ASCO--A phase III multinational trial has shown docetaxel(Drug information on docetaxel) (Taxotere) to be more effective than doxorubicin(Drug information on doxorubicin) (Adriamycin) as single-agent treatment of patients with metastatic breast cancer who have failed an alkylating-containing regimen.
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 said.
On the docetaxel arm, seven patients discontinued treatment because of neuropathy, which was reversible. Only three patients discontinued treatment due to fluid retention.
Risk-to-Benefit Ratio
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 seem worthwhile."
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(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil), prednisolone(Drug information on prednisolone)) or with single-agent doxorubicin. Dr. Coates is a leading member of the Australian/New Zealand Breast Cancer Group.
"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.
Three-Drug Combinations
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(Drug information on 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, he said.
"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."
