Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial

Our plain-English summary of Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial, by B.C.J. Cho, L. Donahoe, P.A. Bradbury, et al (The Lancet. Oncology, 2021).

The study

• Authors: B.C.J. Cho, L. Donahoe, P.A. Bradbury, N. Leighl, S. Keshavjee, A. Hope, P. Pal, M. Cabanero, K. Czarnecka, K. McRae, M.S. Tsao, M. de Perrot
• Journal: The Lancet. Oncology
• Published: 2021;22(2):190-197
• Cited by: 54 articles, as counted by NIH iCite
• Read it: 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.

In plain English

This single-centre phase 2 trial tested SMART, a treatment for malignant pleural mesothelioma. Patients had one week of radiotherapy to one side of the chest (25 Gy in five daily doses plus 5 Gy to high-risk areas), then extrapleural pneumonectomy surgery, planned within one week. Of 532 patients assessed, 96 were treated and analysed in the study; 27 ineligible patients had SMART outside it. Within 30 days of surgery, 47 (49%) had grade 3 or 4 complications, significantly above a preset 35% threshold. One patient (1%) died of pneumonia. Median overall survival was 24.4 months (95% CI 18.5 to 31.1). Estimated five-year cumulative incidence of recurrence outside the treated side of the chest was 63.3% (95% CI 52.3 to 74.4). Recurrences most often first appeared in the opposite chest or peritoneal cavity. In an after-the-fact analysis by tissue type at surgery, median survival was 42.8 months (95% CI 23.9 to 65.9) for epithelial and 18.0 months (12.0 to 28.2) for biphasic tumours. The authors concluded SMART requires surgical and radiation expertise and should not be adopted outside expert centres.

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: Single-centre, phase 2 clinical feasibility trial (prospective), analysed on an intention-to-treat basis
• Who was studied: Adults with previously untreated, resectable malignant pleural mesothelioma (stage cT1–3N0M0) at Princess Margaret Cancer Centre, Toronto. Between Nov 1, 2008, and Oct 31, 2019, 532 patients were assessed and 102 were eligible and consented. 96 were treated on study and included in the analysis. Median age was 67; 76 (79%) were male.
• Exposure: The study examined a treatment, not asbestos exposure. Patients received intensity modulated radiotherapy of 25 Gy in five daily fractions over 1 week to the whole affected side of the chest, with a 5 Gy boost to high-risk areas. Extrapleural pneumonectomy was planned within 1 week of completing radiotherapy; the authors state that all patients had to proceed to surgery to avoid potential radiation-induced pulmonary toxicity. Adjuvant chemotherapy was offered to patients with mediastinal lymph node involvement.
• Main results:
  • Within 30 days of surgery, 47 (49%) of 96 patients had grade 3 (33 patients) or grade 4 (14 patients) complications. This significantly exceeded the prespecified 35% threshold (p=0.0018).
  • One (1%) patient died of pneumonia within 30 days of surgery. This did not exceed the prespecified 8% threshold (p=0.997).
  • Median overall survival for the 96 patients was 24.4 months (95% CI 18.5–31.1).
  • Median disease-free survival was 18.0 months (95% CI 12.6–21.7).
  • After a median follow-up of 46.8 months, the estimated 5-year cumulative incidence of local recurrence was 17 patients (20.1% [95% CI 11.4–28.8]). The estimated 5-year cumulative incidence of distant recurrence was 62 patients (63.3% [52.3–74.4]).
  • Among the 72 patients with a recurrence, the most common first sites were the contralateral chest (33 [46%] of 72) and the peritoneal cavity (32 [44%]).
  • In a post-hoc analysis by postoperative histology, median overall survival was 42.8 months (95% CI 23.9–65.9) for epithelial malignant pleural mesothelioma. For biphasic malignant pleural mesothelioma it was 18.0 months (12.0–28.2) (p=0.0007).
  • A further 27 patients who were ineligible for the study were treated on the SMART protocol outside the study; their overall survival was similar to that of the 96 patients in the study.
  • In an exploratory analysis, epithelial histology, ypN0 nodal status and absence of grade 4 complications correlated with significantly better overall survival.
  • 60 (62%) of the 96 patients had pathologically involved lymph nodes on postoperative histology.
• The authors' conclusion: The authors concluded that SMART achieved the best overall survival results of a large prospective surgical trial for malignant pleural mesothelioma. They also concluded that it requires surgical and radiation expertise and should not be adopted outside expert centres with substantial surgical experience.
• Limitations the authors state:
  • Quality-of-life data were not consistently collected.
  • Strict inclusion criteria meant the trial was subject to selection bias.
  • Patients were not routinely tested for germline BAP1 mutations. Their possible presence in the study might be a confounder.
  • The protocol is technically demanding and hard to learn, which affects whether it can be transferred to other surgeons and centres.
  • The analysis of grade 4 toxicity should have been done as a landmark analysis 30 days after surgery rather than from randomisation.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Extrapleural Pneumonectomy (EPP), Performance Status, Hemithorax, Chemotherapy, Pathology, Peritoneal Cavity.

Related studies

• A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" approach for resectable malignant pleural mesothelioma — B.C. Cho, R. Feld, et al. (2014)
• Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial — N.L. de Boer, J.P. van Kooten, et al. (2019)
• Mesothelioma at era of helical tomotherapy: results of two institutions in combining chemotherapy, surgery and radiotherapy — A. Sylvestre, M.A. Mahé, et al. (2011)
• 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, et al. (2016)
• Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma — M. de Perrot, R. Feld, et al. (2016)
• Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16) — Y. Metaxas, M. Früh, et al. (2020)

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