title: Dose escalation of docetaxel and ifosfamide in patients with advanced breast cancer failing prior anthracyclines: mature results of a phase I-II study.
abstract: OBJECTIVE
  Single-agent docetaxel and ifosfamide are clinically active in anthracycline-pretreated advanced breast cancer. We conducted a phase I-II study aiming to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the activity of the docetaxel-ifosfamide combination in this setting.
  
  
  METHODS
  Cohorts of 3-6 patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel (70-100 mg/m(2) over 1 h on day 1), followed by ifosfamide 5-6 g/m(2) divided over days 1 and 2 (2.5-3.0 g/m(2)/day over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs.
  
  
  RESULTS
  Sixty-five patients (median age 57 years, range 32-72) and performance status (PS) (World Health Organization-WHO) of 1 (range 0-2) were treated at 5 DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 44 were treated at DL4 (total of 50 patients at DL4), which was defined as the level for phase II testing. All patients were evaluable for toxicity and 62 for response. DLT (with the addition of G-CSF after DL2) was reached at DL5 with 2/3 initial patients developing febrile neutropenia. Clinical response rates (RRs), on an intention-to-treat basis, in phase II were 56% (95% CI 42.2-69.7): complete remission (CR) 4, partial remission (PR) 24, stable disease (SD) 10 and progressive disease (PD) 12. The median response duration was 7 months (range 3-24), the median time to progression (TTP) 6.5 months (range 0.1-26), and the median overall survival (OS) 13 months (range 0.1-33). Grade 3/4 toxicities included neutropenia in 72% of patients-with 60% developing grade 4 neutropenia (</= 7 days) and 10% of these febrile neutropenia (FN), while no grade 3/4 thrombocytopenia was observed. Other toxicities included grade 2 peripheral neuropathy only in 10% of the patients, grade 1/2 reversible CNS toxicity in 16%, no renal toxicity, grade 2 myalgias in 8%, grade 3 diarrhea in 8%, skin/nail toxicity in 14%, and grade 2 fluid retention in 2%. One patient treated at the phase II part of the study died of acute liver failure after the first cycle.
  
  
  CONCLUSIONS
  The present phase I-II study determined the feasibility, defined the MTD and demonstrated the encouraging activity of the docetaxel-ifosfamide combination in the phase II part of the study. Therefore, future randomized phase III studies versus single-agent docetaxel or combinations of the latter with other active agents are warranted.
authors.affiliation: Department of Medical Oncology-B, "Metaxa" Cancer Hospital, Piraeus, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Cosmas
authors.forename: N
authors.initials: N
authors.lastname: Tsavaris
authors.forename: N
authors.initials: N
authors.lastname: Malamos
authors.forename: G
authors.initials: G
authors.lastname: Tsakonas
authors.forename: A
authors.initials: A
authors.lastname: Gassiamis
authors.forename: H
authors.initials: H
authors.lastname: Skopelitis
authors.forename: G
authors.initials: G
authors.lastname: Soukouli
authors.forename: A
authors.initials: A
authors.lastname: Polyzos
authors.forename: N
authors.initials: N
authors.lastname: Mylonakis
authors.forename: A
authors.initials: A
authors.lastname: Karabelis