Dose-Intensified Treatment of Advanced-Stage Diffuse Large B-Cell Lymphomas

The introduction of the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen 30 years ago was the great breakthrough in the treatment of advanced-stage aggressive lymphomas. About 50% of all patients treated with CHOP achieved complete remission, and about one third experienced long-term disease-free survival and cure. Attempts to improve results by modifications of CHOP using escalated doses, additional drugs, or the alternative use of putatively non–cross-resistant chemotherapy regimens were not confirmed in randomized trials. With the availability of granulocyte colony-stimulating factor (G-CSF) and the tool of autologous stem cell support in the 1990s, dose escalation, dose densification (by interval reduction), or combinations thereof were pursued to increase dose intensity. While dose-escalation strategies, including high-dose approaches necessitating stem cell support, have not been demonstrated unequivocally yet to be superior to a baseline CHOP-21, dose-dense (biweekly) modifications improved the outcome of young and elderly patients with aggressive lymphomas compared to baseline CHOP-21. The challenges in the era of the monoclonal antibody rituximab are the identification of the ideal chemotherapy partner for rituximab both with respect to potential synergistic effects and to the lack of interference with its effector mechanisms. Finally, the issue of intensifying rituximab within such approaches must be addressed by appropriately designed randomized trials.