Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study

Autor: A C Humphreys, J Dent, S Rodwell, S M Crawford, J K Joffe, C Bradley, D Dodwell, T J Perren
Jazyk: angličtina
Rok vydání: 2004
Předmět:
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
Popis: The treatment of metastatic or advanced breast cancer has evolved over the last few years, and in the 1990s this was largely due to the introduction of the taxane family of drugs. Docetaxel (taxotere) is a semisynthetic taxane derived from 10-deacetyl baccatin III, a precursor isolated from the needles of Taxus baccata. As with the other taxane compounds, it acts by promoting microtubule assembly and inhibiting microtubule depolymerisation. This blocks cells in M phase and so prevents cell division. Docetaxel has well-documented activity in advanced breast cancer with a single agent dose of 100 mg m−2. The dose-limiting toxicity of docetaxel is grade 3 and 4 neutropenia. The response rate ranges from 19–57% in pretreated patients and 54–67% in those with minimal pretreatment (Clemons et al, 1997). Following the single-agent studies, docetaxel was combined with other active agents. The most attractive combination, initially, was with anthracyclines, as docetaxel is known to have activity in anthracycline-resistant disease (Miller et al, 2001). Studies were carried out using epirubicin and docetaxel. For example, docetaxel was escalated with a fixed dose of epirubicin (Venturini et al, 2001). It was found that the dose-limiting toxicity was neutropenia, which was ameliorated to some extent by G-CSF. Other side effects were mild. There were however two toxic deaths. The recommended doses for further investigation were epirubicin 75 mg m−2 and docetaxel 80 mg m−2. In a further study (Viens et al, 2001), escalating doses of epirubicin were given with a fixed dose of docetaxel 75 mg m−2. Dose-limiting toxicities were grade 3 and 4 asthenia, febrile neutropenia and stomatitis and diarrhoea. There was an overall response rate of 69.4%, and a median duration of response of 7.8 months. The recommended dose was epirubicin 100 mg m−2 with docetaxel 75 mg m−2. An overview of these studies in 2001 (Trudeau and Pagani, 2001) concluded that epirubicin and docetaxel was effective, with high response rates, and no significant cardiotoxicity. Docetaxel has also been combined with 5-fluorouracil (5-FU). A phase I study (Lortholary et al, 2000) escalated doses of docetaxel, given on day 1, along with escalating doses of 5-FU given as a 5-day intravenous infusion, every 3 weeks. The most common toxicity was grade 4 neutropenia, which occurred in 91% of patients. The recommended dose for phase II studies was 85 mg m−2 docetaxel with 750 mg m−2 day−1 5-FU for 5 days. At the time this study was initiated, a very active regimen that was used was the ECF regimen of epirubicin, 50 mg m−2, cisplatin, 60 mg m−2 and infusional 5-FU, 200 mg m−2 day−1. A phase II study of eight courses of ECF in 43 patients with metastatic and locally advanced breast cancer (Jones et al, 1994) gave an overall response rate of 84%. This regimen has also been used in a phase II study in patients with large but operable breast cancer in the neoadjuvant setting (Smith et al, 1995). A total of 50 patients were treated with an overall response rate of 98% and 66% complete response rate. Grade 3 and 4 toxicities were rare. The ECF regimen was of sufficient interest to investigate it further in phase III studies in both the neoadjuvant (TOPIC Trial) and high-risk adjuvant (TRAFIC) settings. The ECF regimen, in general, is well tolerated. However, the inclusion of cisplatin in the regimen usually necessitates an overnight stay for each course of treatment. We therefore looked at the possibility of using epirubicin and 5-FU in the doses used in the ECF regimen, but combining them with docetaxel, a very active agent in metastatic breast cancer, which can be given as an outpatient.
Databáze: OpenAIRE
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