Increasing the dose density of active drugs by delivering maximum
tolerated doses sequentially with minimal intervals between cycles
could potentially increase response rate and benefit in metastatic
breast cancer. We tested this hypothesis by assigning patients with
no prior chemotherapy for measurable metastatic breast cancer to
receive an equal total dose of doxorubicin plus docetaxel (Taxotere)
as induction treatment, randomizing the schedule to either
simultaneous (SIM: doxorubicin 45 mg/m² plus docetaxel 75
mg/m² every 21 days for four cycles) or sequential (SEQ:
doxorubicin 90 mg/m² every 14 days for two cycles followed by
docetaxel 100 mg/m² every 14 days for three cycles) administration.
Response was assessed after induction; responding patients were
eligible for high-dose consolidation. Granulocyte colony-stimulating
factor (G-CSF, filgrastim [Neupogen]) was scheduled for days 310
in the SEQ arm, and given only after a neutropenic episode in the
SIM arm. A total of 94 patients were randomized with an equal balance
of pretreatment characteristics. 37% were metastatic at diagnosis,
54% had prior adjuvant therapy, and 31% had liver involvement. The
median delivered dose intensity and cumulative dose for both drugs
were similar in both arms. However, the median dose density was
markedly higher for SEQ vs SIM: SEQ doxorubicin, 4.5 times higher;
SEQ docetaxel, 2.3 times higher. Efficacy results for the two arms
are shown in the table.
Grade 3/4 toxicity (National Cancer Institute Common Toxicity
Criteria) for SIM vs SEQ, respectively, was as follows: neutropenia,
67% vs 34%; infection, 0% vs 4%; nausea/vomiting, 10% vs 16%;
stomatitis, 10% vs 7%; pulmonary, 7% vs 2%; hyperglycemia, 17% vs
14%; skin, 0% vs 7%. The latter was manifest by grade 4 hand/foot
syndrome and/or total body rash in three patients in the SEQ arm.
CONCLUSION: We conclude that doxorubicin/docetaxel is a very active
regimen in metastatic breast cancer, but a dose-dense,
growth-factorsupported sequential treatment offers no advantage
over a standard combination schedule.