Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer

Pagani, Olivia; Sessa, Cristiana; Martinelli, Giovanni; Cerny, Thomas; Jong, J. de; Goldhirsch, Aron; Zimatore, Matteo; Cavalli, Franco

doi:10.1023/a:1008211629858

Cited by 11 publications

(10 citation statements)

References 12 publications

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“…The response rate compares favourably with more standard FAC/FEC chemotherapy regimens, where responses of 44–57% have been reported [1, 2, 3], and is in keeping with response rates reported for combinations of paclitaxel/epirubicin (54–84%) and paclitaxel/cyclophosphamide (50%) [12, 16, 17, 18, 20]. …”

Section: Discussionsupporting

confidence: 79%

Paclitaxel, Epirubicin and Cyclophosphamide Combination in First-Line Treatment of Metastatic Breast Cancer: A Dose Escalation Study

Bonneterre

Tubiana-Hulin²,

Catimel³

2004

Oncology

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The purpose of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of combined paclitaxel, epirubicin and cyclophosphamide in patients with metastatic breast cancer. The dose of paclitaxel was planned to be escalated from 150 to 225 mg/m²in 25 mg/m² steps, while the doses of epirubicin and cyclophosphamide were fixed at 50 and 500 mg/m², respectively. Because of DLT, the dose of paclitaxel was maintained at 200 mg/m² and the dose of epirubicin was increased to 90 mg/m². The MTD was reached at a dose of paclitaxel and epirubicin of 200 and 75 mg/m²,respectively. DLT were mainly febrile neutropenia and grade 4 neutropenia lasting for ≧7 days. Among the 35 evaluable patients, there were 2 (6%) complete responses and 19 (53%) partial responses for an overall response rate of 59% [95% confidence interval (CI): 41–74%]. The triplet paclitaxel/epirubicin/cyclophosphamide is an effective and well-tolerated combination worthy of further investigation in the treatment of patients with metastatic breast cancer.

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Section: Discussionsupporting

confidence: 79%

Paclitaxel, Epirubicin and Cyclophosphamide Combination in First-Line Treatment of Metastatic Breast Cancer: A Dose Escalation Study

Bonneterre

Tubiana-Hulin²,

Catimel³

2004

Oncology

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“…In the aforementioned phase I -II study of Pagani et al (1997) evaluating the paclitaxel/cyclophosphamide doublet, a doseresponse effect was suggested for pretreated patients, with a lower RR reported for those receiving o1500 mg m À2 of cyclophosphamide (Pagani et al, 1997). As equivalent cytotoxic alkylator doses of ifosfamide are anticipated at 4.5 -6.0 mg m À2 , the recommended phase II dose derived from our study regarding ifosfamide might represent an optimal alternative to cyclophosphamide with less haematologic toxicity.…”

Section: Discussionmentioning

confidence: 75%

“…The highest degree of haematologic toxicity was encountered when paclitaxel was administered by 24-h or 72-h continuous infusion with high doses of cyclophosphamide (Kennedy et al, 1996;Tolcher et al, 1996). However, when paclitaxel, given by 3-h infusion, was followed by cyclophosphamide, bone marrow toxicity was of much less severity (Pagani et al, 1997). In contrast, with the docetaxel -ifosfamide combination, the schedule of administering the taxane first led to less haematologic toxicity and a higher MTD than did the reverse drug sequence (Pronk et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Kosmas

Tsavaris²,

Malamos

et al. 2003

Br J Cancer

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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 À2 over 1 h on day 1 followed by ifosfamide 5 -6 g m À2 divided over days 1 and 2 (2.5 -3.0 g m À2 day À1 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 1 (range, 0 -2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 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 (p7 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 singleagent docetaxel or combinations of the latter with other active agents. ) has demonstrated a broad spectrum of activity against a variety of advanced solid tumours, and breast cancer represents the first in which docetaxel has been successfully tested (Salminen et al, 1999). In particular, for patients with prior anthracycline-based therapy, taxanes represent the treatment of choice in the salvage setting, since previously applied agents have demonstrated infe...

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“…The highest degree of hematologic toxicity was encountered when paclitaxel was combined in 24 or 72-h continuous infusion with high doses of cyclophosphamide [26,27]. However, when paclitaxel, given by 3-h infusion, was followed by cyclophosphamide, bone marrow toxicity was of much less severity [28]. It is therefore realistic to consider that the sequence of administration of docetaxel followed by ifosfamide could account for the tolerable hematologic toxicity, ie, neutropenia and thrombocytopenia, encountered in our present extended phase II experience.…”

Section: Discussionmentioning

confidence: 99%

Docetaxel–ifosfamide combination in patients with HER2-non-overexpressing advanced breast cancer failing prior anthracyclines

Kosmas

Tsavaris²,

Malamos

et al. 2007

Invest New Drugs

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The feasibility of the docetaxel-ifosfamide combination, as well as the definition of maximum tolerated doses (MTD) in a previous phase I study, led us to continue evaluating the regimen in an extended phase II study in patients with HER2-non-overexpressing, anthracycline pre-treated advanced breast cancer. Patients with histologically confirmed metastatic breast cancer failing prior anthracycline-based chemotherapy were treated with docetaxel 100 mg/m2 over 1 h on day 1 followed by ifosfamide 5 g/m2 divided over days 1 and 2 (2.5 g/m2/day over 1 h), and recycled every 21 days with prophylactic granulocyte-colony stimulating factor (G-CSF) administration from day 3-until a neutrophil count >10,000/microl. Between March 1999 and June 2002, 71 patients with a median age of 55 years (range, 28-72) and performance status (World Health Organization; WHO) of 1 (range, 0-2) were treated; all were assessable for toxicity and 70 patients for response. Clinical response rates (RRs), on an intention-to-treat basis were: 41/71 [58%; 95% CI, 46.5-69.5%]; 7 complete remissions (CRs), 34 partial remissions (PRs), 15 stable disease (SD) and 15 progressive disease (PD). The median response duration was 7.5 months (2-28 months), median time-to-progression (TTP) 6 months (0.1-30 months), and median overall survival (OS) 12 months (0.1-36 months). Grade 3/4 toxicities included; neutropenia in 63% of patients-with 52% developing grade 4 neutropenia (>or=7 days) and in 11% of these febrile neutropenia (FN), while no grade 3/4 thrombocytopenia was observed. Other toxicities included; peripheral neuropathy grade 2 only in 7%, grade 1/2 reversible central nervous system (CNS) toxicity in 11%, no renal toxicity, grade 2 myalgias in 7%, grade 3 diarrhea in 4%, skin/nail toxicity in 11%, and grade 1/2 fluid retention in 28% of patients. The present report has demonstrated encouraging activity of the docetaxel-ifosfamide combination in anthracycline-pretreated, HER2-negative advanced breast cancer. Therefore, future randomized phase III studies versus single-agent docetaxel or currently established combinations of the latter with other agents in this setting with established clinical activity, such as capecitabine or gemcitabine, will be warranted.

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Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer

Abstract: Paclitaxel at 200 mg/m2 and cyclophosphamide at 1,750 mg/m2 can be safely administered every three weeks to women with advanced breast cancer. The moderate antitumour activity observed with the schedule tested argues against its use as initial therapy for advanced breast cancer.

Cited by 11 publications

References 12 publications

Paclitaxel, Epirubicin and Cyclophosphamide Combination in First-Line Treatment of Metastatic Breast Cancer: A Dose Escalation Study

Paclitaxel, Epirubicin and Cyclophosphamide Combination in First-Line Treatment of Metastatic Breast Cancer: A Dose Escalation Study

Phase I–II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Docetaxel–ifosfamide combination in patients with HER2-non-overexpressing advanced breast cancer failing prior anthracyclines

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