Triplet chemotherapy combinations with new agents: is there a rationale?

Lung cancer remains the major cause of cancer-related death in North America and Europe. Lung cancer causes 28% of all cancer deaths, more than breast, prostate, colorectal, and ovarian cancers combined. Eighty-five percent to 90% of cases of lung cancer are known to be a direct consequence of smoking. Despite this, the incidence of the disease continues to increase dramatically in women, although in the United States, the incidence and mortality rates of lung cancer in men have declined slightly in the last few years. Non-small cell lung cancer (NSCLC) represents 75% to 80% of all primary lung cancers, and approximately 70% of these patients present with unresectable disease. These patients are candidates for palliative radiotherapy and/or chemotherapy, but most of these patients will develop locally advanced or metastatic disease. Currently, the 5-year survival rate across all stages of the disease is 14% in the United States. Until recently, chemotherapy was considered to be more successful in the treatment of small cell lung cancer than NSCLC, but this is no longer true. In a recent meta-analysis of randomized trials in NSCLC, cisplatin-based chemotherapy was shown to prolong survival for patients across all stages of the disease. A role for adjuvant cisplatin-based therapy has been shown in early stage disease, and cisplatin-based therapy was shown to improve survival when combined with radiotherapy in locally advanced disease and as a single modality in metastatic disease. Other randomized trials have shown that cisplatin-based therapy improved quality of life in both stage III and IV NSCLC patients and reduced the cost of medical care compared with best supportive care. Cisplatin-based therapy should therefore be considered the standard treatment for all NSCLC patients with locally advanced or metastatic disease. However, over the last 5 years, five new agents have emerged that have increased single-agent response rates, increased survival, and, for the most part, reduced toxicity. The use of these in two-drug combinations with conventional agents will be compared with new two- and three-drug combinations.