Unresolved issues in diffuse large B-cell lymphomas

For more than 25 years, the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was considered the 'gold standard' for the treatment of aggressive lymphomas, 90% of which are diffuse large B-cell lymphomas (DLBCLs). After the demonstration of rituximab's single-agent activity in DLBCL, a pivotal trial in elderly patients demonstrated that combining rituximab with eight applications of CHOP significantly improved complete remission rates, and event-free and overall survival rates compared with CHOP alone. These positive results have meanwhile been confirmed by two additional randomized trials and have been extended to young patients with good-prognosis DLBCL by a fourth trial and rituximab, in combination with CHOP, has become accepted worldwide as the new standard for all DLBCL. Remaining issues concern biology-based approaches and the guidance of therapy by PET, the definition of the optimal dosage and schedule of rituximab for DLBCL, as well as the optimal chemotherapy regimen partner for rituximab. Finally, patients failing after rituximab-containing immunochemotherapy have a dismal prognosis and the treatment of these patients has become a prime challenge in the rituximab era.