Combination chemotherapy with cyclophosphamide, fluorouracil, and either epirubicin or mitoxantrone: a comparative randomized multicenter study in metastatic breast carcinoma

From February 1987 to January 1989, 60 patients with advanced breast cancer and no prior chemotherapy for advanced disease were randomized and studied, with 31 treated with fluorouracil, epirubicin, and cyclophosphamide (FEC) and 29 patients with fluorouracil, mitoxantrone, and cyclophosphamide (FNC). Doses were 500 mg/m2 fluorouracil, 500 mg/m2 cyclophosphamide, and 50 mg/m2 epirubicin2 or 10 mg/m mitoxantrone, i.v. Day 1 every 3 weeks. There were no statistically significant differences in pretreatment patient characteristics between the groups. Fifty-six patients were evaluable for response (29 in the FEC arm and 27 in the FNC arm). The response rates were 48.2% for the FEC group (complete response (CR) 10.3% and partial response (PR) 37.9%) and 40.7% for the FNC group (CR 3.7% and PR 37%) (not significantly different, NS). The median response duration was 247 and 267 days, respectively (NS), the median time to progression and time to treatment failure was 244 and 155.5 days for the FEC group and 86 and 98 days for the FNC group, respectively (NS). The incidence of nausea/vomiting was 87.1% in the FEC group and 79.3% in the FNC group, with comparable severity. Alopecia occurred in 80.6% of FEC patients and 44.8% of FNC patients (p less than 0.05). The incidences and degrees of severity of leukopenia, anemia, and cardiotoxicity were comparable in the two treatment groups. Efficacy and toxicity of the two regimens were quite similar. FNC can improve the quality of life of patients by providing significantly less alopecia.     

A phase III randomized trial of cyclophosphamide,mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide,adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer

Summary One hundred patients with metastatic breast cancer were randomly selected to receive combined chemotherapy treatment with adriamycin (50 mg/m²) or mitoxantrone (12 mg/m²) associated with 5-fluorouracil (600 mg/m²) and cyclophosphamide (600 mg/m²) administered intravenously every 21 days with a maximum of ten cycles. All patients included in this study were under 75 years of age and had ECOG performance status of less than 4. They had not been treated previously with chemotherapy for metastatic disease. Patients treated with adjuvant chemotherapy, which could not have included anthracyclines, had to have relapsed at least 12 months after the completion of therapy. There were no statistically significant differences in pretreatment characteristics or metastatic disease location between the two groups. Ninety-four patients were assessable for response. No differences were observed in response rate or in survival between the groups. The response rate (complete response (CR) and partial response (PR)) was 68% (13% CR and 55% PR for CAF; 0% CR and 68% PR for CNF). Median survival for all patients was 19 months (18 months with CAF and 19 months with CNF). All patients were assessable for toxicity. There were no differences in gastrointestinal and cardiac toxicity. More grade I-II hematologic toxicity episodes (p < 0.001) and treatment delays (p = 0.05) due to leucopenia were observed with the CNF group, and more grade III alopecia (p < 0.001) was observed with the CAF group. Patients received further therapeutic manoeuvres after finishing the study with a sequential treatment consisting of hormonal therapy and chemotherapy with mitomycin (M) -vinblastine (Vbl) (M 10 mg/m² day 1, Vbl 5 mg/m² days 1, 15 and 29; maximum 5 cycles). This chemotherapy treatment was received by 32 patients, with a response rate of 34% and grade III-IV hematologic toxicity of 37%. Treatment with CNF can be considered a good alternative to CAF for first-line treatment of metastatic breast cancer. M-Vbl treatment is useful as second-line treatment in patients with prior adriamycin exposure.     

Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140.

PURPOSE: To determine whether biochemical modulation with LV (leucovorin) enhances the efficacy of CAF (cyclophosphamide, doxorubicin, and fluorouracil) against metastatic breast cancer. PATIENTS AND METHODS: Women with histologically confirmed stage IV breast cancer, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, and no prior chemotherapy for metastatic disease were randomly assigned to receive CAF (cyclophosphamide 500 mg/m2 day 1, doxorubicin 40 mg/m2 day 1, and fluorouracil [FU] 200 mg/m2 intravenous bolus days 1 to 5) with or without LV (LV 200 mg/m2 over 30 minutes days 1 to 5 given 1 hour before FU). RESULTS: Two hundred forty-two patients were randomly assigned to treatment; 124 patients had visceral crisis and 40 patients had a CALGB performance status score of 2. The median follow-up was 6 years. The two study arms were similar with regard to serious adverse events; four patients died from treatment-related causes, two patients on each study arm. Predictive variables for time to treatment failure and survival were visceral disease and performance status. The overall response rate was 29% for CAF versus 28% for CAF plus LV. The median time to treatment failure (9 months) and median survival (1.7 years) did not differ by treatment arm. CONCLUSION: Modulation of CAF with LV improved neither response rates nor survival among women with metastatic breast cancer, compared with CAF alone. Multivariate analyses confirmed the prognostic importance of performance status and visceral crisis. However, the overall and complete response rates, response durations, time to treatment failure, and survival were the same in the two treatment arms.     

Combination chemotherapy with cmf (cyclophosphamide, methotrexate, 5-Fluorouracil) versus cnf (mitoxantrone, 5-Fluorouracil, cyclophosphamide) in advanced breast-cancer - a multicenter randomized study

A multicentric randomized study was conducted to compare the CNF regimen (cyclophosphamide at 600 mg/m2/iv, mitoxantrone at 10 mg/m2/iv, 5-fluorouracil at 600 mg/m2/iv) with the CMF regimen (methotrexate at 40 mg/m2/iv instead of mitoxantrone) administered every 3 weeks to previously untreated locally advanced or metastatic breast cancer patients. In 119 patients evaluable for therapeutic response, complete plus partial response rate was 44% for CNF and 29% for CMF (p>0.05; 95% C.I.: CNF=32%-56%, CMF=18%-40%). No statistically significant difference regarding time to progression, over survival or response to second-line chemotherapy with Epidoxorubicin was observed between the two regimens. Both regimens were well tolerated, but the percent of alopecia and leucopenia was significantly higher in the CNF patient group (31% versus 5% and 18% versus 0%, respectively; p<0.01). In conclusion, CNF was demonstrated to be slightly more toxic but more effective as compared to CMF (global response: 44% versus 29%, respectively). These findings should be taken into consideration when planning future studies of adjuvant chemotherapy.     

Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study.

PURPOSE: To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer. PATIENTS AND METHODS: Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m(2) IV, epirubicin 50 mg/m(2) IV, and fluorouracil 500 mg/m(2) IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles. RESULTS: A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P =.01) and in the assessable subset (66% v 52%, respectively; P =.005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P =.0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P =.01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P =.23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF. CONCLUSION: This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.     

Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5.

PURPOSE: Certain anthracycline-containing adjuvant chemotherapy regimens are associated with improved relapse-free survival (RFS) and overall survival (OS) compared with the classic regimen of cyclophosphamide, methotrexate, and fluorouracil in women with early-stage breast cancer. PATIENTS AND METHODS: Between 1989 and 1993, 710 pre- and perimenopausal women with axillary node-positive breast cancer were randomly assigned to either cyclophosphamide 75 mg/m(2) orally days 1 through 14, epirubicin 60 mg/m(2) intravenously days 1 and 8, and fluorouracil 500 mg/m(2) intravenously days 1 and 8 (CEF) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14, methotrexate 40 mg/m(2) intravenously days 1 and 8, and fluorouracil 600 mg/m(2) intravenously days 1 and 8). On the basis of follow-up to May 1997 (median follow-up time, 59 months), there was a statistically significant improvement in RFS and OS for CEF compared with CMF. RESULTS: The trial results are now updated, with a median follow-up of 10 years for live patients. The 10-year RFS is 52% for patients who received CEF compared with 45% for CMF patients (hazard ratio [HR] for CMF v CEF = 1.31; stratified log-rank, P = .007). The 10-year OS for patients who received CEF and CMF are 62% and 58%, respectively (HR for CMF v CEF = 1.18; stratified log-rank, P = .085). The rates of acute leukemia have not changed since the original report, whereas the rates of congestive heart failure are slightly higher but acceptable (four patients [1.1%] in the CEF group v one patient [0.3%] in the CMF group). CONCLUSION: The previously demonstrated benefit of CEF compared with CMF adjuvant chemotherapy is maintained with longer follow-up in the MA5 trial.     

Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer

Background: The mitoxantrone combination CNF and the epirubicin combination CEF have shown similar activity and less toxicity than the standard CAF combination in metastatic breast cancer (MBC). A prospective randomised study was started to compare safety and activity between CEF and CNF administered using a classical chemotherapeutic schedule in MBC.Patients and methods: From December 1987 to June 1993, 151 patients were randomised to receive cyclophosphamide (C) 100mgm^–2 p.o. days 1–14, fluorouracil (F) 500mgm^–2 i.v. days 1 and 8, and epirubicin (E) 30mgm^–2 i.v. days 1 and 8, or mitoxantrone (N) 6 mgm^–2 i.v. days 1 and 8, every 4 weeks. Seventythree patients were eligible for CEF and 72 for CNF.Results: Objective responses were observed in 61.6 of the CEF group and 44.4 in CNF group (p=0.004). The median duration of response was 64 weeks in CEF and 50 weeks in CNF group (p=0.02) and median time to progression was 51 and 33 weeks, respectively (p=0.0004). At the time of analysis, all except six patients (one in CNF and five in CEF) had died and the median survival time in the CEF group was longer than in CNF (74.4 weeks vs 51.4 weeks; log-rank ² test p=0.015). CNF produced more hematologic toxicity than CEF (WHO scale; grades 2–4): leucopenia 84% vs 68% (p=0.03) and trombocytopenia 17% vs 4.5% (p=0.01); CEF caused more grade 2 and 3 alopecia: 93% vs 70% (p=0.00 1).Conclusion: The combination CEF using this schedule and dosage in metastatic breast cancer is more effective with less toxicity than CNF, except for alopecia, and was associated with longer survival.     

Mitoxantrone, cyclophosphamide, and fluorouracil in metastatic breast cancer unresponsive to hormonal therapy

Fifty-two patients with hormonally unresponsive or estrogen receptor negative metastatic breast cancer who had not received prior chemotherapy received mitoxantrone 10 mg/m2, cyclophosphamide 500 mg/m2, and 5-fluorouracil 1000 mg/m2 (MCF) by short intravenous infusion every 21 days. Disease that was resistant or stable to this regimen was treated with doxorubicin 25 mg/m2/day for two days and vinblastine 1.4 mg/m2/day for four days (DV). Both drugs were given by continuous infusion. Thirty-one partial remissions and four complete remissions occurred after treatment with MCF. Only thirty-four evaluable patients crossed to the DV phase with partial remission (11 patients), stable (five patients), or resistant (18 patients) disease. Eleven patients' responses were upgraded. The median overall time to progression (TTP), defined as the sum of the TTP on MCF and TTP on DV, was 12 months. The median survival of all patients was 19 months. Granulocytopenia was the dose limiting toxicity for MCF, but cumulative thrombocytopenia was noted. Nausea and vomiting occurred in most patients but was mild. Severe alopecia occurred in half the patients. One patient developed congestive heart failure after receiving a cumulative dose of 206 mg/m2 of mitoxantrone. The incidence of infectious complications was 35% on each regimen; 50% of these were mild. MCF is an effective combination that was well tolerated. Objective responses, durations of response, and survival were similar, but not superior, to standard doxorubicin-based combinations. Toxicity was somewhat less.     

Phase I/II study of cyclophosphamide, doxorubicin, fluorouracil, and leucovorin for treatment of metastatic adenocarcinoma

Leucovorin enhances the cytotoxicity of fluorouracil (5-FU) in patients with colorectal cancer and may increase the efficacy of combination chemotherapy regimens containing 5-FU. To determine the maximum tolerated dose of 5-FU with leucovorin for use in combination with cyclophosphamide and doxorubicin, we conducted a phase I/II trial in 20 patients. The doses of leucovorin (200 mg/m2 on days 1-5), cyclophosphamide (500 mg/m2 on day 1), and doxorubicin (40 mg/m2 on day 1) were held constant, while the dose of 5-FU was escalated in cohorts of patients beginning at 150 mg/m2 on days 1-5. Cycles were repeated every 3 weeks. Significant mucositis, diarrhea, and myelosuppression were infrequently observed in patients receiving up to 250 mg/m2 5-FU on days 1-5. In contrast, at a dose of 300 mg/m2 on days 1-5, three of six patients had granulocyte count nadirs of less than 500/microL during the first cycle of therapy, and two of these three had platelet counts of less than 25,000/microL. In addition, two patients treated at this dose had significant mucosal toxic effects, and three had insufficient recovery to permit a second course by day 22. Among 14 patients with assessable breast cancer, there were one complete and nine partial responses (response rate 71%). Leucovorin modulation of 5-FU can be safely incorporated into combination chemotherapy with cyclophosphamide and doxorubicin and provides a highly active regimen for treatment of metastatic breast cancer. Further study will be required to determine whether the addition of leucovorin significantly enhances the activity of this regimen.     

Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study.

PURPOSE: Although hormonal therapy represents standard therapy for metastatic hormone-sensitive disease, many patients receive initial chemotherapy because of the location, bulk, or aggressiveness of their disease. It is uncertain whether simultaneous hormonal therapy provides additional benefit compared with chemotherapy alone. Eastern Cooperative Oncology Group trial E3186 was initiated to explore this question. PATIENTS AND METHODS: Between January 1988 and December 1992, 231 patients with estrogen receptor (ER)-positive or ER-unknown metastatic breast cancer were randomized to receive either chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil ?CAF) or chemohormonal therapy (CAF plus tamoxifen and Halotestin ?fluoxymesterone; Pharmacia-Upjohn, Kalamazoo, MI ?CAFTH) as front-line therapy for metastatic breast cancer. Patients who experienced a complete response to induction therapy either received or did not receive maintenance cyclophosphamide, methotrexate, fluorouracil, prednisone, and TH as a secondary randomization. RESULTS: The response rates (complete response and partial response) of patients who received CAF and CAFTH were similar (69.2% v 68.9%, respectively; P =.99). Time to treatment failure (TTF) was slightly longer for patients who received chemohormonal therapy compared with chemotherapy alone patients (13.4 months v 10.3 months, respectively; P =.087), and TTF was significantly longer in ER-positive compared with ER-negative patients (17.4 months v 10.3 months, respectively; P =.048). However, ER status had no effect on overall survival (30.0 months for CAF v 29.3 months for CAFTH). CONCLUSION: In patients with potentially hormone-sensitive metastatic breast cancer, chemohormonal therapy prolongs TTF for ER-positive patients without improving overall survival.     

Phase II trial of liposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil as first-line therapy in patients with metastatic breast cancer.

PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed. RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to < or = 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related. CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.     

Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group.

PURPOSE: To evaluate whether an accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) chemotherapy regimen with the support of granulocyte colony-stimulating factor (G-CSF) induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients. PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive as first-line chemotherapy either standard CEF (cyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2), and fluorouracil 600 mg/m(2)) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m(2), epirubicin 80 mg/m(2), and fluorouracil 600 mg/m(2)) administered every 14 days (HD-CEF14) with the support of G-CSF. Treatment was administered for eight cycles. RESULTS: A total of 151 patients were randomized (74 patients on the CEF21 arm and 77 on the HD-CEF14 arm). In both arms, the median number of administered cycles was eight. The dose-intensity actually administered was 93% and 86% of that planned, in CEF21- and HD-CEF14-treated patients, respectively. Compared with the CEF21 arm, the dose-intensity increase in the HD-CEF14 arm was 80%. Both nonhematologic and hematologic toxicities were higher in the HD-CEF14 arm than in the CEF21 arm. During chemotherapy, four deaths occurred in the HD-CEF14 arm. No difference in overall response rate (complete plus partial responses) was observed: 49% and 51% in the CEF21 and HD-CEF14 arms, respectively (P =.94). A slightly non-statistically significant higher percentage of complete response was observed in the HD-CEF14 arm (20% v 15%). No difference in efficacy was observed. The median time to progression was 14.3 and 12.8 months in the CEF21 and HD-CEF14 arms, respectively (P =.69). Median overall survival was 32.7 and 27.2 months in the CEF21 and HD-CEF14 arms, respectively (P =.16). CONCLUSION: In metastatic breast cancer patients, an 80% increase in dose-intensity of the CEF regimen, obtained by both acceleration and dose intensification, does not improve the activity and the efficacy compared with a standard dose-intensity CEF regimen.     

Long-term outcome of adjuvant chemotherapy cyclophosphamide, mitoxantrone, and fluorouracil in women with breast cancer

The aim of the study is to report the long-term outcome and secondary tumours of early breast cancer patients of adjuvant CNF (cyclophosphamide, mitoxantrone, and 5-fluorouracil) chemotherapy. One hundred and ninety four patients, 185 primary early breast cancer and nine locoregionally recurrent breast cancer patients, were entered onto the trial between May 1986 and November 1993. The therapies included surgery, radiation therapy, adjuvant CNF chemotherapy, and tamoxifen according to hormonal status. Some of patients were treated twice with CMF (methotrexate). The median follow-up time was 12.9 years. Eighty nine (48%) primary breast cancers relapsed, and six locoregional breast cancers relapsed. After 5-10 years the relapse incidence decreased notably. Eighty three patients died of breast cancer, and nine of other causes. Two cases of leukemia, six cases of skin cancer, two cases of Hodgkin's disease, two cases of meningioma, and two cases of endometrial cancer were observed. This article confirms the feasibility of adjuvant CNF for early breast cancer patients. Questions of possible causability of secondary cancer have yet to be explored.     

Results of clinical trials with a CMitF (cyclophosphamide, mitoxantrone, and 5-fluorouracil) regimen versus a CAF (cyclophosphamide, adriamycin, and 5-fluorouracil) regimen in advanced/relapsed breast cancer

Randomized clinical trials were conducted in patients with advanced/relapsed breast cancer, using CMitF (mitoxantrone, cyclophosphamide, and 5-fluorouracil) regimen in comparison with CAF (cyclophosphamide, adriamycin, and 5-fluorouracil) regimen. The response rate was 50% (13/26) for the CMitF group and 50% (10/20) for the CAF group. Classified by disease site, CAF group showed a tendency for a higher response rate in soft tissue, but in bone and viscera the rates were similar for both regimen groups. The median weeks to response (range) was 5 (3-21) weeks for the CMitF group, and 8 (3-22) weeks for CAF group, a tendency for slightly earlier response thus being shown in the CMitF group. The median duration of response (range) was 10 (4-47) weeks for the CMitF group, and 9 (4-50) weeks for CAF group, whereas by the method of Kaplan-Meier, at 40 weeks after the start of therapy, the proportion showing response still continued to be 60% for the CMitF group, which was a higher rate than the 27% for CAF group. The survival rate at 48 weeks was for both groups with no difference shown. Leukopenia, gastrointestinal symptoms and alopecia were major side effects in both groups, but the incidence and severity grade of gastrointestinal symptoms (nausea and vomiting) and alopecia were significantly less in the CMitF group than in CAF group. In both groups, the WBC nadir was 2,100/microliter and the time to nadir was 14 days, with no difference shown in hematological toxicity between the two groups. No severe cardiac, hepatic, or renal toxicity was noted.     

Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan

Background

To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter.

Methods

A total of 294 patients with axillary node-positive primary breast cancer of STAGE I–IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m² i.v. days 1 and 8; epirubicin (EPI) 60 mg/m² i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m² i.v. days 1 and 8] or CMF [CPA 500 mg/m² i.v. days 1 and 8; methotrexate (MTX) 40 mg/m² i.v. days 1 and 8; and 5-FU 500 mg/m² i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years.

Results

The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50–1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57–1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF.

Conclusion

Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m²) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.     

Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study

In 1980, a consensus chemotherapy intergroup study for advanced malignant mesothelioma was initiated based on a collaborative agreement among the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), and the Southeastern Cancer Study Group (SECSG). The purpose of the study was to evaluate cyclophosphamide (500 mg/m2 day 1), imidazole carboxamide (250 mg/m2 days 1 through 5), and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (50 mg/m2 day 1) v cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) in a randomized prospective clinical trial involving 76 fully evaluable patients with advanced stages II to IV malignant mesothelioma. A total of nine responses (12%) were documented, including three complete and six partial responses. There was no significant difference in response duration or survival between treatment arms. Leukopenia (greater than 2,000/microL) was observed in 46% of patients treated with the three-drug combination and 38% of patients receiving the two-drug combination. The variables of performance status 0-1 and the absence of prior chemotherapy/radiotherapy were significant with respect to favorable impact on survival. We conclude, based on the minimal benefit observed, that the combination of cyclophosphamide and doxorubicin with or without imidazole carboxamide does not warrant further investigation in patients with advanced-stage malignant mesothelioma.     

A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.     

高剂量表阿霉素治疗进展期和晚期乳腺癌

目的评价高剂量表阿霉素（ＨＤ－ＥＰＩ）合并环磷酰胺（ＣＴＸ）、氟脲嘧啶（５－Ｆｕ）治疗进展期和晚期乳腺癌的安全性和有效性。方法对３２例可评价的Ⅲ、Ⅳ期乳腺癌患者静脉给予ＣＴＸ６００ｍｇ／ｍ２、ＥＰＩ９０ｍｇ／ｍ２～１１０ｍｇ／ｍ２、５－Ｆｕ９００ｍｇ／ｍ２,每２１天重复。并与３０例非同期低剂量组比较（ＥＰＩ为５０ｍｇ／ｍ２）。结果高剂量组的总有效率为７１．９％,完全缓解率为１２．５％,明显高于低剂量组（５６．７％和６．７％）;初治的有效率（８０．０％）略高于复治者（６８．２％）。全组中位缓解期７．４个月,中位生存期１２．５个月。白细胞减少为主要的毒副反应,发生率为８９．５％（６８／７６）,Ⅲ、Ⅳ度分别为２７．６％和１８．４％;胃肠道毒性为轻、中度,未见明显的心肝肾毒性。结论ＨＤ－ＥＰＩ＋ＣＴＸ＋５－Ｆｕ方案治疗晚期乳腺癌安全有效,可在临床进一步试用     

Doxorubicin versus methotrexate both combined with cyclophosphamide, 5-fluorouracil and tamoxifen in postmenopausal patients with advanced breast cancer--a randomised study with more than 10 years follow-up from the Danish Breast Cancer Cooperative Group. Danish Breast Cancer Cooperative Group (DBCG)

To evaluate the substitution of methotrexate with doxorubicin (Dox) in CMF-(cyclophosphamide, methotrexate, 5-fluorouracil) containing regimen for advanced breast cancer, 415 postmenopausal patients below the age of 66 years, na?ve to chemotherapy, were accrued from 1980 to 1984 and followed-up until 1995. They received tamoxifen 30 mg daily orally and by randomisation either 400 mg/m2, cyclophosphamide, 25 mg/m2 doxorubicin and 500 mg/m2 5-fluorouracil (CAF) or 40 mg/m2 methotrexate instead of Dox (CMF) intravenously (i.v.) days 1 + 8 repeated every 4 weeks. Dox was substituted by methotrexate at a cumulative dose of 550 mg/m2. Among 341 eligible patients the response rate and median time to progression was significantly in favour of CAF: 53% CAF versus 36% CMF (P = 0.002) and 11.8 months CAF versus 6.5 months CMF (P = 0.001). Median duration of response was 19.5 CAF versus 18.0 CMF months, and survival 20.8 CAF versus 17.4 CMF months (non-significant). The two regimens were equimyelotoxic. There were no treatment-related fatalities but 1 patient with congestive heart failure on CAF was reported. Nausea/vomiting, stomatitis and infections were modest in both groups, whilst alopecia was more common with CAF. Regression analysis showed that long recurrence free interval, good performance status, and no visceral involvement was significantly related to long-term survival, whilst the treatment regimen was not. It is concluded that in chemotherapy-na?ve patients with advanced breast cancer Dox-containing regimens are superior and remain the first choice of chemotherapy, especially in patients with visceral metastases, until newer drugs and combinations have been proven to be superior.     

A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.