High-dose chemotherapy in breast cancer: Dutch randomized studies

The role of high-dose chemotherapy in the adjuvant treatment of breast cancer will eventually be defined by a range of randomized trials that still require years for maturation. Two underpowered single-institution studies (from the MD Anderson Cancer Center and from the Netherlands Cancer Institute) failed to show an advantage for high-dose therapy. A randomized Scandinavian study compared prolonged and intensive chemotherapy without stem-cell support with brief chemotherapy followed by the STAMP-V regimen. The intensive conventional treatment arm was shown to be superior in terms of relapse-free survival. Two large studies comparing conventional dose adjuvant chemotherapy with high-dose chemotherapy have been reported in abstract form: the American Intergroup study (ASCO 1999) and the Dutch National Study (ASCO 2000). The American study shows fewer relapses in the high-dose arm. The Dutch study suggests a modest disease-free survival advantage for the high-dose arm, but further follow up is required to ascertain statistical significance (P = 0.057, two-sided, at the early analysis). In 2002, a 24% reduction in hazard rate will be detectable with 80% power. Both the efficacy and toxicity of high-dose therapy may depend on the drugs, dosage and schedules selected. In the Dutch study, a regimen was employed that is similar to the frequently used CTCb (STAMP-V) regimen. The carboplatin dose is, however, twice as high, and the agents are administered as short-term infusions rather than as continuous 96-h infusions. This may have an impact on the activation of the prodrug cyclophosphamide; the activation route is strongly inhibited by the presence of even low concentrations of thiotepa.