Topics:

Docetaxel in Combination With Fluorouracil for Advanced Solid Tumors

Docetaxel in Combination With Fluorouracil for Advanced Solid Tumors

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]

Introduction

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%.[1]
Docetaxel also demonstrates a high level of activity in second- and third-line
regimens,[1] 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%.[4] Docetaxel appears to have activity in usually chemotherapy-resistant
gastric carcinomas as well, with reports of a response rate of 26%.[4]

Fluorouracil (5-FU) has shown activity in a variety of advanced solid
tumor types, including metastatic breast cancer.[5] Further, the combination
of docetaxel and 5-FU has shown synergistic cytotoxicity in preclinical
studies using murine tumor models.[6]

A tumor-free survival rate of 60% was noted with this combination using
70% of the highest nontoxic dose in C38 colon adenocarcinoma.[6] 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.

Docetaxel/5-FU
in Patients With Advanced Solid Tumors

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[7] 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[8] 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

Preliminary Results

The third phase I trial[9] 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[9] 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.

Pages

 
Loading comments...
Please Wait 20 seconds or click here to close