Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma

Abstract

Background: Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to unimodal approaches. Multimodal treatment has provided encouraging results.

Methods: Phase II, open-label study of the combination of chemotherapy (pemetrexed 500 mg/m²+cisplatin 75 mg/m² IV every 21 days × 3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3-8 weeks after chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4-8 weeks post-surgery). The primary endpoint was event-free survival, defined as the time from enrollment to time of first observation of disease progression, death due to any cause, or early treatment discontinuation.

Results: Fifty-four treatment-naïve patients with T1-3 N0-2 malignant pleural mesothelioma were enrolled, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median overall survival was 15.5 months (95%CI 11.0-NA) while median time-to-tumor response was 4.8 months (95%CI: 2.5-8.0). Eighteen (33.3%) and 13 (24.1%) patients were still event-free after 1 and 2 years, respectively. The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%).Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were already enrolled in the study): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate selection of patients was recommended.

Conclusions: The combination of pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients. It may be worthy of further investigation.

Trial registration: Clinicaltrial.com registrationID #NCT00087698.

Figures

Figure 1

Study design and patients disposition adopted in this study. Study design highlights the trimodality therapy adopted: patients disposition is provided for patients enrolled before the protocol amendment (PA) as well as for those enrolled after PA and overall. Trimodality therapy was considered completed for those patients who received ≥28 doses of radiotherapy (RT) while the study was considered completed for those subjects completing RT and the 90-day post-radiation follow-up. pts = patients; MPM = malignant pleural mesothelioma; HTR = hemithoracic radiation; EPP = extrapleural pneumonectomy; BA = before amendment; AA = post amendment.

Figure 2

Efficacy variables of this study. Kaplan-Meier plots for efficacy variables analyzed for this study are presented: Median EFS (panel A), Median PFS (panel B), Median OS (panel C) and median TTR (panel D). Results are expressed in months. EFS= event-free survival; PFS= progression-free survival; OS= overall survival; TTR= time to tumor response.