ORLANDO-Results from the European Cooperative Trial
in Operable Breast Cancer (ECTO) show that the addition of paclitaxel to a
commonly used breast cancer chemotherapy regimen improved time to progression
without increasing toxicities, Luca Gianni, MD, reported at the American
Society of Clinical Oncology 41st Annual Meeting (abstract 513). "ECTO is the
first study to show therapeutic benefit from adjuvant paclitaxel by directly
comparing two regimens of identical duration and similar tolerability," said
Dr. Gianni, Istituto Nazionale Tumori, Milan, Italy.
Prior studies have proven the effectiveness of doxorubicin (Adriamycin)
followed by cyclophosphamide, methotrexate, and fluorouracil (CMF) in treating
high-risk breast cancer, and have shown that paclitaxel and doxorubicin (AT)
followed by CMF prior to surgery is well tolerated.
ECTO was designed to test whether adding paclitaxel to
doxorubicin followed by CMF improved efficacy and whether primary systemic
therapy produced a better result than adjuvant therapy. Researchers randomized
1,355 patients (1,324 evaluable for chemotherapy) with tumors larger than 2 cm
to one of three treatment arms. Almost 90% of patients completed the plan of
In the first cohort, 444 women received surgery followed by
standard therapy (A→CMF): doxorubicin, 75
mg/m2, IV bolus every 3 weeks for four cycles, followed by
cyclophosphamide, 600 mg/m2, methotrexate 40 mg/m2, and
fluorouracil 600 mg/m2 IV on days 1 and 8, every 4 weeks for four
The 432 patients in the second cohort had surgery followed
by AT→CMF: paclitaxel (Taxol) 200 mg/m2
3 hours and doxorubicin 60 mg/m2 every 3 weeks for four cycles
followed by CMF, as previously outlined. The third cohort of 448 women received
AT→CMF, in the doses already described,
prior to surgery. All women took tamoxifen 20 mg daily for 5 years and received
radiation therapy as indicated. Endpoints were disease-free and overall
survival. Cardiac status was monitored, and pathological responses were
determined. Patients were followed every 6 months for the first 2 years, then
"Results at 5 years of follow-up indicate freedom from
progression is better for women who received the paclitaxel-containing regimen,
with a hazard ratio [HR] of 0.66 and a P value of .01," Dr. Gianni said.
In the second planned analysis to determine if giving the paclitaxel-containing
regimen prior to surgery was better than adjuvant therapy, the data showed
freedom from progression was the same in the two treatment arms. Freedom from
progression increased significantly among the primary systemic chemotherapy
patients who achieved a pathologic complete response, 89% vs 75% in those who
did not obtain a pathologic complete response (HR 2.80, P = .006).
"Pathological complete response is an independent variable for predicting
efficacy," Dr. Gianni said.
There was no significant difference in risk of local
recurrence between women who received conservative therapy and those who
underwent a radical mastectomy, independently of administration of chemotherapy
before or after surgery.
At 5 years, 87% of the women receiving the traditional
therapy were still alive, as were 91% of women who received the adjuvant
paclitaxel-containing regimen and 90% of those patients receiving the
paclitaxel-containing regimen prior to surgery. "Overall survival shows that
there is no significant difference at 5 years," Dr. Gianni said. "However,
there is a trend toward improved overall survival in the patients who received
the doxorubicin/paclitaxel combination."
The investigators saw no dramatic difference in left
ventricular ejection fraction (LVEF) in the traditional vs paclitaxel groups
during therapy or follow-up. A minority of patients experienced an LVEF below
normal limits or more than 20% of the basal value. Dr. Gianni found no
significant difference between the treatment arms. "Cardiac tolerability so far
ranks AT→CMF among the safest anthracycline-containing
regimens for early breast cancer," he said.
Dr. Gianni concluded that adjuvant AT→CMF
significantly prolongs freedom from progression, compared with A→CMF,
in patients with operable breast cancer, and at 5 years, efficacy of adjuvant
vs primary AT→CMF is similar.
"This study clearly demonstrates that adding paclitaxel to
doxorubicin in the context of sequential treatment is superior in terms of
event-free survival," said Gabriel N. Hortobagyi, MD, of M.D. Anderson Cancer
Center, during the discussion. He cautioned, however, that this trial with
fewer than 500 patients in each arm, may have been underpowered for some
questions it sought to answer.