ABSTRACT: The results from preclinical studies using murine tumor models show that the combination of docetaxel (Taxotere) and fluorouracil (5-FU) is highly synergistic. Phase I studies in patients with advanced solid tumors indicate that 60 mg/m² of docetaxel administered as a 1-hour intravenous infusion followed by a daily intravenous bolus of 300 mg/m² of 5-FU on days 1 through 5 is the recommended dose for phase II studies. Preliminary results from another phase I study using a continuous infusion regimen for 5-FU suggest that 85 mg/m² of docetaxel administered as a 1-hour intravenous infusion followed by continuous infusion of 750 mg/m² per day of 5-FU on days 1 through 5 may be the recommended dose for phase II studies. As expected, dose-limiting toxicities included neutropenia and mucositis. Ongoing phase I/II and II studies are investigating the combination of docetaxel with continuous infusion of 5-FU in patients with metastatic breast cancer and with cisplatin (Platinol) and continuous infusion of 5-FU, with and without leucovorin, in patients with head and neck cancer. Preliminary results are encouraging and warrant further study. [ONCOLOGY 11(Suppl 8):50-52, 1997]
A number of ongoing clinical trials are investigating the use of docetaxel (Taxotere) in combination with fluorouracil (5-FU) in a variety of solid tumors. Interest in the use of docetaxel in combination regimens was generated by the unique mechanism of action of the taxanes, a single dose-limiting toxicity of neutropenia, and a broad spectrum of antitumor activity.
As first-line therapy in patients with metastatic breast cancer, single-agent docetaxel administered at a dose of 100 mg/m² as an intravenous infusion over 1 hour, once every 3 weeks, has produced a response rate of 59%. Docetaxel also demonstrates a high level of activity in second- and third-line regimens, as well as in patients with anthracycline-resistant or -refractory metastatic breast cancer.[2,3]
Preliminary trials in patients with advanced head and neck tumors show that docetaxel at the same dosage produces a response rate of approximately 31%. Docetaxel appears to have activity in usually chemotherapy-resistant gastric carcinomas as well, with reports of a response rate of 26%.
Fluorouracil (5-FU) has shown activity in a variety of advanced solid tumor types, including metastatic breast cancer. Further, the combination of docetaxel and 5-FU has shown synergistic cytotoxicity in preclinical studies using murine tumor models.
A tumor-free survival rate of 60% was noted with this combination using 70% of the highest nontoxic dose in C38 colon adenocarcinoma. Each has a unique mechanism of action; docetaxel promotes microtubule assembly and 5-FU acts as an antimetabolite. Finally, docetaxel and 5-FU possess toxicity profiles that do not completely overlap.
Phase I Studies
Three phase I trials have been performed to determine the maximum tolerated dose and tolerability of docetaxel and 5-FU in patients with advanced solid tumors, including metastatic breast, head and neck, and gastric cancers.[7-9] Peacock and colleagues evaluated this combination when administered on a 28-day cycle in 28 patients with advanced solid tumors. Docetaxel was administered as a 1-hour intravenous infusion on day 1, followed by a once-daily intravenous bolus dose of 5-FU for days 1 through 5.
The dose-escalation schedule of docetaxel/5-FU started at 25/100 mg/m² and progressed to 35/150, 50/200, 60/200, or 60/300 mg/m². Premedication with 8 mg of dexamethasone was given twice daily for 3 days beginning 1 day prior to the administration of docetaxel. Growth factor support was not provided.
Among the 28 patients, tumor types included gastric, non-small-cell lung, head and neck, colon, sarcoma, and pancreas. The median Karnofsky performance score was at least 60%, with the majority of patients (68%) having received prior chemotherapy. The maximum tolerated dose was 60 mg/m² of docetaxel followed by 300 mg/m² of 5-FU.
This was also the dose the authors recommended for phase II trials. At this dose, grade 3 to 4 neutropenia was noted in 4 of 6 patients, 2 of whom also had fever. At each dose level, grade 1 to 2 mucositis, diarrhea, and asthenia were seen and did not appear to be dose-dependent. The authors noted antitumor activity in patients with breast, gastric, head and neck, and non-small-cell lung cancers. In particular, a complete response was noted in 1 patient with anthracycline-resistant breast cancer (personal communication, Peacock and Burris, May 1997).
Recently, de Valeriola and colleagues reported their findings in 40 patients with advanced solid tumors using a 21-day cycle of the docetaxel combined with continuous-infusion of 5-FU on days 1 through 5. The dose-escalation schedule of docetaxel/continuous-infusion 5-FU was 60/300 mg/m² and progressed to 75/300, 75/500, 75/750, 85/750, or 85/1,000 mg/m², without prophylactic growth factor support. To date, a median of 2 courses (range: 1 to 10) of each dose level have been administered.
The median age of patients was 52 years (range: 28 to 72) and there was a median World Health Organization performance status of 1 (range: 0 to 2). A total of 83% of patients had received prior chemotherapy for advanced disease. Preliminary analysis indicates that the maximum tolerated dose was 85 mg/m² of docetaxel and 1,000 mg/m² of 5-FU. The dose-limiting toxicities were mucositis and complications of neutropenia. Antitumor activity was seen at each dose level. The authors recommended a dose of docetaxel/continuous-infusion 5-FU for phase II trials of 85/750 mg/m²
The third phase I trial also used a 21-day cycle of docetaxel administered as a 1-hour intravenous infusion on day 1 followed by continuous infusion of 5-FU on days 1 through 5. Lortholary and colleagues reported preliminary results in 20 patients with metastatic breast cancer who had failed previous anthracycline-based chemotherapy. The dose-escalation schedule of docetaxel/5-FU started at 60/250 mg/m² and progressed to 75/250, 75/350, 75/500, 85/500, or 100/500 mg/m². Premedication with 8 mg of dexamethasone was given twice daily for 3 days beginning 1 day prior to the administration of docetaxel. Growth factor support was not provided.
The median age of patients was 58 years, with 60% of the patients having a World Health Organization performance status of 0 and 40% having a WHO performance status of 1. A total of 83% of patients had received prior chemotherapy for advanced disease. Visceral metastases consisted of those associated with bone (65%), soft tissue (5%), and bone and soft tissue (30%). Approximately 60% of the patients had metastasis in more than 2 sites.
The median cumulative dose of docetaxel and 5-FU was 571 mg/m² (range: 196 to 1,045 mg/m²) and 14 mg/m² (range: 5 to 35 mg/m2). Preliminary analysis indicates an overall response rate of 40% and stable disease in 45% of patients. The authors noted that the maximum tolerated dose has not yet been reached. Grade 4 neutropenia was noted in 90% of the patients; however, febrile neutropenia developed in only 1 patient.
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