Tumor responses after daily
oral administration of low-dose
etoposide have been demonstrated in both hematological and solid
tumors. The aim of the present phase II trial was to determine
tumor response, and toxicity and to delineate the pharmacokinetics of oral low-dose
etoposide in patients with
hematological malignancies in a
palliative treatment setting. Thirty-two patients with
non-Hodgkin's lymphoma (NHL), acute myeloblastic (AML) and
lymphoblastic leukemia,
multiple myeloma, and
myelodysplastic syndrome (MDS) were included. Patients were given oral
etoposide, 100 mg once daily for 14 d in a 21-d cycle. Serum
etoposide concentrations were determined on d 1, 7, and 14 of every cycle before
etoposide administration and, in addition, 1, 2, 3, 4, and 24 h after
drug intake on d 1. The median age of patients was 68 yr (range: 50-89 yr). The median time from diagnosis to inclusion in the study was 21 mo (range: 0.5-144 mo) and most patients had advanced disease and were heavily pretreated. Eleven patients completed three or more cycles. Eight of 11 patients with acute
leukemia and 1 of 2 with MDS received only 1 course because of toxicity (n = 5) or progression (n = 4). One patient with AML, a Jehovah's Witness, was treated up-front and achieved a complete remission and two patients with low-grade NHL gained a complete and a partial remission, respectively. Twenty-one of 32 patients were evaluable for toxicity during the first cycle. In 67%, the white blood cell count nadir was < 2.0 x 109/L and in 38% < 1.0 x 10(9)/L. Platelet count nadir was less than 25 x 10(9)/L in 24% of evaluable patients. During all cycles (n = 79), eight patients developed
febrile neutropenia, four of whom with a fatal outcome. The correlation between the area under the curve (AUC) of the free fraction of
etoposide and
leukopenia was statistically significant at a log analysis (n = 12; p < 0.05). There was also a statistically significant correlation between the AUC and the 24-h concentration (n = 15; p < 0.005) and between the concentrations at 24 h and d 7 (n = 11; p < 0.005) of the free fractions of
etoposide. In conclusion,
etoposide had a moderate clinical effect in this group of heavily pretreated patients. Moreover, toxicity was substantial, in particular
leukopenia, which correlated to the free-
etoposide AUC.