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 regimen.
ASCO--A phase III multinational trial has shown docetaxel (Taxotere)to be more effective than doxorubicin (Adriamycin) as single-agent treatmentof patients with metastatic breast cancer who have failed an alkylating-containingregimen.
Patients who received docetaxel had a 50% better overall response ratethan those on doxorubicin, Dr. Stephen Chan, of the City Hospital BreastClinic, Nottingham, UK, said at an ASCO scientific session.
A total of 326 patients were entered into the trial, to receive eitherdocetaxel, 100 mg/m² as a one-hour infusion given every three weeks,or doxorubicin, 75 mg/m² as a short infusion every three weeks. Mostpatients completed the planned number of treatment cycles. The median relativedose 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 significantlyshorter," Dr. Chan said, "which confirmed the higher efficacyof Taxotere in this direct comparison."
A preliminary analysis of time to progression in the first 200 patientswho had completed the study showed an eight-week difference between thetwo arms in favor of docetaxel. The final analysis should be availablewithin the next six months, Dr. Chan said.
Thirteen patients in the doxorubicin group withdrew from the study dueto cardiotoxicity, and two of these patients died. "These patientshad no feature predictive of cardiotoxicity such as radiotherapy to theleft chest wall or a history of ischemic heart disease," Dr. Chansaid.
On the docetaxel arm, seven patients discontinued treatment becauseof neuropathy, which was reversible. Only three patients discontinued treatmentdue to fluid retention.
The incidence of neutropenia, infection, and asthenia was similar inboth treatment groups. Skin and allergic events were more common in thedocetaxel patients, but the majority of these cases were mild. Docetaxelhad a lower incidence of nausea and vomiting and stomatitis, while thedoxorubicin 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 analysisof time to progression, quality of life, and survival," Dr. Chan said,adding that since the two agents have different toxicity profiles, "combinationsseem worthwhile."
Combination Trials Needed
The need for combination trials was the theme of Dr. Alan Coates' discussionof Dr. Chan's study and two other papers presented at the session in whichsingle-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 CancerGroup.
"As a result of these three trials of single-agent taxanes, wecan reach two firm conclusions," Dr. Coates said. "Both of thesetaxanes are active in metastatic breast cancer, and their toxicity profilesare different from those of doxorubicin and CMFP. Neither of those conclusionsis in any way new, however."
Dr. Coates suggested the need for a "more rapid track" toanswer the question of how taxanes should be used in metastatic breastcancer, "whereby we would establish schedule and dose in phase I studies,establish that the drug has activity in phase II studies, and finally explorecombinations and compare them with standard treatment in phase III studies."
He thinks that such a scheme would allow drug companies to meet FDAand other regulations. "The perceived need to show single-agent activityin large clinical trials to meet regulatory requirements is placing a straitjacketaround the design of randomized trials of new agents," he commented.
A number of taxane combinations are ready for evaluation in comparativestudies, 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 combinationsthat 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 cyclophosphamideproduced an 82% overall response rate in metastatic breast cancer patientswho had not previously received an anthra-cycline or a taxane. At fivemonths, there was no disease progression or clinical evidence of cardiotoxicityin the 28 evaluable patients.
Two large international randomized trials are now being planned to comparethe 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 itto our patients to get on with it."