The role of irinotecan combined with Cisplatin or Carboplatin in the treatment of advanced non-small-cell lung cancer.
More than one third of all non-small-cell lung cancer (NSCLC) patients present with advanced stage IV disease with metastases or with stage IIIB disease with a malignant pleural or pericardial effusion. The prognosis for these patients remains poor despite some improvement in survival produced by 2-drug chemotherapy combinations. With the best 2-drug combinations, the expected median survival is 8-9 months and > 80% of patients die within 2 years of diagnosis. The overall response rate to the best combination is < 40% and the complete response rate is only 1%. Clearly, superior therapies are needed. The topoisomerase I inhibitors have been developed because the topoisomerase I enzyme plays a critical role in the DNA repair process. Irinotecan is a topoisomerase I inhibitor developed during the 1990s. It was initially approved in the United States for the treatment of colorectal cancer. In early trials, considerable activity was seen in both small-cell lung cancer and NSCLC. These observations led to combination studies with cisplatin. Cisplatin-based therapy had become a standard approach in both stage IV disease and in combination with chest radiotherapy in stage IIIB disease because metaanalyses of randomized trials showed that cisplatin-based therapy significantly improved survival. Randomized trials also showed that cisplatin-based therapy improved symptoms in the majority of patients and improved quality of life. In early combination studies, the irinotecan/cisplatin combination produced responses in an average of 40% of patients and produced median survival times that averaged about 10 months. In randomized trials comparing irinotecan/cisplatin to vindesine/cisplatin, the irinotecan/cisplatin combination was slightly better than irinotecan alone and vindesine/cisplatin. These encouraging results led to ongoing randomized trials comparing the 2-drug combination of irinotecan/cisplatin to other 2-drug combinations. Irinotecan has also been combined safely and effectively with carboplatin. The 2-drug combination of irinotecan/carboplatin produced results similar to those achieved with irinotecan/cisplatin. Irinotecan has also been incorporated into 3-drug combinations such as irinotecan/carboplatin/paclitaxel with encouraging results. A randomized trial comparing docetaxel/irinotecan to docetaxel/cisplatin showed similar results. Randomized trials comparing the 3-drug combination to a 2-drug combination are in progress. The irinotecan/cisplatin combination has considerable activity in the second-line setting. Randomized trials comparing this combination to docetaxel are needed. Irinotecan is an active agent in the first- and second- line therapy of NSCLC.
Bunn
Paul A
PA
University of Colorado Cancer Center, Denver; e-mail: paul.bunn@uchsc.edu