Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG.

One hundred five patients with metastatic breast cancer were treated with 5-fluorouracil, Adriamycin, cyclophosphamide and BCG (FAC-BCG). The results were compared to those observed in a group of 44 patients treated with FAC chemotherapy alone. Although the overall response rates were similar (76% for FAC-BCG and 73% for FAC), the duration of remission was of 9 months for FAC and 14 months for FAC-BCG (p = 0.008). Similarly, survival of responding patients treated with FAC-BCG was significantly longer (24 months) than that observed in the chemotherapy alone treated group (15 months). There was no difference in survival or duration on study for nonresponders. Analysis of response rates by known prognostic factors was unrewarding. The duration of remission and survival, however, were significantly longer for patients with bone soft tissue involvement than for patients with visceral metastasis. Similarly patients with 1 or 2 metastatic sites survived significantly longer than those with more than 3 organ sites involved (p = 0.02). This chemotherapeutic combination is highly effective in inducing remissions. In addition, nonspecific immunotherapy with BCG appears to prolong duration of remission and survival for responding patients.     

Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG.

One hundred and five patients with metastatic breast cancer were treated with 5-fluorouracil, Adriamycin, cyclophosphamide and BCG (FAC-BCG). The results were compared to those observed in a group of 44 patients treated with FAC chemotherapy alone. Although the overall response rates were similar (76% for FAC-BCG and 73% for FAC), the duration of remission was of 9 months for FAC and 14 months for FAC-BCG (p = 0.04). Similarly, survival or responding patients treated with FAC-BCG was significantly longer (24 months) than that observed in the chemotherapy alone treated group (15 months). There was no difference in survival or duration on study for non-responders. Response rates were not influenced by dominant site of disease, menopausal status or disease-free interval. The duration of remission and survival, however, were significantly longer for patients with bone and soft tissue involvement than for patients with visceral metastasis. Similarly patients with 1 or 2 metastatic sites survived significantly longer than those with more than 3 organ sites involved (p = 0.02). This chemotherapeutic combination is highly effective in inducing remissions. In addition, nonspecific immunotherapy with BCG appears to prolong duration of remission and survival for responding patients.     

Combined chemoimmunotherapy and radiation therapy of inflammatory breast carcinoma.

Thirty-two patients with a diagnosis of primary inflammatory breast carcinoma were treated with combination chemoimmunotherapy consisting of 5-fluorouracil, doxorubicin hydrochloride (Adriamycin), and cyclophosphamide (FAC) plus BCG followed by radiation therapy. This group of patients was compared to a group of 32 consecutive historical controls treated with radiation therapy alone. The estimated mean disease-free interval for the FAC-BCG group was 16 months, compared to 9 months for the radiation therapy alone group (P less than 0.01). The estimated median survival for the FAC-BCG treated group was 24 months, compared to 18 months for the radiation therapy alone group (P = less than 0.03). The combined modality approach consisting of chemoimmunotherapy and radiation therapy significantly improved the disease-free interval and survival of patients with inflammatory breast carcinoma.     

Adjuvant chemoimmunotherapy following regional therapy for isolated recurrences of breast cancer (stage IV NED).

A combination of 5-fluorouracil, Adriamycin, cyclophosphamide, and BCG (FAC-BCG) was evaluated as adjuvant treatment in breast cancer patients following surgical excision and/or radiation of first site of recurrent disease. In a group of 68 patients treated with FAC-BCG, the estimated proportion remaining free of disease at 2 years from first recurrence was 69%, compared to 24% in 60 historical control patients (P less than 0.01). Estimated 2-year survival rate from first recurrence was 85% for the FAC-BCG patients and 78% for the controls (P = 0.07). This regimen has significantly prolonged the disease-free interval from the first recurrence, but additional follow-up is needed to determine its effect on long-term survival.     

Chemoimmunotherapy with or without oophorectomy in premenopausal patients with advanced breast cancer.

Ninety-eight premenopausal patients with stage IV breast cancer were treated with chemoimmunotherapy alone, or with combination oophorectomy-chemoimmunotherapy either simultaneously (chemoimmunotherapy within four weeks of oophorectomy) or sequentially (delayed chemoimmunotherapy until evidence of progressive disease or no response to oophorectomy). The chemoimmunotherapy consisted of a three-drug combination of Adriamycin, cyclophosphamide, and 5-fluorouracil or Ftorafur; immunotherapy consisted of either oral levamisole, BCG by scarification, or a combination of both. Forty patients underwent simultaneous oophorectomy-chemoimmunotherapy, with a response rate of 85% and a median duration of response of 25 months. Response rate of 69% and a median duration of response of 16.6 months was observed with the 29 patients who received sequential oophorectomy-chemoimmunotherapy. Another 29 patients were treated with chemoimmunotherapy alone and achieved a response rate of 87% and a median duration of response of 11.8 months. Though there were no significant differences in the response rate, patients treated with chemoimmunotherapy alone had a significantly shorter median duration of response (P less than 0.05). This would suggest that oophorectomy in combination with chemoimmunotherapy is the most favorable treatment modality for premenopausal patients with advanced metastatic breast cancer.     

Intensive postoperative chemoimmunotherapy for patients with stage II and stage III breast cancer

For the past 34 months, a combination of 5-fluorouracil, adriamycin, cyclophosphamide, and BCG (FAC-BCG) was evaluated as adjuvant treatment in stage II and III breast cancer patients with positive axillary nodes. In the group of 131 patients receiving FAC-BCG, the estimated proportion remaining disease-free at 2 years from surgery was 91% compared to an estimated 69% in a group of 151 historical control patients (p less than .01). This advantage was statistically significant in all subgroups except for patients with primary tumor less than 3 cm and for patients with less than 4 positive nodes. Estimated 2-year survival rates were 9,6% for FAC-BCG patients and 86% for control (p = .02). Treatment was well tolerated. Adjuvant FAC-BCG seems effective in prolonging disease-free interval and early survival in patients with stage II and III breast cancer. Its long term efficacy will require longer follow-ups.     

Phase I study of ftorafur, an analog of 5-fluorouracil.

Ftorafur, a furanyl analog of 5-fluorouracil (5-FU), is reported to be five to six times less toxic and possibly more effective in cancer of the breast and colon than 5-FU. The drug was synthesized, formulated, and utilized in toxicologic studies, and then in 24 patients with advanced incurable malignancies. When Ftorafur is given by intravenous push, it results in immediate flushing, dizziness, nausea, retching, and in some cases transient hypotension. These immediate side effects are largely eliminated by administering the drug slowly by infusion. In patients, 60 mg/kg of Ftorafur given i.v. daily for up to 10 days resulted in mild toxicity. However, 80 mg/kg given i.v. daily for 7 days resulted in severe toxicity, with nausea, vomiting, stomatitis, leukopenia, and thrombocytopenia. These studies confirm those of the Russian investigators as to toxicity and dosage, even with a different method of administration more convenient for therapy. Phase II studies are presently being carried out to compare the effectiveness of Ftorafur and 5-FU.     

Combined chemoimmunotherapy for advanced breast cancer: a comparison of BCG and levamisole.

One hundred and fourteen evaluable patients with metastatic breast cancer were treated with a program consisting of 5-FU, Adriamycin, cyclophosphamide (FAC) and nonspecific immunotherapy with Levamisole. The results of this treatment program were compared to those observed with FAC and Bacillus Calmette Guerin (BCG) and FAC chemotherapy alone, both groups treated prior to the study reported in this paper. The overall response rates and complete response rates for all three treatment regimens were identical. The duration of remission, survival of all patients and survival of responders was similar for both chemoimmunotherapy regimens, being superior to the FAC chemotherapy alone group. Immunotherapy with Levamisole was well tolerated and side-effects were experienced by less than one-fourth of the patients. Overall, Levamisole was better tolerated than BCG and was easier to administer than the latter drug. These results suggest than nonspecific immunotherapy with Levamisole might prolong remission and survival of patients with metastatic breast cancer. Since the results achieved with BCG and Levamisole appear similar, the therapeutic ratio favors the use of Levamisole.     

Four-drug sequential regimen in advanced breast cancer

Summary The results of two empirically designed and potentially non-cross-resistant combinations administered sequentially in advanced breast cancer with the intent of achieving a high rate of durable complete remissions were analyzed. The two drug combinations consisted of cyclophosphamide plus Adriamycin and high-dose methotrexate plus cisplatin given for a total of three cycles; twenty evaluable patients, not previously treated with chemotherapy, were entered into the study. Ten patients were allocated to receive cyclophosphamide and Adriamycin first followed by high-dose methotrexate and cisplatin, while the remaining patients received the opposite sequence. The overall response rate for the entire group was 85% (17 of 20). However, only three of 20 (15%) patients achieved complete remission. One additional complete response was observed when treatment was prolonged for an additional complete cycle. The overall median duration of response was 13 months (range, 5–20⁺ months). Responses were similarly distributed among different sites of lesions. Myelosuppression and gastrointestinal toxicity were mild and transient. Reversible acute renal failure was observed after methotrexate administration in three cases. Present results indicate that overall this sequential treatment appears effective in patients with advanced breast cancer. However, the lack of an increased complete remission rate over conventional regimens coupled with a potential risk of renal toxicity prevents further studies with this multiple drug combination.     

Combination chemotherapy of metastatic breast carcinoma with cyclophosphamide, adriamycin, and peptichemio

Thirty patients with metastatic carcinoma of the breast were treated with a combination of cyclophosphamide, Adriamycin (doxorubicin), and peptichemio (CAP) as an induction regimen, and maintenance regimen consisting of thiotepa, methotrexate, and 5-fluorouracil (TMF). Twenty-four patients were evaluable. Thirteen patients achieved an objective response for a response rate of 54.0% (complete remission plus partial remission). Median duration of response was 9.5 months (0-32+). The CAP regimen had severe myelotoxicity that led to dose reductions in 67% of patients. Furthermore, 50% of the patients required delay (greater than 28-day interval) in chemotherapy courses because of myelosuppression, and peptichemio had to be discontinued in seven patients. The CAP chemotherapy as an induction regimen for metastatic breast carcinoma resulted in underutilization of Adriamycin, and proved to be inferior to other Adriamycin-containing regimens. Although peptichemio used as a single agent had significant activity against breast cancer, it was not suitable for prolonged use in conjunction with other myelosuppressive agents. However, it may have a role in second-line therapy of metastatic breast cancer in conjunction with nonmyelosuppressive agents. The authors were unable to test the efficacy of non-cross-resistant maintenance therapy with TMF in this trial.     

A Feasibility Study of Intensive CAF as Outpatient Adjuvant Therapy for Stage II Breast Cancer in a Cooperative Group: CALGB 8443

In preparation for a national Phase III say of dose and dose intensity in the treatment of node-positive, Stage II adenocarcinoma of the female breast, CALGB instituted a pilot study of intensive intravenous outpatient CAF (cyclophosphamide, Adriamycin, 5-fluorouracil) for four months. This study was designed to give full doses of drugs without dose reduction for hematologic toxicity. In order to evaluate the feasibility of physician and patient compliance with a potentially toxic therapy, a multi-institution pilot study was performed. lEs protocol demonstrated that a cooperative group could deliver toxic drug doses to outpatients with a median of 98% of cyclophosphamide, 97% of Adriamycin (doxorubicin), and 91% of 5-fluorouracil administered on schedule. Major side effects, as expected, were leukopenia, nausea, and vomiting. Disease-free survival is at least equivalent to that observed in previous studies.     

An Eastern Cooperative Oncology Group evaluation of combinations of methyl-CCNU, mitomycin C, Adriamycin, and 5-fluorouracil in advanced measurable gastric cancer (EST 2277)

In a prospectively randomized trial, patients with advanced locally recurrent or metastatic gastric adenocarcinoma were randomized to receive 5-fluorouracil (5-FU) and methyl-CCNU; 5-FU, Adriamycin (Adria Laboratories, Columbus, Ohio), and methyl-CCNU; 5-FU, Adriamycin, and mitomycin C; or Adriamycin and mitomycin C alone. One hundred eighty-three previously untreated evaluable patients were randomized among the four arms. An additional 39 patients previously treated with 5-FU, were assigned to treatment directly to Adriamycin and mitomycin C. Response rates were 14%, 29%, 39%, and 29%, respectively, among previously untreated patients and 21% for Adriamycin and mitomycin C among previously treated patients. 5-Fluorouracil, Adriamycin, and mitomycin C, the arm containing the largest number of responders (18), was the combination associated with the longest median survival. A larger proportion of patients in this arm survived one year or more. In addition, the 5-FU, Adriamycin, and mitomycin C program had the lowest rate of severe or worse toxicity of any of the treatments and was effective in patients who were less than fully ambulatory and in those who had lost weight. 5-Fluorouracil, Adriamycin, and mitomycin C appear to be a likely combination to be considered in a surgical adjuvant program.     

Cyclophosphamide, methotrexate and infusional 5-fluorouracil (infusional CMF) in metastatic breast cancer.

Bolus 5-fluorouracil (5-FU) is a phase-specific drug with a short plasma half-life that is used in combination with bolus cyclophosphamide and methotrexate in the treatment of breast cancer. The efficacy of 5-FU can be improved by continuous intravenous infusion using portable infusion pumps (infusional 5-FU). Infusional 5-FU, 200 mg m(-2) day(-1), in combination with standard doses of bolus cyclophosphamide and methotrexate, was evaluated in a phase I/II dose-finding study. The cyclophosphamide and methotrexate were administered in 28-day cycles as follows: cohort 1, cyclophosphamide 600 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1; cohort 2, cyclophosphamide 400 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1; cohort 3, cyclophosphamide 480 mg (m-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1; cohort 4, cyclophosphamide 480 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), days 1 and 8. Median overall survival was 10 months (range 3-21 months). Objective tumour responses were seen in 9 of 25 patients (36%, 95% CI 18-58%), including 3 of 13 patients (23%) previously treated for metastatic disease. Cohorts 1 and 4 proved to be too toxic, with five of six patients in cohort 1 and three of four in cohort 4 developing grade III/IV neutropenia. The dose intensity of cyclophosphamide achieved was as follows: cohort 1, 82%; cohort 2, 86%; cohort 3, 97%; cohort 4, 90%. Infusional 5-FU can be administered safely and is effective in combination with cyclophosphamide 480 mg m(-2), days 1 and 8, and methotrexate 40 mg m(-2), day 1, in the treatment of metastatic breast cancer.     

Comparison of oral ftorafur and intravenous 5-fluorouracil in patients with advanced cancer of the stomach, colon or rectum

In this prospective randomized study the effect of oral Ftorafur was compared with that of intravenous 5-fluorouracil in patients with advanced adenocarcinoma of the stomach, colon or rectum. Forty-five patients were evaluable. The overall response rates were 26.9% in the 5-fluorouracil group, 26.7% in the Ftorafur group. The median duration of response was 6 months in both groups. Survival in the 5-fluorouracil group was slightly better than in the Ftorafur group, but the difference was not statistically significant. The myelosuppressive effect of 5-fluorouracil was significantly stronger than that of Ftorafur. Gastrointestinal side effects were more pronounced in the Ftorafur group, but the difference was not statistically significant.     

A comparative study of PALA, PALA plus 5-FU, and 5-FU in advanced breast cancer

Sixty-three patients with Stage IV breast carcinoma refractory to standard combination chemotherapy agents such as 5-fluorouracil (5-FU) were entered into a study to determine the efficacy of a multiple dose schedule of N-(phosphonacetyl)-L-aspartic acid (PALA) and whether the addition of PALA improves the therapeutic efficacy of 5-FU. Patients were randomized to receive either PALA, 800 to 1000 mg/m2 per day for 5 days every 2 weeks; or PALA + 5-FU, 400 mg/m2 per day for 5 days, and 300 mg/m2 per day for 5 days every 28 days, respectively. The PALA alone arm of the study was closed after 20 patients had been treated and was replaced by 5-FU, 300 to 400 mg/m2 per day for 5 days every 21 days. Overall response rates were 5% for PALA alone, 28% for PALA + 5-FU, and 14% for 5-FU alone. All patients who responded to PALA + 5-FU or 5-FU alone had received prior therapy in which 5-FU was part of the combination chemotherapy program and were considered refractory to this drug. Toxicity affected the gastrointestinal tract but was tolerable in all three arms of the study. Myelosuppression was negligible for PALA and PALA + 5-FU and moderate for 5-FU. The authors concluded that PALA + 5-FU was superior to PALA alone in the therapy of these heavily pretreated patients. PALA alone had marginal efficacy. In view of its low hematologic toxicity, PALA + 5-FU may be combined with more myelosuppressive drugs. Additional studies are necessary to ascertain whether PALA + 5-FU is therapeutically superior to a full-dose schedule of 5-FU.     

Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy

Metronomic antiangiogenic chemotherapy, the prolonged administration of relatively low drug doses, at close regular intervals with no significant breaks, has been mainly studied at the preclinical level using single chemotherapeutic drugs, frequently in combination with a targeted antiangiogenic drug, and almost always evaluated on primary localized tumors. We tested a "doublet" combination metronomic chemotherapy treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug administered by gavage, and cyclophosphamide, for efficacy and toxicity in a new mouse model of advanced, terminal, metastatic human breast cancer. The optimal biological dose of each drug was first determined by effects on levels of circulating endothelial progenitor cells as a surrogate marker for angiogenesis, which was assessed to be 15 mg/kg for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was then evaluated in mice with advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer.     

Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes

To improve current adjuvant results in high-risk breast cancer, in February 1982 we activated a prospective randomized trial using both intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) and Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy) involving patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. The objective of the study was to assess the effectiveness of four courses of Adriamycin followed by eight courses of CMF versus two courses of CMF alternated with one course of Adriamycin for a total of 12 courses. All drug courses were recycled every 3 weeks. Rather than temporarily reducing doses in the event of myelosuppression on the planned day of treatment, drug administration was delayed for 1 to 2 weeks. At a median follow-up of 59 months, treatment outcome was significantly superior for patients who received Adriamycin followed by CMF (Adriamycin----CMF) than for those given alternating regimens (CMF/Adriamycin). The 5-year relapse-free survival was superior post-Adriamycin----CMF (61%) compared with post-CMF/Adriamycin administration (38%; P = .001). The corresponding figures for the 5-year total survival were 78% and 62%, respectively (P = .005). The benefit of Adriamycin----CMF was observed in all patient subsets. Treatment was fairly well tolerated, and we documented only one case of fatal congestive heart failure in a patient who received postoperative irradiation to the left breast in addition to Adriamycin. Present findings indicate that in women with extensive nodal involvement, Adriamycin----CMF yielded superior results compared with CMF/Adriamycin.     

Cyclophosphamide (NSC 26271) versus the combination of adriamycin (NSC 123127), 5-fluorouracil (NSC 19893), and cyclophosphamide in the treatment of metastatic prostatic cancer: a randomized trial.

Twenty-seven patients with a diagnosis of metastatic adenocarcinoma of the prostate were treated in a randomized, prospective trial with either Cyclophosphamide or a combination of Adriamycin, 5-Fluorouracil, and Cyclophosphamide. Doses were either Cyclophosphamide alone (800-1200 mg/m2 iv q 3 weeks) or Cyclophosphamide (150-200 mg/m2 po Day 3-6) plus 5-FU (400-500 mg/m2 iv Day 1, 8) plus Adriamycin (30-50 mg/m2 iv Day 1) given as a 4 week treatment cycle. Patients with compromised bone marrow reserve initially received the lower dose level. Objectively stable disease as defined by a modification of the National Prostatic Cancer Project criteria was seen in 53% of the 15 Cyclophosphamide treated patients and in 50% of the 12 combination treated patients. Survival was not significantly different in the two arms. However, the survival of patients responding to Cyclophosphamide was significantly longer than that of patients responding to the combination (median 18.6 months versus 8.1 months, p less than 0.05). Gastrointestinal and hematologic toxicity was moderate with both regimens. Therefore, in the present study, Cyclophosphamide alone was as effective as the combination of Cyclophosphamide, 5-FU and Adriamycin for patients with disseminated prostatic carcinoma. The moderate hematologic toxicity noted with both regimens suggests further evaluation of drug combinations utilizing higher dosages of active agents in this disease.     

Treatment of locoregionally advanced breast cancer with surgery, radiotherapy, and combination chemoimmunotherapy

Fifty-two patients with locally advanced primary breast cancer (T3, T4, N2, N3) but no evidence of distant metastases were treated with three cycles of combination chemotherapy. The regimen consisted of 5-fluorouracil, Adriamycin, cyclophosphamide, and Bacillus Calmette-Guerin (FAC-BCG), followed by local therapy (simple mastectomy and/or radiotherapy to the breast/chest wall and the regional lymphatic system) and adjuvant chemotherapy for two full years. The results were compared with those in an historical control group of 52 patients matched for initial stage of disease who were treated by a simple mastectomy and postoperative radiotherapy only. Forty-nine (94%) of 52 FAC-treated patients and 48 (92%) of the control patients became free of clinically detectable disease. At the median follow-up time of 56 months, 37.5% of the FAC-treated patients and 19.5% of the control patients had remained free of disease. FAC-treated patients who completed 2 years of therapy and in whom adjuvant chemotherapy was started promptly after local treatment had a 48% disease-free survival rate of 4 years. In those in whom the initial manifestation was supraclavicular involvement, the estimated 5-year disease-free survival rate was 42% for patients treated with FAC and 9% for control patients. There were local recurrences in 25% of FAC-treated patients and 23% of control patients (not significant). Distant metastases developed in 50% of FAC-treated patients and 77% of control patients (p less than 0.01). The median disease-free interval was 25 months in the FAC-treated group and 11 months in the control group (p = 0.025). The greatest improvement in prognosis was in patients with supraclavicular involvement; the median disease-free survival was 26 months in FAC-treated patients and 6 months in the control group (p = 0.007). This multimodal approach effectively renders the majority of patients with locoregionally advanced breast cancer free of disease and prolongs the disease-free survival period.     

Mitomycin C and mitoxantrone chemotherapy for advanced breast cancer: efficacy with minimal gastrointestinal toxicity and alopecia

In an attempt to examine the possibility of decreased toxicity in patients with advanced breast cancer who had not previously received chemotherapy, 33 women were given combination chemotherapy consisting of mitomycin C (10 mg/m2) every 6 weeks and mitoxantrone (6 mg/m2) every 3 weeks. The patients had predominantly visceral disease and received a median of two cycles of therapy. Of the 32 evaluable subjects, 15 (47%) achieved a partial response lasting a median of 7 months. Hematological toxicity was generally mild, although there were two episodes of sepsis. One patient developed hemolytic-uremic syndrome, and one subject developed pulmonary fibrosis, both presumably attributable to treatment with mitomycin C. Another patient died of hepatic failure (hepar lobatum). Thus, there were five patients who sustained life-threatening toxicities; this may have been due to the poor performance status and advanced age of some of the patients. Gastrointestinal toxicity and alopecia were minimal. Patient acceptance was high and there was an improvement in symptomatology in the majority of patients. In conclusion, mitomycin C and mitoxantrone chemotherapy is an active drug combination for the treatment of advanced breast cancer that seldom causes significant distressing gastrointestinal side effects or alopecia; however, the duration of response to this regimen appears to be shorter than that obtained with either cyclophosphamide - methotrexate - 5-fluorouracil (CMF) or cyclophosphamide - Adriamycin - 5-fluorouracil (CAF) combination chemotherapy.