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


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.
Department of Oncology Transplants ancd Advanced Technologies in Medicine, St. Chiara Hospital and University of Pisa, Italy.
C
C
Bengala
I
I
Pazzagli
F
F
Innocenti
S
S
Donati
C
C
Favre
M C
MC
Menconi
F
F
Greco
R
R
Danesi
C
C
Orlandini
V
V
Guarneri
M
M
Del Tacca
P F
PF
Conte
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D016019:Survival Analysis; D013852:Thiotepa / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; D015251:Epirubicin; D013852:Thiotepa; D017239:Paclitaxel; D008558:Melphalan; D000093542:Gemcitabine