Cellular and clinical pharmacokinetic/pharmacodynamic basis for lack of efficacy of 21-day continuous topotecan in patients with untreated advanced adenocarcinoma of the pancreas.
BACKGROUND
In a phase II study, topotecan was evaluated for response and toxicity in patients with advanced pancreatic carcinoma at the schedule of 0.7 mg/m2/day q 21 days q 28 days.


METHODS
Responses were assessed after at least 2 courses using WHO criteria, and toxicity was evaluated after each course according to the CTC-NCI standards. Between December 1995 and September 1997, 15 assessable patients (median age, 55 years; range, 36-74; median ECOG performance, 1; 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 renal function. None of the patients had undergone prior cytotoxic or radiation therapy, and 10 were initially treated by surgery. Twenty-five cycles were assessable for toxicity. Plasma was collected from 7 patients who had received a total of 10 cycles and was, after extraction with methanol at -20 degrees C, analyzed for total topotecan by an HPLC method. The thus determined 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 sulforhodamine B staining assay, and agarose gel electrophoresis, respectively.


RESULTS
Grades 3-4 leukopenia, thrombocytopenia, granulocytopenia, and anemia 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 BxPC-3 cells. Fifty percent cell growth inhibition and appreciable oligonucleosomal DNA fragmentation were only evident with 21 days topotecan > or = 50 ng/mL.


CONCLUSIONS
Our data suggest that the lack of clinical activity of 0.7 mg/m2 daily topotecan for 21 days q 28 days in patients with advanced pancreatic carcinoma might be partially attributed to the achievement of non-tumoricidal plasma drug concentrations.
Mans
D R
DR
South-American Office for Anticancer Drug Development (SOAD), Lutheran University of Brazil, Canoas.
Di Leone
L
L
Ferrary Caldas
A P
AP
Maino
M
M
Almeida
L
L
Cancela
A I
AI
Grivicich
I
I
Brondani da Rocha
A
A
Schwartsmann
G
G
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D017211:Treatment Failure
D000970:Antineoplastic Agents; D019772:Topotecan