Methotrexate and 5-fluorouracil following tamoxifen and premarin in advanced breast cancer.
Complete remissions in patients with advanced breast cancer using either endocrine therapy or chemotherapy are infrequent. Breast tumors are known to be heterogeneous with respect to estrogen receptor (ER) status, and the low complete remission rate may be secondary to this biochemical heterogeneity. Laboratory experiments using breast cancer cells in long-term tissue culture revealed that tamoxifen is cytotoxic, estrogen stimulates the growth of ER-positive cells and can rescue cells from tamoxifen's effect, and sequential MTX/5-FU is synergistic in rapidly growing breast cancer cells. Based on this, a phase II protocol was designed using tamoxifen, 10 mg p.o. b.i.d. for days 1 to 10. This was followed by Premarin, 0.625 mg p.o. b.i.d., on days 11 to 14. On day 14 the patients were given MTX, 200 mg/m2 i.v., followed in 1 hr by 5-FU, 600 mg/m2 i.v. The patients were rescued with leucovorin, 10 mg/m2 24 hr later. This dose of leucovorin was repeated every 6 hr for six doses. The cycle is repeated every 18 days. Thus far, 35 patients have been entered and 32 are currently evaluable for response. The median age is 57 years. The median Karnofsky performance status was 90. Of the 35 patients, 63% were ER-positive, and 23% had received prior endocrine therapy or chemotherapy; 71% were postmenopausal. One third of the patients had visceral-dominant disease. The overall response rate was 69%; 15 of 32 (47%) attained a complete remission, and 7 of 32 (22%) had a partial remission. Toxicity was minimal. Median nadir white blood cell counts were 5600/cu mm, and median nadir platelet counts were 252,000/cu mm. Nausea and vomiting occurred in 25% of patients, but there was no hair loss, rash, or diarrhea. Mucositis was rare. In summary, this combination hormonal-chemotherapy regimen is highly effective with a high complete remission rate and minimal toxicity.
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000008:administration & dosage*
D004966:Estrogens, Conjugated (USP); D011960:Receptors, Estrogen; D013629:Tamoxifen; D005472:Fluorouracil; D008727:Methotrexate