Infusional 5-Fluorouracil Plus Leucovorin and Paclitaxel in Metastatic Breast Cancer
ABSTRACT & COMMENTARY
Synopsis: This new drug combination induced an overall response rate of 55% in previously treated patients with metastatic breast cancer, including a 59% response rate in patients with anthracycline-resistant disease. Median duration of response was 12 months, and median survival was 15 months. The regimen produced grade 2-3 myelotoxocity and grade 1-2 nonhematologic toxicity.
Source: Klaassen U, et al. Ann Oncol 1998;9:45-50.
Many drugs and regimens are touted to produce responses in up to 25% of patients with metastatic breast cancer in whom the primary treatment program has failed. Klaassen and colleagues from Essen, Germany, have now reported much higher response rates in patients with metastatic breast cancer who have had progressive disease on the primary treatment regimen.
Fifty-four patients were entered onto a phase II study of paclitaxel, leucovorin, and 5-fluorouracil. Paclitaxel is given at 175 mg/m2 by three-hour infusion on days 1 and 22, and leucovorin is given at 500 mg/m2 by two-hour infusion followed by 5-fluorouracil at 2 gm/m2 by 24-hour weekly infusion on days 1, 8, 15, 22, 29, and 36. On days where all three drugs are given together, paclitaxel is given first. Patients then have week 7 off and begin another cycle on day 50.
All 54 patients had received one chemotherapy regimen for metastatic disease before entering this study and 29 patients had also received adjuvant chemotherapy at the time the primary breast cancer was diagnosed.
The median age of patients in the study was 48 years; 63% had ECOG performance status of 1. Metastatic sites of involvement included lung (46%), liver (55%), lymph nodes (33%), bone (57%) and skin (17%). Patients had a median of two disease sites. Ninety-four percent of patients had received radiation therapy; 78% had received hormonal adjuvant therapy; and 70% had received hormonal therapy for metastatic disease. Seventy percent of patients had received received anthracyclines before entering this study, and 59% had demonstrated progressive disease while receiving anthracyclines.
Thirty-two of 54 patients (59%) had an objective response to therapy; 55% of treated patients had a partial response; and 4% had a complete response. An additional 20 patients (37%) had stable disease. Only two patients had disease progression on treatment. Among the 32 patients who had anthracycline-resistant disease, there were one (3%) complete and 18 (56%) partial responders. The median duration of response was 12 months (range, 3-22 months); median survival was 15 months (range, 2-28 months), and nineteen patients were still alive at the time of the report. The median duration of treatment was six months and the median number of cycles delivered was three.
The toxicity of the regimen was mild to moderate. Only 27% of patients had grade 3 or 4 neutropenia, and no hospitalizations for febrile neutropenia were noted. The duration of the neutropenia was generally 3-5 days. Three patients received a single blood transfusion for anemia, and no platelet transfusions were needed. No dose modifications of paclitaxel were required. Nonhematopoietic toxicity included mild-to-moderate myalgia, mucositis, diarrhea, nausea, and vomiting. Grade 3 diarrhea was noted in 3% of 151 cycles of chemotherapy. Peripheral neuropathy was cumulative (grade 1 or 2 at its worst) and was noted in a minority of patients. The neuropathy resolved when therapy was discontinued.
COMMENTARY
For patients whose initial therapy for metastatic breast cancer does not include paclitaxel, this combination of paclitaxel with infusional leucovorin and 5-fluorouracil appears to be a reasonable candidate for second line therapy. It is active in anthracycline-resistant disease and was also effective in patients who had previously received 5-fluorouracil in the adjuvant setting or as bolus therapy as part of a combination of drugs for metastatic disease. Leucovorin is said to enhance the affinity of fluorodeoxyuridylate for thymidine synthase and thereby enhance the ability of 5-fluorouracil to block thymidylate synthesis. It is unclear whether paclitaxel, which attacks the microtubules of a cell, can act synergistically with an antimetabolite that interferes with DNA synthesis. However, this particular combination appears to be more active than either paclitaxel alone or 5-fluorouracil plus leucovorin alone. The duration of response (median, 12 months), overall survival (median, 15 months), and modest toxicity suggest that this is a regimen worth trying in our patients in need of palliative therapy for metastatic breast cancer.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.