with 717 patients who received radical fractionated radiotherapy; this benefit was seen for both stage Ia and stage Ib disease. The median overall survival was also longer for SABR versus radical radiotherapy (715 days versus 648 days). Exploratory travel time analysis shows that compared with stage I NSCLC patients receiving SABR, those receiving fractionated radiotherapy and those receiving no active treatment would have to travel longer and further to reach their nearest radiotherapy SABR centre., Conclusion: This study adds to the data that SABR has a survival benefit when compared with fractionated radical radiotherapy. Although the use of SABR increased in England over this study period, it has still not reached levels of use seen in other countries. This study also highlights that one quarter of stage I NSCLC patients overall received no active treatment., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: Curative-intent (radical) radiotherapy aims to control local disease and cure non-small cell lung cancer (NSCLC). The predominant subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma (SCC). The radiotherapy paradigm offered to patients does not differ according to these two subtypes. Relapse patterns and disease control rates for adenocarcinoma and SCC treated with radical radiotherapy were determined., Materials and Methods: A radical radiotherapy database covering the period from 2004 to June 2016 was examined to determine the first sites of relapse and the actuarial local and distant control rates., Results: In total, 537 patients with known pathological subtype were treated over the period. In 39 (7%), the site of first relapse was uncertain. Of the remainder, 203 (41%) had adenocarcinoma and 295 (59%) had SCC. At a median follow-up of 16.4 months, 58% had relapsed. There was a difference in relapse patterns (chi-squared test P < 0.0005), with a higher rate of first relapse locally in SCC (42% of all patients versus 24%) and a higher rate of first relapse in the brain for adenocarcinoma (14% versus 3%). The actuarial local control rate was worse for SCC (hazard ratio 0.6, 95% confidence interval 0.5-0.9, P = 0.002). The brain metastasis-free survival was worse for adenocarcinoma (hazard ratio 4.1, 95% confidence interval 2.2-7.5, P < 0.0001)., Conclusion: There is a difference in relapse patterns between NSCLC histological subtypes, indicating that these are distinct entities. This may have implications for follow-up policy and strategies to improve disease control., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Definitive treatment of locally advanced non-small-cell lung cancer with radiation is challenging. During the course of treatment, anatomical changes such as tumor regression, tumor displacement/deformation, pleural effusion, and/or atelectasis can result in a deviation of the administered radiation dose from the intended prescribed treatment and thereby worsen local control and toxicity. Adaptive radiotherapy can help correct for these changes and can be generally categorized into 3 philosophical paradigms: (1) maintenance of prescribed dose to the initially defined target volume; (2) dose reduction to healthy organs while maintaining initial prescribed dose to a regressing tumor volume; or (3) dose escalation to a regressing tumor volume with isotoxicity to healthy organs. Numerous single institution studies have investigated these methods, and results from large prospective clinical trials will hopefully provide consensus on the method, utility, and efficacy of implementing adaptive radiation therapy (ART) in a clinical setting. Additional development into standardization and automation of the ART workflow, specifically in identifying when ART is warranted and in reducing the manual clinical effort needed to produce an adaptive plan, will be paramount to making ART feasible for the broader radiation therapy community., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Concomitant chemoradiation is the standard of care in patients with inoperable non-small cell lung cancer. The purpose of this study was to analyse the survival outcome and toxicity data of using hypofractionated chemoradiation., Materials and Methods: One hundred patients were treated from June 2011 to November 2016. Treatment consisted of 55 Gy in 20 daily fractions concurrently with split-dose cisplatin vinorelbine chemotherapy over 4 weeks followed by two cycles of cisplatin vinorelbine only. Survival was estimated using Kaplan-Meier and Cox regression was carried out for known prognostic factors. A systematic search of literature was conducted using Medline, Embase and Cochrane databases and relevant references included., Results: In total, 97% of patients completed radiotherapy and 73% of patients completed all four cycles of chemotherapy. One patient died of a cardiac event during consolidative chemotherapy. There were two cases of grade 4 toxicities (one sepsis, one renal impairment). Grade 3 toxicities included nausea/vomiting (17%), oesophagitis (15%), infection with neutropenia (12%) and pneumonitis (4%). Clinical benefit was seen in 86%. Two-year progression-free survival and overall survival rates were 49% and 58%, respectively. The median progression-free survival and overall survival were 23.4 and 43.4 months, respectively. The only significant prognostic factor was the number of chemotherapy cycles received (P = 0.02). The systematic review identified 13 relevant studies; a variety of regimens were assessed with variable reporting of outcomes and toxicity but with overall an improvement in survival over time., Conclusion: Our experience compared with the original phase II trial showed improved treatment completion rates and survival with acceptable morbidity. With appropriate patient selection this regimen is an effective treatment option for locally advanced non-small cell lung cancer. This study helps to benchmark efficacy and toxicity rates while considering the addition of new agents to hypofractionated concurrent chemoradiotherapy. The agreement of a standard regimen for assessment in future trials would be beneficial., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Early-stage non-small cell lung cancer (NSCLC) is on the rise due to the implementation of screening guidelines for patients at risk for developing lung cancer. It is anticipated that as the US population continues to age, there will be a higher percentage of medically inoperable early-stage lung cancer patients. For this reason, noninvasive ablative therapies are necessary. Stereotactic body radiation therapy (SBRT) is an effective modality in addressing early-stage NSCLC. SBRT consists of high-dose radiation delivered over 3-5 treatments. Several randomized trials comparing surgery to SBRT in early-stage operable patients have unfortunately closed early due to poor accrual. However, a recent pooled analysis from 2 randomized trials (StereoTActic Radiotherapy and Radiosurgery Or Surgery for operable Early-stage non-small cell Lung cancer) comparing surgery to SBRT did show comparable local control and overall survival rates between surgery and SBRT, offering a very effective, noninvasive modality for older adult patients with early-stage NSCLC. In this review, we summarize the role of SBRT in early-stage NSCLC, in particularly applied to the older adult population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009., Materials and Methods: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance., Results: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity., Conclusion: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

In spite of recent improvements in both the technical delivery of radiotherapy and systemic therapy in the treatment of non-small cell lung cancer, local recurrence rates after radiotherapy remain a significant challenge. In the setting of local relapse after radiotherapy, treatments such as surgical resection or radiofrequency ablation are often not appropriate owing to disease and patient factors. Re-irradiation may be a potential treatment option. This overview considers the published evidence and potential treatment strategies., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: The objective of this phase II clinical trial was to prospectively evaluate the safety and efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy (3DCRT) in localised non-resectable/non-operable non-small cell lung cancer (NSCLC)., Materials and Methods: Sixty patients with stage I-III NSCLC were enrolled in a prospective single-arm All Ireland Co-operative Oncology Research Group (ICORG 99-09) toxicity end point phase II trial. The protocol allocated patients between three radiation schedule dose levels (60, 66 or 72 Gy, in 20, 22 and 24 fractions, respectively, 3 Gy daily, five fractions per week) according to combined lung V 25Gy (V 25Gy  ≤ 30%) with built-in early stopping toxicity rules. The primary end point was toxicity with evaluation of dose-limiting toxicity. The secondary objectives included radiological tumour response rate at 3 months after the completion of radiation therapy and the thoracic progression-free survival time., Results: Sixty patients were recruited from August 1999 to June 2009. Forty-nine patients were included in the primary per-protocol analysis. Eleven patients were not evaluable. In the first 30 evaluable patient cohort, severe oesophageal toxicity was reported in two patients (2/49; 4% experiencing grade 5 oesophageal late toxicity, related to the 97% oesophageal length). The trial was temporarily closed and was then reopened to validate an oesophageal dose volume constraint (DVC) of limiting the length of oesophagus fully encompassed by the 97% isodose to less than 1 cm (applied to 21 patients). The trial prospectively showed the safety of the oesophageal DVC, with no oesophageal toxicity above grade 3 thereafter. Thirty-nine per cent of patients had disease progression at 3-4 months after radiotherapy, 22% had stable disease, 20% had a complete response and 14% had a partial response. The median overall survival was 13.6 months (95% confidence interval 10.5-16.7) and overall survival at 1 and 3 years was 57% and 29%, respectively., Conclusion: A strategy using accelerated hypofractionated 3DCRT is feasible and reasonably safe for patients with inoperable NSCLC. It is safe to deliver for centrally located tumours if DVCs are applied to the oesophagus, which is the primary dose-limiting toxicity. Further studies are required to assess the efficacy of hypofractionated regimens for centrally located tumours using an oesophageal DVC and monitoring for oesophageal toxicity., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Lung cancer is the leading cause of cancer death worldwide. Recurrence rates at all stages are high, but evidence-based post-treatment surveillance imaging strategies to detect recurrence are poorly defined, and salvage options are frequently limited. A number of national and international oncology guidelines address post-treatment imaging, but are largely based on low-level, retrospective evidence because of a paucity of high-quality data, particularly in regard to cost-effectiveness and quality-of-life endpoints. Given the lack of randomized data addressing appropriate surveillance imaging modality and interval following definitive treatment of lung cancer, there remains an unmet clinical need. Meaningful surveillance endpoints should include the financial impact, patient quality-of-life outcomes, and access-to-care issues associated with intensive follow-up to ensure that guidelines reflect quality and sustainability. A need for prospective randomized data on the subject of imaging surveillance after definitive local therapy remains an unmet need, and an opportunity for collaboration and further research., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: The National Institute for Healthcare Excellence recommends continuous hyperfractionated, accelerated radiotherapy (CHART), concurrent chemoradiation (cCRT) and stereotactic ablative radiotherapy (SABR) for appropriate patients with non-small cell lung cancer (NSCLC), but these are not universally available in all UK radiotherapy centres. Reduced access to these treatments may be contributing to reduced survival, with the concern that elderly patients are less likely to receive guideline-recommended therapy (GRT)., Materials and Methods: We report a prospective, UK national study of patients treated with curative-intent radiotherapy for NSCLC over a 2 month period. Clinical oncologists in all UK radiotherapy centres were contacted and asked to complete a proforma on all patients treated with curative-intent radiotherapy., Results: Three hundred and seventeen records were returned from 82% of centres. Only 49% (95% confidence interval 43-55%) of patients received the GRT for their tumour type. Patients aged 70 years or over were less likely to access GRT than those under 70 years (40% compared with 60%, P = 0.001), both as a result of clinicians offering therapy less frequently (52% compared with 65%, P = 0.03) and a higher refusal of therapy (22% versus 8%, P = 0.02). A reluctance to travel to a different centre was a key component of these decisions. SABR was delivered to only 52% of suitable patients, mainly because it was not available in the local centre., Conclusions: In this study of UK curative-intent radiotherapy practice, a lack of local access seems to limit uptake of advanced radiotherapy techniques such as SABR, especially for patients aged over 70 years., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Aims: Almost all patients with epidermal growth factor receptor (EGFR) mutations will develop resistance to first-line EGFR tyrosine kinase inhibitors (TKIs). The management of oligoprogression on EGFR TKI is controversial. Irradiating progressing tumours may potentially eradicate the resistant clone and allow continuation of EGFR TKI, but the clinical data remain sparse. We aimed to assess the effect of radiotherapy on survival outcomes in patients with oligoprogression in a matched-cohort study., Materials and Methods: This was a retrospective matched-cohort study comparing patients with EGFR mutation-positive stage IV non-small cell lung cancer receiving radiotherapy versus chemotherapy for progression. Patients in the radiotherapy group received radiotherapy (mainly stereotactic ablative radiotherapy) for oligoprogression, whereas the chemotherapy group received only systemic chemotherapy upon progression. Key prognostic factors including gender, age, performance status, time to first progression and mutation subtypes were matched., Results: Twenty-five patients with oligoprogression (radiotherapy group) were identified, and a matched chemotherapy group with the same number of patients was generated. The median duration of follow-up was 24.3 and 34 months for the radiotherapy and chemotherapy groups, respectively. The median overall survival of the radiotherapy group was significantly longer than the chemotherapy group, 28.2 versus 14.7 months (P = 0.026). The median progression-free survival (PFS) was 7.0 and 4.1 months after radiotherapy and chemotherapy, respectively (P = 0.0017). The use of radiotherapy was an independent predictive factor of overall survival and PFS in multivariate analysis. Only one patient had ≥grade 3 toxicity after radiotherapy. The frequency of secondary T790M mutation and subsequent Osimertinib exposure were similar in both groups., Conclusion: Radiotherapy may effectively extend EGFR TKI therapy for patients with oligoprogression on TKI. Improved PFS and overall survival were observed, although potential biases should not be overlooked. Further randomised studies are warranted., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)