Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial.

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.

• Authors: Rolf A Stahel, Oliver Riesterer, Alexandros Xyrafas, Isabelle Opitz, Michael Beyeler, Adrian Ochsenbein, Martin Früh, Richard Cathomas, Kristiaan Nackaerts, Solange Peters, Christoph Mamot, Alfred Zippelius, Carlo Mordasini, Clemens B Caspar, Katrin Eckhardt, Ralph A Schmid, Daniel M Aebersold, Oliver Gautschi, Wolfgang Nagel, Michael Töpfer, Jerome Krayenbuehl, Karin Ribi, Ilja Ciernik, Walter Weder
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 16 Issue 16 Pg. 1651-8 (12 2015) ISSN: 1474-5488 [Electronic] England
• PMID: 26538423 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Pemetrexed
• Cisplatin

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Chemotherapy, Adjuvant
• Cisplatin (therapeutic use)
• Disease Progression
• Disease-Free Survival
• Europe
• Female
• Humans
• Intention to Treat Analysis
• Kaplan-Meier Estimate
• Lung Neoplasms (mortality, pathology, therapy)
• Lymphatic Metastasis
• Male
• Mesothelioma (mortality, pathology, therapy)
• Mesothelioma, Malignant
• Middle Aged
• Neoadjuvant Therapy (adverse effects, mortality)
• Neoplasm Recurrence, Local
• Neoplasm Staging
• Pemetrexed (therapeutic use)
• Pleural Neoplasms (mortality, pathology, therapy)
• Pneumonectomy (adverse effects, mortality)
• Proportional Hazards Models
• Radiotherapy Dosage
• Radiotherapy, Adjuvant
• Risk Factors
• Time Factors
• Treatment Outcome