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

Our plain-English summary of 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, by A.O. Clive, H. Taylor, L. Dobson, et al (The Lancet. Oncology, 2016).

The study

• Authors: A.O. Clive, H. Taylor, L. Dobson, P. Wilson, E. de Winton, N. Panakis, J. Pepperell, T. Howell, S.A. Stewart, E. Penz, N. Jordan, A.J. Morley, N. Zahan-Evans, S. Smith, T.J.P. Batchelor, A. Marchbank, L. Bishop, A.A. Ionescu, M. Bayne, S. Cooper, A. Kerry, P. Jenkins, E. Toy, V. Vigneswaran, J. Gildersleve, M. Ahmed, F. McDonald, M. Button, C. Lewanski, C. Comins, M. Dakshinamoorthy, Y.C.G. Lee, N.M. Rahman, N.A. Maskell
• Journal: The Lancet. Oncology
• Published: 2016;17(8):1094-1104
• Type of article: Randomized trial
• Cited by: 101 articles, as counted by NIH iCite
• Read it: 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.

In plain English

This randomised trial in 22 UK hospitals compared two radiotherapy approaches for people with malignant pleural mesothelioma who had recently had a large-bore chest procedure, such as surgery or thoracoscopy. Between December 2011 and August 2014, 203 patients were randomly assigned either to immediate radiotherapy to the procedure site (21 Gy in three sessions, 102 patients) or to radiotherapy only if a tumour nodule later grew along the procedure tract (101 patients). The study did not examine asbestos exposure. Within 12 months, tract tumours developed in 9 of 102 patients (8.8%) assigned to immediate radiotherapy and 16 of 101 (15.8%) assigned to deferred radiotherapy. This difference was not statistically significant (odds ratio 0.51, 95% CI 0.19 to 1.32). A secondary analysis that left out patients with major protocol deviations found a statistically significant difference (5 of 84 vs 16 of 99). No differences were found in chest pain, quality of life, painkiller use or survival. Radiotherapy was generally well tolerated. The authors concluded that their data do not support routine prophylactic radiotherapy after large-bore pleural procedures for all patients with mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicentre, open-label, phase 3 randomised controlled trial (SMART trial) comparing immediate (prophylactic) with deferred radiotherapy
• Who was studied: 457 patients assessed and 203 randomised (102 immediate, 101 deferred radiotherapy) between Dec 23, 2011, and Aug 4, 2014, at 22 UK hospitals. All had histocytologically proven malignant pleural mesothelioma and had had a large-bore pleural intervention in the previous 35 days.
• Exposure: Not an asbestos exposure study. The intervention was immediate prophylactic radiotherapy (21 Gy in three fractions, started within 42 days of the procedure) to the procedure site. It was compared with the same dose given only if a procedure-tract metastasis developed. 99 of the 102 patients assigned to immediate radiotherapy received it.
• Main results:
  • Primary intention-to-treat analysis: procedure-tract metastases within 12 months in 9 of 102 (8.8%) assigned to the immediate group vs 16 of 101 (15.8%) assigned to the deferred group. The difference was not statistically significant: odds ratio 0.51 (95% CI 0.19 to 1.32), p=0.14.
  • Secondary per-protocol analysis, excluding patients with major protocol violations: procedure-tract metastases in 5 of 84 (6%) immediate vs 16 of 99 (16%) deferred. Odds ratio 0.33 (95% CI 0.09 to 1.00), p=0.037; reported as significantly lower in the immediate group.
  • Painful metastases: 2 of 9 (22%) tract metastases in the immediate group vs 6 of 16 (38%) in the deferred group. Odds ratio 0.48 (95% CI 0.04 to 3.94), p=0.66.
  • Median overall survival from randomisation was 357 days in the immediate group vs 365 days in the deferred group (hazard ratio 1.00, 95% CI 0.68 to 1.46, p=0.98, per Figure 3).
  • No difference between groups was reported in chest pain or analgesia use during follow-up.
  • Immediate radiotherapy was generally well tolerated, with no treatment-related deaths or withdrawals. Among 92 immediate-group patients assessed, skin toxicity within 3 months was grade 1 in 50 (54%) and grade 2 in four (4%).
  • In a predefined subgroup of patients who did not receive chemotherapy after trial entry, the immediate group had a lower rate of tract metastases: 2 of 46 (4%) vs 8 of 37 (22%), odds ratio 0.16, 95% CI 0.02 to 0.93, p=0.021, per Table 3.
• The authors' conclusion: The authors concluded that their data do not support routine prophylactic radiotherapy after large-bore pleural interventions for all patients with mesothelioma, provided patients receive regular clinical follow-up. They added that more randomised trial data are needed for the subgroups that showed some suggestion of benefit.
• Limitations the authors state:
  • Participants and outcome assessors were not blinded.
  • A high screening failure rate.
  • The number of protocol deviations, specifically in delivering immediate radiotherapy.
  • A larger or differently configured radiotherapy field might have been more effective.
  • Few patients had large surgical procedures such as thoracotomies, so no specific recommendation can be made for that group.
  • The subgroup findings rest on small numbers.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Histological Subtype, Indwelling Pleural Catheter, Odds Ratio.

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