NEW YORKAlthough IV topo-tecan (Hycamtin) has been in use
for several years and has shown activity in a number of different
malignancies, oncologists now are turning their attention to
delivering this camptothecin analog orally to maximize its effectiveness.
In a presentation at the Chemotherapy Foundation symposium, Howard A.
Burris III, MD, of the Sarah Cannon Cancer Center, Nashville, said
that oral topotecan offers more than an interesting and useful
way of delivering a topoisomerase I inhibitor. It also
opens the door for the exploration of a variety of schedules and combinations.
Because the cytotoxicity of topotecan appears to be specific to the
S-phase of the cell cycle, prolonged exposure at that point could
lead to increased activity against cancer cells.
Numerous preclinical studies, both in vitro and in vivo, have
demonstrated better efficacy with topotecan utilizing prolonged vs
short-term exposure, Dr. Burris said. Developing an oral
formulation would greatly facilitate schedules using multiple days of
administration to allow optimal drug exposure.
In one study of intravenous vs oral dosing, the oral route was shown
to have a longer mean exposure time with a bioavailability of between
30% and 40%. Researchers postulate that greater absorption of the
active lactone is due to the lower pH of the GI tract. This results
in the increase in half-life measurements with oral formulations.
Another phase I trial of oral topotecan evaluated twice daily dosing
for 21 consecutive days, but unexpected grade 2-3 diarrhea occurred
during the third week of therapy. The maximum tolerated dose was 0.5
mg/m² twice daily.
Studies of topotecan given as a 21-day continuous infusion have shown
that optimal down-regulation of topoisomerase I on peripheral blood
cells occurs after 10 days. The oral schedule then was shortened to
10 days, again given twice daily and repeated every 21 days.
Dose-limiting toxicities included grade 2-3 diarrhea and
noncumulative myelosuppression. A phase II trial using an oral
topotecan dose of 0.7 mg/m² twice daily for 10 days every 21
days showed similar toxicities.
The current dose commonly used in trials of intravenous topotecan is
1.5 mg/m²/d for 5 days every 21 days. Toxicities include
neutropenia and thrombocytopenia. There are minimal GI side effects.
Comparison of the clinical pharmaco-dynamics of oral topotecan
schedules showed that the type and degree of toxicity are related to
the schedule (number of days of consecutive administration) rather
than the AUC per course, Dr. Burris said. Clearly, the
prolonged schedules result in greater intestinal effects, whereas
shorter schedules are limited by granulocytopenia, he said.
Trials are underway to explore intermittent oral dosing, for example,
5 days a week, repeated weekly for 3 to 4 weeks, followed by 1 week
of rest. The purpose here is twofold, he said. This
will diminish the occurrence of diarrhea and possibly alter one
mechanism of resistance, upregulation of topoisomerase II.
He reported that phase II trials utilizing this 5-day schedule of 2.3
mg/m²/d are underway in a number of tumor types, including
ovarian cancer and small-cell lung cancer (SCLC).
Preliminary results from the trials in patients with refractory
ovarian cancer are promising, he said, with a response
rate of approximately 20% and an excellent toxicity profile of 19%
grade 4 neutropenia; 4% grade 3 anemia; 13% grade 3-4
thrombocytopenia; no grade 3 diarrhea; and 10% grade 2 alopecia.
Randomized trials comparing 5-day dosing schedules of IV topotecan
(1.5 mg/m²) vs oral topotecan (2.3 mg/m²) are underway in
refractory ovarian cancer and previously treated SCLC. Initial data
are encouraging, he said.