ASCO--A phase III multinational trial has shown docetaxel (Taxotere)
to be more effective than doxorubicin (Adriamycin) as single-agent treatment
of patients with metastatic breast cancer who have failed an alkylating-containing
Patients who received docetaxel had a 50% better overall response rate
than those on doxorubicin, Dr. Stephen Chan, of the City Hospital Breast
Clinic, Nottingham, UK, said at an ASCO scientific session.
A total of 326 patients were entered into the trial, to receive either
docetaxel, 100 mg/m² as a one-hour infusion given every three weeks,
or doxorubicin, 75 mg/m² as a short infusion every three weeks. Most
patients completed the planned number of treatment cycles. The median relative
dose intensity was more than 90% in both arms.
An intent-to-treat analysis of all randomized patients showed a 47.2%
total objective response rate for the docetaxel patients (39.1% PR, 8.1%
CR), compared with 31.5% for the doxorubicin group (27.3% PR and 4.2% CR)
(P = .0004).
"The median time to response in the Taxotere arm was significantly
shorter," Dr. Chan said, "which confirmed the higher efficacy
of Taxotere in this direct comparison."
A preliminary analysis of time to progression in the first 200 patients
who had completed the study showed an eight-week difference between the
two arms in favor of docetaxel. The final analysis should be available
within the next six months, Dr. Chan said.
Thirteen patients in the doxorubicin group withdrew from the study due
to cardiotoxicity, and two of these patients died. "These patients
had no feature predictive of cardiotoxicity such as radiotherapy to the
left chest wall or a history of ischemic heart disease," Dr. Chan
On the docetaxel arm, seven patients discontinued treatment because
of neuropathy, which was reversible. Only three patients discontinued treatment
due to fluid retention.
The incidence of neutropenia, infection, and asthenia was similar in
both treatment groups. Skin and allergic events were more common in the
docetaxel patients, but the majority of these cases were mild. Docetaxel
had a lower incidence of nausea and vomiting and stomatitis, while the
doxorubicin patients had a lower incidence of diarrhea.
"The risk-to-benefit ratio clearly favors Taxotere in this analysis,
and more definite statements will only be possible after the final analysis
of time to progression, quality of life, and survival," Dr. Chan said,
adding that since the two agents have different toxicity profiles, "combinations
Combination Trials Needed
The need for combination trials was the theme of Dr. Alan Coates' discussion
of Dr. Chan's study and two other papers presented at the session in which
single-agent paclitaxel (Taxol) was compared with standard CMFP (cyclophosphamide,
methotrexate, fluorouracil, prednisolone) or with single-agent doxorubicin.
Dr. Coates is a leading member of the Australian/New Zealand Breast Cancer
"As a result of these three trials of single-agent taxanes, we
can reach two firm conclusions," Dr. Coates said. "Both of these
taxanes are active in metastatic breast cancer, and their toxicity profiles
are different from those of doxorubicin and CMFP. Neither of those conclusions
is in any way new, however."
Dr. Coates suggested the need for a "more rapid track" to
answer the question of how taxanes should be used in metastatic breast
cancer, "whereby we would establish schedule and dose in phase I studies,
establish that the drug has activity in phase II studies, and finally explore
combinations and compare them with standard treatment in phase III studies."
He thinks that such a scheme would allow drug companies to meet FDA
and other regulations. "The perceived need to show single-agent activity
in large clinical trials to meet regulatory requirements is placing a straitjacket
around the design of randomized trials of new agents," he commented.
A number of taxane combinations are ready for evaluation in comparative
studies, Dr. Coates said. Maximum tolerated dose, appropriate toxicity,
and recommended dose have been established for docetaxel plus vinorelbine
(Navelbine), for example.
The Australian/New Zealand group is studying three-drug combinations
that include a taxane, as are others. Dr. Coates mentioned, in particular,
a phase II study presented in an ASCO poster session by Jean-Marc Nabholtz,
MD, senior medical oncologist, Cross Cancer Institute, Edmonton, Alberta,
Canada, and chair of the Alberta Breast Cancer Program.
In this trial, docetaxel in combination with doxorubicin and cyclophosphamide
produced an 82% overall response rate in metastatic breast cancer patients
who had not previously received an anthra-cycline or a taxane. At five
months, there was no disease progression or clinical evidence of cardiotoxicity
in the 28 evaluable patients.
Two large international randomized trials are now being planned to compare
the docetaxel-doxorubicin-cyclophosphamide regimen with standard FAC (fluorouracil,
Adriamycin, cyclophosphamide) in the metastatic and adjuvant settings,
"Optimal regimens remain to be defined," Dr. Coates concluded.
"That's the challenge that faces us as investigators, and we owe it
to our patients to get on with it."