NEW YORKTwo new strategies for treating advanced ovarian
cancer may improve the outlook for this difficult to treat disease.
Early data from trials of repeating and sequential doublets of
cisplatin (Platinol)-based drug combinations have shown encouraging
results, according to presentations at the Chemotherapy Foundation
Robert A. Nagourney, MD, adjunct associate professor, University of
California, Irvine, and medical and laboratory director, Rational
Therapeutics Inc., Long Beach, California, reported on trials of
gemcitabine (Gemzar) and cisplatin delivered in repeating doublets in
women with relapsed ovarian cancer. Gemcitabine has been shown to be
active against ovarian cancer, with a 20% response rate in patients
with advanced disease when used as a single agent.
Using the Ex Vivo Apoptotic (EVA) assay, designed to measure
drug-induced cell death in tumor cells, Dr. Nagourneys group
selected 24 heavily pretreated and drug-refractory ovarian cancer
patients with tumors sensitive to the gemcitabine and cisplatin
combination. They received cisplatin 30 mg/m² plus gemcitabine
600 to 750 mg/m² administered on days 1 and 8, with cycles
repeated every 21 days.
Dr. Nagourney reported that objective responses were observed in 12
of the 24 patients, with 7 (29%) achieving a complete response and 5
(21%) a partial response. Stable disease was seen in 4 patients
(17%). The duration of response ranged from 1 to 17 months, with a
median of 9 months.
Dr. Nagourney called the regimen both tolerable and active, even in
women for whom single-agent therapy with cisplatin or gemcitabine had
failed. As such, he said, it is an attractive alternative to
current regimens. A phase II trial of the regimen is ongoing,
Despite high initial response rates, advanced epithelial ovarian
cancer is subject to rapid relapse. Even with the addition of
paclitaxel (Taxol) to platinum-based chemotherapy, the cure rate is
in the single digits, Paul J. Hoskins, MD, clinical assistant
professor, British Columbia Cancer Agency, Vancouver, said at the symposium.
Dr. Hoskins reported on attempts to improve on the outcome of
first-line cisplatin/paclitaxel therapy with the addition of a
sequential doublet of cisplatin/topotecan (Hycamtin). Giving
the three drugs together, Dr. Hoskins said, causes
significant myelotoxicity, and strategies to avoid that, including
the use of G-CSF [Neupogen], are themselves problematic.
In a study of 44 previously untreated women with advanced epithelial
ovarian cancer, 50 mg/m² of cisplatin was given on day 1,
followed by topotecan 0.75
mg/m2 on days 1 through 5. Patients received four 21-day cycles. That
sequence was followed by 135 mg/m² of paclitaxel given over 24
hours on day 1 and 75 mg/m² of cisplatin on day 2; again there
were four 21-day cycles.
Dr. Hoskins explained that the sequencing of the individual
chemotherapy agents within the doublets was crucial. Cisplatin given
before topotecan is synergistic, although it is more myelotoxic.
Paclitaxel given before cisplatin is more active than the reverse order.
The response rate was based on CT scanning. Of 37 evaluable patients,
62% showed a response after the first sequence and 78% after
completion of the total regimen. Progression over the total regimen
was seen in 5% of 41 patients evaluable for progression. Median time
to progression was 16 months.
Nonhematologic toxicity was minimal. Myelotoxicity was high,
but of short duration, Dr. Hoskins said. Because the
myelotoxicity was noncumulative, it did not prevent treatment delivery.
Based on these encouraging results, the National Cancer Institute of
Canada is planning a phase III study with a slightly modified
regimen, replacing cisplatin with carboplatin (Paraplatin) in the
second (paclitaxel) sequence and using a paclitaxel dose of 175
mg/m² given over 3 hours.