Twenty-five years of treating advanced NSCLC: what have we achieved?

At the end of the 1970’s, cisplatin was introduced as a breakthrough agent for the treatment of advanced testicular cancer. A few years later, this drug was also tested in advanced nonsmall-cell lung cancer (NSCLC) and was found to have some modest activity as a single agent. Until then, regimens including alkylating agents and nitrosoureas were used to a limited extent. At that time, the median survival of patients with advanced NSCLC was 6 months. Cisplatin was found in preclinical models to be synergic with a number of other agents, and striking activity of the combination cisplatin/ etoposide was observed in small-cell lung cancer at that time. Novel combinations of cisplatin were therefore tested in the 1980’s, the most common being cisplatin/vindesine, cisplatin/ vinblastine and cisplatin/etoposide. In the cisplatin era, a number of studies were conducted where chemotherapy was compared with best supportive care in patients with advanced NSCLC. Many of these studies, and older studies not including cisplatin, were small studies that did not have enough power to show a reasonable difference in survival and, because of the substantial toxicity of cisplatin combinations, despite a response rate of 30%, there was broad skepticism about its standard use. A large meta-analysis was published in 1995, which compiled all studies of chemotherapy versus best supportive care in advanced NSCLC [1]. In this meta-analysis there were 11 trials with 1190 patients analyzed, two trials used long-term alkylating agents and one used etoposide as a single agent, whereas the remaining eight trials used cisplatinbased chemotherapy. Only one trial allowed entry only to patients with metastatic disease, while all other trials also included locally advanced stage III disease. The cisplatinbased trials showed a benefit of chemotherapy, with a reduction in the risk of death of 20%, equivalent to an absolute improvement in survival of 10% or an increased median survival of 1.5 months. Interestingly, the trials with long-term alkylating agents suggested a detrimental effect of chemotherapy. This large meta-analysis prompted some new generation studies with novel chemotherapies compared with best supportive care, which confirmed the effectiveness of chemotherapy in prolonging survival and also improving quality of life. Three-drug regimens were also developed in the 1980’s, which were based on cisplatin, mitomycin and a vinca alkaloid or ifosfamide. These three-drug regimens appeared to have some advantage over doublets in some studies, but the results were not confirmed by other studies. Some of these regimens became standard in several centers for a number of years. At the beginning of the 1990’s, a number of novel chemotherapeutic agents were introduced in the treatment of advanced cancers, several of which achieved a response rate of approximately 20% to 25% in first-line. These drugs are paclitaxel, docetaxel, gemcitabine, vinorelbine and irinotecan. These drugs were soon combined with cisplatin or carboplatin, and several of these regimens were reported to have superior response rates compared with older platinum regimens. Several randomized studies were performed with these new doublets and some of these studies also demonstrated improved survival of these combinations compared with older regimens. For a number of years, three major doublets have been in use for first-line treatment of advanced NSCLC: cisplatin/ vinorelbine, cisplatin/gemcitabine and carboplatin/paclitaxel. A recent Eastern Cooperative Oncology Group (ECOG) study compared cisplatin/paclitaxel versus these three regimens, and no differences in survival or response rates were found [2]. Some differences in side-effects were, however, observed, with in general a milder toxicity profile in the carboplatin arm. A longer time to progression was observed in the cisplatin/gemcitabine arm. The major conclusion of this study was essentially comparable activity of these regimens in first-line treatment of advanced NSCLC, and the use of these regimens is presently dictated by toxicity issues and economical issues rather than activity. More recently, docetaxel/cisplatin has been shown to be superior to cisplatin/vinorelbine in a large randomized study [3]. Based on this study, docetaxel has also been approved in first-line therapy of advanced NSCLC.