Dose-Intensive Chemo Improves Disease-Free Survival in High-Risk Cancer

HAMBURG—Preliminary 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 relatively short.”

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.”