Targeting the VEGF pathway: antiangiogenic strategies in the treatment of non-small cell lung cancer.

The management of advanced non-small cell lung cancer (NSCLC) has evolved considerably in recent years, due to a progressive understanding of tumour biology and the identification of promising molecular targets. Several agents have been developed so far inhibiting vascular endothelial growth factor (VEGF) - a key protein in tumour neoangiogenesis, growth and dissemination - or its receptor signalling system. The finding in study E4599 of a survival benefit for carboplatin-paclitaxel plus bevacizumab - a humanised anti-VEGF monoclonal antibody - over chemotherapy (CT) alone led the U.S. Food and Drug Administration (FDA) to approve the novel combination for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. In a randomised phase III trial presented at the American Society of Clinical Oncology (ASCO) 2007 Annual Meeting, patients receiving cisplatin-gemcitabine plus bevacizumab experienced a significantly longer progression-free survival (PFS) compared to the standard arm. Based on these data, the European Medicines Agency (EMEA) has granted marketing authorisation for bevacizumab in addition to any platinum-based CT for first-line treatment of advanced NSCLC other than predominantly squamous histology. Aim of this report is to provide an overview on bevacizumab in NSCLC, with special emphasis on clinical results presented at ASCO last meeting. Multitargeted tyrosine kinase inhibitors (TKIs), sharing a focus on both the angiogenesis process and additional cell-surface receptors, and VEGF Trap, a novel fusion protein with markedly higher affinity for VEGF than bevacizumab, will be briefly discussed as well.

Sequential, alternating, and maintenance/consolidation chemotherapy in advanced non-small cell lung cancer: a review of the literature.

A platinum-based doublet with a third-generation agent (paclitaxel, vinorelbine, gemcitabine, docetaxel) represents the standard first-line treatment for advanced non-small cell lung cancer patients with good performance status (PS). Traditional chemotherapy provides response rates of 20%-40% and a median survival of 8-10 months. In an attempt to improve its outcome, alternative schedules have been proposed, namely sequential, alternating, and maintenance/consolidation therapy. Sequential chemotherapy with a platinum-based doublet followed by a single agent is feasible in patients with good PS; preliminary results from randomized phase III trials with combination chemotherapy as a comparator are promising, suggesting similar efficacy and a better toxicity profile for the sequential arm. The use of sequential single agents is an option for elderly and frail patients unsuitable for a platinum-based combination. Based on trials published so far, it is unlikely that an alternating chemotherapy strategy will be proven superior to standard chemotherapy in patients with good PS. However, sufficient evidence exists that it could be appropriate in the elderly or in unfit individuals. Consolidation/maintenance chemotherapy may provide additional benefit for patients achieving disease control after standard first-line chemotherapy. Better results are seen when maintenance consists of an agent that has proven active in the induction phase. Further evaluation of this strategy, as well as of consolidation/maintenance therapy with targeted agents, is warranted. In conclusion, these approaches may improve the outcome in selected patients with advanced non-small cell lung cancer, but further results from randomized trials are needed. In the meantime, sequential, alternating, and maintenance/consolidation therapy should still be considered investigational.