Are we moving towards continuous treatment in small cell lung cancer (SCLC)?

In the late sixties the first randomized placebo controlled study with cyclophosphamide demonstrated improved survival in patients with extensive small cell lung cancer (SCLC). Since then chemotherapy has become the mainstay of treatment of SCLC. A number of active combination chemotherapy programs for SCLC were developed during the 1970s and early 1980s. Administration of three or four effective drugs simultaneously appeared to be required for optimal results, but the particular regimen selected was of less importance than the delivery of doses that induced moderately severe but not life-threatening myelosuppression. The drugs chosen for a combination were justified on the basis of single agent activity, difference in mechanism of action and non-overlapping toxic effects. The actual doses were usually the result of feasibility studies in which the doses of all except one drug were held constant. Certain combinations became popular quickly, long before it was appreciated that one of the drugs in the combination added more toxicity than benefit. It is therefore not surprising that the old concept that two drugs in combination are better than one, or three drugs in combination are better than two, is being increasingly criticized. There is recognition that at the time of diagnosis SCLC may already be partially resistant to multiple chemotherapeutic agents and that the strategy simulated by Goldie and Coldman may only partly be applicable to SCLC. Moreover, the development of hematopoietic growth factors has provided a reason to re-evaluate the doses of individual cytostatic agents in current combination regimes and to combine drugs that previously were thought to be incompatible. But even without growth factors, recent investigations with the single agent etoposide and the combination of etoposide and cisplatin have provided arguments against the old theories of "more is better". Drug combinations must preferably be selected on the basis of pharmacokinetic studies. Dose intensity has to be revised and fascinating opportunities will arrive as soon as efficient oral formulations of active drugs, such as platinum, ifosfamide and etoposide become available.