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Introduction: In ES-SCLC patients with residual intrathoracic disease after first-line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial., Materials/ Methods: Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation., Results: The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO=0 performance status (24% vs 45%), and a higher proportion had WHO=2 (15% vs 5%; p<0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p=0.02) and PFS (p=0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p=0.03) and/or bone metastases (p=0.04) were present., Discussion: This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction Patients who present with locally advanced inoperable non-small cell lung cancer (NSCLC) may be suitable for radical radiotherapy. A randomised trial of 563 patients compared CHART and conventional radical radiotherapy (60 Gy/30f) given over 6 weeks and suggested that CHART resulted in a 9% improvement in 2-year survival (Saunders et al., 1999). RT dose escalation for both conventional and CHARTWEL (CHART-WeekEndLess) – fractionation schedules is feasible with modern 3-dimensional CT-based planning techniques and we initiated a phase I CHART dose escalation study in 2009. Methods Patients with WHO performance status 0–2 histologically confirmed, inoperable, stage I–III non-small cell lung cancer were recruited into an open phase I dose escalation trial. Three cohorts of six patients were recruited sequentially. Total dose was escalated from standard CHART radiotherapy of 54 Gy/36f/12 days to 57.6 Gy (2 × 1.8 Gy fractions on day 15, Group 1), 61.2 Gy (4 × 1.8 Gy fractions on days 15–16, Group 2) and 64.8 Gy (6 × 1.8 Gy fractions on days 15–17, Group 3). Results Between April 2010 and May 2012, 18 patients were enrolled from 5 UK centres and received escalated dose radiotherapy. 14 were male, 16 squamous cell histology and 12 were stage IIIA or IIIB. The median age was 70 years and baseline characteristics were similar across the three dose cohorts. One patient did not start escalated radiotherapy but all remaining patients completed their planned radiotherapy schedules. Of these 9 patients have died to date with a median survival of 2 years across the three cohorts. Grade 3 or 4 adverse events (fatigue, dysphagia, nausea and anorexia – classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) were reported in 6 patients but the pre-specified dose limiting toxicities (grade 4 early oesophagitis; grade 3 cardiac, spinal cord and pneumonitis) were not observed. Conclusions CHART remains a radiotherapy schedule in routine use across the UK and in this dose escalation study no dose limiting toxicities were observed. We feel the dose of 64.8 Gy/42f/17 days should be taken forward into further clinical trials. The sample size used in this study was small so we plan a randomised phase II study that includes other radiotherapy schedules to confirm safety and select an accelerated sequential chemo-radiotherapy schedule to take into phase III studies. [ABSTRACT FROM AUTHOR]

Purpose: Recent clinical trials and meta-analyses have shown that both CHART (continuous hyperfractionated accelerated radiation therapy) and induction chemotherapy offer a survival advantage over conventional radical radiotherapy for patients with inoperable non–small cell-lung cancer (NSCLC). This multicenter randomized controlled trial (INCH) was set up to assess the value of giving induction chemotherapy before CHART. Methods and Materials: Patients with histologically confirmed, inoperable, Stage I–III NSCLC were randomized to induction chemotherapy (ICT) (three cycles of cisplatin-based chemotherapy followed by CHART) or CHART alone. Results: Forty-six patients were randomized (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Twenty-eight patients were male, 28 had squamous cell histology, 34 were Stage IIIA or IIIB, and all baseline characteristics were well balanced between the two treatment arms. Seventeen (74%) of the 23 ICT patients completed the three cycles of chemotherapy. All 42 (22 CHART + 20 ICT) patients who received CHART completed the prescribed treatment. Median survival was 17 months in the CHART arm and 25 months in the ICT arm (hazard ratio of 0.60 [95% CI 0.31–1.16], p = 0.127). Grade 3 or 4 adverse events (mainly fatigue, dysphagia, breathlessness, and anorexia) were reported for 13 (57%) CHART and 13 (65%) ICT patients. Conclusions: This small randomized trial indicates that ICT followed by CHART is feasible and well tolerated. Despite closing early because of poor accrual, and so failing to show clear evidence of a survival benefit for the additional chemotherapy, the results suggest that CHART, and ICT before CHART, remain important options for the treatment of inoperable NSCLC and deserve further study. [ABSTRACT FROM AUTHOR]

Purpose: Not all patients with stage III non-small cell lung cancer (NSCLC) are suitable for concurrent chemoradiation therapy (CRT). Local failure rate is high for sequential concurrent CRT. As such, there is a rationale for treatment intensification.Methods and Materials: Isotoxic intensity modulated radiation therapy (IMRT) is a multicenter feasibility study that combines different intensification strategies including hyperfractionation, acceleration, and dose escalation facilitated by IMRT. Patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and unsuitable for concurrent CRT were recruited. A minimum of 2 cycles of platinum-based chemotherapy was compulsory before starting radiation therapy (RT). Radiation dose was increased until a maximum dose of 79.2 Gy was reached or 1 or more of the organs at risk met predefined constraints. RT was delivered in 1.8-Gy fractions twice daily, and an RT quality assurance program was implemented. The primary objective was the delivery of isotoxic IMRT to a dose >60 Gy equivalent dose in 2-Gy fractions (EQD2 assuming an α/β ratio of 10 Gy for acute reacting tissues).Results: Thirty-seven patients were recruited from 7 UK centers. Median age was 69.9 years (range, 46-86 years). The male-to-female ratio was 17:18. ECOG PS was 0 to 5 in 14.2% of patients; PS was 1 to 27 in 77.1% of patients; PS was 2 to 3 in 8.6% of patients. Stage IIIA:IIIB ratio was 22:13 (62.9%:37.1%). Of 37 patients, 2 (5.4%) failed to achieve EQD2 > 60 Gy. Median prescribed tumor dose was 77.4 Gy (range, 61.2-79.2 Gy). A maximum dose of 79.2Gy was achieved in 14 patients (37.8%). Grade 3 esophagitis was reported in 2 patients, and no patients developed grade 3 to 4 pneumonitis. There were 3 grade 5 events: acute radiation pneumonitis, bronchopulmonary hemorrhage, and acute lung infection. Median follow-up at time of analysis was 25.4 months (range, 8.0-44.2) months for 11 of 35 survivors. The median survival was 18.1 months (95% confidence interval [CI], 13.9-30.6), 2-year overall survival was 33.6% (95% CI, 17.9-50.1), and progression-free survival was 23.9% (95% CI, 11.3-39.1).Conclusions: Isotoxic IMRT is a well-tolerated and feasible approach to treatment intensification. [ABSTRACT FROM AUTHOR]

• Deep learning (DL) predicts overall survival of NSCLC patients receiving RT most accurately. • Dosemteric organ-at-risk variables play a key role in survival prediction. • Explainable techniques are utilised to provide insights into hitherto black-box DL-based survival models. Survival is frequently assessed using Cox proportional hazards (CPH) regression; however, CPH may be too simplistic as it assumes a linear relationship between covariables and the outcome. Alternative, non-linear machine learning (ML)-based approaches, such as random survival forests (RSFs) and, more recently, deep learning (DL) have been proposed; however, these techniques are largely black-box in nature, limiting explainability. We compared CPH, RSF and DL to predict overall survival (OS) of non-small cell lung cancer (NSCLC) patients receiving radiotherapy using pre-treatment covariables. We employed explainable techniques to provide insights into the contribution of each covariable on OS prediction. The dataset contained 471 stage I-IV NSCLC patients treated with radiotherapy. We built CPH, RSF and DL OS prediction models using several baseline covariable combinations. 10-fold Monte-Carlo cross-validation was employed with a split of 70%:10%:20% for training, validation and testing, respectively. We primarily evaluated performance using the concordance index (C-index) and integrated Brier score (IBS). Local interpretable model-agnostic explanation (LIME) values, adapted for use in survival analysis, were computed for each model. The DL method exhibited a significantly improved C-index of 0.670 compared to the CPH and a significantly improved IBS of 0.121 compared to the CPH and RSF approaches. LIME values suggested that, for the DL method, the three most important covariables in OS prediction were stage, administration of chemotherapy and oesophageal mean radiation dose. We show that, using pre-treatment covariables, a DL approach demonstrates superior performance over CPH and RSF for OS prediction and use explainable techniques to provide transparency and interpretability. [ABSTRACT FROM AUTHOR]

• CHART and hypofractionated accelerated radiotherapy remain deliverable, safe and effective schedules for NSCLC. • A median survival of 22.5 months and a 2-year survival of 48% demonstrate a continued need for improvement. • Earlier diagnosis and optimal treatment of co-morbidities is likely to help improve outcomes. • Dose escalation to improve outcomes is currently being investigated. Numerous fractionation regimes are used for inoperable NSCLC patients not suitable for stereotactic ablative radiotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART, 54 Gy, 36 fractions over 12 days) and hypofractionated accelerated radiotherapy (55 Gy, 20 fractions over 4 weeks) are recommended UK schedules. In this single-centre retrospective analysis, we compare both fractionation schemes for patients treated at our institution from 2010 to 15. Clinical demographic, tumour and survival data were collected alongside radiotherapy dosimetric data from the Varian Eclipse Scripting application programming interface. Differences were assessed using independent samples t-tests. Multivariate survival analysis was performed using Cox regression. We identified 563 eligible patients; 43% received CHART and 57% hypofractionated radiotherapy. Median age was 71 years, 56% were male, 95% PET staged with 53% WHO performance status 0–1. 30%, 14%, 50% and 6% were stage I, II, III and IV, respectively. 38% of patients underwent induction chemotherapy. 99% completed their prescribed radiotherapy treatment. Overall response rate was 50% with a 6.5% 90-day mortality rate. Median disease-free survival was 19 months, 50% recurred locally. Median overall survival was 22.5 months with 48% alive at 2 years. Multivariate analysis identified histology, stage, performance status, chemotherapy and radiotherapy response as independent predictors of survival; no significant differences between radiotherapy regimes were observed. In our centre, CHART and hypofractionated accelerated radiotherapy produce similar outcomes. Dose escalation studies are in progress to develop these schedules to match outcomes reported in concurrent chemo-radiation studies. [ABSTRACT FROM AUTHOR]

Purpose: To develop and apply an image acquisition and analysis strategy for spatial comparison of computed tomography (CT)-ventilation images with hyperpolarized gas magnetic resonance imaging (MRI).Methods and Materials: Eleven lung cancer patients underwent xenon-129 (129Xe) and helium-3 (3He) ventilation MRI and coregistered proton (1H) anatomic MRI. Expiratory and inspiratory breath-hold CTs were used for deformable image registration and calculation of 3 CT-ventilation metrics: Hounsfield unit (CTHU), Jacobian (CTJac), and specific gas volume change (CTSGV). Inspiration CT and hyperpolarized gas ventilation MRI were registered via same-breath anatomic 1H-MRI. Voxel-wise Spearman correlation coefficients were calculated between each CT-ventilation image and its corresponding 3He-/129Xe-MRI, and for the mean values in regions of interest (ROIs) ranging from fine to coarse in-plane dimensions of 5 × 5, 10 × 10, 15 × 15, and 20 × 20, located within the lungs as defined by the same-breath 1H-MRI lung mask. Correlation of 3He and 129Xe-MRI was also assessed.Results: Spatial correlation of CT-ventilation against 3He/129Xe-MRI increased with ROI size. For example, for CTHU, mean ± SD Spearman coefficients were 0.37 ± 0.19/0.33 ± 0.17 at the voxel-level and 0.52 ± 0.20/0.51 ± 0.18 for 20 × 20 ROIs, respectively. Correlations were stronger for CTHU than for CTJac or CTSGV. Correlation of 3He with 129Xe-MRI was consistently higher than either gas against CT-ventilation maps over all ROIs (P < .05). No significant differences were observed between CT-ventilation versus 3He-MRI and CT-ventilation versus 129Xe-MRI.Conclusion: Comparison of ventilation-related measures from CT and registered hyperpolarized gas MRI is feasible at a voxel level using a dedicated acquisition and analysis protocol. Moderate correlation between CT-ventilation and MRI exists at a regional level. Correlation between MRI and CT is significantly less than that between 3He and 129Xe-MRI, suggesting that CT-ventilation surrogate measures may not be measuring lung ventilation alone. [ABSTRACT FROM AUTHOR]

Background: Postmastectomy radiotherapy in patients with four or more positive axillary nodes reduces breast cancer mortality, but its role in patients with one to three involved nodes is controversial. We assessed the effects of postmastectomy radiotherapy on quality of life (QOL) in women with intermediate-risk breast cancer.Methods: SUPREMO is an open-label, international, parallel-group, randomised, controlled trial. Women aged 18 years or older with intermediate-risk breast cancer (defined as pT1-2N1; pT3N0; or pT2N0 if also grade III or with lymphovascular invasion) who had undergone mastectomy and, if node positive, axillary surgery, were randomly assigned (1:1) to receive chest wall radiotherapy (50 Gy in 25 fractions or a radiobiologically equivalent dose of 45 Gy in 20 fractions or 40 Gy in 15 fractions) or no radiotherapy. Randomisation was done with permuted blocks of varying block length, and stratified by centre, without masking of patients or investigators. The primary endpoint is 10-year overall survival. Here, we present 2-year results of QOL (a prespecified secondary endpoint). The QOL substudy, open to all UK patients, consists of questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23, Body Image Scale, Hospital Anxiety and Depression Scale [HADS], and EQ-5D-3L) completed before randomisation, and at 1, 2, 5, and 10 years. The prespecified primary outcomes within this QOL substudy were global QOL, fatigue, physical function, chest wall symptoms, shoulder and arm symptoms, body image, and anxiety and depression. Data were analysed by intention to treat, using repeated mixed-effects methods. This trial is registered with the ISRCTN registry, number ISRCTN61145589.Findings: Between Aug 4, 2006, and April 29, 2013, 1688 patients were enrolled internationally and randomly assigned to receive chest wall radiotherapy (n=853) or not (n=835). 989 (79%) of 1258 patients from 111 UK centres consented to participate in the QOL substudy (487 in the radiotherapy group and 502 in the no radiotherapy group), of whom 947 (96%) returned the baseline questionnaires and were included in the analysis (radiotherapy, n=471; no radiotherapy, n=476). At up to 2 years, chest wall symptoms were worse in the radiotherapy group than in the no radiotherapy group (mean score 14·1 [SD 15·8] in the radiotherapy group vs 11·6 [14·6] in the no radiotherapy group; effect estimate 2·17, 95% CI 0·40-3·94; p=0·016); however, there was an improvement in both groups between years 1 and 2 (visit effect -1·34, 95% CI -2·36 to -0·31; p=0·010). No differences were seen between treatment groups in arm and shoulder symptoms, body image, fatigue, overall QOL, physical function, or anxiety or depression scores.Interpretation: Postmastectomy radiotherapy led to more local (chest wall) symptoms up to 2 years postrandomisation compared with no radiotherapy, but the difference between groups was small. These data will inform shared decision making while we await survival (trial primary endpoint) results.Funding: Medical Research Council, European Organisation for Research and Treatment of Cancer, Cancer Australia, Dutch Cancer Society, Trustees of Hong Kong and Shanghai Banking Corporation. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: A variety of radiotherapy fractionations are used as potentially curative treatments for non-small cell lung cancer. In the UK, 55Gy in 20 fractions over 4weeks (55/20) is the most commonly used fractionation schedule, though it has not been validated in randomized phase III trials. This audit pooled together existing data from 4 UK centres to produce the largest published series for this schedule. Materials and methods: 4 UK centres contributed data (Cambridge, Cardiff, Glasgow and Sheffield). Case notes and radiotherapy records of radically treated patients between 1999 and 2007 were retrospectively reviewed. Basic patient demographics, tumour characteristics, radiotherapy and survival data were collected and analysed. Results: 609 patients were identified of whom 98% received the prescribed dose of 55/20. The median age was 71.3years, 62% were male. 90% had histologically confirmed NSCLC, 49% had stage I disease. 27% had received chemotherapy (concurrent or sequential) with their radiotherapy. The median overall survival from time of diagnosis was 24.0months and 2year overall survival was 50%. Conclusion: These data show respectable results for patients treated with accelerated hypo-fractionated radiotherapy for NSCLC with outcomes comparable to those reported for similar schedules and represent the largest published series to date for 55/20 regime. [Copyright &y& Elsevier]

Abstract: Background: Preclinical and phase I data suggest gemcitabine to be a potent radiosensitiser. This multicentre study addressed whether the addition of low dose gemcitabine to radical radiotherapy improved 2year event-free survival in patients with medically inoperable stages I–II non-small cell lung cancer. Aim: To determine whether low dose gemcitabine increased event–free survival in patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery. Methods: Patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery were randomised to 3D conformal radiotherapy delivering 55Gy in 20 fractions over 4weeks to known sites of cancer with (Arm B) or without (Arm A) 100mg/m2 weekly gemcitabine. Results: Study entry was terminated early because of slow accrual. 111 patients were randomised between March 2003 and December 2005, of whom 4 withdrew consent and 2 were lost to follow-up. Median age was 75 (range 49–88)years and 67 (63%) were male. 86 (81%) were PS 0–1 and 31 (30%) Charlson index 2 or greater. Event-free survival in arm A and B, respectively, was 42% and 46% at 2years and 20% and 31% at 5years (p =0.72), while overall survival was 56% and 52% at 2years and 20% and 33% at 5years (p =0.87). Two deaths from accelerated interstitial lung disease were seen in arm B, but toxicity was otherwise mild. Conclusion: No evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low. [Copyright &y& Elsevier]

Purpose: To report the results from continuous, hyperfractionated, accelerated radiotherapy (CHART) used as the standard fractionation for radical RT in the management of non–small cell lung cancer (NSCLC) in five United Kingdom centers. Methods and Materials: In 2005, the CHART consortium identified six U.K. centers that had continued to use CHART after the publication of the CHART study in 1997. All centers had been using CHART for >5 years and agreed to use a common database to audit their results. Patients treated with CHART between 1998 and December 2003 were identified to allow a minimum of 2 years of follow-up. Patient demographics, tumor characteristics, treatment details, and survival were recorded retrospectively. Five centers completed the data collection. Results: A total of 583 patients who had received CHART were identified. Of these patients, 69% were male, with a median age of 68 years (range, 31–89); 83% had performance status 0 or 1; and 43% had Stage I or II disease. Of the 583 patients, 99% received the prescribed dose. In only 4 patients was any Grade 4-5 toxicity documented. The median survival from the start of RT was 16.2 months, and the 2-year survival rate of 34% was comparable to that reported in the original study. Conclusion: The results of this unselected series have confirmed that CHART is deliverable in routine clinical practice, with low levels of toxicity. Importantly, this series has demonstrated that the results of CHART reported from the randomized trial can be reproduced in routine clinical practice. [Copyright &y& Elsevier]

A response by Ben J. Slotman, Harm van Tinteren, and John O. Praag to a letter to the editor about their article on thoracic radiotherapy for the treatment of extensive-stage small-cell lung cancer (ES SCLC) in a 2015 issue is presented.