What is the role of maintenance therapy in the treatment of non-small cell lung cancer?

Introduction Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death in both men and women in the United States. The poor prognosis is largely attributed to advanced stage at diagnosis. Over the past decade, palliative chemotherapy has shown survival benefit in patients with advanced disease [Belani et al. 2005; Martoni et al. 2005; Rudd et al. 2005; Sederholm et al. 2005; Fossella et al. 2003; Non-small Cell Lung Cancer Collaborative Group, 1995]. Platinumbased doublet regimens have been established as the current ‘standard of care’ with improvements in both overall survival (OS) and quality of life [Scagliotti et al. 2008; Belani et al. 2005; Martoni et al. 2005; Rudd et al. 2005; Scagliotti et al. 2002]. Recently, with better understanding of the molecular pathogenesis, targeted agents have been introduced in the treatment of NSCLC. The epidermal growth factor receptor (EGFR) inhibitors have advanced to front-line therapy of patients with tumors that harbor the EGFR tyrosine kinase mutations [Mok et al. 2009; Rosell et al. 2009; Kobayashi et al. 2005]. These are usually continued until disease progression. The addition of bevacizumab to chemotherapy [Reck et al. 2009; Sandler et al. 2006] improves the outcome of a select group of patients with NSCLC but has yet to be adopted worldwide. Although these targeted agents are continued indefinitely until progression, cytotoxic chemotherapeutic intervention has been restricted to four to six cycles in treating patients with advanced NSCLC. Continuation of combination chemotherapy beyond four to six cycles only results in added toxicity without a meaningful improvement in response, progression-free survival (PFS) or OS [Pfister et al. 2004]. The current practice guideline entails a ‘treatment holiday’ and introduction of second-line therapy at the time of disease progression [Azzoli et al. 2009; Pfister et al. 2004]. It is imperative to state that patients who are able to receive second-line interventions represent a select subgroup and again have a modest but significant benefit in overall outcome with treatment. Continued chemotherapeutic intervention with single-agent docetaxel [Fidias et al. 2009] or gemcitabine [Brodowicz et al. 2006] has shown improvement in PFS at the expense of side effects in a subset of patients. The concept of maintenance or prolonged therapy has been adopted in other tumor types such as lymphoma, leukemia and colorectal cancer. With the addition of targeted agents, prolonged administration of bevacizumab has been utilized in NSCLC after initial platinum-based chemotherapy. While this is a biologically rational approach, there is no convincing clinical evidence that patient outcomes are improved with such prolonged administration of this targeted therapy. Recently, three randomized phase III studies have documented improvement in outcome with the use of ‘maintenance therapy’ for patients with advanced stage NSCLC (Table 1) [Cappuzzo et al. 2009; Ciuleanu et al. 2009; Miller et al. 2009]. In this article we discuss current data on maintenance therapy and the implications for routine patient care.