Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial

Abstract

Background: Malignant pleural mesothelioma is almost always fatal, and few treatment options are available. Although active symptom control (ASC) has been recommended for the management of this disease, no consensus exists for the role of chemotherapy. We investigated whether the addition of chemotherapy to ASC improved survival and quality of life.

Methods: 409 patients with malignant pleural mesothelioma, from 76 centres in the UK and two in Australia, were randomly assigned to ASC alone (treatment could include steroids, analgesic drugs, bronchodilators, palliative radiotherapy [n=136]); to ASC plus MVP (four cycles of mitomycin 6 mg/m2, vinblastine 6 mg/m2, and cisplatin 50 mg/m2 every 3 weeks [n=137]); or to ASC plus vinorelbine (one injection of vinorelbine 30 mg/m2 every week for 12 weeks [n=136]). Randomisation was done by minimisation, with stratification for WHO performance status, histology, and centre. Follow-up was every 3 weeks to 21 weeks after randomisation, and every 8 weeks thereafter. Because of slow accrual, the two chemotherapy groups were combined and compared with ASC alone for the primary outcome of overall survival. Analysis was by intention to treat. This study is registered, number ISRCTN54469112.

Findings: At the time of analysis, 393 (96%) patients had died (ASC 132 [97%], ASC plus MVP 132 [96%], ASC plus vinorelbine 129 [95%]). Compared with ASC alone, we noted a small, non-significant survival benefit for ASC plus chemotherapy (hazard ratio [HR] 0.89 [95% CI 0.72-1.10]; p=0.29). Median survival was 7.6 months in the ASC alone group and 8.5 months in the ASC plus chemotherapy group. Exploratory analyses suggested a survival advantage for ASC plus vinorelbine compared with ASC alone (HR 0.80 [0.63-1.02]; p=0.08), with a median survival of 9.5 months. There was no evidence of a survival benefit with ASC plus MVP (HR 0.99 [0.78-1.27]; p=0.95). We observed no between-group differences in four predefined quality-of-life subscales (physical functioning, pain, dyspnoea, and global health status) at any of the assessments in the first 6 months.

Interpretation: The addition of chemotherapy to ASC offers no significant benefits in terms of overall survival or quality of life. However, exploratory analyses suggested that vinorelbine merits further investigation.

Figure 1

Trial profile After 3 years accrual, the trial design was changed to a two-group comparison by combining the two chemotherapy groups. The three-way randomisation was retained to allow some exploratory analyses of the two different chemotherapy groups. ASC=active symptom control. MVP=mitomycin, vinblastine, and cisplatin. V=vinorelbine.

Figure 2

Clinicians assessment of symptoms and side-effects (A) Proportion of patients with moderate or severe chest pain. (B) Proportion of patients with moderate or severe lethargy. Error bars indicate 95% CIs. ASC=active symptom control. MVP=mitomycin, vinblastine, and cisplatin. V=vinorelbine.

Figure 3

Mean standardised scores for the four predefined quality-of-life endpoints (A) Physical functioning; (B) pain; (C) dyspnoea; and (D) global quality of life. Error bars indicate 95% CIs. ASC=active symptom control. MVP=mitomycin, vinblastine, and cisplatin. V=vinorelbine.

Figure 4

Overall survival (A) Two-group comparison: ASC vs ASC plus chemotherapy. (B) Three-group comparison: ASC vs ASC plus MVP vs ASC plus vinorelbine. ASC=active symptom control. MVP=mitomycin, vinblastine, and cisplatin. V=vinorelbine. CT=chemotherapy.

Figure 5

Progression-free survival ASC=active symptom control. MVP=mitomycin, vinblastine, and cisplatin. V=vinorelbine.