VIENNA, AustriaFor 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. Its 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
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.