Περίληψη:
Given the established individual activity of docetaxel and ifosfamide in
anthracycline pretreated advanced breast cancer, the present phase I-II
study aimed to define the maximum tolerated dose (MTD), the
dose-limiting toxicities (DLTs), and activity of the
docetaxel-ifosfamide combination in this setting. Cohorts of three to
six 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 I and
2 (2.5-3.0 g m(-2) day(-1) 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. In total, 56 patients with a median age of 54.5 (range, 32-72)
years and performance status (WHO) of I (range, 0-2) were treated at
five DLs as follows: 21 in phase I DLs (DL I : 3, DL2: 6, DL3: 3, DL4:
6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41
patients at DL4), which was defined as the level for phase II testing.
All patients were assessable for toxicity and 53 for response.
Dose-limiting toxicity (with the addition of G-CSF after DL2) was
reached at DL5 with two out of three initial patients developing febrile
neutropenia (FN). Clinical response rates, on an intention-to-treat
basis, in phase II were: 53.6% (95% CI, 38.3-68.9%); three complete
remissions, 19 partial remissions, seven stable disease, and 12
progressive disease. The median response duration was 7 months (3-24
months), median time to progression 6.5 month (0.1-26 month), and median
overall survival 13 months (0.1-33 months). Grade 3/4 toxicities
included time to progression neutropenia in 78% of patients-with 63%
developing grade 4 neutropenia (less than or equal to7 days) and in 12%
of these FN, while no grade 3/4 thrombocytopenia was observed. Other
toxicities included peripheral neuropathy grade 2 only in 12%, grade
1/2 reversible CNS toxicity in 17%, no renal toxicity, grade 2 myalgias
in 10%, grade 3 diarrhoea in 10%, skin/nail toxicity in 17%, and
grade 2 fluid retention in 2% of patients. One patient in the study
treated at phase II died as a result of acute liver failure after the
first cycle. In conclusion, the present phase I-II study determined the
feasibility of the docetaxel-ifosfamide combination, defined the MTD and
demonstrated the encouraging activity of the regimen in phase II, thus
warranting further randomised phase III comparisons to single-agent
docetaxel or combinations of the latter with other active agents. (C)
2003 Cancer Research UK.
Συγγραφείς:
Kosmas, C
Tsavaris, N
Malamos, N
Stavroyianni, N and
Gregoriou, A
Rokana, S
Polyzos, A
