The Lancet. Oncology

Our medical research library holds 61 studies published in The Lancet. Oncology (2009–2024). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 25 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 15 studies PubMed has no abstract for, we give the abstract printed in the article or, where there is none, a summary we wrote from it, each labeled as such.

About the journal

• Publisher: Lancet Pub. Group
• Published: 2000 to the present, England
• Language: English
• ISSN: 1470-2045 (print), 1474-5488 (electronic)
• Its record in the NLM Catalog

2020s

• EPA ruling to ban chrysotile asbestos. T. Burki. 2024;25(5):537. News PubMed · Publisher

• Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial. H.L. Kindler, S. Novello, A. Bearz, et al. 2022;23(4):540-552. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Background: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab.

  Methods: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.

  Findings: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).

  Interpretation: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.

  Funding: Bayer Healthcare Pharmaceuticals.

  Copyright © 2022 Elsevier Ltd. All rights reserved.

• CONFIRMing single-drug immune checkpoint blockade efficacy in mesothelioma. A.K. Nowak. 2021;22(11):1485-1487. PubMed · Publisher

• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial. C. Pinto, P.A. Zucali, M. Pagano, et al. 2021;22(10):1438-1447. Randomized trial PubMed · Publisher

  Abstract

  Background: There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma.

  Methods: RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36.

  Findings: Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths.

  Interpretation: Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting.

  Funding: Eli Lilly Italy.

  Translation: For the Italian translation of the abstract see Supplementary Materials section.

  Copyright © 2021 Elsevier Ltd. All rights reserved.

• Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. D.A. Fennell, S. Ewings, C. Ottensmeier, et al. 2021;22(11):1530-1540. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Background: No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients.

  Methods: This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450.

  Findings: Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group.

  Interpretation: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy.

  Funding: Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.

  Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

• SMART: logical radiotherapy and surgery beyond MARS. H.I. Pass. 2021;22(2):156-157. Comment PubMed · Publisher

• Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial. B.C.J. Cho, L. Donahoe, P.A. Bradbury, et al. 2021;22(2):190-197. PubMed · Publisher

  Abstract

  Background: A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol.

  Methods: In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719.

  Findings: Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]).

  Interpretation: Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period.

  Funding: Princess Margaret Hospital Foundation Mesothelioma Research Fund.

  Copyright © 2021 Elsevier Ltd. All rights reserved.

• Understanding the new therapeutic options for mesothelioma. H.L. Kindler. 2021;22(10):1353-1355. PubMed · Publisher

• Yale Cancer Center Precision Medicine Tumor Board: molecular findings alter a diagnosis and treatment plan. J.A. Gibson, K.E. Finberg, I. Nalbantoglu, et al. 2021;22(3):306-307. Case report PubMed · Publisher

• Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. A. Marabelle, M. Fakih, J. Lopez, et al. 2020;21(10):1353-1365. PubMed · Publisher

  Abstract

  Background: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours.

  Methods: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing.

  Findings: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0-38·3). Objective responses were observed in 30 (29%; 95% CI 21-39) of 102 patients in the tTMB-high group and 43 (6%; 5-8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3-5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related.

  Interpretation: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours.

  Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

  Copyright © 2020 Elsevier Ltd. All rights reserved.

• COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. M.C. Garassino, J.G. Whisenant, L.C. Huang, et al. 2020;21(7):914-922. PubMed · Publisher · Free full text

  Abstract

  Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies.

  Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data.

  Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death.

  Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference.

  Funding: None.

  Copyright © 2020 Elsevier Ltd. All rights reserved.

• Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in. A.K. Nowak, W.J. Lesterhuis, P.S. Kok, et al. 2020;21(9):1213-1223. PubMed · Publisher

  Abstract

  Background: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma.

  Methods: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415.

  Findings: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment.

  Interpretation: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial.

  Funding: AstraZeneca.

  Copyright © 2020 Elsevier Ltd. All rights reserved.

• Orbital metastases from malignant mesothelioma. I. Mian, E. Padiernos, R. Hassan, et al. 2020;21(2):e117. Case report PubMed · Publisher · Free full text

• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. B. Geoerger, H.J. Kang, M. Yalon-Oren, et al. 2020;21(1):121-133. PubMed · Publisher

  Abstract

  Background: Pembrolizumab is approved for the treatment of advanced cancer in adults; however, no information is available on safety and efficacy in paediatric patients. We aimed to establish the recommended phase 2 dose of pembrolizumab and its safety and antitumour activity in advanced paediatric cancer.

  Methods: KEYNOTE-051 is an ongoing phase 1-2 open-label trial. In this interim analysis, children aged 6 months to 17 years were recruited at 30 hospitals located in Australia, Brazil, Canada, France, Germany, Israel, Italy, South Korea, Sweden, the UK, and the USA. Patients with melanoma or a centrally confirmed, PD-L1-positive, relapsed or refractory solid tumour or lymphoma, and a Lansky Play/Karnofsky Performance status score of 50 or higher, received intravenous pembrolizumab at an initial dose of 2 mg/kg every 3 weeks. Pharmacokinetics and dose-limiting toxicities were used to establish the recommended phase 2 dose, and the safety and antitumour activity of this dose were assessed. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to pembrolizumab for each tumour type according to the Response Evaluation Criteria in Solid Tumours version 1.1 or the International Neuroblastoma Response Criteria. Safety and efficacy were assessed in all treated patients who received at least one dose of pembrolizumab. Separate reporting of the cohort of patients with relapsed or refractory classical Hodgkin lymphoma was a post-hoc decision. The data cutoff for this interim analysis was Sept 3, 2018. This trial is still enrolling patients and is registered with ClinicalTrials.gov, number NCT02332668.

  Findings: Of 863 patients screened between March 23, 2015, and Sept 3, 2018, 796 had tumours that were evaluable for PD-L1 expression (278 [35%] were PD-L1-positive); 155 eligible patients were enrolled and 154 had at least one dose of pembrolizumab. The median age of the enrolled patients was 13 years (IQR 8-15). Median follow-up was 8·6 months (IQR 2·5-16·4). No dose-limiting toxicities were reported in phase 1, and pembrolizumab plasma concentrations were consistent with those previously reported in adults; the recommended phase 2 dose was therefore established as 2 mg/kg every 3 weeks. Of the 154 patients treated, 69 (45%) experienced grade 3-5 adverse events, most commonly anaemia in 14 (9%) patients and decreased lymphocyte count in nine (6%) patients. 13 (8%) of the 154 patients had grade 3-5 treatment-related adverse events, most commonly decreased lymphocyte count in three (2%) patients and anaemia in two (1%) patients. 14 (9%) patients had serious treatment-related adverse events, most commonly pyrexia (four [3%]), and hypertension and pleural effusion (two [1%] each). Four patients (3%) discontinued treatment because of treatment-related adverse events, and two (1%) died (one due to pulmonary oedema and one due to pleural effusion and pneumonitis). Of 15 patients with relapsed or refractory Hodgkin lymphoma, two had complete and seven had partial responses; thus, nine patients achieved an objective response (60·0%; 95% CI 32·3-83·7). Of 136 patients with solid tumours and other lymphomas, eight had partial responses (two patients each with adrenocortical carcinoma and mesothelioma, and one patient each with malignant ganglioglioma, epithelioid sarcoma, lymphoepithelial carcinoma, and malignant rhabdoid tumour); the proportion of patients with an objective response was 5·9% (95% CI 2·6-11·3).

  Interpretation: Pembrolizumab was well tolerated and showed encouraging antitumour activity in paediatric patients with relapsed or refractory Hodgkin lymphoma, consistent with experience in adult patients. Pembrolizumab had low antitumour activity in the majority of paediatric tumour types, and responses were observed in only a few rare PD-L1-positive tumour types, suggesting that PD-L1 expression alone is not sufficient as a biomarker for the selection of paediatric patients who are likely to respond to PD-1 checkpoint inhibitors. Final results of KEYNOTE-051, expected by September, 2022, with the possibility for extension, will report further on the activity of pembrolizumab in Hodgkin lymphoma, microsatellite instability-high tumours, and melanoma.

  Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co.

  Copyright © 2020 Elsevier Ltd. All rights reserved.

• Tumour Treating Fields for mesothelioma - Authors' reply. G.L. Ceresoli, L. Gianoncelli, F. Grosso, et al. 2020;21(1):e10. Letter · Comment PubMed · Publisher

• Tumour Treating Fields for mesothelioma. C.J. de Gooijer, J.A. Burgers. 2020;21(1):e9. Letter · Comment PubMed · Publisher

• Tumour Treating Fields for mesothelioma. M. Barbarino, M. Bottaro, L. Luzzi, et al. 2020;21(1):e8. Letter · Comment PubMed · Publisher

2010s

• Asbestos exposure: the dust cloud lingers. The Lancet Oncology. 2019;20(8):1035. Editorial PubMed · Publisher

• Checkpoint inhibitors in mesothelioma: hope for the future?. A. Bibby, N. Maskell. 2019;20(2):172-174. Comment PubMed · Publisher

  Summary

  In this invited comment, the authors discussed two phase 2 trials of immune checkpoint inhibitors in previously treated malignant pleural mesothelioma. They described the disease as an aggressive, asbestos-related tumour with a poor prognosis and no established second-line or third-line treatment. In the French MAPS2 randomised, non-comparative trial, patients received nivolumab alone (n=63) or nivolumab plus ipilimumab (n=62). Among the first 108 eligible patients, 12-week disease control was achieved in 24 of 54 (44%) and 27 of 54 (50%), respectively, and median overall survival was 11.9 and 15.9 months. In the single-arm INITIATE trial, 34 patients received nivolumab plus ipilimumab. Of these, 23 (68%) achieved 12-week disease control, and 1-year overall survival was 64%. The authors noted that these results appeared better than those reported for second-line chemotherapy and were consistent with earlier studies. Combination treatment caused grade 3–4 treatment-related adverse events in 26% (MAPS2) and 34% (INITIATE) of patients, and there were three treatment-related deaths in the MAPS2 combination group. The authors cautioned about selection and survivorship bias and unverified external validity. They also pointed to earlier promising phase 2 results with tremelimumab that were not confirmed in a 569-patient randomised trial. They concluded that the trials were an encouraging advance, but that definitive phase 3 trials were needed.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. A. Scherpereel, J. Mazieres, L. Greillier, et al. 2019;20(2):239-253. Randomized trial PubMed · Publisher

  Abstract

  Background: There is no recommended therapy for malignant pleural mesothelioma that has progressed after first-line pemetrexed and platinum-based chemotherapy. Disease control has been less than 30% in all previous studies of second-line drugs. Preliminary results have suggested that anti-programmed cell death 1 (PD-1) monoclonal antibody could be efficacious in these patients. We thus aimed to prospectively assess the anti-PD-1 monoclonal antibody alone or in combination with anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody in patients with malignant pleural mesothelioma.

  Methods: This multicentre randomised, non-comparative, open-label, phase 2 trial was done at 21 hospitals in France. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, histologically proven malignant pleural mesothelioma progressing after first-line or second-line pemetrexed and platinum-based treatments, measurable disease by CT, and life expectancy greater than 12 weeks. Patients were randomly allocated (1:1) to receive intravenous nivolumab (3 mg/kg bodyweight) every 2 weeks, or intravenous nivolumab (3 mg/kg every 2 weeks) plus intravenous ipilimumab (1 mg/kg every 6 weeks), given until progression or unacceptable toxicity. Central randomisation was stratified by histology (epithelioid vs non-epithelioid), treatment line (second line vs third line), and chemosensitivity to previous treatment (progression ≥3 months vs <3 months after pemetrexed treatment) and used a minimisation method with a 0·8 random factor. The primary outcome was the proportion of patients who achieved 12-week disease control, assessed by masked independent central review; the primary endpoint would be met if disease control was achieved in at least 40% of patients. The primary endpoint was assessed in the first 108 eligible patients. Efficacy analyses were also done in the intention-to-treat population and safety analyses were done in all patients who received at least one dose of their assigned treatment. This trial is registered at ClinicalTrials.gov, number NCT02716272.

  Findings: Between March 24 and August 25, 2016, 125 eligible patients were recruited and assigned to either nivolumab (n=63) or nivolumab plus ipilimumab (n=62). In the first 108 eligible patients, 12-week disease control was achieved by 24 (44%; 95% CI 31-58) of 54 patients in the nivolumab group and 27 (50%; 37-63) of 54 patients in the nivolumab plus ipilimumab group. In the intention-to-treat population, 12-week disease control was achieved by 25 (40%; 28-52) of 63 patients in the nivolumab group and 32 (52%; 39-64) of 62 patients in the combination group. Nine (14%) of 63 patients in the nivolumab group and 16 (26%) of 61 patients in the combination group had grade 3-4 toxicities. The most frequent grade 3 adverse events were asthenia (one [2%] in the nivolumab group vs three [5%] in the combination group), asymptomatic increase in aspartate aminotransferase or alanine aminotransferase (none vs four [7%] of each), and asymptomatic lipase increase (two [3%] vs one [2%]). No patients had toxicities leading to death in the nivolumab group, whereas three (5%) of 62 in the combination group did (one fulminant hepatitis, one encephalitis, and one acute kidney failure).

  Interpretation: Anti-PD-1 nivolumab monotherapy or nivolumab plus anti-CTLA-4 ipilimumab combination therapy both showed promising activity in relapsed patients with malignant pleural mesothelioma, without unexpected toxicity. These regimens require confirmation in larger clinical trials.

  Funding: French Cooperative Thoracic Intergroup.

  Copyright © 2019 Elsevier Ltd. All rights reserved.

• Pressurised intraperitoneal aerosol chemotherapy: rationale, evidence, and potential indications. M. Alyami, M. Hübner, F. Grass, et al. 2019;20(7):e368-e377. Review PubMed · Publisher

  Abstract

  Pressurised intraperitoneal aerosol chemotherapy (PIPAC) was introduced as a new treatment for patients with peritoneal metastases in November, 2011. Reports of its feasibility, tolerance, and efficacy have encouraged centres worldwide to adopt PIPAC as a novel drug delivery technique. In this Review, we detail the technique and rationale of PIPAC and critically assess its evidence and potential indications. A systematic search was done to identify all relevant literature on PIPAC published between Jan 1, 2011, and Jan 31, 2019. A total of 106 articles or reports on PIPAC were identified, and 45 clinical studies on 1810 PIPAC procedures in 838 patients were included for analysis. Repeated PIPAC delivery was feasible in 64% of patients with few intraoperative and postoperative surgical complications (3% for each in prospective studies). Adverse events (Common Terminology Criteria for Adverse Events greater than grade 2) occurred after 12-15% of procedures, and commonly included bowel obstruction, bleeding, and abdominal pain. Repeated PIPAC did not have a negative effect on quality of life. Using PIPAC, an objective clinical response of 62-88% was reported for patients with ovarian cancer (median survival of 11-14 months), 50-91% for gastric cancer (median survival of 8-15 months), 71-86% for colorectal cancer (median survival of 16 months), and 67-75% (median survival of 27 months) for peritoneal mesothelioma. From our findings, PIPAC has been shown to be feasible and safe. Data on objective response and quality of life were encouraging. Therefore, PIPAC can be considered as a treatment option for refractory, isolated peritoneal metastasis of various origins. However, its use in further indications needs to be validated by prospective studies.

  Copyright © 2019 Elsevier Ltd. All rights reserved.

• Tumour Treating Fields for mesothelioma: controversy versus opportunity. D.A. Fennell. 2019;20(12):1623-1625. Comment PubMed · Publisher

  Summary

  In this invited comment, the author discussed the STELLAR trial, a single-arm phase 2 study reported in the same journal by Ceresoli and colleagues. The trial combined Tumour Treating Fields (TTFields), a non-invasive alternating electric field therapy, with standard first-line pemetrexed and platinum chemotherapy for unresectable malignant pleural mesothelioma. The author noted that standard chemotherapy had been very difficult to improve upon since 2004, and that TTFields had previously shown efficacy in glioblastoma. STELLAR met its primary endpoint, and TTFields received US Food and Drug Administration approval for mesothelioma on May 23, 2019. The author argued that it remained unanswered whether TTFields gave a real overall survival benefit over historical controls, for two reasons: single-arm trials were prone to sampling bias in a heterogeneous cancer, and more than half of STELLAR patients received post-study therapy, including vinorelbine and immunotherapy. Response and progression-free survival were similar to historical controls. However, overall survival was 18.2 months in the 80 patients, 27 (34%) of whom had the more aggressive non-epithelioid subtype, and 21.2 months in the epithelioid subgroup. By comparison, overall survival was 15.2 months in the control group of the LUME-Meso trial, which was enriched for epithelioid-only patients. The author concluded that STELLAR showed a promising signal of efficacy that urgently needed confirmation in a randomised phase 3 trial, and that predictive biomarkers of benefit should be sought.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial. G.L. Ceresoli, J.G. Aerts, R. Dziadziuszko, et al. 2019;20(12):1702-1709. PubMed · Publisher

  Abstract

  Background: Tumour Treating Fields (TTFields) are a regional, antimitotic treatment for solid tumours, which is based on the delivery of low-intensity alternating electric fields. The aim of the STELLAR study was to test the activity of TTFields delivered to the thorax in combination with systemic chemotherapy for the front-line treatment of patients with unresectable malignant pleural mesothelioma.

  Methods: STELLAR was a prospective, single-arm, phase 2 trial done at 12 European academic and non-academic sites (five in Italy, three in Poland, one in France, one in Belgium, one in Spain, and one in the Netherlands) for treatment-naive patients with histologically confirmed unresectable malignant pleural mesothelioma. Patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, and at least one measurable or evaluable lesion according to modified Response Evaluation Criteria in Solid Tumors for mesothelioma. Patients received continuous TTFields at a frequency of 150 kHz to the thorax and concomitant chemotherapy with intravenous pemetrexed (500 mg/m2 on day 1) plus intravenous platinum (either cisplatin 75 mg/m2 on day 1 or carboplatin area under the curve 5 on day 1) every 21 days for up to six cycles. Patients not progressing after completion of chemotherapy received TTFields as maintenance treatment until progression, patient or physician decision, or unacceptable toxic effects. The primary endpoint of the trial was overall survival. Survival analyses were done in the intention-to-treat population, and safety analyses were done in all patients who received at least 1 day of TTFields treatment. This trial is registered with ClinicalTrials.gov, NCT02397928.

  Findings: Between Feb 9, 2015 and March 21, 2017, 80 patients were enrolled in the study. Median follow-up was 12·5 months (IQR 7·4-16·6). Median overall survival was 18·2 months (95% CI 12·1-25·8). The most common grade 3 or worse adverse events were anaemia (nine [11%] patients), neutropenia (seven [9%]), and thrombocytopenia (four [5%]). Skin reaction was the only adverse event associated with TTFields and was reported as grade 1-2 in 53 (66%) patients, and as grade 3 in four (5%) patients. No treatment-related deaths were observed.

  Interpretation: The trial showed encouraging overall survival results, with no increase in systemic toxicity. TTFields (150 kHz) delivered to the thorax concomitant with pemetrexed and platinum was an active and safe combination for front-line treatment of unresectable malignant pleural mesothelioma. Further investigation in a randomised trial is warranted.

  Funding: Novocure.

  Copyright © 2019 Elsevier Ltd. All rights reserved.

• Unexpected pleural finding after a fall. C. Giraudo, A.S. Fraia, A. Bellini, et al. 2019;20(10):e606. Case report PubMed · Publisher

• Miracle mineral or mesothelioma: cancer and asbestos in the USA. C. Lucas. 2018;19(7):868. PubMed · Publisher

• NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. V. Gregorc, R.M. Gaafar, A. Favaretto, et al. 2018;19(6):799-811. Randomized trial PubMed · Publisher

  Abstract

  Background: Malignant pleural mesothelioma is an aggressive cancer with highly vascularised tumours. It has poor prognosis and few treatment options after failure of first-line chemotherapy. NGR-hTNF is a vascular-targeting drug that increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment. In this trial, we aimed to investigate the efficacy and safety of NGR-hTNF in patients with malignant pleural mesothelioma who had progressed during or after a first-line treatment.

  Methods: NGR015 was a randomised, double-blind, placebo-controlled phase 3 trial done in 41 centres in 12 countries. Eligible participants had malignant pleural mesothelioma of any histological subtype (epithelial, sarcomatoid, or mixed), were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-2 and radiologically documented progressive disease after one pemetrexed-based chemotherapy regimen. Participants were randomly assigned to receive weekly NGR-hTNF 0·8 μg/m2 intravenously plus best investigator choice (n=200), or placebo plus best investigator choice (n=200). Best investigator choice was decided before random assignment and could be single-agent gemcitabine (1000-1250 mg/m2 intravenously), vinorelbine (25 mg/m2 intravenously or 60 mg/m2 orally), doxorubicin (60-75 mg/m2 intravenously), or best supportive care only. Patients were randomised (1:1) with a block size of four after stratification for performance status and best investigator choice. The primary study endpoint was overall survival in the intention-to-treat population. The trial is closed to new participants and is registered with ClinicalTrials.gov (NCT01098266).

  Findings: Between April 12, 2010 and Jan 21, 2013, we enrolled 400 eligible participants. 381 (95%) of 400 patients were selected to receive chemotherapy before all participants were randomly assigned to receive NGF-hTNF plus best investigator choice (n=200) or placebo plus best investigator choice (n=200). At the cutoff date (April 29, 2014), the median follow-up was 18·7 months (IQR 15·1-24·4), and overall survival did not differ between the two treatment groups (median 8·5 months [95% CI 7·2-9·9] in the NGR-hTNF group vs 8·0 months [6·6-8·9] in the placebo group; hazard ratio 0·94, 95% CI 0·75-1·18; p=0·58). Grade 3 or worse study-emergent adverse events occurred in 136 (70%) of patients receiving NGR-hTNF versus 118 (61%) of patients receiving placebo, with the most common being neutropenia (35 [18%] of 193 patients vs 36 [19%] of 193 patients), pain (11 [6%] vs 16 [8%]), dyspnoea (nine [5%] vs seven [4%]), and chills (nine [5%] vs none). 50 (26%) patients in the NGR-hTNF group had a serious adverse event, compared with 47 (24%) in the placebo group. Treatment-related serious adverse events occurred in 17 (9%) patients in the NGR-hTNF group and 20 patients (10%) in the placebo group. There were 12 deaths in the NGR-hTNF group and 13 deaths in the placebo group, but none were treatment related.

  Interpretation: The study did not meet its primary endpoint. The hypothesis-generating findings from the subgroup analyses deserve a confirmatory randomised trial because patients who rapidly progress after first-line treatment have a poor prognosis.

  Funding: MolMed.

  Copyright © 2018 Elsevier Ltd. All rights reserved.

• Novel therapies for malignant pleural mesothelioma. A. Scherpereel, F. Wallyn, S.M. Albelda, et al. 2018;19(3):e161-e172. Review PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma is a rare cancer that is typically associated with exposure to asbestos. Patients with malignant pleural mesothelioma have poor outcomes with suboptimal therapeutic options and currently no treatment is curative. The standard frontline treatment, cisplatin plus pemetrexed chemotherapy, has only short and insufficient efficacy, and no validated treatment beyond first-line therapy is available. New therapeutic strategies are therefore needed. The addition of bevacizumab (an anti-VEGF antibody) combined with cisplatin plus pemetrexed has shown some promise. However, immunotherapy, especially immune checkpoint inhibitors, has generated a lot of excitement because of data suggesting the potential value of immune checkpoint inhibitors for patients who have failed chemotherapy. In this Review, we describe immune checkpoint inhibitors, other immunotherapies, targeted therapies, or combinations of novel drugs being investigated in malignant pleural mesothelioma, as well as the issues surrounding the selection of the best candidates for these treatments.

  Copyright © 2018 Elsevier Ltd. All rights reserved.

• Targeting the tumour vasculature in mesothelioma. D.A. Fennell. 2018;19(6):723-724. Comment PubMed · Publisher

• Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. E.W. Alley, J. Lopez, A. Santoro, et al. 2017;18(5):623-630. PubMed · Publisher

  Abstract

  Background: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort.

  Methods: Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria included measurable disease, failure of standard therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1. PD-L1 positivity was defined as expression in 1% or more of tumour cells by immunohistochemistry. Response was assessed based on investigator review using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Primary endpoints were safety and tolerability, analysed in the all-patients-as-treated population, and objective response, analysed for the full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT02054806, and is ongoing but not recruiting participants.

  Findings: As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%]). Five (20%) patients reported grade 3 treatment-related adverse events. Three (12%) patients required dose interruption because of immune-related adverse events: one (4%) of 25 each had grade 3 rhabdomyolysis and grade 2 hypothyroidism; grade 3 iridocyclitis, grade 1 erythema multiforme, and grade 3 erythema; and grade 2 infusion-related reaction. No treatment-related deaths or discontinuations occurred. Five (20%) patients had a partial response, for an objective response of 20% (95% CI 6·8-40·7), and 13 (52%) of 25 had stable disease. Responses were durable (median response duration 12·0 months [95% CI 3·7 to not reached]); two patients remained on treatment at data cutoff.

  Interpretation: Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation.

  Funding: Merck.

  Copyright © 2017 Elsevier Ltd. All rights reserved.

• CTLA-4 blockade in mesothelioma: ineffective or reason for optimism?. A. Thomas, R. Hassan. 2017;18(9):1150-1151. Comment PubMed · Publisher

  Summary

  In this comment, the authors discussed the DETERMINE trial, reported by Maio and colleagues in The Lancet Oncology. DETERMINE was a phase 2b, randomised, double-blind, placebo-controlled study of the anti-CTLA-4 antibody tremelimumab in patients with advanced unresectable pleural or peritoneal mesothelioma that had progressed after first-line or second-line therapy. The authors noted that pemetrexed plus cisplatin was the only approved therapy for unresectable malignant pleural mesothelioma and that no therapy was approved after progression. In DETERMINE, 571 of 658 enrolled patients were randomly assigned (2:1) to tremelimumab (n=382) or placebo (n=189). Most had pleural mesothelioma (95%) and epithelial histology (83%). Median overall survival, the primary endpoint, was 7·7 months with tremelimumab and 7·3 months with placebo, showing no difference. Grade 3 or worse diarrhoea (15% vs <1%) and colitis (7% vs none) were more common with tremelimumab. The authors described ongoing approaches. One was combined checkpoint blockade: the phase 3 CheckMate743 trial of ipilimumab plus nivolumab, and a reported randomised trial of 108 patients with objective responses in 17% receiving nivolumab and 27% receiving nivolumab plus ipilimumab. Another was checkpoint inhibition combined with chemotherapy. The authors concluded that the results, though disappointing, would inform future development of immune checkpoint inhibitors for mesothelioma. They said that identifying biomarker-defined patient populations likely to benefit would become imperative.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Immune checkpoint inhibitors in malignant pleural mesothelioma. G.L. Ceresoli, A. Mantovani. 2017;18(5):559-561. Comment PubMed · Publisher

  Summary

  This invited comment discussed immune checkpoint inhibitors in malignant pleural mesothelioma. Most patients receive first-line chemotherapy with pemetrexed and a platinum agent, and no standard second-line or further-line therapy was available. The authors noted that tremelimumab, an anti-CTLA-4 antibody, had not improved survival in a randomised, double-blind, placebo-controlled phase 2–3 study. Preliminary data on drugs targeting the PD-1 pathway had shown partial responses in around 20% of patients and disease control in 50–80%. They commented on the study by Alley and colleagues in the same issue, in which pembrolizumab was given to 25 patients with pretreated malignant pleural mesothelioma expressing PD-L1. Five (20%) had a partial response and 13 (52%) had disease stabilisation. Median progression-free survival was 5·4 months and median overall survival was 18·0 months. The authors urged caution because the timing between diagnosis and the start of pembrolizumab was not reported, modified RECIST criteria for mesothelioma were not used for the primary analysis, and no central imaging review was done. They concluded that single-agent immunotherapy had proven but limited benefit, possibly because of the disease's complex biology: it does not rank high in mutational load, and its pathogenesis seems to be driven by inflammation. They hypothesised that tumour-associated macrophages contribute to immunosuppression. They suggested that targeting these cells, transforming growth factor β, VISTA or mesenchymal transition might complement PD-1 inhibition in rationally designed combination therapies.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• miR-16: expanding the range of molecular targets in mesothelioma. D. Fennell. 2017;18(10):1296-1297. Comment PubMed · Publisher

  Summary

  In this invited comment, the author discussed a first-in-human phase 1 study by van Zandwijk and colleagues, published in the same issue of The Lancet Oncology. That study tested a miR-16 microRNA mimic delivered in bacterially derived minicells to patients with relapsed mesothelioma. The author noted that malignant mesothelioma is caused by asbestos exposure and has a devastating prognosis. Cisplatin plus pemetrexed had remained the only approved standard therapy for more than 10 years, and no somatic mutations in oncogenic kinases had been found in mesothelioma. miR-16 is a tumour suppressor microRNA that silences oncogenes such as BCL2, CCND1 and WNT3A. The same group had earlier shown that mesotheliomas often downregulate miR-16 and that restoring it was feasible in laboratory cells and in mice. The miR-16 mimic was packaged in an EGFR-targeted EnGeneIC Dream Vector, a product termed a TargomiR. In the trial, maximum glucose uptake on PET-CT fell in 9 (60%) of 15 patients assessed. Disease control was achieved in 16 (73%) of 22 patients assessed by CT, including one partial response. The author called this a respectable signal that warranted further investigation. He also noted that no post-treatment biopsies were done to confirm that the treatment acted on its target, and that no molecular stratification was applied. He suggested selecting patients by miR-16 expression and concluded that miR-16 TargomiRs could be added to a growing list of molecular targets in mesothelioma.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Radiotherapy for the treatment of malignant pleural mesothelioma. M. de Perrot, L. Wu, M. Wu, et al. 2017;18(9):e532-e542. Review PubMed · Publisher

  Abstract

  Malignant pleural mesothelioma is an aggressive disease that continues to be associated with poor outcomes. Although, traditionally this disease is considered to be resistant to radiotherapy, more recent evidence suggests that radiotherapy can produce positive outcomes. Over the past 15 years, the development of new, highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), has enabled investigators to optimise the delivery of high-dose radiotherapy to the whole of the hemithorax. Prospective single-arm trials have shown that the median survival of patients who have completed high-dose hemithoracic radiotherapy after extrapleural pneumonectomy could reach 23·9-39·4 months independent of the chemotherapeutic response, suggesting that IMRT could potentially have an intrinsic benefit to this subset of patients. These observations have led to a change in practice, with the introduction of adjuvant pleural IMRT after pleurectomy-decortication and the development of induction-accelerated hemithoracic IMRT followed by extrapleural pneumonectomy. This Review focuses on recent observations on the role of radiotherapy in the treatment of malignant pleural mesothelioma, with particular emphasis on the results of clinical trials that evaluate the role of high-dose hemithoracic radiotherapy.

  Copyright © 2017 Elsevier Ltd. All rights reserved.

• Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. N. van Zandwijk, N. Pavlakis, S.C. Kao, et al. 2017;18(10):1386-1396. PubMed · Publisher

  Abstract

  Background: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma.

  Methods: In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 109, 7 × 109, and 9 × 109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 109 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651.

  Findings: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 109 TargomiRs once weekly. We established that 5 × 109 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation.

  Interpretation: The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors.

  Funding: Asbestos Diseases Research Foundation.

  Copyright © 2017 Elsevier Ltd. All rights reserved.

• Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. M. Maio, A. Scherpereel, L. Calabrò, et al. 2017;18(9):1261-1273. Randomized trial PubMed · Publisher

  Abstract

  Background: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma.

  Methods: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374.

  Findings: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient.

  Interpretation: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing.

  Funding: AstraZeneca.

  Copyright © 2017 Elsevier Ltd. All rights reserved.

• Arginine deprivation for ASS1-deficient mesothelioma. T.K. Burki. 2016;17(10):e423. News PubMed · Publisher

  Summary

  This news report summarised a phase 2 trial by Szlosarek and colleagues, published in JAMA Oncology, of arginine deprivation therapy in malignant pleural mesothelioma deficient in argininosuccinate synthetase 1 (ASS1). The investigators screened 201 patients with mesothelioma from centres in the UK, of whom 97 (48%) showed ASS1 deficiency. Sixty-eight patients were randomly assigned to pegylated arginine deiminase (ADI-PEG20; 36·8 mg/m2 per week for up to 6 months) plus best supportive care (n=44) or best supportive care alone (n=24). Median progression-free survival was 3·2 months with ADI-PEG20 versus 2·0 months with best supportive care (hazard ratio [HR] 0·56; 95% CI 0·33–0·96; p=0·03). Serious adverse events were similar in both groups. Patients with ASS1 loss exceeding 75% received greater benefit than those with ASS1 loss of 50–75% (HR 0·25; 95% CI 0·09–0·70; p=0·08 vs HR 0·72; 95% CI 0·34–1·49; p=0·37). The lead author called ASS1 a predictive and prognostic biomarker and said arginine deprivation should be used in combination. His group was studying ADI-PEG20 with standard chemotherapy. An independent expert called the small study very promising. The report noted that heavy asbestos use continued in India and China. It also noted that the UK, which banned all forms of asbestos in 1999, had yet to reach its epidemic peak.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Asbestos concerns in Australian buildings. T.K. Burki. 2016;17(9):e377. News PubMed · Publisher

• Hemithoracic radiotherapy for mesothelioma: lack of benefit or lack of statistical power?. A. Rimner, C.B. Simone, M.G. Zauderer, et al. 2016;17(2):e43-e44. Letter · Comment PubMed · Publisher

  Summary

  This is a letter to the editor responding to the SAKK 17/04 randomised phase 2 trial by Stahel and colleagues. That trial concluded that hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy was not supported in patients with malignant pleural mesothelioma. The trial reported median locoregional relapse-free survival of 7·6 months (95% CI 4·5–10·7) without radiotherapy and 9·4 months (6·5–11·9) with radiotherapy. The letter writers argued that the trial's conclusions were not supported by its data.

  They noted several problems with the trial:

  • It closed early because of slow accrual.
  • It did not meet its primary endpoint in part 2.
  • Many patients dropped out between registration and randomisation.
  • Only 23 patients received radiotherapy as prescribed, using three different fractionation regimens across 14 centres.
  • One patient developed grade 4 pneumonitis and another died of pneumonitis during radiotherapy, yet the study gave no details on radiotherapy guidelines, dose to the contralateral lung, or links between dose and toxicity.
  • It was unclear how boost volumes were chosen.
  • There was no central review of contours or treatment plans. The only requirement was dosimetry on the first patient at each centre.

  The writers concluded that the trial should be seen as inconclusive, like the MARS study of extrapleural pneumonectomy. They cited newer radiotherapy approaches under assessment and called for careful patient selection, meticulous radiotherapy technique and multidisciplinary care at high-volume centres. They declared no competing interests.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Hemithoracic radiotherapy for mesothelioma: lack of benefit or lack of statistical power? - Authors' reply. O. Riesterer, W. Weder, R. Stahel. 2016;17(2):e44-e45. Letter · Comment PubMed · Publisher

• Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial. A.O. Clive, H. Taylor, L. Dobson, et al. 2016;17(8):1094-1104. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Background: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial.

  Methods: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336.

  Findings: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy.

  Interpretation: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified.

  Funding: Research for Patient Benefit Programme from the UK National Institute for Health Research.

  Copyright © 2016 Clive et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

• Prophylactic radiotherapy to prevent procedure-tract metastases. D. Landau, E. Lim. 2016;17(10):e418. Letter · Comment PubMed · Publisher

• Prophylactic radiotherapy to prevent procedure-tract metastases. G. Zalcman, S. Brosseau, A. Scherpereel. 2016;17(10):e417. Letter · Comment PubMed · Publisher

  Summary

  In this letter, the authors responded to the SMART randomised trial by Clive and colleagues. That trial compared early with deferred radiotherapy to prevent procedure-tract metastases (PTM) in malignant pleural mesothelioma, and the authors argued that its main conclusion could be challenged. The trial had assumed a PTM incidence of 2% with immediate radiotherapy, but 8·8% was observed, in line with earlier reports of 7% to 24%. The authors calculated that detecting a fall from 10% to 5% would have required 239 patients per group, so the trial was underpowered. PTM occurred in 16 of 101 patients given deferred radiotherapy and nine of 102 given early radiotherapy (p=0·14). The authors noted major protocol violations in the early group: radiation fields under 7 cm in eight patients, and a first fraction after the 42-day limit in three. They noted that the prespecified per-protocol analysis showed PTM in 16 (16%) of 99 versus five (6%) of 84 patients (p=0·037). They also cited a significant effect in patients who received no chemotherapy (OR 0·16 [0·02–0·93]; p=0·021). They argued that the quality-of-life and pain analyses were prone to be negative. They concluded that early prophylactic radiotherapy to intervention sites has a place in mesothelioma, provided technical requirements (high energy electrons, cutaneous bolus, 7 cm margins, daily 7 Gy fractions for 3 days) are respected.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Radiotherapy to intervention sites in mesothelioma: no more?. G.L. Ceresoli, V. Vavassori. 2016;17(8):1025-1027. Comment PubMed · Publisher

• A lesson from vorinostat in pleural mesothelioma. M.C. Garassino, S. Marsoni. 2015;16(4):359-60. Comment PubMed · Publisher

• Multimodal treatment for malignant pleural mesothelioma. R.C. Rintoul, T. Treasure, F. Macbeth. 2015;16(16):1576-7. Comment PubMed · Publisher

• Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. R.A. Stahel, O. Riesterer, A. Xyrafas, et al. 2015;16(16):1651-8. Randomized trial PubMed · Publisher

  Abstract

  Background: Postoperative hemithoracic radiotherapy has been used to treat malignant pleural mesothelioma, but it has not been assessed in a randomised trial. We assessed high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with malignant pleural mesothelioma.

  Methods: We did this phase 2 trial in two parts at 14 hospitals in Switzerland, Belgium, and Germany. We enrolled patients with pathologically confirmed malignant pleural mesothelioma; resectable TNM stages T1-3 N0-2, M0; WHO performance status 0-1; age 18-70 years. In part 1, patients were given three cycles of neoadjuvant chemotherapy (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 given every 3 weeks) and extrapleural pneumonectomy; the primary endpoint was complete macroscopic resection (R0-1). In part 2, participants with complete macroscopic resection were randomly assigned (1:1) to receive high-dose radiotherapy or not. The target volume for radiotherapy encompassed the entire hemithorax, the thoracotomy channel, and mediastinal nodal stations if affected by the disease or violated surgically. A boost was given to areas at high risk for locoregional relapse. The allocation was stratified by centre, histology (sarcomatoid vs epithelioid or mixed), mediastinal lymph node involvement (N0-1 vs N2), and T stage (T1-2 vs T3). The primary endpoint of part 1 was the proportion of patients achieving complete macroscopic resection (R0 and R1). The primary endpoint in part 2 was locoregional relapse-free survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00334594.

  Findings: We enrolled patients between Dec 7, 2005, and Oct 17, 2012. Overall, we analysed 151 patients receiving neoadjuvant chemotherapy, of whom 113 (75%) had extrapleural pneumonectomy. Median follow-up was 54·2 months (IQR 32-66). 52 (34%) of 151 patients achieved an objective response. The most common grade 3 or 4 toxic effects were neutropenia (21 [14%] of 151 patients), anaemia (11 [7%]), and nausea or vomiting (eight [5%]). 113 patients had extrapleural pneumonectomy, with complete macroscopic resection achieved in 96 (64%) of 151 patients. We enrolled 54 patients in part 2; 27 in each group. The main reasons for exclusion were patient refusal (n=20) and ineligibility (n=10). 25 of 27 patients completed radiotherapy. Median total radiotherapy dose was 55·9 Gy (IQR 46·8-56·0). Median locoregional relapse-free survival from surgery, was 7·6 months (95% CI 4·5-10·7) in the no radiotherapy group and 9·4 months (6·5-11·9) in the radiotherapy group. The most common grade 3 or higher toxic effects related to radiotherapy were nausea or vomiting (three [11%] of 27 patients), oesophagitis (two [7%]), and pneumonitis (two [7%]). One patient died of pneumonitis. We recorded no toxic effects data for the control group.

  Interpretation: Our findings do not support the routine use of hemithoracic radiotherapy for malignant pleural mesothelioma after neoadjuvant chemotherapy and extrapleural pneumonectomy.

  Funding: Swiss Group for Clinical Cancer Research, Swiss State Secretariat for Education, Research and Innovation, Eli Lilly.

  Copyright © 2015 Elsevier Ltd. All rights reserved.

• Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. L.M. Krug, H.L. Kindler, H. Calvert, et al. 2015;16(4):447-56. Randomized trial PubMed · Publisher

  Abstract

  Background: Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival.

  Methods: This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov, number NCT00128102.

  Findings: From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7-36·1) versus 27·1 weeks (23·1-31·9) for placebo (hazard ratio 0·98, 95% CI 0·83-1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 [16%] patients in the vorinostat group vs 25 [8%] in the placebo group]) and dyspnoea (35 [11%] vs 45 [14%]).

  Interpretation: In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma.

  Funding: Merck & Co.

  Copyright © 2015 Elsevier Ltd. All rights reserved.

• Biomarkers for immune checkpoint inhibitors--authors' reply. L. Calabrò, M. Maio. 2014;15(1):e1-2. Letter · Comment PubMed · Publisher

• Biomarkers for immune checkpoint inhibitors. L.A. Lievense, J.P. Hegmans, J.G. Aerts. 2014;15(1):e1. Letter · Comment PubMed · Publisher

• Carcinogenicity of fluoro-edenite, silicon carbide fibres and whiskers, and carbon nanotubes. Y. Grosse, D. Loomis, K.Z. Guyton, et al. 2014;15(13):1427-1428. News PubMed · Publisher

  Summary

  This news report summarised the evaluations made in October 2014 by 21 experts from ten countries who met at the International Agency for Research on Cancer (IARC) in Lyon, France, to assess the carcinogenicity of fluoro-edenite, silicon carbide (SiC) fibres and whiskers, and carbon nanotubes (CNTs). The assessments were to be published as Volume 111 of the IARC Monographs. Fluoro-edenite, which can occur as asbestiform fibres, was identified near the Etna volcano at Biancavilla, Italy. There, surveillance studies reported excess mesothelioma that was similar in men and women and most prominent in young adults, and most cases had no history of occupational asbestos exposure. Fibrous fluoro-edenite was classified as carcinogenic to humans (Group 1). Occupational exposures in the Acheson process were classified as Group 1 because of lung cancer in Canadian and Norwegian worker cohorts. Fibrous SiC was classified as possibly carcinogenic (Group 2B) because its effects were difficult to separate from those of cristobalite. SiC whiskers, produced as asbestos substitutes, caused mesotheliomas in rats. In a decision that was not unanimous, they were classified as probably carcinogenic (Group 2A) because they resemble asbestos and erionite fibres. No human cancer data were available for CNTs. MWCNT-7, which caused mesotheliomas in rats and mice, was classified as possibly carcinogenic (Group 2B). Single-walled CNTs and other multi-walled CNTs were not classifiable (Group 3).

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Asbestos is not just asbestos: an unrecognised health hazard. F. Baumann, J.P. Ambrosi, M. Carbone. 2013;14(7):576-8. PubMed · Publisher

  Summary

  In this comment, the authors argued that the regulatory definition of asbestos is too narrow. They noted that about 107 000 people die every year from mesothelioma and other asbestos-related diseases. Of roughly 400 minerals that occur naturally in fibrous form, only six (actinolite, amosite, anthophyllite, chrysotile, crocidolite and tremolite) are regulated, because these were the only fibres used commercially when regulations were introduced. They described the differing definitions of asbestos and stated that fibre dimension and biopersistence are the main factors in its toxic effects. They cited examples of non-regulated fibres linked to disease. Erionite, described as the most potent carcinogenic mineral fibre, caused a mesothelioma epidemic in Cappadocian villages in Turkey and is present in western USA, where it has been used to pave roads and playgrounds. Asbestiform winchite and richterite contaminated vermiculite mined at Libby, Montana. Fibrous antigorite was linked to asbestosis among nickel workers in Poland and to mesothelioma in New Caledonia, where roads paved with serpentinite were the main source of exposure. They also noted that chrysotile, identified as a human carcinogen, is still mined and sold worldwide. The authors concluded that all fibrous minerals should be handled as potentially pathogenic until proven safe. They also concluded that a wider regulatory definition of asbestos should include all potentially carcinogenic mineral fibres, without distinction of type and commercial use.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Immunological checkpoint inhibitors enter adolescence. A.K. Nowak. 2013;14(11):1035-1037. Letter · Comment PubMed · Publisher

  Summary

  In this invited comment, the author discussed the trial by Calabrò and colleagues, published in the same issue, which was described as the first clinical trial of an immunological checkpoint inhibitor in malignant mesothelioma. The author first explained how CTLA4 blockade reduces negative regulatory signals on T cells, so that these drugs have potential activity against cancers of any origin. In the trial, all participants had progressed after standard chemotherapy and received tremelimumab. Two of 29 patients had durable partial responses and seven had prolonged stable disease, giving a disease control rate of 31%. Median progression-free survival was 6.2 months (95% CI 1.3–11.1), and almost 40% of participants were alive at 2 years. One participant had progression followed by a lengthy partial response, which the author said suggested a need for immune response criteria in future trials. The study also assessed peripheral blood biomarkers and found that an increase in circulating CD4-positive, ICOS-positive T cells after treatment was a potential biomarker of response, which required further validation. The author cautioned that drawing conclusions about efficacy from an uncontrolled phase 2 study was presumptuous, but called the results encouraging. She concluded that the study provided a solid foundation for a large randomised phase 2 trial of tremelimumab in mesothelioma (NCT01843374). She also noted open questions about how tremelimumab compares with ipilimumab and about combinations with other therapies.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Mesothelioma: closer to the target?. H.I. Pass. 2013;14(6):448-9. Comment PubMed · Publisher

  Summary

  This commentary discussed the NVALT 5 trial by Buikhuisen and colleagues, a randomised trial run over 5 years in 222 patients with malignant mesothelioma. The trial compared switch maintenance thalidomide with active supportive care after first-line chemotherapy. The author called the trial a landmark achievement, although it found no improvement in time to progression (median 3·6 vs 3·5 months; HR 0·95, 95% CI 0·73–1·20, p=0·72). Median overall survival was shorter with thalidomide (10·6 vs 12·9 months), but the difference was not significant (HR 1·2, 95% CI 0·9–1·6, p=0·21). The author noted subgroup hints, limited by lack of power, that thalidomide might favour patients with raised interleukin 6 (HR 0·7) and non-epithelial histology (HR 0·8). He reviewed possible targets. EGFR is overexpressed in mesothelioma, but gefitinib and erlotinib showed no efficacy. Mesothelin-targeted immunotoxins and antibodies have had encouraging preliminary responses with pemetrexed and cisplatin. WT1 peptide vaccination has elicited immune responses. He argued that progress was slow because accrual in this orphan disease takes a long time. He called for archives of longitudinally collected samples to distinguish responders from non-responders, better definitions of response such as tumour or metabolic volumes, adequately powered phase 2 trials, central interpretation of endpoints, and forward-looking trial planning and funding.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): an open-label, multicentre, randomised phase 3 study. W.A. Buikhuisen, J.A. Burgers, A.D. Vincent, et al. 2013;14(6):543-51. Randomized trial PubMed · Publisher

  Abstract

  Background: Standard chemotherapy does not lead to long-term survival in patients with malignant pleural mesothelioma. Malignant pleural mesothelioma is strongly dependent on vasculature with high vessel counts and high concentrations of serum vascular growth factors. Thalidomide has shown antiangiogenic activity, and we hypothesised that its use in the maintenance setting could improve outcomes.

  Methods: In this open-label, multicentre, randomised phase 3 study, eligible patients had proven malignant pleural or peritoneal mesothelioma and had received a minimum of four cycles of first-line treatment containing at least pemetrexed, with or without cisplatin or carboplatin, and had not progressed on this treatment. Patients were randomly assigned (in a 1:1 ratio, stratified by previous first-line chemotherapy, histological subtype, and recruiting hospital) to receive thalidomide 200 mg per day (including a 2 week run in of 100 mg per day) plus active supportive care or active supportive care alone until disease progression. Patients were required to be registered and to start treatment with thalidomide within 10 weeks after the end of the first-line chemotherapy. Thalidomide was given for a maximum of 1 year or until unacceptable toxicity. The primary endpoint was time to progression. The primary analyses were by intention to treat. The study is registered, ISRCTN13632914.

  Findings: Between May 11, 2004, and Dec 23, 2009, we randomly assigned 222 patients, 111 in each group (one patient on active supportive care later withdrew consent and was excluded from analyses). At the time of this final analysis, median follow-up was 33.1 months (IQR 22.3-66.8), and physician-reported disease progression had occurred in 104 patients in the thalidomide group and 107 in the active supportive care group; 92 patients in the thalidomide group and 93 in the active supportive care group had died. Median time to progression in the thalidomide group was 3·6 months (95% CI 3.2-4.1) compared with 3.5 months (2.3-4.8) in the active supportive care group (hazard ratio 0.95, 95% CI 0.73-1.20, p=0.72). 43 (39%) grade 3 or 4 adverse events were reported in the thalidomide group and 31 (28%) in the active supportive care group; neurosensory events were reported by two (2%) patients on thalidomide and none on active supportive care, cardiac events by two (2%) patients on thalidomide and three (3%) on active supportive care, and thromboembolic events by three (3%) patients on thalidomide and none on active supportive care.

  Interpretation: No benefit was noted in time to progression with the addition of thalidomide maintenance to first-line chemotherapy. Different treatment strategies are needed to improve outcomes in patients with malignant mesothelioma.

  Funding: Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.

  Copyright © 2013 Elsevier Ltd. All rights reserved.

• Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. L. Calabrò, A. Morra, E. Fonsatti, et al. 2013;14(11):1104-1111. PubMed · Publisher

  Abstract

  Background: Monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA4) have therapeutic activity in different tumour types. We aimed to investigate the efficacy, safety, and immunological activity of the anti-CTLA4 monoclonal antibody, tremelimumab, in advanced malignant mesothelioma.

  Methods: In our open-label, single-arm, phase 2 study, we enrolled patients aged 18 years or older with measurable, unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen. Eligible patients had to have a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and no history of autoimmune disease. Patients received tremelimumab 15 mg/kg intravenously once every 90 days until progressive disease or severe toxicity. The primary endpoint was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Analyses were done according to intention to treat. This trial is registered with EudraCT, number 2008-005171-95, and ClinicalTrials.gov, number NCT01649024.

  Findings: Between May 27, 2009, and Jan 10, 2012, we enrolled 29 patients. All patients received at least one dose of tremelimumab (median two doses, range one to nine). No patients had a complete response and two patients (7%) had a durable partial response (one lasting 6 months and one lasting 18 months); one partial response occurred after initial progressive disease. Thus, the study did not reach its primary endpoint. However, we noted disease control in nine (31%) patients and a median progression-free survival of 6·2 months (95% CI 1·3-11·1) and a median overall survival of 10·7 months (0·0-21·9). 27 patients (93%) had at least one grade 1-2 treatment-emergent adverse event (mainly cutaneous rash, pruritus, colitis, or diarrhoea), and four patients (14%) had at least one grade 3-4 treatment-emergent adverse event (two gastrointestinal, one neurological, two hepatic, and one pancreatic).

  Interpretation: Although the effect size was small in our phase 2 trial, tremelimumab seemed to have encouraging clinical activity and an acceptable safety and tolerability profile in previously treated patients with advanced malignant mesothelioma.

  Funding: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, Pfizer, and Fondazione Buzzi Unicem.

  Copyright © 2013 Elsevier Ltd. All rights reserved.

• Immunotherapies for non-small-cell lung cancer and mesothelioma. A. Thomas, R. Hassan. 2012;13(7):e301-10. Review PubMed · Publisher · Free full text

  Abstract

  Non-small-cell lung cancer and mesothelioma are thoracic malignancies, which in their advanced stages are incurable and have poor prognosis. Advances in our understanding of immune responses to tumours, tumour immunosuppression mechanisms, and tumour-specific shared antigens enabled successful early clinical trials of several specific and non-specific immunotherapies. For non-small-cell lung cancer, phase 3 clinical trial results of Toll-like receptor agonists show little promise. However, ongoing phase 3 trials are assessing melanoma-associated antigen A3 vaccine, liposomal BLP25, belagenpumatucel-L, and talactoferrin. In mesothelioma, immunotherapies being investigated include dendritic cell-based and Listeria-based vaccines, and allogeneic tumour cell and WT1 analogue peptide vaccines. Selection of appropriate patients and disease stages for immunotherapy, measurement of tumour-specific immune responses, and understanding the association between immune and clinical responses are some of the major challenges for the development of immunotherapies for these malignancies.

  Copyright © 2012 Elsevier Ltd. All rights reserved.

• Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England. G. Lyratzopoulos, R.D. Neal, J.M. Barbiere, et al. 2012;13(4):353-65. PubMed · Publisher

  Abstract

  Background: Information from patient surveys can help to identify patient groups and cancers with the greatest potential for improvement in the experience and timeliness of cancer diagnosis. We aimed to examine variation in the number of pre-referral consultations with a general practitioner between patients with different cancers and sociodemographic characteristics.

  Methods: We analysed data from 41,299 patients with 24 different cancers who took part in the 2010 National Cancer Patient Experience Survey in England. We examined variation in the number of general practitioner consultations with cancer symptoms before hospital referral to diagnose cancer. Logistic regression was used to identify independent predictors of three or more pre-referral consultations, adjusting for cancer type, age, sex, deprivation quintile, and ethnic group.

  Findings: We identified wide variation between cancer types in the proportion of patients who had visited their general practitioner three or more times before hospital referral (7·4% [625 of 8408] for breast cancer and 10·1% [113 of 1124] for melanoma; 41·3% [193 of 467] for pancreatic cancer and 50·6% [939 of 1854] for multiple myeloma). In multivariable analysis, with patients with rectal cancer as the reference group, those with subsequent diagnosis of multiple myeloma (odds ratio [OR] 3·42, 95% CI 3·01-3·90), pancreatic cancer (2·35, 1·91-2·88), stomach cancer (1·96, 1·65-2·34), and lung cancer (1·68, 1·48-1·90) were more likely to have had three or more pre-referral consultations; conversely patients with subsequent diagnosis of breast cancer (0·19; 0·17-0·22), melanoma (0·34, 0·27-0·43), testicular cancer (0·47, 0·33-0·67), and endometrial cancer (0·59, 0·49-0·71) were more likely to have been referred to hospital after only one or two consultations. The probability of three or more pre-referral consultations was greater in young patients (OR for patients aged 16-24 years vs 65-74 years 2·12, 95% CI 1·63-2·75; p<0·0001), those from ethnic minorities (OR for Asian vs white 1·73, 1·45-2·08; p<0·0001; OR for black vs white 1·83, 1·51-2·23; p<0·0001), and women (OR for women vs men 1·28, 1·21-1·36; p<0·0001). We identified strong evidence of interactions between cancer type and age group and sex (p<0·0001 for both), and between age and ethnicity (p=0·0013). The model including these interactions showed a particularly strong sex effect for bladder cancer (OR for women vs men 2·31, 95% CI 1·98-2·69) and no apparent ethnic group differences in young patients aged 16-24 years, whilst the only cancers without an apparent age gradient were testicular cancer and mesothelioma.

  Interpretation: Our findings could help to prioritise and stratify early diagnosis initiatives and research, focusing on patients with cancers and sociodemographic characteristics with the largest potential for improvement.

  Funding: None.

  Copyright © 2012 Elsevier Ltd. All rights reserved.

• Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. T. Treasure, L. Lang-Lazdunski, D. Waller, et al. 2011;12(8):763-72. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Background: The effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study.

  Methods: MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524.

  Findings: Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92-3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21-6·26; p=0·016). Median survival was 14·4 months (5·3-18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group.

  Interpretation: In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients.

  Funding: Cancer Research UK (CRUK/04/003), the June Hancock Mesothelioma Research Fund, and Guy's and St Thomas' NHS Foundation Trust.

  Copyright © 2011 Elsevier Ltd. All rights reserved.

• Surgery for mesothelioma? The debate continues. H.L. Kindler. 2011;12(8):713-4. Comment PubMed · Publisher

  Summary

  In this invited comment, the author discussed the debate over surgery for pleural mesothelioma, in response to the Mesothelioma and Radical Surgery (MARS) randomised feasibility study by Treasure and colleagues. She noted that neither extrapleural pneumonectomy (EPP) nor radical pleurectomy/decortication (P/D) removes all microscopic tumour, and that randomised trials are uncommon. She summarised non-randomised data from US referral centres. Three-year survival was 18% among 636 patients who had EPP at Brigham and Women's Hospital (1998–2007). Surgical resection predicted overall survival among 945 patients at Memorial Sloan Kettering (1990–2005). Five-year overall survival was 12% among 663 patients having EPP or P/D at three centres. Phase 2 trials of neoadjuvant chemotherapy followed by EPP reported median overall survival of 16.8 to 23.0 months. In MARS, the target of randomly assigning 50 patients in 1 year took 3 years. Its authors concluded that a larger trial could not be done and that EPP offered no benefit and was potentially harmful. The author agreed on feasibility. She noted that the 14.4-month median survival with EPP was measured from randomisation and that perioperative mortality was somewhat higher than expected. However, she considered the conclusion of no benefit premature from a small feasibility study. She called for future studies using clinical and molecular prognostic factors to select patients for resection, and noted that MARS2 was being designed around P/D.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• The MARS feasibility trial: conclusions not supported by data. W. Weder, R.A. Stahel, P. Baas, et al. 2011;12(12):1093-4; author reply 1094-5. Letter · Comment PubMed · Publisher

  Summary

  In this letter, the authors disputed the conclusions of the MARS feasibility trial, which compared extrapleural pneumonectomy (EPP) with no EPP in patients with malignant pleural mesothelioma. They summarised six prospective phase 2 studies of neoadjuvant chemotherapy, EPP and postoperative radiotherapy. In these studies around three-quarters of patients underwent EPP, about three-fifths received radiotherapy, median survival ranged from 16.8 to 25.5 months, and operative mortality from EPP ranged from 0% to 5%. They noted that MARS aimed to randomly assign 50 patients within 1 year but took 3 years, and so in their view the feasibility study failed. They also noted that it was not designed to test the benefit of EPP: an estimated 670 patients would be needed, but the survival results were based on only 30 deaths. Of 112 registered patients, 50 (42%) were randomised, and no information was given on the 58% not considered eligible. For this reason, they said, its survival results could not be compared directly with the earlier studies. They also cited several problems: chemotherapy that was not standardised, no data on the time from chemotherapy to EPP, possible treatment delays, and protocol violations, with three patients in the non-surgical group undergoing EPP. Operative mortality among the 17 patients who underwent EPP per protocol was 18%. The authors concluded that the MARS interpretation that EPP offers no benefit and possibly harms patients was inappropriate.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

2000s

• Asbestos production increases despite WHO opposition. T. Burki. 2009;10(9):846. News PubMed · Publisher

  Summary

  This news special report examined why world asbestos production had not declined despite national bans and World Health Organization (WHO) opposition. It stated that more than 40 countries, including all European Union members, had banned chrysotile (white asbestos), the only form still mined. Even so, production had stabilised at roughly 2·2 million metric tonnes a year, about the 1960 level, driven largely by development projects in China and India. It cited estimates that about 125 million people worked in environments with asbestos exposure, that at least 90 000 people died each year from asbestos-related lung cancer, mesothelioma or asbestosis, and that WHO expected 5–10 million eventual deaths. The report focused on Canada. Canada produced 8% of the world's asbestos, exported virtually all of it, and opposed adding chrysotile to the Rotterdam Convention registry, which requires prior informed consent before export. It contrasted the government-funded Chrysotile Institute's claim that chrysotile could be used safely at exposures not exceeding one fibre/cm3 with WHO's position that all forms of asbestos are carcinogenic and that there is no evidence of a threshold. Critics, including Canadian MP and former asbestos miner Pat Martin and Kathleen Ruff, argued that safe use was not possible in developing countries. They cited unprotected handling in Pakistan and heavy exposure in India. The report noted that a bill to ban exports was under debate, while Canadian production rose in 2008.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

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