Radiotherapy to intervention sites in mesothelioma: no more?
Authors: Giovanni Luca Ceresoli, Vittorio Vavassori
Journal: The Lancet Oncology (2016)

Malignant pleural mesothelioma is a tumour with a dismal prognosis, and its incidence is increasing worldwide as a result of widespread exposure to asbestos. Because of the pattern of tumour growth, the ipsilateral chest wall is often involved. Moreover, histological diagnosis is usually obtained by pleural biopsy, via video-assisted thoracoscopic surgery or other invasive procedures, which can result in tumour seeding at the site of the intervention. Chest wall involvement, including procedure-tract metastases, can lead to severe symptoms, mostly pain. Accordingly, local control in malignant pleural mesothelioma is a major challenge. Radiotherapy has been widely used in the past decades in the treatment of patients with malignant pleural mesothelioma, as a part of a multimodality therapy for early-stage disease,1Stahel RA Riesterer O Xyrafas A et al.Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.Lancet Oncol. 2015; 16: 1651-1658Summary Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 2Rosenzweig KE Zauderer MG Laser B et al.Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma.Int J Radiat Oncol Biol Phys. 2012; 83: 1278-1283Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar in the palliation of pain,3Macleod N Chalmers A O'Rourke N et al.Is radiotherapy useful for treating pain in mesothelioma?: A phase II trial.J Thorac Oncol. 2015; 10: 944-950Summary Full Text Full Text PDF PubMed Scopus (53) Google Scholar and in the prophylaxis of track-site recurrence. Three small randomised trials4Boutin C Rey F Viallat JR Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy.Chest. 1995; 108: 754-758Summary Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 5Bydder S Phillips M Joseph DJ et al.A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma.Br J Cancer. 2004; 91: 9-10Crossref PubMed Scopus (143) Google Scholar, 6O'Rourke N Garcia JC Paul J et al.A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma.Radiother Oncol. 2007; 84: 18-22Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar assessed the role of prophylactic external-beam radiotherapy in reducing the frequency of thoracic procedure-tract metastases, and the results were conflicting. In a French trial done in 1995,4Boutin C Rey F Viallat JR Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy.Chest. 1995; 108: 754-758Summary Full Text Full Text PDF PubMed Scopus (427) Google Scholar a significant reduction in tract malignant seeding with radiotherapy compared with no radiotherapy was reported, whereas two more recent studies from Australia5Bydder S Phillips M Joseph DJ et al.A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma.Br J Cancer. 2004; 91: 9-10Crossref PubMed Scopus (143) Google Scholar and the UK6O'Rourke N Garcia JC Paul J et al.A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma.Radiother Oncol. 2007; 84: 18-22Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar found no benefit from the use of radiotherapy. When the data were pooled, there was insufficient evidence to definitively recommend prophylactic radiotherapy on thoracic diagnostic tracts.7Price A What is the role of radiotherapy in malignant pleural mesothelioma?.Oncologist. 2011; 16: 359-365Crossref PubMed Scopus (29) Google Scholar Limitations of these early trials include the heterogeneity of radiotherapy schedules and portal size—in the Australian study,5Bydder S Phillips M Joseph DJ et al.A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma.Br J Cancer. 2004; 91: 9-10Crossref PubMed Scopus (143) Google Scholar a single fraction of 10 Gy was delivered, whereas in the French and the UK studies4Boutin C Rey F Viallat JR Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy.Chest. 1995; 108: 754-758Summary Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 6O'Rourke N Garcia JC Paul J et al.A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma.Radiother Oncol. 2007; 84: 18-22Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar patients were given a total dose of 21 Gy in three daily fractions. Of note, the incidence of procedure-tract metastases in the control group differed between the French study and the other two trials (20% vs 10–12%), suggesting a bias in patient selection or that different methods were used for nodule assessment, or both. All three studies were done in an era when active chemotherapy with platinum–pemetrexed combinations was not available. However, despite the lack of any convincing evidence that prophylactic radiotherapy to intervention sites reduces subcutaneous nodule formation or improves quality of life, and the fact that it is not recommended by international guidelines,8Baas P Fennell D Kerr KM et al.Malignant pleural mesothelioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2015; 26: v31-v39Crossref PubMed Scopus (246) Google Scholar this procedure has been extensively used in clinical practice. The SMART trial investigators must be commended for having done an adequately powered open-label, randomised trial, as Amelia Clive and colleagues report in The Lancet Oncology.9Clive AO Taylor H Dobson L et al.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.Lancet Oncol. 2016; (published online June 23.)http://dx.doi.org/10.1016/S1470-2045(16)30095-XGoogle Scholar This phase 3 trial assessed, as primary endpoint, whether prophylactic radiotherapy (given at a dose of 21 Gy in three fractions over 3 working days, initiated within 42 days of the procedure after which the patient had been randomised) reduces the incidence of procedure-tract metastases in patients with malignant pleural mesothelioma, observed until 12 months or death. Patients randomised to the observation group could receive deferred radiotherapy at the same dose if a procedure-tract nodule was diagnosed during trial follow-up. Two independent observers examined the chest wall at any time point during the study. Of note, several secondary outcomes were analysed, including chest pain control, quality of life, and cost-effectiveness. The trial eligibility criteria were strict, as shown by the high screen failure rate (254 [56%] of the 457 screened patients were not randomised). Intention-to-treat analysis showed no significant difference in the frequency of procedure-tract metastases between the groups receiving immediate and deferred radiotherapy (nine [9%] of 102 vs 16 [16%] of 101, odds ratio 0·51 [95% CI 0·19–1·32]; p=0·14). Even more importantly, no difference was identified in quality of life, chest pain, and requirements of analgesic drugs between the two groups, suggesting that the use of prophylactic radiotherapy has no effect on symptom control or on patients' perception of the natural history and progression of the disease. More than half of the enrolled patients received first-line pemetrexed–platinum chemotherapy during the study. Although patients were not stratified according to the addition of systemic treatment, its use was balanced between the two groups. Of note, patients who were not receiving chemotherapy had a significant reduction of procedure-tract metastasis risk by immediate radiotherapy (odds ratio 0·16 [95% CI 0·02–0·93]; p=0·021). These data seem to suggest a benefit of chemotherapy on loco-regional disease control in malignant pleural mesothelioma. Although the data were derived from a subgroup analysis and should be confirmed by further studies, they are potentially relevant for clinical practice. In conclusion, results from the SMART trial provide convincing evidence that the routine use of prophylactic radiotherapy to thoracic intervention sites is not justified in all patients with malignant pleural mesothelioma, although a benefit is suggested in patients who are not receiving chemotherapy. Together with the upcoming, similarly designed PIT trial,10Bayman N Ardron D Ashcroft L et al.Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention.BMJ Open. 2016; 6: e010589Crossref Scopus (22) Google Scholar this study will establish the standard of practice in this setting. We declare no competing interests. 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 trialRoutine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. Full-Text PDF Open Access