Optimization of high-dose therapy for the treatment of patients with metastatic breast cancer

Abstract

Objective. To determine the effect of chemorespon siveness and dose intensity on event-free survival (EFS) for metastatic breast cancer patients following high-dose chemotherapy and autologous stem cell rescue. Design. This is a retrospective review of data from three allocated, parallel, dose escalation, high dose phase I/II trials. Setting. These trials were carried out at H. Lee Moffitt Cancer, Tampa, Florida. Patients. Since October 1989, 215 patients with metastatic (stage IV) breast cancer receiving the following high-dose treatment regimens with stem cell rescue: (1) ifosfamide, carboplatin, and etoposide (ICE); (2) mitoxantrone and thiotepa (MITT); and (3) Taxol, Novantrone, thiotepa (TNT). Intervention. Patients received either escalating doses of ICE (ifosfamide 6000 to 24,000 mg/m 2, carboplatin 1200 to 2100 mg/m2, etoposide 1800 to 3000 mg/m2), or MITT (mitoxantrone 45 to 105 mg/m2, thiotepa 900 to 1350 mg/m2) or TNT (thiote pa 900 mg/m2, Novantrone 45 to 75 mg/m2, Taxol 120 to 360 mg/m2) followed by stem cell rescue. Patients were then grouped by degree of dose inten sity and chemoresponsiveness. Main Outcome Measures. EFS curves were generated by the Kaplan-Meier product limit method and compared by log rank or Kruskal-Wallis analysis. Events were defined as disease progression or death (from whatever cause) which ever came first. P values reported are two-tailed. Results. Probability of EFS (±SE) for all 215 metastatic breast cancer patients treated with ICE divided by degree of dose intensity (Phase I—lower dose intensity vs Phase II— higher dose intensity) at 3 years is 2.4 ± 2.3% for Phase I patients as compared with 18.4 ± 3.8% for phase II patients (P = .0951). The EFS for Phase II anthracycline responsive patients (n = 42) at 2 years is 36 ± 10%, 33 ± 19%, 29 ± 17% for MITT, ICE dose 11 through 15, and ICE dose level 16, respectively. The EFS for TNT at 5 months is 43 ± 19%. Overall percentages of toxic deaths were higher for patients receiving MITT (32%) and TNT (29%) as compared with the patients receiving ICE (8%) (P = .24). These differences are mainly attributed to an increased risk of cardiac toxicity in patients treated with MITT or TNT. All phase II patients (n = 139) treated with ICE, MITT and TNT were categorized by chemotherapy sensitivity status, the EFS at 3 years for the anthracycline responsive group is 31 ± 8%, as compared with for the anthracycline refractory/mini- ICE (lower doses of ICE) responsive group 19 ± 9% and 0% for the refractory group (P = .004). Conclusions. These results suggest that ICE, MITT, and TNT in the high-dose setting suggests that there may be a therapeutic advantage for delivering "highest" dose intensive therapy in patients with metastatic breast cancer. When all phase II patients treated with ICE, MITT, and TNT were categorized by chemotherapy sensitivity status, a significant differ ence in EFS among the three categories of sensitivity to anthracyclines and mini-ICE was observed. Further study of dose intensity in the setting of high-dose therapy for the treatment of metastatic breast cancer is warranted.