DALLASDoxorubicin encapsulated in liposomes (Doxil) and
topotecan (Hycamtin) were equally effective in women with relapsed
ovarian cancer, but had different toxicities, according to results
presented at the 36th annual meeting of the American Society of
The phase III open-label randomized trial, presented by Alan Gordon,
MD, of the Sammons Cancer Center, Baylor University Medical Center,
took place at 104 sites and had 474 assessable subjects. All had
failed first-line platinum-based chemotherapy for ovarian cancer.
A total of 239 patients were given liposomal doxorubicin at 50
mg/m² over 1 hour every 4 weeks. Doxil consists of doxorubicin
encapsulated in a polyethylene glycol liposome. The drug remains
within the liposome until it reaches the tumor, where it is broken
down by macrophages. The other 235 patients received topotecan, a
topoisomerase I inhibitor, at 1.5 mg/m² over 30 minutes daily
for 5 days every 3 weeks.
The studys primary endpoint was time to progression. This was
18.4 weeks in the liposomal doxorubicin arm vs 18.3 weeks in the
topotecan arm. The difference was nonsignificant and remained
nonsignificant when results were broken down by platinum sensitivity
or refractoriness and presence or absence of bulky disease, said Dr.
Gordon, who is also director of gynecologic research, US Oncology,
A secondary endpoint was response rate. Here, too, there was no
significant difference between the arms as a whole (20% of those in
the doxorubicin arm had a complete or partial response, compared with
17% of those in the topotecan arm) or when broken down into subgroups.
Although overall survival rates were similar for both arms (53.4
weeks for liposomal doxorubicin vs 51.1 weeks for topotecan) among
platinum-resistant patients, there was a slight trend toward longer
survival in the topotecan arm.
Among patients who were platinum sensitive, those on liposomal
doxorubicin lived significantly longer (median, 86.1 weeks vs 63.6
In response to a question from the audience about the possible effect
of crossover on this survival advantage, Dr. Gordon said that we
need to go back and look at that. We would presume that many of
these patients may have crossed over to topotecan as third-line
therapy. Its also possible that these platinum-sensitive
patients may have received carboplatin or cisplatin again as the next
agent. Right now we just don't know.
Safety of the two drugs was the other secondary endpoint, and
adverse events were seen in all patients enrolled within the
study, Dr. Gordon said. The two drugs had different
arrays of side effects. He noted that the effects of these adverse
events on quality of life are not yet known. Quality-of-life
data were included in the study but are not available from the
patients at this time, he said.
Rates of grade 1-3 toxicities were roughly equal in the two arms. But
the number of grade 4 adverse reactions was significantly higher in
the topotecan arm than in the doxorubicin arm, due to greater
hematologic toxicity. Nonhematologic toxicities for topotecan were
generally grade 1-2.
The topotecan toxicities included more cases of neutropenia, anemia,
thrombocytopenia, leukopenia, and alopecia. Three patients in the
topotecan arm died from infections. Patients on topotecan more often
needed transfusions and growth factor treatments.
The patients on doxorubicin, on the other hand, had a significantly
increased risk of hand-foot syndrome (palmar-plantar
erythrodysesthesia) (49% vs 1% for topotecan) and stomatitis (40% vs
15%). Hand-foot syndrome was severe in 25% of liposomal doxorubicin patients.
We feel that liposomal doxorubicin is an active agent with
similar efficacy to topotecan in patients with advanced ovarian
cancer, Dr. Gordon concluded. Liposomal doxorubicin does
appear to show a survival advantage for patients with platinum-sensitive
disease. Topotecan was associated with more serious adverse events.
The favorable safety profile, comparable efficacy, and convenient
monthly dosing schedule support the role of liposomal doxorubicin for
patients with recurrent ovarian cancer.