PARIS--The demonstration that adding paclitaxel (Taxol) to platinum boosts survival in advanced ovarian cancer has made this combination the gold standard of chemotherapy for previously untreated patients. [ODAC recently recommended to the FDA that paclitaxel be formally approved for this indication; see page 33.] However, although as many as three-quarters of women will respond to platinum-paclitaxel and one-half will achieve complete clinical remission, most will eventually relapse.
The critical question of what constitutes optimal salvage therapy was on the table at the 8th International Congress on Anti-Cancer Treatment (ICACT).
More and more data are accumulating to suggest that retreatment with paclitaxel may be more effective if given weekly, reported Robert Ozols, MD, PhD, of Fox Chase Cancer Center. He emphasized that this could apply not only for women with drug-sensitive disease but also for those with apparently resistant disease whose period of remission lasted less than 6 months.
"This may, in fact, have an antiangio-genesis effect, and were looking at whether prolonged weekly paclitaxel may be a way to maintain patients in long-term clinical remission," he said.
Turning to high-dose chemotherapy with stem cell or bone marrow transplant support, Dr. Ozols noted that although response rates are high and the toxicity is acceptable, the relapse rate is also high and the survival benefit unknown. "Most of us feel that high-dose chemotherapy with stem cell support should not be used in patients with recurrent disease, but needs to be tested up front in untreated patients," he said.
An ongoing Intergroup study is evaluating high-dose chemotherapy in patients with stage III-IV ovarian cancer who have responded to standard chemotherapy but have residual disease. Patients are randomized to continue with six cycles of paclitaxel plus carboplatin (Paraplatin) or to receive a high-dose regimen with transplantation.
A major controversy is how to manage patients in remission who have rising CA-125 levels but show no clinical signs of recurrence. Although the median interval between the appearance of elevated CA-125 levels and the appearance of symptoms or clinical disease progression is 2 to 4 months, Dr. Ozols said, many patients with rising CA-125 levels may remain clinically asymptomatic for months.
"Do you treat these patients immediately with chemotherapy or not treat them at all or treat them with a less toxic drug?" he said, summing up the dilemma. While acknowledging that there is no evidence that immediate chemotherapy is beneficial, he nonetheless advocates measurement of CA-125 levels every 2 months.
As key considerations in selecting second-line therapy, Dr. Ozols cited prior response to treatment, quality of life, the patients previous experiences with drug toxicity, and route of administration. "Since we have so many agents, if the patient has good performance status and wants to be treated, we should select a drug on the basis of these criteria and then, if it doesnt work after two cycles, go on to another drug," he advised.
Role of Topotecan
William McGuire, MD, of the University of Mississippi, said that a randomized trial has shown topotecan (Hycamtin) to be equal in efficacy to paclitaxel for salvage therapy, with both drugs achieving response rates of approximately 20%. "There was more hematologic toxicity with topotecan and more neuromuscular toxicity with paclitaxel, but all of the other outcome measures were essentially the same," he said. "In my clinical practice experience, in some patients who respond to topotecan, the response is durable."
Dr. McGuire pointed out, however, that intravenous administration of topotecan, which is given for 5 consecutive days, can be burdensome for many patients. An oral formulation of the agent now under investigation may hold promise as a more convenient and less toxic alternative, he said.
Dr. McGuire mentioned that docetaxel (Taxotere) may have a role in salvage therapy, provided that a lack of cross-resistance with paclitaxel can be proven.
Other alternatives for salvage therapy include liposomal doxorubicin, gemci-tabine (Gemzar), oral etoposide (VePesid), and tamoxifen (Nolvadex), Dr. McGuire said.
He pointed to a small study of liposomal doxorubicin that showed a 26% response rate and an average 6-month response duration in patients with platinum-resistant disease.
Using gemcitabine, Dr. McGuire said, Danish investigators have reported a 19% response rate and an average 8-month response duration in previously treated women, not all of whom had platinum-resistant disease. The combination of gemcitabine with platinum makes sense biologically, he said, although it poses a greater hazard of hematologic toxicity.
Oral etoposide has been more extensively studied as salvage therapy for ovarian cancer, Dr. McGuire said. One study involving more than 80 patients has demonstrated response rates of 27% in platinum-resistant patients and 34% in platinum-sensitive patients, with responses lasting an average of 5 months.
Although tamoxifen is active only in patients with ER-positive tumors, it is often used in asymptomatic patients with rising CA-125 levels, Dr. McGuire said. Compared with chemotherapy, he said, tamoxifen achieves lower response rates but is also less toxic. "In my clinical practice, I have found this drug to be extraordinarily effective in papillary serous carcinomas that histopathologically have a number of psammoma bodies," he said.
Although most recurrences are treated with single-agent therapy, Dr. McGuire called it "not inappropriate" to reintroduce the original combination regimen in patients who have experienced a very long treatment-free interval.