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

Summary

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/m² and pemetrexed 500 mg/m² 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.

Introduction

Malignant pleural mesothelioma is a rare form of thoracic cancer associated with asbestos exposure. Because of the long latency period, its peak incidence in Europe has been estimated to occur around 2020, given the ban on asbestos use in the late 1980s.¹ Cisplatin-based combination chemotherapy has become the standard of care, primarily since a study² showed better survival and symptom control with cisplatin combined with pemetrexed compared with cisplatin alone.

Malignant pleural mesothelioma is usually localised to one hemithorax and regional lymph nodes, with local extension into the peritoneal cavity or the contralateral pleural space occasionally occurring late in the course of disease and only seldom haematogenic metastases. Thus, surgery and radiotherapy to treat local disease are being investigated, in addition to systemic chemotherapy.

Research in context

Evidence before this study

The development of this study was based on the one hand on our study of neoadjuvant chemotherapy and extrapleural pneumonectomy with a favourable outcome (median overall survival of 23 months) and the SAKK 17/04 study showing the feasibility of neoadjuvant chemotherapy and extrapleural pneumonectomy in malignant pleural mesothelioma, and on the other hand on the report from Memorial Sloan Kettering Cancer Center on the reduction of local relapses by hemithoracic radiation of patients with mesothelioma after extrapleural pneumonectomy. We did a systemic search of PubMed for the terms “extrapleural pneumonectomy” and “hemithoracic radiotherapy” to obtain data for elaboration of the study design.

Added value of this study

Our study shows that hemithoracic radiotherapy after macroscopically complete resection by extrapleural pneumonectomy results in an additional treatment burden without benefiting patients.

Implication of all available evidence

Taken together with recent developments in lung-sparing surgery with extended pleurectomy and decortication, these are sobering results suggesting that our concepts for the treatment of malignant pleural mesothelioma developed over the past two decades need to be revised and alternative treatment options need to be considered.

Extrapleural pneumonectomy is a radical form of surgery in which the ipsilateral pleura, pericardium, and hemidiaphragm are resected. It has been investigated in conjunction with chemotherapy in single centre and multicentre studies. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy has been tested in a single centre study and the results supported in a prospective multicentre trial.3, 4 Prospective studies of neoadjuvant chemotherapy, extrapleural pneumonectomy, and—in some patients—various forms of postoperative radiotherapy, showed a median overall survival of 15·5–19·8 months.4, 5, 6, 7 Although a cure remains elusive, the results from these non-randomised studies suggested a better overall survival with a combination of chemotherapy and extrapleural pneumonectomy compared with chemotherapy alone. The randomised MARS trial comparing chemotherapy alone with chemotherapy followed by extrapleural pneumonectomy with or without radiotherapy attempted to clarify the role of extrapleural pneumonectomy. However, after a pilot study of 50 randomly assigned patients, it became evident that doing a definitive study to answer this question was not feasible, mainly because of the high mortality associated with extrapleural pneumonectomy. The authors concluded that although limited, their data suggested that radical surgery in the form of extrapleural pneumonectomy offered no benefit and possible harm, an interpretation which gave rise to controversies.8, 9

Better locoregional control of malignant pleural mesothelioma might offer patients a significant benefit. After a phase 2 trial¹⁰ showed the tolerability of extrapleural pneumonectomy followed by high-dose hemithoracic radiotherapy and suggested better local control, we designed the trial SAKK 17/04, a two part multicentre randomised phase 2 trial assessing the effect of high-dose hemithoracic radiotherapy after neoadjuvant chemotherapy and extrapleural pneumonectomy in patients with stage I–III malignant pleural mesothelioma.