SAN ANTONIO, TexasIn women with node-positive breast cancer,
shortening the time between adjuvant chemotherapy cycles significantly reduces
mortality and risk of recurrence, with no significant increase in toxicity,
according to results of a large, randomized cooperative group trial. Interim
analysis from Cancer and Leukemia Group B (CALGB) 9741 showed that dose-dense
chemotherapy reduced mortality by 31% and risk of recurrence by 26% vs
Lead investigator Marc L. Citron, MD, clinical professor of
medicine with Albert Einstein College of Medicine, Bronx, New York, presented
the results at the 25th Annual San Antonio Breast Cancer Symposium.
"While previous research has evaluated the use of different
forms of ‘dose-dense’ chemotherapy, this is the first major controlled study to
show a clear survival benefit for women with node-positive breast cancer,"
according to a statement by the National Cancer Institute.
Dr. Citron said that the improved rates for disease-free
survival and overall survival warrant further research and have implications
Four Treatment Groups
Investigators accrued 2,005 patients between September 1997 and
March 1999 and 1,973 of those patients received therapy and were evaluable. The
median age was 50 and about half of the women were premenopausal. The median
number of positive nodes was three.
All women had received lumpectomy and axillary dissection, or a
modified radical mastectomy with clear margins. Following surgical removal of
their tumors, the women were randomized to one of four treatment groups
involving the following schedule of doxorubicin 60 mg/m2, paclitaxel
175 mg/m2 over 3 hours, and cyclophosphamide 600 mg/m2.
The trial was designed to test dose dense vs conventional
chemotherapy and concurrent vs sequential chemotherapy. Filgrastim (Neupogen)
was added to the dose-dense groups to help prevent neutropenia. The dose of
filgrastim was 5 mg/kg subcutaneously for a total of seven doses, starting on
day 3 of each cycle of chemotherapy. Tamoxifen 20 mg/day starting within 12
weeks after completing chemotherapy was recommended but not required for all of
the receptor-positive patients and postmenopausal receptor-negative patients.
Arm I: sequential administration of doxorubicin, followed by
paclitaxel, followed by cyclophosphamide in 3-week intervals.
Arm II: sequential administration of doxorubicin, followed by
paciltaxel, followed by cyclophosphamide in 2-week intervals (dose dense), with
Arm III: concurrent administration of doxorubicin and
cyclophosphamide, followed by paclitaxel in 3-week intervals.
Arm IV: concurrent administration of doxorubicin and
cyclophosphamide, followed by paclitaxel in 2-week intervals (dose dense), with
Significantly Superior Survival
At 36 months median follow-up, dose-dense treatment was
associated with a 26% relative reduction in relapse (P = .01) vs every 3
weeks administration. Four-year disease-free survival was 82% in the dose-dense
group and 75% for the conventional dosing schedule.
There was also a 31% relative reduction in mortality for
dose-dense treatment vs conventional dose scheduling (P = .013).
Three-year overall survival was 92% for the dose-dense group and 90% for the
every 3 weeks group.
Giving chemotherapy sequentially vs concurrently had no impact
Toxicities Were Acceptable
While toxicities were acceptable for both arms, the hematologic
toxicity profile of the dose-dense approach was somewhat more favorable (see
Table 1). Granulocytopenia was
significantly less common for the dose-dense group, according to Dr. Citron.
Postchemotherapy sensory loss or motor weakness was slightly more common for
Investigators cautioned that additional follow-up will be
needed to confirm this survival benefit. "The maximum follow-up is only 5
years, and treatment-related patterns of recurrence and toxicity may emerge"
with longer follow-up, Dr. Citron said. Economic issues may also need to be
addressed, since filgrastim may make the dose-dense approach more expensive.