High-dose thiotepa and melphalan with hemopoietic progenitor support following induction therapy with epirubicin-paclitaxel-containing regimens in metastatic breast cancer (MBC)

Ann Oncol. 2001 Jan;12(1):69-74. doi: 10.1023/a:1008302402687.

Abstract

Background: Preliminary data from phase III randomized studies have failed to show benefit of HDC given as consolidation after anthracycline and alkylating-based chemotherapy in metastatic breast cancer (MBC). Moderate activity of induction regimens and selection of chemoresistant clones are among the possible reasons for these disappointing results. We therefore have designed a phase II study where high-dose alkylating agents are given as consolidation after an induction treatment including the most active agents (epirubicin and paclitaxel) without alkylating agents.

Patients and methods: Patients with MBC not previously treated with chemotherapy for metastatic disease were eligible. After six courses of epirubicin-paclitaxel +/- gemcitabine patients received a course of thiotepa 600 mg/m2 + melphalan 160 mg/m2 with hemopoietic support. Pharmacokinetic parameters of thiotepa and melphalan were measured and related to treatment outcomes. The L-VEF of the patients was monitored before and after treatment.

Results: Forty-eight patients have been treated. Before HDC 14 patients were in CR, and 34 in PR. A median of 6.92 x 10(6) (range 1.53-16.6) CD34+ cells/kg were reinfused after HDC. Median days (range) to neutrophils > 0.5 x 10(9)/l and platelets > 20,000 x 10(9)/l were 9.5 (9-33) and 10 days (9-32), respectively. Symptomatic CHF was observed in two patients (4.1%). Cmax and AUC of thiotepa showed a linear relationship with time to progression (TTP) and overall survival (OS): r2 = 0.6. After HDC the conversion rate from PR to CR was 44.1%. At five years progression-free and overall survival rates are 37.5% and 65%, respectively. A treatment-related death was observed.

Conclusions: High-dose thiotepa and melphalan after an epirubicin-paclitaxel-containing treatment is feasible, devoid of significant cardiotoxicity and very active. Pharmacokinetic parameters of high-dose thiotepa might be linked to treatment outcome.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Disease Progression
  • Epirubicin / administration & dosage
  • Female
  • Gemcitabine
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Melphalan / administration & dosage
  • Melphalan / pharmacokinetics
  • Middle Aged
  • Paclitaxel / administration & dosage
  • Survival Analysis
  • Thiotepa / administration & dosage
  • Thiotepa / pharmacokinetics
  • Treatment Outcome

Substances

  • Deoxycytidine
  • Epirubicin
  • Thiotepa
  • Paclitaxel
  • Melphalan
  • Gemcitabine