DALLASDoxorubicin encapsulated in liposomes (Doxil) and topotecan(Drug information on 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 Clinical Oncology.
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(Drug information on 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, Houston.
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 weeks).
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(Drug information on carboplatin) or cisplatin(Drug information on 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.