Dose intensive chemotherapy in small cell lung cancer

Abstract

The rationale for treatment intensification is to overcome the occurrence of drug resistance and to improve the outcome in SCLC. Several different approaches have been tested in the past two decades. Increasing the dose of conventional chemotherapy has failed to improve survival in extensive stage. In limited stage patients one randomized trial demonstrated a significant survival advantage by a 20% increase of the dose of cisplatin and cyclophosphamide given during the first cycle of chemotherapy. Shortening treatment intervals is achievable by weekly chemotherapy or by use of hematopoietic growth factors. Neither weekly chemotherapy, tested in four randomized trials, nor the application of hematopoietic growth factors significantly improved survival. However, two studies described a better survival for patients receiving chemotherapy in shorter treatment intervals. In one trial a 3-week interval was superior to a 4-week interval, and in a second one a 2-week interval superior to a 3-week interval. One smaller study, comparing a 4-week interval with a 2-week interval with stem cell augmentation by whole blood, revealed no difference in survival between both groups. A randomized trial comparing chemotherapy in intervals as short as possible with or without growth factor application showed no difference for the two groups. Thus, growth factor application seems not to be essential for treatment in short intervals and was not associated with superior survival in randomized trials. To achieve a more than two-fold increase in dose intensity some kind of stem cell support is mandatory. Several phase II trials with small patient numbers tested the concept of late intensification with bone marrow support in the 1980s. These trials did not show any convincing benefit. There is one randomized trial available testing the late intensification approach in which a superior progression free survival and a trend for better survival was demonstrated, but this difference was not statistically significant due to a high mortality rate and a substantial number of local relapses in the high dose arm. Newer concepts involving high dose therapy are combining high dose strategies with approaches for better local tumor control, administer high dose regimens earlier in the treatment course, or use multiple sequential high dose cycles. With these approaches 3-year survival rates of up to 40% have been reported. So up to date, the superiority of an intensified treatment strategy has not been demonstrated in a convincing way and further controlled trials will be necessary to clarify the role of dose intense chemotherapy in SCLC.