title: A Randomized Phase II Study Adding Axitinib to Pemetrexed-Cisplatin in Patients with Malignant Pleural Mesothelioma: A Single-Center Trial Combining Clinical and Translational Outcomes.
abstract: Mesothelioma often presents with a high vessel count and increased vascular growth factors levels. Interference with angiogenesis may therefore improve outcome. This study reports on clinical and translational parameters in patients treated with the small molecule tyrosine kinase inhibitor axitinib and chemotherapy.
  
  
  
  Chemonaive patients with mesothelioma were eligible. Patients received pemetrexed (500 mg/m(2) every 3 weeks) and cisplatin (75 mg/m(2) every 3 weeks) and were randomized to receive axitinib daily (two 5-mg tablets on days 2-19) or observation. Before treatment and after three cycles of chemotherapy, a thoracoscopy was performed to evaluate vascular changes.
  
  
  
  Twenty-five patients were randomized after a successful lead-in with six patients who received axitinib. Median follow-up was 45 months. In all but one patient, it was feasible to perform a second thoracoscopy. However, there was more grade 3 or 4 neutropenia leading to pneumonia in the axitinib group. The rates of partial response and stable disease in the axitinib arm were 36% and 43% compared with 18% and 73% in the chemotherapy-only arm. Median progression-free survival and overall survival (5.8 and 18.9 months versus 8.3 and 18.5 months) were not different between the two groups. Axitinib reduced vessel number and vessel immaturation. Yet, the mRNA levels of a number of vascular growth factors, their receptors, serum VEGF levels, and activation of tissue vascular endothelial growth factor receptor 2 were increased. Gene expression of platelet-derived growth factor receptor beta, fms-related tyrosine kinase 1, and fms-related tyrosine kinase 4 even correlated with outcome.
  
  
  
  Axitinib was well tolerated in combination with cisplatin and pemetrexed. Despite the lack of a clinical benefit, axitinib reduced angiogenesis. Whether changes in differentially expressed growth factors in tissue and serum may serve as a biomarker needs further investigation.
authors: Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: w.buikhuisen@nkl.nl.
authors: Wieneke A
authors: WA
authors: Buikhuisen
authors: Department of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Marion
authors: M
authors: Scharpfenecker
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Arjan W
authors: AW
authors: Griffioen
authors: Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Catharina M
authors: CM
authors: Korse
authors: Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Harm
authors: H
authors: van Tinteren
authors: Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pulmonary Disease, Academic Medical Center, Amsterdam, The Netherlands.
authors: Paul
authors: P
authors: Baas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077784:Axitinib; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007191:Indazoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate
chemical_list: D007093:Imidazoles; D007191:Indazoles; D000068437:Pemetrexed; D000077784:Axitinib; D002945:Cisplatin
keywords: Angiogenesis, Phase II; Axitinib; Mesothelioma; Translational research; VEGF