We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43-0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36-0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25-0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.
Summary We investigated the effects of all-trans retinoic acid (ATRA) and fenretinide (4-HPR) on c-erbB-2 expression in SK-BR-3, and MCF-7 breast cancer cells and on the growth, differentiation, apoptosis and cisplatin (CDDP) sensitivity of SK-BR-3 cells. It has been reported that oestrogen inhibits c-erbB-2 in oestrogen receptor-positive breast cancer cells. Using ELISA, Westem and Northem analysis we have demonstrated that ATRA and 4-HPR exert similar effects down-regulating c-erbB-2 protein and mRNA in c-erbB-2-overexpressing SK-BR-3 and BT-474 and in normally expressing MCF-7 cells. Both retinoids inhibit SK-BR-3 cell growth. ATRA induces cellular enlargement and flattening, suggesting epithelial differentiation. 4-HPR causes nuclear and cytoplasmic condensation, DNA fragmentation and externalization of phosphabdylserine, indicating apoptosis. c-erbB-2 expression/activity has been linked to sensitivity against CDDP. Therefore, combinations of ATRA or 4-HPR with CDDP were tested for their anti-proliferative activity. Retinoid-conditioned cells were either exposed to retinoid and CDDP (schedule 1, 'continuous retinoid treatment') or to CDDP alone (schedule II, 'retinoid pretreatment'). This retinoid-conditioning followed by CDDP ± retinoid yields stronger growth inhibition compared with unconditioned cells, which were exposed to CDDP ± retinoid (schedule 111, 'no retnoid pretreatment'). The inefficacy of schedule Ill indicates that retioidconditioning is essential for the improvement of the antiproliferative effect. The interactions in schedules I and II are synergistic for ATRA and CDDP, but slightly antagonistic for 4-HPR and CDDP. However, 4-HPR + CDDP is more effective in growth inhibition than each drug alone.
A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.
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