This is a phase I dose-escalation study of uracil and tegafur (in a molar ratio of 4:1 [UFT]) administered in combination with calcium folinate and paclitaxel in metastatic breast cancer. This trial was initiated to 1)
ABSTRACT: This is a phase I dose-escalation study of uracil and tegafur (in a molar ratio of 4:1 [UFT]) administered in combination with calcium folinate and paclitaxel in metastatic breast cancer. This trial was initiated to 1) determine the maximum tolerated dose and dose-limiting toxicities of UFT plus calcium folinate (Orzel) administered three times per day for 21 days in combination with paclitaxel; and 2) define the appropriate dose for phase II testing. Thus far, 14 patients have been accrued to three dose levels. Two patients developed dose-limiting toxicities at dose level 3. One patient experienced grade 3 hypotension. A second patient experienced grade 3 vomiting, grade 4 diarrhea, and severe hand-foot syndrome. Two partial responses and one complete response have been observed. Early trends suggest that this regimen is active in metastatic breast cancer and is well tolerated. Completion of this study is anticipated in 1999. [ONCOLOGY 7(Suppl 3):69-70, 1999]
Paclitaxel and 5-fluorouracil (5-FU) are active as single agents in metastatic breast cancer. Preclinical data demonstrate additive cytotoxicity of paclitaxel and 5-FU in MCF-7 breast carcinoma cell lines that is sequence-dependent, requiring that paclitaxel be administered prior to 5-FU. A phase II trial of paclitaxel, 5-FU, and calcium folinate has demonstrated this combination to be active and well tolerated for the treatment of metastatic breast cancer.
UFT is an oral agent composed of uracil and tegafur in a molar ratio of 4:1. Tegafur is converted to 5-FU in vivo, and thus, its side-effect profile is similar to that of 5-FU. UFT has been shown to be active in metastatic breast cancer, yielding response rates of up to 32% in phase I/II trials when used singly or in combination with calcium folinate. UFT plus calcium folinate (Orzel) has the additional benefit of combining the biomodulator calcium folinate into one oral prescription. This agent may be more advantageous than 5-FU, as it can be orally administered over long periods without the inconvenience of an intravenous infusion. Prolonged drug administration may enhance cytotoxicity as a higher percentage of tumor cells are exposed during the sensitive phase of the growth cycle.
Patients with histologically documented metastatic breast cancer are eligible for this study. Eligibility criteria include 1) age > 18 years; 2) Eastern Cooperative Oncology Group (ECOG) performance status £ 2; 3) life expectancy ³ 3 months; 4) adequate hematopoietic, hepatic, and renal function; 5) at least one prior chemotherapy regimen either for adjuvant or palliative treatment; 6) a maximum of one prior chemotherapy regimen for metastatic disease; 7) complete recovery from toxicities resulting from previous therapy regimens; and 8) no uncontrolled medical disorder or febrile illness. All patients are required to provide written informed consent.
Dose escalation is being conducted according to Table 1. The starting dose at level 1 is paclitaxel 135 mg/m² administered on day 1 as a 3-hour infusion; UFT 200 mg/m²/day and calcium folinate 90 mg/day administered orally in three divided doses, days 2 to 22. The paclitaxel dose is increased in dose level 2 to 175 mg/m² and remains fixed at this dose for all subsequent dose levels. UFT is escalated by 50-mg/m²/day increments, in cohorts of three to six patients, until a dose-limiting toxicity is observed. Calcium folinate remains at 90 mg/day in three divided doses and is administered concurrently with UFT. Physical examination and symptom assessments are scheduled each week during the treatment phase, then every 3 weeks thereafter, until all study treatment-related toxicities resolve. Patients are treated every 28 days.
A total of 47 courses of therapy have been administered to 14 patients at three dose levels. The number of courses ranged from one to eight. Twelve of the 14 patients enrolled have completed cycle 1 of treatment and are assessable for response and toxicity.
Patient characteristics are outlined in Table 2. The median patient age was 52 years (range 33 to 66). The median performance status was 0 (range 0 to 1). Patients had up to three sites of metastatic disease; two patients had bone-only disease, one patient had skin/soft tissue disease only, and eight patients had lung and/or liver involvement.
Myelosuppression during the first cycle was mild to moderate, with only one patient developing grade 4 neutropenia. No episodes of febrile neutropenia occurred. Drug effects on red blood cells and platelets were minimal; no grades 3 or 4 anemia or thrombocytopenia were observed.
Paclitaxel-related myalgia and arthralgia were the most common nonhematologic toxicities noted in the first cycle. One patient experienced grade 3 nausea and vomiting, grade 4 diarrhea, and severe hand-foot syndrome, requiring discontinuation of treatment. Grade 1 paclitaxel-induced sensory neuropathy was noted in only two patients; both had a history of diabetes mellitus. In addition, one patient experienced grade 3 hypotension.
Two patients experienced dose-limiting toxicities at the third dose level (paclitaxel 175 mg/m², UFT 250 mg/m², calcium folinate 90 mg/day). One patient in the first cohort at this level experienced grade 3 hypotension as noted above. This occurred 48 hours after the paclitaxel infusion, but it was unclear whether this complication was
secondary to the study medication. Therefore, an additional three patients were accrued to dose level 3 as mandated by the protocol. Of these, one patient developed grade 4 diarrhea that was attributed to UFT plus calcium folinate. To better define the dose-limiting toxicity, three additional patients will be treated at dose level 3.
Twelve patients were assessable for response. There was one complete response and one partial response; six patients had stable disease and four patients had progressive disease.
The maximum tolerated dose for the combination of paclitaxel and UFT plus calcium folinate has not yet been established. Dose-limiting toxicitiesincluding hypotension and diarrheahave necessitated the addition of a third cohort of patients at dose level 3 to further characterize the pattern of toxicity. To date, the experience suggests that this regimen is relatively well tolerated and conducive to good compliance.
1. Nicholson B, Paul D, Hande KR, et al: A phase II trial of paclitaxel (T), 5-fluorouracil (5-FU), and leucovorin (L) in metastatic breast cancer (MBC) (abstract 72). Proc Am Soc Clin Oncol 15:102, 1996.
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