VIENNA, Austria—For Stanley Kaye, MD, of the University of Glasgow, the milestones of the ’90s in the treatment of ovarian cancer were the discovery that taxanes are superior to alkylating agents in combination with platinum and the recognition that the “soft option” carboplatin (Paraplatin) is equivalent in efficacy to cisplatin (Platinol).

“Those of us who felt that there could be no gain without pain were wrong,” he said at the 10th European Cancer Conference (ECCO 10). He predicted that paclitaxel (Taxol)/carboplatin could soon become the gold standard of treatment.

However, Dr. Kaye said, the results of treatment are still far from satisfactory, with most women ultimately dying of the disease. He cited the controversial preliminary results of the European ICON-3 study, which questioned the advantage of combination paclitaxel/carboplatin therapy over single-agent carboplatin. [See Oncology News International supplement No. 3, July 1999, p. 15.] “This should alert us to the possibility that the conventional 3-hour infusion of paclitaxel, 175 mg/m², may not necessarily be the end of the story, and further studies of scheduling should be conducted,” he said.

A recent meta-analysis has suggested that the addition of an anthracycline to combination therapy affords a small but significant survival advantage. Dr. Kaye noted that this issue is being addressed in a recently completed French AGO study and in a soon-to-be-launched EORTC Intergroup trial.

A major drawback, he said, is the lack of reliable experimental data to point the way toward doublet vs triplet regimens and concurrent vs sequential vs alternating schedules.

The results of an ongoing randomized trial are awaited to determine how the combination of docetaxel (Taxotere)/carboplatin will compare with paclitaxel/carboplatin in terms of activity, platelet suppression, and neuropathy.

Although a Scottish study suggested that dose intensification might confer a survival advantage, Dr. Kaye pointed out the actual gain was short term and achieved only at the expense of significant toxicity. “A twofold increase in cisplatin dose intensity was of limited value, and one would have to go significantly higher, which one can do with carboplatin,” he said. Meta-analysis of the results from nonrandomized studies of high-dose chemotherapy has been inconclusive, however, and randomized trials are now underway.

“Intraperitoneal (IP) chemotherapy has a long history and is still worth considering in patients with a minimal residual disease burden after initial surgery,” Dr. Kaye said. He noted that the SWOG trial, conducted in the pretaxane era, revealed a striking survival advantage with IP cisplatin. However, he said, the jury is still out on the benefits of IP paclitaxel because flaws in the original randomized GOG trial have necessitated a repeat of that study. “It’s not a particularly convenient way of delivering the drug, so the results would have to be very positive for it to influence practice,” Dr. Kaye said.

Overcoming Drug Resistance

Clinical drug resistance is still the major obstacle to effective treatment, and elucidation of the mechanisms involved in resistance remains the top priority for ovarian cancer research, Dr. Kaye said. A possible basis for resistance to platinum and other drugs is a mismatch repair deficiency. That is, the cell fails to recognize that its DNA has been damaged by the drug, tolerates the damage, does not undergo apoptosis, and continues to divide, thus expanding the resistant population.

Dr. Kaye said that a deficiency in the major repair enzyme hMLH1 could be reversed with the drug 5-aza-2´-deoxy-cytidine, which hypomethylates the gene-encoding enzyme. “The SCOTROC trial is attempting to determine the clinical relevance of this mechanism by analyzing the free tumor cell DNA found in the blood of many patients with heavy cancer loads,” he said.