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Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma., Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor., Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023., Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months., Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only., Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo)., Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology., Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.

Background: Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better., Methods: We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals., Results: We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy., Conclusion: We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade., Competing Interests: Competing interests: KH: Grant support: MSD, Roche, BMS, Molecular Partners, Travel grant: BMS, MSD, Astra-Zeneca. MO: Ad boards for MSD and Roche. RS: Ad board for MSD, Merck and Pierre Fabre., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy., Methods: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment., Results: In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified., Conclusions: The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Identification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use., Patients and Methods: We analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). Tumour exome sequencing identified somatic mutations and plasma was analyzed using patient-specific RaDaR™ assays with up to 48 amplicons targeting tumour-specific variants unique to each patient., Results: ctDNA was detected before treatment in 24%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <0.01%. ctDNA detection had clinical specificity >98.5% and preceded clinical detection of recurrence of the primary tumour by a median of 212.5 days. ctDNA was detected after treatment in 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (HR: 5.48, P <0.0003). ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively)., Conclusions: ctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention., Competing Interests: Disclosure NR and DGa are co-founders, and NR, DGa, MP, KHo, SH, GM, CGS and GS are current or former employees/officers/consultants of Inivata Ltd. Inivata provided analysis of samples using the RaDaR™ assays. DGa and KHe are current employees of AstraZeneca Inc. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. 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.)

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.)

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke 1-3 . As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

Purpose: Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM., Methods: After undergoing a chest wall procedure, patients with MPM were randomly assigned to receive prophylactic radiotherapy (within 42 days of the procedure) or no radiotherapy. Open thoracotomies, needle biopsies, and indwelling pleural catheters were excluded. Prophylactic radiotherapy was delivered at a dose of 21 Gy in three fractions over three consecutive working days, using a single electron field adapted to maximize coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CWM within 6 months from random assignment, assessed in the intention-to-treat population. Stratification factors included epithelioid histology and intention to give chemotherapy., Results: Between July 30, 2012, and December 12, 2015, 375 patients were recruited from 54 centers and randomly assigned to receive prophylactic radiotherapy (n = 186) or no prophylactic radiotherapy (n = 189). Participants were well matched at baseline. No significant difference was seen in the incidence of CWM at 6 months between the prophylactic radiotherapy and no radiotherapy groups (no. [%]: 6 [3.2] v 10 [5.3], respectively; odds ratio, 0.60; 95% CI, 0.17 to 1.86; P = .44). Skin toxicity was the most common radiotherapy-related adverse event in the prophylactic radiotherapy group, with 96 patients (51.6%) receiving grade 1; 19 (10.2%), grade 2; and 1 (0.5%) grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events, version 4.0)., Conclusion: There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.

Purpose: Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin). On this basis, we designed a randomized, phase II trial to investigate whether defactinib as maintenance therapy after standard first-line chemotherapy could improve progression-free survival (PFS) in patients with malignant pleural mesothelioma (MPM)., Methods: This global, double-blind, randomized, placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy. Patients were stratified for merlin and then randomly assigned (in a 1:1 fashion) to receive either oral defactinib or placebo until disease progression, unacceptable toxicity, or withdrawal occurred. The coprimary end points were PFS and overall survival (OS). Quality of life (QoL) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool., Results: Three hundred forty-four patients were randomly assigned to receive either defactinib (n = 173) or placebo (n = 171). The median PFS was 4.1 months (95% CI, 2.9 to 5.6 months) for defactinib versus 4.0 months (95% CI, 2.9 to 4.2 months) for placebo. The median OS was 12.7 months (95% CI, 9.1 to 21 months) for defactinib versus 13.6 months (95% CI, 9.6 to 21.2 months) for placebo (hazard ratio, 1.0; 95% CI, 0.7 to 1.4). Although shorter survival for both defactinib- and placebo-treated patients was observed, in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM, there were no statistical differences in response rate, PFS, OS, or QoL between the treatment groups. The most common grade 3 or worse adverse events were nausea, diarrhea, fatigue, dyspnea, and decreased appetite., Conclusion: Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinib cannot be recommended as maintenance therapy for advanced MPM.

Introduction: Breathlessness is a common symptom of advanced disease placing a huge burden on patients, health systems and informal carers (families and friends providing daily help and support). It causes distress and isolation. Carers provide complex personal, practical and emotional support yet often feel ill-prepared to care. They lack knowledge and confidence in their caring role. The need to educate carers and families about breathlessness is established, yet we lack robustly developed carer-targeted educational interventions to meet their needs., Methods: We conducted a qualitative interview study with twenty five purposively-sampled patient-carer dyads living with breathlessness in advanced disease (half living with advanced cancer and half with advanced chronic obstructive pulmonary disease (COPD). We sought to identify carers' educational needs (including what they wanted to learn about) and explore differences by diagnostic group in order to inform an educational intervention for carers of patients with breathlessness in advanced disease., Results: There was a strong desire among carers for an educational intervention on breathlessness. Six key topics emerged as salient for them: 1) understanding breathlessness, 2) managing anxiety, panic and breathlessness, 3) managing infections, 4) keeping active, 5) living positively and 6) knowing what to expect in the future. A cross-cutting theme was relationship management: there were tensions within dyads resulting from mismatched expectations related to most topics. Carers felt that knowledge-gains would not only help them to support the patient better, but also help them to manage their own frustrations, anxieties, and quality of life. Different drivers for education need were identified by diagnostic group, possibly related to differences in caring role duration and resulting impacts., Conclusion: Meeting the educational needs of carers requires robustly developed and evaluated interventions. This study provides the evidence-base for the content of an educational intervention for carers of patients with breathlessness in advanced disease.

Importance: Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer., Objective: To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma., Design, Setting, and Participants: A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma., Interventions: Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography., Results: Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, -1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS., Conclusions and Relevance: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers., Trial Registration: clinicaltrials.gov Identifier: NCT01279967.

Over the past decade the field of lung cancer management has seen many developments. Coupled with an ageing population and increasing rates of comorbid illness, the work-up for treatments with curative intent has become more complex and detailed. As well as improvements in imaging and staging techniques, developments in both surgery and radiotherapy may now allow patients who would previously have been considered unfit or not appropriate for treatment with curative intent to undergo radical therapies. This overview will highlight published studies relating to investigation and staging techniques, together with assessments of fitness, with the aim of helping clinicians to determine the most appropriate treatments for each patient. We also highlight areas where further research may be required., (Copyright © 2016 The Royal College of Radiologists. All rights reserved.)

Objective: Extensive research exists on breaking bad news by clinicians. This study examines perspectives of patients and those accompanying them at diagnosis-giving of subsequently sharing news of lung cancer with adult family/friends, and views of healthcare professionals, to inform development of a supportive intervention., Methods: Qualitative interviews with 20 patients, 17 accompanying persons; focus groups and interviews with 27 healthcare professionals from four Thoracic Oncology Units. Intervention development workshops with 24 healthcare professionals and six service users with experience of sharing a cancer diagnosis. Framework thematic analysis., Results: Patients and accompanying persons shared news of lung cancer whilst coming to terms with the diagnosis. They recalled general support from healthcare professionals but not support with sharing bad news. Six elements were identified providing a framework for a potential intervention: 1-people to be told, 2-information to be shared, 3-timing of sharing, 4-responsibility for sharing, 5-methods of telling others and 6-reactions of those told., Conclusion: This study identifies the challenge of sharing bad news and a potential framework to guide delivery of a supportive intervention tailored to individual needs of patients., Practice Implications: The identified framework could extend the portfolio of guidance on communication in cancer and potentially in other life-limiting conditions., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: A variety of radiotherapy fractionations are used as potentially curative treatments for non-small cell lung cancer. In the UK, 55 Gy in 20 fractions over 4 weeks (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 71.3 years, 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 24.0 months and 2 year 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 © 2013 Elsevier Ireland Ltd. All rights reserved.)

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 2 year 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 55 Gy in 20 fractions over 4 weeks to known sites of cancer with (Arm B) or without (Arm A) 100mg/m(2) 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 2 years and 20% and 31% at 5 years (p=0.72), while overall survival was 56% and 52% at 2 years and 20% and 33% at 5 years (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 © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aims: This report reviews current radiotherapy practice across the UK in the management of lung cancer, and the way new treatments and technologies are being introduced, where improvements have occurred, and where work is still required. We wanted to determine adherence to both National Radiotherapy Advisory Group and National Institute for Health and Clinical Excellence (NICE) guidance. This survey was conducted on behalf of the Department of Health Lung Cancer & Mesothelioma Advisory Group., Materials and Methods: We sent a questionnaire to all UK radiotherapy departments. It covered radical radiotherapy dose fractionation, the use of concurrent or sequential chemotherapy for both non-small cell and small cell lung cancers, the use of continuous hyperfractionated accelerated radiotherapy, new radiotherapy techniques, the use of positron emission tomography/computed tomography for planning purposes and patient accrual into current National Cancer Research Network UK trials., Results: This UK-wide survey of radiotherapy practice for lung cancer showed broad compliance with NICE clinical guidance, but highlighted significant variation in fractionation schedules and the use of concomitant chemoradiotherapy. Clinical trial entry into lung cancer radiotherapy trials was variable and many centres are not fully participating in recruitment into these trials., Conclusions: This report has shown the variability of radiotherapy provision nationally. Current practice is largely consistent with current and updated NICE recommendations and best practice and should be recognised as such. It has also highlighted areas where improvements are still needed, particularly fractionation and new technologies. One particular aspect of concern is the poor recruitment to current UK-based clinical trials in lung cancer., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL)., Results: The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001)., Conclusion: In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.

Background: The combination of cisplatin and etoposide (PE) has been a standard treatment for patients with poor-prognosis small cell lung cancer (SCLC). This non-inferiority design trial aimed to determine whether the combination of gemcitabine and carboplatin (GC) results in similar survival but is less toxic with better quality of life., Methods: Previously untreated patients with SCLC with extensive disease or limited stage with poor prognostic factors were randomly assigned to six 3-weekly cycles of GC or PE., Results: 241 patients (121 GC, 120 PE) were recruited, of which 216 (90%) had died. There was no difference in overall survival (HR 1.01, 95% CI 0.77 to 1.32). Median survival with GC and PE was 8.0 and 8.1 months, respectively. Median progression-free survival was 5.9 months with GC and 6.3 months with PE. Grade 3 or 4 myelosuppressions were more frequent with GC (anaemia: 14% GC vs 2% PE; leucopenia: 32% GC vs 13% PE; thrombocytopenia: 22% GC vs 4% PE), but these were not associated with increased hospital admissions, infections or fatalities. Grade 2-3 alopecia (68% PE vs 17% GC) and nausea (43% PE vs 26% GC) were more frequent with PE. Patients given GC received more chemotherapy as outpatients (89% GC vs 66% PE of treatment cycles). In QoL questionnaires, more patients receiving PE reported being upset by hair loss (p = 0.004) and impaired cognitive functioning (p = 0.04)., Conclusions: GC is as effective as PE in terms of overall survival and progression-free survival and has a toxicity profile more acceptable to patients., Trial Registration Number: ISRCTN 39679215.

Background: Although surgery offers the best chance of cure for patients with non-small cell lung cancer (NSCLC), the overall 5-year survival rate is modest, and improvements are urgently needed. In the 1990s, much interest was generated from two small trials that reported striking results with neo-adjuvant chemotherapy, and therefore our intergroup randomised trial was designed to investigate whether, in patients with operable non-small cell lung cancer of any stage, outcomes could be improved by giving platinum-based chemotherapy before surgery., Methods: Patients were randomised to receive either surgery alone (S), or three cycles of platinum-based chemotherapy followed by surgery (CT-S). Before randomisation, clinicians chose the chemotherapy that would be given from a list of six standard regimens. The primary outcome measure was overall survival, which was analysed on an intention-to-treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN25582437., Results: 519 patients were randomised (S: 261, CT-S: 258) from 70 centres in the UK, Netherlands, Germany, and Belgium. Most (61%) were clinical stage I, with 31% stage II, and 7% stage III. Neo-adjuvant chemotherapy was feasible (75% of patients received all three cycles of chemotherapy), resulted in a good response rate (49% [95% CI 43%-55%]) and down-staging in 31% (25%-37%) of patients, and did not alter the type or completeness of the surgery (lobectomy: S: 56%, CT-S: 60%, complete resection: S: 80%, CT-S: 82%). Post-operative complications were not increased in the CT-S group, and no impairment of quality of life was observed. However, there was no evidence of a benefit in terms of overall survival (hazard ratio [HR] 1.02, 95% CI 0.80-1.31, p=0.86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1507 patients, HR 0.88, 95% CI 0.76-1.01, p=0.07), equivalent to an absolute improvement in survival of 5% at 5 years, Interpretation: Although there was no evidence of a difference in overall survival with neo-adjuvant chemotherapy, the result is statistically consistent with previous trials, and therefore adds considerable weight to the current evidence.

Purpose: To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC)., Patients and Methods: Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks., Results: TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17)., Conclusion: This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.

Oncologists traditionally assess their patients' ECOG performance status (PS), and few studies have evaluated the accuracy of these assessments. In this study, 101 patients attending a rapid access clinic at Papworth Hospital with a diagnosis of lung cancer were asked to assess their own ECOG PS score on a scale between 0 and 4. Patients' scores were compared to the PS assessment of them made by their oncologists. Of 98 patients with primary non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), weighted kappa statistics showed PS score agreement between patient and oncologist of 0.45. Both patient- and oncologist-assessed scores reflected survival duration (in NSCLC and SCLC) as well as disease stage (in NSCLC), with oncologist-assessed scores being only marginally more predictive of survival. There was no sex difference in patient assessment of PS scores, but oncologists scored female patients more pessimistically than males. This study showed that, with few exceptions, patients and oncologists assessed PS scores similarly. Although oncologists should continue to score PS objectively, it may benefit their clinical practice to involve their patients in these assessments.

We report the case history of a 61-year-old female smoker who presented with an inoperable T2N2M0 squamous cell carcinoma of the right upper lobe bronchus. This was staged by computed tomography (CT), positron emission tomography (PET) using a modified dual-headed gamma camera, and mediastinoscopy. She then underwent three cycles of cisplatin-containing chemotherapy. After the chemotherapy, CT demonstrated a residual 10 mm mass in the right upper lobe and a considerable reduction in size of the mediastinal lymphadenopathy. Functional tumour imaging with PET showed no abnormality, suggesting that there was no remaining viable tumour. At right upper lobectomy a complete pathological response was confirmed. We discuss PET, the potential new applications of gamma camera technology, and the use of cisplatin-containing chemotherapy in non-small cell lung cancer.

Lung cancer is responsible for 25% of all cancer deaths in the UK and it is estimated that over 80% of lung cancers are related to smoking. Despite numerous health education campaigns, large numbers of young people take up smoking, particularly girls. In the past there has been a somewhat nihilistic attitude to the management of lung cancer, but this is changing due to the emergence of sub-specialisation in oncology and the development of new techniques and treatment, which are beginning to show promise.

Background: Surgical resection is the recognised treatment of choice for patients with stage I or II non-small cell lung cancer (NSCLC). In the UK surgical resection rates have remained far lower (< 10%) than those achieved in Europe and the USA (> 20%), despite the recent introduction of fast access investigation units. It remains unclear therefore why UK surgical resection rates lag so far behind those of other countries., Methods: A new quick access two stop investigation service was established at Papworth in November 1995 to investigate all patients presenting to any of three surrounding health districts with suspected lung cancer. Once staging was complete, all patients with confirmed lung cancer were reviewed by a multidisciplinary team which included an oncologist and a thoracic surgeon. Time from presentation to definitive treatment and surgical resection rates were reviewed., Results: Two hundred and nine (76%) of a total of 275 consecutive patients investigated had confirmed lung cancer (28 small cell, 181 non-small cell). Of the remainder, eight patients (2%) had metastatic disease, four (1%) had other thoracic malignancy (thymoma, mesothelioma), four patients (1%) had benign thoracic tumours, and 50 (18%) had other non-malignant diseases. Of the 181 patients with non-small cell primary lung cancer, 47 (25%) underwent successful surgical resection, of whom 59% had stage I and 21% stage II disease. The failed thoracotomy rate was 11%. Median time from presentation at the peripheral clinic to surgical resection was 5 weeks (range 1-13)., Conclusion: Quick access investigation, high histological confirmation rates, routine CT scanning, and review of every patient with confirmed lung cancer by a thoracic surgeon led to a substantial increase in the successful surgical resection rate. These results support the growing concern that many patients with operable tumours are being denied the chance of curative surgery in our present system.