HAMBURGPreliminary findings from a small German study
presented at the San Antonio Symposium have provided what
investigators describe as the first evidence that dose-intensive
adjuvant chemotherapy improves disease-free survival in high-risk
breast cancer patients.
During a median follow-up of 22.4 months, there have been 17
recurrences in 92 evaluable patients who received dose-intensive
combination therapy with epirubicin and cyclophosphamide vs 28
recurrences in 81 patients treated with a standard epirubicin-CMF regimen.
For the first time, we have shown the efficacy of a
dose-intensive adjuvant chemotherapy regimen in terms of improved
disease-free survival in high-risk breast cancer patients, said
Dr. Christoph Thomssen, of the University of Hamburg. The
difference became significant after 2 years of follow-up. We have
observed no difference in overall survival, but follow-up is still
Support for Dose-Dense Concept
Investigators have hypothesized that shortening the interval between
chemotherapy cycles might lead to more effective and complete
eradication of tumor cells. Until now, clinical data to support
the concept have been lacking, he said.
The trial involved high-risk breast cancer patients who had 10 or
more positive lymph nodes or extracapsular node infiltration.
Patients randomized to dose-intensive therapy received 120 mg/m²
of epirubicin and 600 mg/m² of cyclophosphamide every 14 days
for four cycles, supported by G-CSF on days 2 to 14. Conventional
therapy consisted of 90 mg/m² of epirubicin and 600 mg/m²
of cyclophosphamide, repeated every 21 days for four cycles and
followed by three courses of CMF.
With overall follow-up of 22.4 months, the difference in disease-free
survival remains significant in 173 evaluable patients (P = .017).
The TWiST (time without symptoms and toxicity) evaluation provided an
indication of quality of life related to the interval between the end
of therapy and the appearance of disease symptoms or treatment toxicity.
The TWiST data, at median follow-up of 22.4 months, showed 12
recurrences of symptoms or toxicity among 77 evaluable patients in
the dose-intense arm (16%) and 17 recurrences in 49 evaluable
patients in the standard treatment arm (35%). The duration of the
symptom-and-toxicity-free interval was significantly greater in the
dose-intense arm (P = .003).
The dose-intense regimen was associated with relatively mild
hematologic toxicity, Dr. Thomssen said. The median nadir white cell
count was 2.1/nL in the dose-intense arm, 2.7 with
epirubicin-cyclophosphamide, and 3.4 with CMF. Respective median
platelet nadirs were 176, 223.5, and 206/nL.
Two patients in the dose-intense arm had severe cardiotoxicity (one
had a history of supraventricular tachycardia, and the other had
evidence of pericarditis). One of these patients recovered with drug
discontinuation and the other died. No other patients exhibited cardiotoxicity.
Although the dose-intense regimen seems not to be very
cardiotoxic, indications for dose intensity should be considered
carefully in patients with a history of cardiac disease, he said.
The dose-intense regimen did not offer any apparent advantages to
patients who overexpressed HER-2. In the dose-intense arm, there were
7 recurrences in 22 evaluable patients who were HER-2 positive vs 9
in 54 HER-2-negative patients (32% vs 17%). For those on the standard
arm, there were 12 recurrences in 25 HER-2-positive patients vs 16 in
50 HER-2-negative patients (48% vs 32%).
This trial has limitations due to the relatively small number
of patients, Dr. Thomssen said. However, from these first
results, we may conclude that the dose-intense regimen can be used
safely in high-risk patients and appears to be more effective than
the standard regimen.