UFT/Leucovorin Combined With Paclitaxel for Anthracycline-Pretreated Advanced Breast Cancer

ABSTRACT: Taxanes are the most active drugs in the treatment of metastatic breast and ovarian cancer. Weekly therapy with paclitaxel produces notable activity, with remarkably low toxicity. Moreover, combination therapy with paclitaxel and fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer patients: recent studies report response rates of 54% to 69%. UFT plus oral leucovorin constitutes an orally administered compound that provides activity comparable to that of intravenously administered 5-FU plus leucovorin. An open-label phase I study was initiated to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel and UFT plus leucovorin administered to patients with anthracycline-resistant metastatic breast cancer. [ONCOLOGY 14(Suppl 9):44-46, 2000]

Introduction

Metastatic cancer is incurable. Thus, quality of life is a critical treatment issue. High efficacy, few side effects, and an outpatient setting are important criteria for patients receiving second- or third-line therapy. Currently, paclitaxel (Taxol) is the most active drug in the treatment of metastatic breast and ovarian cancer. Single-agent response rates of up to 56%,[1] or as high as 80% when used in combination with an anthracycline, have been reported.[2,3]

In recent trials, paclitaxel was administered via 24- or 3-hour intravenous (IV) infusions. Since premedication with diphenhydramine, cimetidine (Tagamet), and corticosteroids (most often dexamethasone) has been introduced into clinical practice, the frequency of hypersensitivity reactions with 3-hour paclitaxel infusions has been greatly reduced. One-hour paclitaxel infusions have been investigated primarily for the convenience of outpatient treatment. Hainsworth et al showed that 1-hour paclitaxel is safe and has substantial activity in different tumor types.[4]

Several clinical trials have examined weekly administration of paclitaxel, [5-9] which is predominantly cytotoxic for dividing cells.[10] Based on the results of these trials, we can conclude that a high-dose intensity is possible with weekly paclitaxel administration. Hematologic and nonhematologic toxicities are mild and objective response rates are relatively high (30% to 48%). However, paclitaxel administered at doses above 100 mg/m²/wk may result in treatment-limiting neurotoxicity.

The development of new combination drug regimens has become an important area of clinical research in the care of patients who fail to respond during or after first-line treatment. Regimens that are based on anthracycline and alkylating agents are routinely used as first-line chemotherapy in metastatic breast cancer. Klaassen et al demonstrated high activity with combination paclitaxel/high-dose 5-FU in anthracycline-pretreated breast cancer patients. Additionally, recent studies have reported response rates of 54% to 69% for the combination of leucovorin/5-FU/paclitaxel.[11,12]

UFT (uracil and tegafur) plus oral leucovorin (a combination being developed under the trade name Orzel) is an orally available agent that provides activity comparable to 5-FU and has a favorable side-effect profile.

Study Design

This trial is an open-label, single-center, phase I study to investigate the combination of paclitaxel (administered in a weekly 1-hour infusion) with UFT plus leucovorin in patients with anthracycline-resistant metastatic breast cancer. The dose-limiting toxicity, the maximum tolerated dose, and the recommended dose for phase II testing will be determined.

Eligibility

Inclusion Criteria

Patients with metastatic breast cancer who have recurrent or progressive disease following therapy with anthracyclines, or patients who are unable to be treated with anthracyclines due to decreased left-ventricular cardiac function, are eligible. Patients must have histologically or cytologically proven breast cancer, and may have received hormonal, immuno-, or localized radiation, therapy. Additionally, patients must be aged ³ 18 and £ 70 years; have Eastern Cooperative Oncology Group performance status greater than 2; have a life expectancy ³ 12 weeks; and have adequate hematologic, renal, and hepatic functions.

Exclusion Criteria

Exclusion criteria include prior treatment with paclitaxel, significant history of cardiac disease, evidence of peripheral neuropathy greater than Common Toxicity Criteria grade 2, and symptomatic brain metastases.

Dose Administration

Paclitaxel 80 mg/m²/wk is administered intravenously over 1 hour for 6 weeks. Premedication consists of dexamethasone 4 mg IV, clemastine (Tavist) 2 mg IV, and ranitidine (Zantac) 50 mg IV 30 minutes prior to paclitaxel.

UFT plus leucovorin is administered at a starting dose of 200 mg UFT (absolute dose, escalated stepwise to 700-mg absolute dose in subsequent dose levels), together with 90 mg leucovorin on days 1 to 42, followed by a 2-week period without treatment (Table 1 and Figure 1). The total dose for this combination is divided into three doses, administered orally every 8 hours. Depending on tumor response following cycle 1, treatment continues for a maximum of two cycles.

Dose-Limiting Toxicities

The following hematologic parameters will be considered dose-limiting toxicities (DLT): absolute neutrophil count [ANC]) < 0.5 ´ 10⁹/L for > 7 days; ANC < 0.1 ´ 10⁹/L for > 3 days; any episode of febrile neutropenia (temperature >38.2°C, granulocytes < 0.5 ´ 10⁹/L, requiring IV antibiotics; platelets < 25 ´ 10⁹/L; and bleeding requiring platelet transfusion. Additional parameters for dose-limiting toxicities are any nonhematologic toxicity Common Toxicity Criteria grade ³ 3 (excluding alopecia, inadequately treated grade 3 vomiting, and grade 3 severe asthenia).

A minimum of three patients will be treated at any given dose level. Every patient treated at a given dose level must complete course 1. Full evaluation of toxicity at that dose level must correspond to dose-limiting toxicity and maximum tolerated dose criteria before the next dose level is implemented. If one of the first three patients at a given dose level experiences dose-limiting toxicity, up to three more patients will be treated at this level.

Results

Patient Characteristics

This phase I trial opened in September 1998. As of June 1999, 15 patients have entered the study; 11 are evaluable for toxicity. The median age is 55 years. Baseline patient characteristics are noted in Table 2.

 Toxicity by Dose Increments

Of the 11 evaluable patients, four were treated at dose level 1 (paclitaxel 80 mg/m², UFT 200-mg absolute dose) and seven were treated at dose level 2 (paclitaxel 80 mg/m2, UFT 300-mg absolute dose) without any problems. Two patients at dose level 2 received only one treatment cycle due to disease progression. Four patients are still in the study at dose level 3 (paclitaxel 80 mg/m², UFT 400-mg absolute dose). It is too early to provide results from this dose level.

Hematologic and Nonhematologic Toxicities

No severe hematologic or nonhematologic toxicities were observed in dose levels 1 and 2. No cases of febrile neutropenia were observed (Table 3).

Conclusions

The first patients in dose levels 1 and 2 tolerated the treatment without any adverse effects. No severe hematologic and nonhematologic toxicities were observed. At dose level 3 (paclitaxel 80 mg/m2, UFT 400-mg absolute dose), four patients are still in study. Although it is too early to provide results from this dose level, results from recent studies of monotherapy with weekly paclitaxel or UFT plus leucovorin in metastatic breast cancer suggest that the combination may produce higher activity with a low incidence of side effects in anthracycline-pretreated patients.

The final results from this study may offer a second- or third-line therapy for metastatic disease that has high efficacy, few side effects, and takes place in an outpatient setting.

References:

1. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1791-1805, 1991.

2. Gehl J, Boesgaard M, Paaske T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 7:687-693, 1996.

3. Rowinsky EK, Cazenave LA, Donehower RC, et al: Taxol: A novel investigational antimicrotubule agent. J Natl Cancer Inst 82:1247-1259, 1990.

4. Hainsworth JD, Hopkins L, Thomas M, et al: Taxol administered by 1-hour-infusion: Preliminary results of phase I/II study comparing two dose schedules (abstract 413). Proc Am Soc Clin Oncol 13:156, 1994.

5. Klaassen U, Wilke H, Strumberg D, et al: Phase I study with a weekly 1-hour infusion in heavily pretreated patients with metastatic breast and ovarian cancer. Eur J Cancer 32A:547-549, 1996.

6. Fennelly D, Aghajanian F, Shapiro F: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15:187-192, 1997.

7. Breier S, Lebedinsky C, Pelayes L, et al: Phase I/II weekly paclitaxel 80 mg/m2 in pretreated patients with breast and ovarian cancer (abstract 568). Proc Am Soc Clin Oncol 16:163a, 1997.

8. Seidman AD, Murphy B, Hudis C, et al: Activity of Taxol by weekly 1-hour infusion in patients with metastatic breast cancer: A phase II study (abstract 517). Proc Am Soc Clin Oncol 16:148a, 1997.

9. Lück H-L, Marhenke D, Petry KU, et al: Weekly paclitaxel monotherapy as salvage treatment in pretreated patients with metastatic breast cancer: Experience with a 1-hour schedule (abstract 233). Breast Cancer Res Treat 46:59, 1997.

10. Lopes NM, Adams EG, Pitts TW, et al: Cell kill kinetics and cell cycle effects of Taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 32:235-242, 1993.

11. Klaassen U, Wilke H, Philippou Pari C, et al: Phase I/II study with paclitaxel in combination with weekly high-dose 5-FU/folinic acid in the treatment of metastatic breast cancer (abstract 186). Proc Am Soc Clin Oncol 14:122, 1995.

12. Klaassen U, Ehricke S, Hilger R, et al: Phase I/II and pharmacologic study of paclitaxel plus oral UFT and leucovorin in the second-line treatment of patients with metastatic breast cancer (abstract 2187). Proc Am Soc Clin Oncol 17:39, 1998.