Pemetrexed Disodium and Cisplatin Followed by Surgery With or Without Radiation Therapy in Treating Patients With Malignant Pleural Mesothelioma

Pemetrexed Disodium and Cisplatin Followed by Surgery With or Without Radiation Therapy in Treating Patients With Malignant Pleural Mesothelioma

Neoadjuvant Chemotherapy and Extrapleural Pneumonectomy of Malignant Pleural Mesothelioma (MPM) With or Without Hemithoracic Radiotherapy. A Randomized Multicenter Phase II Trial

RATIONALE: Drugs used in chemotherapy, such as pemetrexed disodium and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This randomized phase II trial is studying how well giving pemetrexed disodium together with cisplatin followed by surgery with or without radiation therapy works in treating patients with malignant pleural mesothelioma.

OBJECTIVES: Primary Evaluate the short-term outcomes and feasibility of neoadjuvant therapy with pemetrexed disodium and cisplatin followed by extrapleural pneumonectomy in patients with malignant pleural mesothelioma. Evaluate the long-term outcomes and feasibility of postoperative hemithoracic radiotherapy in patients with R0 or R1 resection. Secondary Determine the quality of life of these patients. Identify predictive and prognostic markers in these patients. Determine relapse-free or progression-free survival and overall survival of these patients. Collect tissue and blood from these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, histology (sarcomatous or other vs epithelial or mixed histology), nodal status (N0-1 vs N2), and extent of disease (T1-2 vs T3). Part 1 (neoadjuvant therapy and surgery): Patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Within 8 weeks after completion of neoadjuvant therapy, patients without progressive disease undergo extrapleural pneumonectomy. Part 2 : Patients achieving R0 or R1 resection proceed to part 2 of study treatment and are randomized to 1 of 2 treatment arms. Patients with R2 resection, disease progression, or symptomatic deterioration after treatment in part 1 are taken off study. Arm I (no postoperative radiotherapy): Patients do not undergo radiotherapy. Quality of life is assessed at baseline and at 6, 10, 16, and 22 weeks after randomization. Arm II (postoperative radiotherapy): Beginning within 10 weeks after surgery, patients undergo radiotherapy to the hemithoracic region 5 days a week for approximately 5 weeks in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline and at 4, 8, 14, and 20 weeks after initiation of radiotherapy. Patients undergo blood and tissue collection at registration and surgery for laboratory and biomarker analysis. After completion of study treatment, patients are followed periodically for up to 5 years after surgery. PROJECTED ACCRUAL: A total of 155 patients will be accrued for this study.

epithelial mesothelioma, sarcomatous mesothelioma, stage IA malignant mesothelioma, stage IB malignant mesothelioma, stage II malignant mesothelioma, stage III malignant mesothelioma

Proportion of patients remaining operable after completing chemotherapy (9 weeks after trial registration)

Reasons for non-randomization include macroscopic incomplete resection, patients' refusal or patient can not be subjected to RT within 10 weeks after surgery.

From registration until death for all registered patients, and from randomization to death for all randomized patients.

DISEASE CHARACTERISTICS: Histologically or cytologically confirmed malignant pleural mesothelioma T1-3, N0-2, M0 disease according to International Mesothelioma Interest Group staging system No obvious invasion of mediastinal structures by CT scan (e.g., heart, aorta, spine, esophagus) No obvious widespread chest wall invasion Resectable chest wall lesions allowed PATIENT CHARACTERISTICS: WHO performance score 0-1 Fit for neoadjuvant therapy, surgery, and postoperative radiotherapy Creatinine clearance > 60 mL/min Hemoglobin ≥ 10.0 g/dL WBC ≥ 3,500/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 1.5 times ULN Alkaline phosphatase ≤ 1.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for up to 12 months after completion of study treatment FEV_1 ≥ 40% of predicted based on spirometry and lung perfusion scan, if necessary No serious underlying medical condition that would preclude study requirements (e.g., active autoimmune disease or uncontrolled diabetes) No known hypersensitivity against pemetrexed disodium, cisplatin, or other platinum-containing substances or any other components used for the preparation of the drugs No restricted power of hearing (especially in the upper frequency range) No acute infections PRIOR CONCURRENT THERAPY: No prior chemotherapy No treatment on another clinical trial within the past 30 days No prior pleurectomy or lung resection No prior radiotherapy of the lower neck, thorax, or upper abdomen No aspirin, cyclooxygenase-2 inhibitors, or nonsteroidal anti-inflammatory agents for 5 days prior to, during, and for 2 days after pemetrexed disodium administration No other concurrent experimental drugs or anticancer therapy No concurrent drugs that would contraindicate study drugs No concurrent vaccination against yellow fever

Stahel RA, Riesterer O, Xyrafas A, Opitz I, Beyeler M, Ochsenbein A, Fruh M, Cathomas R, Nackaerts K, Peters S, Mamot C, Zippelius A, Mordasini C, Caspar CB, Eckhardt K, Schmid RA, Aebersold DM, Gautschi O, Nagel W, Topfer M, Krayenbuehl J, Ribi K, Ciernik IF, Weder W. 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 Dec;16(16):1651-8. doi: 10.1016/S1470-2045(15)00208-9. Epub 2015 Nov 2.