Concurrent cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy and radiotherapy for early breast carcinoma

PURPOSE: The optimal sequencing of adjuvant chemotherapy (CT) and radiation therapy (RT) in patients with early-stage breast cancer remains unclear. PATIENTS AND METHODS: We retrospectively compared 485 patients treated with conservative breast surgery and postoperative whole-breast RT and six courses of CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and 5-fluorouracil 600 mg/m(2)) with 300 patients who received postoperative CMF only and with 509 patients treated with postoperative whole-breast RT only. The mean radiation dose delivered was 50 Gy (range, 46-52 Gy) with standard fractionation. The boost dose was 6-16 Gy according to resection margins and at the discretion of the radiation oncologist. Acute and late RT toxicity were scored using respectively the Radiation Therapy Oncology Group and the Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scale. RESULTS: A slightly higher Grade 2 acute skin toxicity was recorded in the concurrent group (21.2% vs. 11.2% of the RT only group, p < 0.0001). RT was interrupted more frequently in the CMF/RT group respective to the RT group (8.5% vs. 4.1%; p = 0.006). There was no difference in late toxicity between the two groups. All patients in the concurrent group successfully received the planned dose of RT and CT. Local recurrence rate was 7.6% in CT/RT group and 9.8% in RT group; this difference was not statistically significant at univariate analysis (log-rank test p = 0.98). However, at multivariate analysis adjusted also for pathological tumor, pathological nodes, and age, the CT/RT group showed a statistically lower rate of local recurrence (p = 0.04). CONCLUSIONS: Whole-breast RT and concurrent CMF are a safe adjuvant treatment in terms of toxicity.     

Primary chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil in operable breast carcinoma

BACKGROUND: Primary chemotherapy (PC) is becoming an accepted practice to treat large tumors to avoid mastectomies and as a surrogate of outcome. METHODS: A series of 305 patients with tumors >3 cm with T2-3N0-1M0 classification were treated with a multimodal approach that consisted of 3 courses of primary cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) followed by appropriate local treatment and 3 more courses of CMF or 4 courses of doxorubicin. Response was assessed by mammography. RESULTS: The overall response rate was 48% (a 3% pathologic complete response rate). Conservative surgery was achieved in 79.64% of the patients with a low rate of local disease recurrences (5%). Toxicity was minimal. With a median follow-up of 104 months, the 8-year disease-free survival (DFS) rate was 57.63% and the 8-year overall survival (OS) was 67.65%. The DFS and OS rates for patients with a clinical response were significantly longer, i.e., 70% (P=0.0048) and 90% (P=0.0042), respectively. CONCLUSIONS: PC with CMF was feasible. A high rate of breast-conservative surgery was achieved. The current results stressed the value of PC to increase conservative surgery and as a predictor of outcome.     

Postoperative adjuvant radiotherapy and 5-fluorouracil chemotherapy for rectal carcinoma

Postoperative combined modality therapy with radiotherapy and 5-fluorouracil (5FU) chemotherapy is an effective adjuvant approach that reduces locoregional and distant metastatic disease in patients with high-risk rectal carcinoma. However, this approach results in a treatment regimen of at least 6 months’duration. The present prospective study investigates the integration of radiotherapy and 5FU chemotherapy in a protocol designed to minimize toxicity and reduce the overall treatment time. A total of 40 patients with TNM stage II or III disease received postoperative radiotherapy at four fractions per week with weekly 5FU bolus injections delivered on the fifth non-radiotherapy day. Patients also received systemic chemotherapy with leucovorin both before and after pelvic irradiation, with the total treatment duration extending for only 18 weeks. Patients were able to complete radiotherapy in 90% of cases, while the delivery of full-dose chemotherapy was achievable in the vast majority. The incidence of haematologic and gastrointestinal toxicities requiring the cessation of treatment was acceptable. With a median follow-up of 20.9 months among surviving patients, the estimated progression-free and overall survival at 2 years were 71 % and 79%, respectively.     

Two years of cyclophosphamide and 5-fluorouracil as adjuvant chemotherapy for stage II and III breast carcinoma

The results after 6 years of a prospective clinical trial of adjuvant chemotherapy with a regimen of two drugs--cyclophosphamide and 5-fluorouracil (CF)-- for 2 years in 97 women with stage II or III breast cancer are reported. Eligible patients were free from distant metastases. All patients began adjuvant therapy within 4 weeks of surgery; therapy consisted of radical, modified, or extended radical mastectomy. No postoperative radiotherapy was given. The results are compared with a historical control group from previous consecutive patients treated by surgery alone. Patients were stratified by age (younger than 50 or older than or equal to 50) and nodal status (one to three positive axillary nodes vs. four or more positive nodes). The estimated 6-year survival was 60% for CF patients vs. 31% for control patients (P = 0.001). The estimated 6-year disease-free survival was 53.6 and 30.3% for CF and control, respectively (P = 0.007). There was a trend toward longer disease-free survival (DFS) and survival (S) in patients treated with CF, but this was not significant in all the subgroups. Disease-free survival was statistically significant in the subgroup of women greater than or equal to 50 years old with one to three positive nodes (P = 0.038); survival in the patients less than or equal to 49 years old with four or more positive nodes (P = 0.0036); and in patients greater than or equal to 50 years old with one to three lymph nodes involvement (P = 0.038).     

CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus cnf (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study

A multicenter phase III randomized study compared the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer. The standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), was administered to 77 women. The experimental protocol, CNF (cyclophosphamide, mitoxantrone, 5-FU), in which mitoxantrone (Novantrone) replaced methotrexate, was given to 68 patients. Follow-up of the 145 patients by six participating hospitals showed no statistically significant difference (p = 0.6) between the two treatment regimens during a median follow-up of 4.5 years in terms of overall survival. There was, however, a significant advantage (p = 0.04) in the disease-free survival for those receiving mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF). Toxic side effects associated with CNF (particularly alopecia and myelotoxicity) were relatively more frequent but acceptable and did not lead to dose reduction. In light of its association with improved disease-free survival in this study, larger studies should be undertaken on the role of mitoxantrone as adjuvant treatment in stage II breast cancer.     

Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma

BACKGROUND: This randomized controlled trial was to determine whether a combination chemotherapy regimen that contains anthracycline (doxorubicin and cyclophosphamide [AC]) is superior to the conventional cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] combination in premenopausal women with axillary lymph node positive Stage II breast carcinoma. METHODS: Premenopausal women with lymph node positive breast carcinoma were stratified according to age (younger than 35 or 35 years or older) and the number of positive axillary lymph nodes (1-3, 4-9, or >/= 10) and then randomly assigned to receive either doxorubicin 40 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously (i.v.) every 3 weeks or cyclophosphamide 100 mg/m(2) orally on Days 1 through 14, methotrexate 40 mg/m(2) and 5-fluorouracil 500 mg/m(2) i.v. on Days 1 and 8 every 4 weeks. Both arms were scheduled for six cycles. RESULTS: The median follow-up was 57 months. Eighteen of the 55 AC patients developed recurrence compared with 16 of the 69 CMF patients. The corresponding 5-year recurrence free survival rates were 64% and 78%, respectively (P = 0.12). The site of the first recurrence for AC patients was locoregional in 7%, distant in 22%, and combined in 4%. The corresponding data for the CMF arm were 4%, 16%, and 3%, respectively. Six AC patients died compared with 9 CMF patients. The corresponding 5-year survival rates were 90% and 86%, respectively (P = 0.96). More leukopenia (52%, mostly Grade 1-2) occurred in the CMF arm than in the AC arm (33%, P = 0.001), but no febrile episode was accompanied with leukopenia. CONCLUSIONS: This study showed no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma.     

Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy in postmenopausal women with estrogen receptor-positive, node-positive breast cancer

Conflicting results have been published regarding the efficacy of adjuvant cyclophosphamide/methotrexate/5-fluorouracil (CMF)-type chemotherapy in postmenopausal, estrogen receptor (ER)-positive women. The Oxford overview suggests real but limited benefit of any chemotherapy in this group of patients but avoids analyzing smaller subsets. We wished to better quantitate the benefit of adding CMF to tamoxifen in postmenopausal ER-positive women with tumor involvement of axillary lymph nodes. Six randomized studies comparing CMF plus tamoxifen to tomoxifen alone in postmenopausal, ER-positive, node-positive women have been published since 1992. They include 2368 patients. We performed a meta-analysis of 6 endpoints: survival, disease-free survival, locoregional recurrence, distant recurrence, contralateral breast recurrence, and thromboembolic complications. There was a statistically significant increase in disease-free survival from the addition of CMF-type chemotherapy to tamoxifen in this population; the absolute risk of relapse was reduced by 5.5% at 5 years. Effects of locoregional recurrence were greater than those on overall recurrence. No significant survival benefit was observed.     

Combination chemotherapy for breast carcinoma using a combination of cyclophosphamide,methotrexate and 5-fluorouracil (CMF) causes a platelet aggregation defect

Various coagulation parameters including platelet aggregation were evaluated during the course of treatment in 25 patients with breast carcinoma receiving a combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). No significant changes were found in whole blood clotting time (WBCT), prothrombin time (PT), kaolin cephalin clotting time (KCCT), platelet count (PC) and prothrombin consumption index (PCI). The CMF combination induced a significant reduction in platelet factor-3 (PF₃) availability and reduction in platelet aggregation to ADP and adrenaline. These defects occurred without development of thrombocytopenia. The changes occurred on the 8th day of chemotherapy and a progressive suppression in platelet aggregation was noted during subsequent follow-up. This acquired abnormality in platelet aggregation and PF₃ availability may be responsible for various hemorrhagic manifestations such as mucositis, epistaxis and hemorrhagic cystitis following CMF therapy. Further, these changes precede the onset of life-threatening complication of thrombocytopenia. The study of platelet aggregation should be considered besides platelet counting in patients on CMF combination to assess bleeding diathesis. © 1996 Wiley-Liss, Inc.     

Lacrimal duct stenosis and other ocular toxicity associated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer

Certain side-effects of chemotherapy are well recognized but ocular toxicity is often underestimated. This retrospective study was undertaken after we became aware of a case of irreversible lacrimal duct stenosis in a woman receiving adjuvant chemotherapy for early stage breast cancer. Using the chemotherapy records, 128 patients who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy for early stage breast cancer over a 2 1/2-year period were identified. The case notes of these patients were reviewed and an 18% incidence of ocular side-effects, including four other cases of epiphora, was identified. The epiphora resolved fully on completion of chemotherapy in these four patients but not in the index patient. The optimal management of these side-effects is unclear but it needs to be tailored to the particular toxicity experienced by the patient.     

CMF (cyclophosphamide,methotrexate, 5-fluorouracil) versus CNF (cyclophosphamide,mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: results by demographic and clinical subgroups

A multicenter phase III randomized study comparing the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer: the standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), and an experimental protocol, CNF (cyclophosphamide, mitoxantrone [Novantrone], 5-fluorouracil) in which mitoxantrone replaced methotrexate. The finding of a significant advantage ( p= 0.04) in the disease-free survival for those receiving mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF) led the authors to break the data down in subpopulations to determine exactly which groups of women responded more favorably to CNF than CMF. An advantage in disease-free survival was found, most notable in four subgroups: Sephardic women, women less than 45 years of age, premenopausal women, and women with 4 to 10 positive axillary lymph nodes. Although the small numbers of women in each of these subgroups rule out drawing definitive conclusions, the trend merits further study to confirm these observations.     

Population pharmacokinetics of adjuvant cyclophosphamide,methotrexate and 5-fluorouracil (CMF)

Despite the success of adjuvant cyclophosphamide, methotrexate (MTX), 5-fluouracil (5-FU) (CMF) treatment for early stage breast cancer, more than 35% of patients die within 5 years of diagnosis. Optimisation of the dose of each component drug may improve survival and reduce toxicity. In this study, the pharmacokinetics of intravenous (i.v.) cyclophosphamide (600 mg/m(2)), MTX (40 mg/m(2)) and 5-FU (600 mg/m(2)) were determined in 46 women, with data on two consecutive courses available for 41 patients. A population analysis using NONMEM was performed to investigate the effect of patient covariates on pharmacokinetics (PK), and to estimate the relative magnitude of interindividual and interoccasion variability. Patient weight had a significant influence on the clearance of cyclophosphamide and on the volume of central compartment for MTX, whose clearance was dependent on renal function. For all three drugs, interoccasion variability was of the same order (20-40%) as that between individuals, suggesting a limited potential for dose-optimisation of this regimen.     

Primary chemotherapy in operable breast carcinoma comparing CMF (cyclophosphamide, methotrexate, 5-fluorouracil) with an anthracycline-containing regimen: short-term responses translated into long-term outcomes.

BACKGROUND: The role of anthracyclines has been extensively studied in adjuvant chemotherapy, but much less in the primary chemotherapy of early breast carcinoma. This study, comparing CMF (cyclophosphamide, methotrexate, 5-fluorouracil) with the rotational anthracycline-containing regimen CMFEV (CMF plus epirubicin and vincristine) administered as primary chemotherapy, demonstrated a significant increase in clinical complete response in premenopausal women. We report the long-term results. PATIENTS AND METHODS: Two hundred and eleven patients with stage I or II palpable breast carcinoma and a tumour diameter of >2.5 cm were randomised to receive CMF or CMFEV for four cycles before surgery. After surgery, the patients in both arms received adjuvant CMF for three cycles. RESULTS: In the study population as a whole, there was a non-significant 20% reduction in mortality and relapse rates in the CMFEV arm. However, the effect of the experimental regimen was only found in premenopausal patients, especially in terms of relapse-free survival (P=0.07) and locoregional relapse-free survival (P=0.0009), thus mirroring the effect on response rates. After 10 years, the proportions of premenopausal patients free from locoregional relapse as a first event in the CMF and CMFEV groups were 68% and 97%, respectively. No relevant differences were found in postmenopausal patients. CONCLUSION: The overall results of this study showed that the greater activity of the experimental anthracycline-containing combination over CMF as primary chemotherapy in premenopausal patients translated into long-term effects in the same subgroup.     

Variability in the pharmacokinetics of cyclophosphamide,methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer

A total of 23 women with stage II breast cancer receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil had detailed pharmacokinetic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these three drugs varied by a factor of 3–4 among patients. No systematic change in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC for each of the three drugs did not change. However, significant intrapatient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on the third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, methotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses for subsequent courses could be determined.This research was supported by the National Cancer Institute of Canada     

Secondary acute myelocytic leukemia after adjuvant therapy for early-stage breast carcinoma. A new complication of cyclophosphamide, methotrexate, and 5-fluorouracil therapy

The occurrence of treatment-related hematologic malignancies after adjuvant therapy with alkylating agents for gastrointestinal cancers, ovarian carcinoma, and breast cancer and after treatment for Hodgkin's disease, non-Hodgkin's lymphoma, germ-cell tumors, and multiple myeloma has been well documented. Adjuvant chemotherapy is frequently used for the treatment of early stage breast cancer, and to date there has been no increase in the incidence of secondary myelodysplastic syndromes or acute leukemia after cyclophosphamide-based regimens when compared with surgical controls. This report describes two patients who developed acute myelocytic leukemia only after exposure to cyclophosphamide, methotrexate, and 5-fluorouracil adjuvant therapy. These two cases of acute leukemia, which developed 3 years after diagnosis of breast cancer and initiation of chemotherapy, were characterized by trilineage dysplasia and pancytopenia, and had abnormalities of chromosomes 5 and 7: characteristics consistent with treatment-related leukemia. Many women are diagnosed with early stage breast cancer each year who are potential candidates for adjuvant therapy. Although certain subgroups of patients have been shown to benefit from adjuvant therapy, continued efforts must be directed at identifying responders so that others will not be exposed to the additional risks of chemotherapy.     

Comparison of 5-fluorouracil with 5-fluorouracil, cyclophosphamide, and methotrexate in metastatic colorectal carcinoma.

Thirty-eight patients with metastatic colorecal carcinoma were treated with 5-fluorouracil (5-FU), and 38 patients were treated with the combination of 5-FU, cyclophosphamide, and methotrexate. In terms of percent response, response duration, and survival there was no apparent difference between the two regimens. Combination chemotherapy was found to be effective in 6 of 16 patients refractory to treatment with 5-FU alone, but was associated with more morbidity.     

Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, adriamycin, methotrexate, 5-fluorouracil (CAMF) versus sequential cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and adriamycin.

Seventy-eight advanced breast cancer patients with hormone-resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF leads to A). C was given at 50 mg/m2, po, days 1-14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28-day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses-62% vs. 49%; stabilizations-23% vs. 31%). Responses by site of metasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.     

Low-dose mitomycin and weekly low-dose doxorubicin combination chemotherapy for patients with metastatic breast carcinoma previously treated with cyclophosphamide, methotrexate, and 5-fluorouracil

Forty-four evaluable patients with breast carcinoma previously treated with combination chemotherapy consisting of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) were treated with a combination chemotherapy regimen consisting of doxorubicin (A) (20 mg/m2 on days 1, 8, 15, and 22, repeated every 28 days) and mitomycin (MIT) (10 mg/m2 on day 1, repeated every 28 days). Five patients (11%) achieved a complete remission (CR) and 14 patients (32%) had a partial response (PR). The median duration of survival was 11.5 months and the median duration of response was 8 months for responders (CR and PR). Toxicity was moderate and consisted of neutropenia (74%), thrombocytopenia (25%), pneumonitis (11%), and cardiomyopathy (2%). The combination chemotherapy regimen A and MIT is an effective regimen for treating previously treated with CMF.     

Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients.

BACKGROUND: Alkylating agents and topoisomerase-II inhibitors have been associated with the occurrence of secondary leukemias and myelodysplastic syndromes in breast cancer patients treated with adjuvant chemotherapy. Conversely, data on the occurrence of second solid malignancies in this setting are scarce. PATIENTS AND METHODS: This study retrospectively evaluates the occurrence of second hematological and solid malignancies in the context of a prospective multicenter phase III trial comparing epirubicin-cyclophosphamide at intermediate doses (EC), or at full doses (HEC), with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 777 patients with early breast cancer. RESULTS: At a median follow-up of 73 months, the following 8-year actuarial rates of second solid primaries were observed: CMF 5.5% [95% confidence interval (CI) 1.5% to 9.5%], EC 4.1% (95% CI 0.1% to 8.1%), and HEC 7.2% (95% CI 3.2% to 11.2%) (P = 0.79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI 0.0% to 2.5%), which by a three arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = 0.05). CONCLUSIONS: HEC, as delivered in this trial, cannot be recommended in clinical practice because of the lack of superiority over classic CMF and because of the increased risk of AML observed in this arm. Prolongation of conventional anthracycline-based treatment beyond the current standard of four to six cycles is not recommended in clinical practice.     

A prospective study of concurrent cyclophosphamide/methotrexate/5-fluorouracil and reduced-dose radiotherapy in patients with early-stage breast carcinoma

BACKGROUND: Concurrent administration of chemotherapy and radiotherapy has the potential advantage of delaying neither treatment and providing radiation sensitization. However, the optimal approach to concurrent treatment in women with early-stage breast carcinoma remains undefined. We present updated results of a prospective protocol of concurrent cyclophosphamide/methotrexate/5-fluorouracil (CMF) and reduced-dose radiotherapy, focusing on tumor control and patient tolerance. METHODS: One hundred twelve women with AJCC Stage I or Stage II breast carcinoma with 0-3 positive axillary lymph nodes were enrolled in a prospective single-arm study of concurrent CMF and reduced-dose radiotherapy (39.6 gray [Gy] to the whole breast, 16-Gy boost). A high proportion of women had risk factors associated with an increased risk of local disease recurrence, including age <40 (32%), close or positive margins (37%), or lymphatic/vascular invasion (51%). The median follow-up period was 94 months. RESULTS: The 5-year overall survival rate was 94%. By 60 months, 5 patients (4%) experienced local disease recurrence and 19 patients (17%) experienced distant metastasis. There were no isolated regional lymph node recurrences. Local disease recurrence occurred in 1 of 25 patients (4%), 1 of 16 patients (6%), and 3 of 70 patients (4%) with positive, close (<1 mm), and negative margins, respectively. One patient developed acute myelogenous leukemia. An additional patient developed Grade 2 pneumonitis. Cosmetic results were not recorded uniformly for all patients and therefore could not be reliably analyzed. CONCLUSIONS: Concurrent CMF and reduced-dose radiotherapy resulted in a low level of late toxicity and excellent local tumor control, despite the large proportion of patients with substantial risk factors for local disease recurrence. Future studies of concurrent regimens, particularly in patients at high risk of local disease recurrence, are warranted.