Cellular and clinical pharmacokinetic/pharmacodynamic basis for lack of efficacy of 21-day continuous topotecan in patients with untreated advanced adenocarcinoma of the pancreas
Dra. Mans et al., Cellular and clinical pharmacokinetic/pharmacodynamic basis for lack of efficacy of 21-day continuous topotecan in patients with untreated advanced adenocarcinoma of the pancreas, TUMORI, 86(6), 2000, pp. 458-464
Background: In a phase II study, topotecan was evaluated for response and t
oxicity in patients with advanced pancreatic carcinoma at the schedule of 0
.7 mg/m(2)/day q 21 days q 28 days.
Methods: Responses were assessed after at least 2 courses using WHO criteri
a, and toxicity was evaluated after each course according to the CTC-NCI st
andards. Between December 1995 and September 1997, 15 assessable patients (
median age, 55 years; range, 36-74 median ECOG performance, I; range, 0-3)
were included in the study. All had biopsy-proven and measurable disease, a
life-expectancy of at least 3 months, and normal bone marrow, liver, and r
enal function. None of the patients had undergone prior cytotoxic or radiat
ion therapy, and 10 were initially treated by surgery. Twenty-five cycles w
ere assessable for toxicity. Plasma was collected from 7 patients who had r
eceived a total of 10 cycles and was, after extraction with methanol at -20
degreesC, analyzed for total topotecan by an HPLC method. The thus determi
ned steady-state concentrations were assessed for their capacity to affect
growth and DNA integrity in the BxPC-3 human pancreatic carcinoma cell line
after 21 days of continuous exposure. For these purposes, we used a sulfor
hodamine B staining assay, and agarose gel electrophoresis, respectively.
Results: Grades 3-4 leukopenia, thrombocytopenia, granulocytopenia, and ane
mia occurred in 8, 6, 8 and 8 cycles, respectively. Other mild to moderate
side effects (grades 1-2) included malaise, nausea and vomiting, anorexia,
and alopecia. No objective tumor response was documented. HPLC analysis of
patients' plasma showed the attainment of constant steady-state levels of 1
.0 +/- 0.1 ng/mL during the entire infusion period. At such a concentration
, topotecan did not significantly affect growth or DNA Integrity in the BxP
C-3 cells. Fifty percent cell growth inhibition and appreciable oligonucleo
somal DNA fragmentation were only evident with 21 days topotecan greater th
an or equal to 50 ng/mL.
Conclusions: Our data suggest that the lack of clinical activity of 0.7 mg/
m(2) daily topotecan for 21 days q 28 days in patients with advanced pancre
atic carcinoma might be partially attributed to the achievement of non-tumo
ricidal plasma drug concentrations.