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Combination Therapy for Advanced Breast Cancer: Cyclophosphamide, Doxorubicin, UFT, and Tamoxifen

Combination Therapy for Advanced Breast Cancer: Cyclophosphamide, Doxorubicin, UFT, and Tamoxifen

ABSTRACT: A>We evaluated combination therapy for advanced and recurrent breast cancer with cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), uracil and tegafur (UFT), and tamoxifen (Nolvadex) (CAUT), designed as chemoendocrine therapy with a high antitumor effect and less severe adverse reactions. In this therapy, one 3-week cycle consisted of doxorubicin 30 mg/m² intravenously on day 1, cyclophosphamide 65 mg/m² orally (po) and UFT 300 mg/m² po on days 1 to 14, and tamoxifen at 20 mg/day po on days 1 to 21. Twenty patients were registered and 19 were eligible, including seven with advanced breast cancer and 12 with recurrent disease. Six patients had received previous treatment. The comprehensive evaluation for objective response revealed one patient with a complete response and 10 patients with partial responses, producing an overall response rate of 58% (95% confidence interval, 29% to 87%). Three patients experienced no change, and five patients had progressive disease. Adverse events ³ grade 3 were leukopenia in six patients, erythropenia in one patient, alopecia in four, and severe generalized malaise in one. One patient who developed grade 4 leukopenia and one of five patients who developed grade 3 leukopenia recovered after receiving granulocyte colony-stimulating factor. CAUT therapy produced high response rates and relatively mild adverse reactions and is considered useful for the treatment of advanced and recurrent breast cancer. [ONCOLOGY 7(Suppl 3):77-81, 1999]


Introduction

Combination therapy consisting of cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), and 5-fluorouracil (5-FU) (CAF) is among the standard therapies for advanced and recurrent breast cancer. Chemoendocrine therapy combining CAF with an endocrine therapy like tamoxifen (Nolvadex) has been evaluated extensively.

Hansen et al administered 5-FU via continuous infusion to patients with refractory metastatic breast cancer and obtained a response rate of 32% (eight of 25 patients) without causing myelosuppressive adverse reactions (white blood cell count < 3,000/µL, platelets < 100,000/µL).[1] Uracil and tegafur in a 4:1 molar ratio (UFT) has been found to produce sustained high 5-FU concentrations in tumors. Administration of UFT and a continuous infusion of 5-FU at an equal molar ratio generates blood 5-FU levels with similar area under the concentration-time curves.[2-4] UFT administered alone was associated with high response rates of 32% and 38% for advanced and recurrent breast cancer, respectively.[5,6]

We designed a combination-therapy program of cyclophosphamide, doxorubicin, UFT, and tamoxifen (CAUT) in an attempt to reduce adverse reactions in the bone marrow system caused by bolus administration of cyclophosphamide, doxorubicin, and 5-FU. We also hoped to establish an outpatient treatment and determine its efficacy and safety.

Patients and Methods

Patients with histologically confirmed, advanced (stage IIIB, IV, and inflammatory) breast cancer or recurrent breast cancer, aged 20 to under 75 years, and a performance status of 0 to 2 were entered into this study. Patients who were excluded included those who had received prior anthracyclines, endocrine therapy, and/or immunotherapy within the previous 2 weeks, chemotherapy within 4 weeks, or radiation therapy within 6 weeks, as well as those with cerebral metastasis.

Doxorubicin 30 mg/m² was administered intravenously on day 1. UFT capsules 300 mg/m² and cyclophosphamide tablets 65 mg/m² were administered orally for 2 weeks beginning on day 1, followed by drug suspension for 1 week. Tamoxifen 20 mg/day was administered orally on days 1 to 21. This schedule was repeated every 3 weeks. Administration of granulocyte colony-stimulating factor was allowed, at the physician’s discretion, for patients with fever and a reduction in white blood cell count to < 2,000/mL or for patients with a reduction in white blood cell count to < 1,000/mL. Antiemetics were also permitted.

Administration of cyclophosphamide, doxorubicin, and UFT was suspended in the event of adverse reactions ³ grade 2; tamoxifen administration was suspended when adverse events ³ grade 3 occurred. The therapeutic period was 12 weeks (four cycles) or longer. The total doxorubicin dose was limited to 350 mg/m². Antitumor effects and adverse events were classified according to the General Rules for Clinical and Pathological Recording of Breast Cancer in Japan. Survival rates were calculated according to the Kaplan-Meier method, and significance was determined by the log-rank test.

Results

Registered Patients

From February 1995 to December 1996, 20 patients were registered, of whom 19 were eligible (one patient with a performance status of 3 was excluded). The characteristics of the eligible patients are shown in Table 1.

Antitumor Effect

The antitumor efficacy of CAUT is shown in Table 2. One patient experienced a complete response, and there were 10 partial responses. Three patients experienced no change, and five had progressive disease, yielding an overall response rate of 58% (11 of 19 patients; 95% confidence interval, 29% to 87%). In terms of lesion site, antitumor activity was observed in soft tissue in 73% of patients (eight of 11), in bone in 38% of patients (three of eight patients), in lung/pleura in 20% of patients (one of five patients), and in liver in 50% of patients (two of four). The complete response period was 28 days.

Four patients with stage IIIB breast cancer had partial responses, with a median duration of 55.5 days (2.25 cycles of CAUT). One patient was transferred to radiation therapy and three underwent surgery, including one breast-conserving surgery (Table 3). The patient with stage IV disease experienced a partial response. Among patients with recurrent breast cancer, one had a complete response and five had partial responses. In these patients, the median time to response was 94 days (four cycles of CAUT)—longer than the response that was observed among patients with stage IIIB breast cancer. The response period for the patient achieving a complete response was 28 days, and for patients with a partial response, the response period ranged from 51 to 464 days (median, 201 days) (Table 4).

Survival Rate

The survival curves for the 12 patients with recurrent breast cancer are shown in Figure 1. The patient with a complete response survived 220 days, and the two patients with no change survived 350 and 454 days after the start of therapy. The survival rate at 1,001 days after the start of therapy was 80% among the five patients experiencing a partial response, whereas all four patients with progressive disease died by day 554. The prognoses for patients with complete response, partial response, and no change were better than those for patients with progressive disease (P = .068).

Adverse Events

All adverse events ³ grade 3 are shown in Table 5. According to the number of events ³ grade 3, leukopenia was observed in six patients (31.6%) (³ grade 4 in one), erythropenia in one (5.3%), alopecia in four (21.1%), and generalized malaise in one (5.3%). One patient developed grade 4 leukopenia, and one of the five patients with grade 3 leukopenia (the patient with a complete response) had an accompanying fever; both patients received granulocyte colony-stimulating factor and recovered. The other patients recovered after therapy was withdrawn.

Discussion

Combination therapy with cyclophosphamide, doxorubicin, and 5-FU is one of the standard chemotherapies for advanced and recurrent breast cancer. Many variations and combinations with endocrine therapy have been employed. We examined the efficacy and safety of chemoendocrine therapy using oral UFT in place of continuous-infusion 5-FU with the addition of tamoxifen (CAUT).

In a comprehensive efficacy evaluation of this regimen, the response rate was 58% (11 of 19 patients). The response rates were highest in soft tissue, followed in order by liver and bone. Response rates were lowest in lung/pleura. Only a small number of patients had liver metastases; however, this combination therapy can be expected to be effective in these patients. Response rates were higher in the postmenopausal patients (67%) than in the premenopausal patients (43%); and this therapy was effective regardless of estrogen receptor status (67% for estrogen receptor-positive patients and 60% for estrogen receptor-negative patients). Although only a small number of patients had received previous treatment, there was a 50% response rate in this patient subgroup.

Adverse reactions in the bone marrow system were mild, and the grade of alopecia was low. As for gastrointestinal adverse reactions, grade 2 anorexia and nausea/vomiting were observed in only 26% and 21% of patients, respectively; no gastrointestinal adverse reactions ³ grade 3 were observed.

Conclusion

A combination therapy designed by replacing intravenous 5-FU in CAF with UFT with the addition of tamoxifen (CAUT) was administered to patients with advanced and recurrent breast cancer. This regimen was associated with relatively mild adverse reactions compared with anthracycline-based treatment, and achieved a satisfactory response rate of 58%. These findings suggest that CAUT is a useful approach, applicable to outpatient treatment of advanced and recurrent breast cancer.

References

1. Hansen R, Quebbeman E, Beatty P, et al: Continuous 5-fluorouracil infusion in refractory carcinoma of the breast. Breast Cancer Res Treat 10:145-149, 1987.

2. Hirata K, Sasaki K, Yamamitsu S, et al: A comparison of 5-fluorouracil concentration of 5-fluorouracil drip infusion versus oral UFT in plasma of same patients. Gan To Kagaku Ryoho 20:1409-1411, 1993.

3. Namatame K, Sasaki E, Ko Y, et al: A double-blind comparison of FUra plasma concentration by oral (UFT) vs continuous intravenous infusion (5-FU). Gan To Kagaku Ryoho 20:2417-2419, 1993.

4. Ho DH, Pazdur R, Covington W, et al: Comparison of pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2¢-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4(9):2085-2088, 1998.

5. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT phase II study. Cancer Chemother Pharmacol 22:333-338, 1988.

6. Tashiro H, Nomura Y, Osaki A: A double-blind comparative study of tegafur (FT) and UFT (a combination of tegafur and uracil) in advanced breast cancer. Jpn J Clin Oncol 24:212-216, 1994.

 
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