title: 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.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified.
  
  
  BACKGROUND
  Research for Patient Benefit Programme from the UK National Institute for Health Research.
authors.affiliation: Respiratory Research Unit, North Bristol National Health Service (NHS) Trust, Southmead Hospital, Bristol, UK; Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Amelia O
authors.initials: AO
authors.lastname: Clive
authors.affiliation: Research Design Service South West, Bristol, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Taylor
authors.affiliation: South Devon Healthcare NHS Foundation Trust, Torbay, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Dobson
authors.affiliation: University Hospitals Bristol NHS Trust, Bristol, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Wilson
authors.affiliation: Royal United Hospital, Bath, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: de Winton
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Niki
authors.initials: N
authors.lastname: Panakis
authors.affiliation: Musgrove Park Hospital, Taunton, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Pepperell
authors.affiliation: Plymouth Hospitals NHS Trust, Plymouth, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Howell
authors.affiliation: Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Stewart
authors.affiliation: Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: Erika
authors.initials: E
authors.lastname: Penz
authors.affiliation: Respiratory Research Unit, North Bristol National Health Service (NHS) Trust, Southmead Hospital, Bristol, UK.
authors.forename: Nikki
authors.initials: N
authors.lastname: Jordan
authors.affiliation: Respiratory Research Unit, North Bristol National Health Service (NHS) Trust, Southmead Hospital, Bristol, UK.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Morley
authors.affiliation: Respiratory Research Unit, North Bristol National Health Service (NHS) Trust, Southmead Hospital, Bristol, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Zahan-Evans
authors.affiliation: Respiratory Research Unit, North Bristol National Health Service (NHS) Trust, Southmead Hospital, Bristol, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Smith
authors.affiliation: University Hospitals Bristol NHS Trust, Bristol, UK.
authors.forename: Timothy J P
authors.initials: TJP
authors.lastname: Batchelor
authors.affiliation: Plymouth Hospitals NHS Trust, Plymouth, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Marchbank
authors.affiliation: Portsmouth Hospitals NHS Trust, Portsmouth, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Bishop
authors.affiliation: Royal Gwent Hospital, Aneurin Bevan University Health Board, Newport, UK.
authors.forename: Alina A
authors.initials: AA
authors.lastname: Ionescu
authors.affiliation: Poole Hospital NHS Foundation Trust, Poole, UK; Dorset County Hospital NHS Foundation Trust, Dorchester, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Bayne
authors.affiliation: Colchester Hospital University NHS Foundation Trust, Colchester, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Cooper
authors.affiliation: Great Western Hospitals NHS Trust, Swindon, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kerry
authors.affiliation: Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Jenkins
authors.affiliation: Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Toy
authors.affiliation: Singleton Hospital, Swansea, UK; Withybush Hospital, Haverfordwest, UK.
authors.forename: Vallipuram
authors.initials: V
authors.lastname: Vigneswaran
authors.affiliation: Royal Berkshire NHS Foundation Trust, Reading, UK.
authors.forename: James
authors.initials: J
authors.lastname: Gildersleve
authors.affiliation: The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Merina
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: McDonald
authors.affiliation: Nevill Hall Hospital, Abergavenny, UK.
authors.forename: Mick
authors.initials: M
authors.lastname: Button
authors.affiliation: Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Conrad
authors.initials: C
authors.lastname: Lewanski
authors.affiliation: University Hospitals Bristol NHS Trust, Bristol, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Comins
authors.affiliation: Colchester Hospital University NHS Foundation Trust, Colchester, UK.
authors.forename: Muthukumar
authors.initials: M
authors.lastname: Dakshinamoorthy
authors.affiliation: Centre for Respiratory Health, School of Medicine & Pharmacology, University of Western Australia, Perth, WA, Australia.
authors.forename: Y C Gary
authors.initials: YCG
authors.lastname: Lee
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK; Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Oxford, UK.
authors.forename: Najib M
authors.initials: NM
authors.lastname: Rahman
authors.affiliation: Respiratory Research Unit, North Bristol National Health Service (NHS) Trust, Southmead Hospital, Bristol, UK; Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, UK. Electronic address: Nick.maskell@bristol.ac.uk.
authors.forename: Nick A
authors.initials: NA
authors.lastname: Maskell
mesh_terms: D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000532:radiotherapy / Q000556:secondary / Q000601:surgery*; D008297:Male; D008654:Mesothelioma / Q000532:radiotherapy / Q000556:secondary / Q000601:surgery*; D000086002:Mesothelioma, Malignant; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000517:prevention & control* / Q000532:radiotherapy; D010146:Pain / Q000517:prevention & control; D010997:Pleural Neoplasms / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery*; D011183:Postoperative Complications / Q000532:radiotherapy*; D011379:Prognosis; D011788:Quality of Life; D018714:Radiotherapy, Adjuvant; D012107:Research Design; D015996:Survival Rate