Aspects of palliative chemotherapy for lung cancer

Abstract

Lung carcinoma is the main cause of cancer related deaths among the male population in The Netherlands. In females this carcinoma is only surpassed by breast and colon cancer. In The Netherlands in 1987, 8.500 persons died due to lung carcinoma (1). It is anticipated that despite government-installed preventive measures -including stop-smoking programs- the number of persons suffering from lung cancer will continue to rise in the near future (2,3). The results of all therapeutic modalities for lung cancer have reached a plateau for many years with about 10% overall cure (4). For therapeutic reasons, lung cancer is generally divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). For NSCLC surgery is the only curative modality for patients without demonstrable metastatic disease (5). For SCLC, which comprises 20-25% of all cases, combination chemotherapy forms the cornerstone of therapy with the vast majority of patients responding to therapy with prolonged survival and a small percentage of cures. While SCLC is responsive to chemotherapy, NSCLC is only moderately responsive to such therapy (6). Although much knowledge has been gathered on the biology of lung cancer, this basic research did not, however, result in improved survival of patients treated by chemotherapy for lung cancer (7). The failure of chemotherapy to cure lung cancer patients is basically a problem of drug resistance. Several resistance mechanisms have been discovered in the recent years. The most widely studied form is the so called pleiotropic drug resistance (PDR) (8). PDR has emerged as a consistent mechanism of resistance for several structurally unrelated cytotoxic agents in cancer cells. Resistance seems to be caused by a decreased intracellular drug concentration, caused by an increased efflux pump. This efflux pump can be antagonated in vitro by calcium antagonists. It has become clear that reversal of resistance mediated by the PDR-phenotype is in some cases possible in the clinic (9,lO). PDR however, seems to play little or no role in lung cancer (1 1). Resistance mechanisms which have been identified in vitro in lung cancer cell lines include enhanced DNA repair capacity and altered drug-topoisomerase interactions (12). For these and other drug resistance mechanisms it has by no means been elucidated whether they can be circumvented by sophisticated measures in the near future