Second-line treatment options in advanced non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death in both men and women in most of the Western world, with an estimated 900,000 deaths per year worldwide [1]. Most patients (approximately 80%), present with locally advanced stage III or metastatic stage IV NSCLC and are ineligible for curative surgery [2,3]. The long-term prognosis for patients with NSCLC remains poor, with the 5-year survival rate ranging from 8% to 15% [4]. Chemotherapy with cisplatin-based regimens was shown to prolong survival, relieve symptoms in most cases, and to improve quality of life. The introduction of several new agents, including paclitaxel, gemcitabine, and vinorelbine, offered hope for a better outcome because overall survival improved with combination regimens that included these new agents compared with cisplatin alone [5]. The addition of bevacizumab to platinum doublets has added an additional two months of survival time compared with chemotherapy alone [6]. Based on the results of a randomised phase III trial comparing cisplatin plus pemetrexed to cisplatin plus gemcitabine in the first-line setting [7], pemetrexed was approved by both the European Medicinal Evaluation Agency (EMEA) and the FDA, in combination with cisplatin, as first-line treatment for patients with non-squamous NSCLC. Despite these favourable results, most patients receiving front-line chemotherapy experience disease progression. Patients who experience disease progression during or after first-line treatment for advanced NSCLC have a limited life expectancy [8]. The aims of second-line treatment should be palliation of symptoms, benefit in quality of life, and prolongation of survival. Even so, the impact of treatment on the natural history of the disease is modest. As shown in a recent review of 19 phase III trials [9], in the second-line or later setting, the median objective response rate was 6.8%, and median overall survival was 6.6 months. The 1997 guideline of the American Society of Clinical Oncology (ASCO) stated that “there is no current evidence that either confirms or refutes that second-line chemotherapy improves survival in patients with advanced NSCLC” [10]. In recent years, the efficacy of several drugs in the second-line setting has been demonstrated in phase III trials, and now second-line treatment can be considered a standard of care [11]. In first-line treatment of patients with good performance status (PS), doublet chemotherapy has been shown to be more effective than single-agent therapy, both in terms of response and survival [12]. Actually, in patients with NSCLC progressing after first-line chemotherapy, the use of monochemotherapy is necessary, as combination chemotherapy results in increased toxicity without any survival advantage [13–16]. In 2009 Di Maio and colleagues [17] presented a meta-analysis based on individual patient data. The main objective was to compare the efficacy of doublet chemotherapy with single-agent treatment for the second-line treatment of advanced NSCLC. Eight eligible trials were identified. OS was not significantly different between arms (P = 0.32). Median OS was 37.3 and 34.7 weeks in the doublet and single-agent arms, respectively. Hazard ratio (HR) was 0.92 (95% confidence interval [CI], 0.79 to 1.08). Response rate was 15.1% with a doublet and 7.3% with a single agent (P = 0.0004). Median progression-free survival was 14 weeks for doublet and 11.7 weeks for singleagent treatment (P = 0.0009; HR 0.79; 95%CI, 0.68 to 0.91). Patients treated with doublet chemotherapy had significantly more grade 3−4 haematologic (41% versus 25%; P = 0.0001) and grade 3−4 nonhaematologic toxicity (28% versus 22%; P = 0.034). In conclusion, randomised evidence available for this individual patient data meta-analysis does not support the use of combination chemotherapy as second-line treatment for patients with NSCLC, based on an increase in toxicity without any gain in survival.