Irinotecan and platinums in the treatment of non small-cell lung cancer.
Lung cancer is the leading cause of cancer death in the United States and in the world. In the United States, lung cancer ranks first in cancer deaths for both men and women. The 5-year survival rate is only 15%, but this has improved considerably from the 5% rate in the early 1960s. For many years, the standard therapy for patients with advanced, stage IIIB and IV non small-cell lung cancer (NSCLC) was best supportive care, which consisted of palliative radiotherapy, pain management, and other symptom management. The median survival for these patients was only 4 months, and more than 85% died in the first year after diagnosis. Cisplatin was the first drug that was shown to prolong the survival of patients with advanced lung cancer. Meta-analyses of randomized trials showed that cisplatin reduced the hazard rate of death by 26%, increased median survival from 4 to 6 months, and increased 1-year survival from 15% to 25%. Cisplatin-based therapy also relieved symptoms in the majority of patients and improved the quality of life as assessed by patients themselves. Still, further advances are desperately needed, as three fourths of the cisplatin-treated patients die within a year of diagnosis. Topoisomerase I inhibitors are a new class of chemotherapeutic agents introduced into lung cancer therapy during the 1990s. Irinotecan (CPT-11) was shown to be active in patients with both small-cell and non small-cell lung cancers. The activity of irinotecan in advanced NSCLC made it logical to combine irinotecan with the two platinums, cisplatin and carboplatin. The combination of irinotecan with cisplatin produced response rates of about 40% in phase II trials conducted in previously un-treated patients with advanced NSCLC. The median survival in these studies ranged from 6-8 months, and the 1-year survival rates ranged from 40%-60%. Because carboplatin is more convenient and better tolerated than cisplatin, a number of more recent phase II trials have evaluated the combination of irinotecan and carboplatin in patients with advanced NSCLC. These trials produced results similar to those achieved with irinotecan/cisplatin and with other two-drug combinations such as paclitaxel/carboplatin and gemcitabine/ cisplatin. The excellent activity of the two-drug combination or irinotecan and a platinum led to trials of three-drug combinations, such as irinotecan/carboplatin/paclitaxel. Preliminary results from these studies showed excellent survival, although the toxicity required some dosage reductions. Randomized trials will be necessary to determine whether such three-drug combinations will be preferred over standard two-drug combinations.
Bunn
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University of Colorado Cancer Center, Denver, CO 80262, USA. paul.bunn@uchsc.edu