Current status of Milan adjuvant chemotherapy trials for node-positive and node-negative breast cancer

This report summarizes the most important clinical results achieved at the Milan Cancer Institute through various randomized trials with systemic adjuvant chemotherapy. In the study testing surgery versus surgery plus 12 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in node-positive patients, the reduction in failure rate (34%) significantly favored CMF-treated patients (P less than 0.001). Despite a reduction in the death rate of 23%, the overall survival showed only a trend for CMF compared to surgery alone (P = 0.10). In a second study, the 8-year results confirmed the lack of difference in relapse-free survival and total survival rates between patients who received 12 and 6 cycles of CMF. The third study indicated that at 6 years, postmenopausal women who had 1-3 positive lymph nodes and were treated with full-dose sequential non-cross-resistant combinations had rates of relapse-free survival and total survival that were superior to those previously achieved with CMF in the same menopausal subset. In a limited series of patients with negative axillary nodes as well as negative estrogen receptors, there was clear evidence of very poor prognosis in women given only local-regional therapy, compared to women treated with adjuvant CMF. Within the node-negative subset, the proliferative activity (labeling index) of the primary tumor appears to be a more effective prognostic discriminant than estrogen receptor status. The proportion of primary drug-resistant tumor cells as well as the lack of relative dose intensity in the drug programs tested so far probably represent the two most important causes for the failure of adjuvant chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer: Updated results

BACKGROUND:: Node-negative breast cancers are considered to comprise a subgroupwhich is amenable to cure with localregional therapy alone.However, approximately 30% of affected patients present newdisease manifestations within 10 years after surgery. To testthe hypothesis that node-negative and estrogen receptor-negativebreast cancer patients can benefit from adjuvant chemotherapy,a prospective randomized study was activated at the IstitutoNazionale Turnori of Milan in 1980. PATIENTS AND METHODS:: The study was conducted in 90 patients operated on for unilateralbreast cancer who were then assigned to receive either 12 intravenouscycles of cyclophosphamide, methotrexate and fluorouracil (CMF)every three weeks, or no further treatment. Adjuvant chemotherapywas administered in the outpatient clinic of the Division ofMedical Oncology. Patient characteristics were fairly well balancedbetween the two treatment groups except for primary tumor size:58% of those with a primary tumor measuring>2 cm in its largestdiameter were randomized in the control group compared with38% in the CMF regimen (P=0.06). RESULTS:: At 12 years after surgery treatment outcome was significantlysuperior for patients given adjuvant CMF. The relapse-free survivalrate was 71% (95% confidence limits (CL): 56–86) versus43% (95% CL: 28–58), and total survival was 80% (95% CL:68–92) versus 50% (95% CL: 34–66), respectively.The benefit from the administration of CMF was evident in allpatient subsets and was not influenced by menopausal status. CONCLUSIONS:: The long-term results of this trial of adjuvant combinationchemotherapy confirm our previous observations on the efficacyof adjuvant chemotherapy in node-negative breast cancer patientsat high risk of early disease relapse. adjuvant treatment, node-negative breast cancer     

Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: Long-term follow up on IBCSG Trial IX

BackgroundThe benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed.Patients and methodsAfter stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of ‘classical’ CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years.ResultsERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes.ConclusionCMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy.     

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.     

Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study.

PURPOSE: According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials, we investigated whether node-negative breast cancer patients, defined as high-risk cases on the basis of tumor cell proliferation, could benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant therapy. PATIENTS AND METHODS: Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors, defined according to thymidine labeling index (TLI), were randomized to receive six cycles of CMF or no further treatment after surgery +/- radiotherapy. RESULTS: The 5-year disease-free survival (DFS) was 83% for patients treated with CMF compared with 72% in the control group (P: =.028). Adjuvant treatment reduced both locoregional and distant metastases. When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria, compared with patients in the control arm, 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second (78% v 88%, respectively; P: =.037) and third tertiles (58% v 78%, respectively; P: =.024). CONCLUSION: The results from this randomized clinical study indicate that patients with node-negative, rapidly proliferating tumors significantly benefit from adjuvant CMF.     

Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive,hormone receptor-negative breast cancer patients

AIM: A randomised, controlled clinical trial was initiated in 1984 to test whether 1 cycle of anthracycline-containing adjuvant chemotherapy improves the outcome of breast cancer patients presenting with stage II disease and negative oestrogen and progesterone receptors (ER, PgR), as compared with 6 cycles of dose-reduced CMF. PATIENTS AND METHODS: Within 7 years 263 women with stage II breast cancer were randomised either to receive 1 cycle of doxorubicin, vinblastine, cyclophosphamide, methotrexate and 5- fluorouracil (AV-CMF) or to receive 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients were stratified for tumour stage, nodal stage, menopausal status, type of surgery and participating centre. RESULTS: After a median follow-up of 100 months, neither disease-free (DFS) nor overall survival (OS) differed significantly between the two groups. CONCLUSIONS: Compared to 6 cycles of a non-standard low-dose CMF regimen 1 cycle of anthracycline- containing adjuvant chemotherapy failed to improve the outcome in women with stage II receptor-negative breast cancer in terms of DFS and OS.     

Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy

Risk factors for isolated local-regional (LR) recurrence following mastectomy for breast cancer were analyzed in a review of 627 women entered into Eastern Cooperative Oncology Group (ECOG) adjuvant chemotherapy trials between 1978 and 1982. Premenopausal patients were randomized to cyclophosphamide, methotrexate, and fluorouracil (5-FU) (CMF), cyclophosphamide, methotrexate, 5-FU, and prednisone (CMFP), or cyclophosphamide, methotrexate, 5-FU, prednisone, and tamoxifen (CMFPT). Postmenopausal patients were randomized to observation, CMFP, or CMFPT. Median follow-up time was 4.5 years. At 3 years, 225 patients relapsed and in 70 (31% of failures, 11% of all patients) the initial site was LR without distant metastases. In a multivariate analysis, the risk of an isolated LR recurrence significantly correlated with the number of positive axillary nodes, the primary tumor size, the presence of tumor necrosis, and the number of axillary nodes examined. Factors that significantly discriminated between an isolated LR recurrence and distant metastasis were the number of positive nodes and primary tumor size. Patients with four to seven positive nodes or tumor size greater than or equal to 5 cm had a chance of developing an isolated LR recurrence almost equal to the risk of distant metastases. These findings suggest a potential for improved survival in this subset of patients with the addition of postmastectomy radiation to chemotherapy, and continue to emphasize the presence of a group of patients at high risk for isolated LR recurrence despite adjuvant chemotherapy.     

Tamoxifen versus control after adjuvant, risk-adapted chemotherapy in postmenopausal, receptor-negative patients with breast cancer: a randomized trial (GABG-IV D-93)--the German Adjuvant Breast Cancer Group.

PURPOSE: To investigate the effect of adjuvant sequential tamoxifen after chemotherapy in postmenopausal patients with hormone receptor-negative breast cancer. METHODS: Patients were randomly assigned to oral tamoxifen (30 mg daily for 5 years; n = 421) or no additional treatment (n = 408) after risk-adapted polychemotherapy consisting of three 28-day cycles of CMF (cyclophosphamide, 500 mg/m(2), methotrexate, 40 mg/m(2), and fluorouracil, 600 mg/m(2)) in patients with negative or one to three positive lymph nodes and four 21-day cycles of epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2) followed by three cycles of CMF in patients with four to nine positive lymph nodes. RESULTS: Thirty-six percent of the patients included were older than 60 years, 63% were node negative, 13% had four to nine positive nodes, 55% had tumor grade 3, and 41% received breast-preserving surgery. At 5.3 years' median follow-up, the first event of failure (recurrence, secondary tumor, or death) had occurred in 123 patients in the tamoxifen group and 107 patients of the control group. Event-free survival rates after 5 years were 70.3% (95% CI, 65.5% to 75.0%) and 72.8% (95% CI, 68.2% to 77.5%) for the tamoxifen and control groups, respectively. The estimated hazard ratio of tamoxifen versus control was 1.13 (95% CI, 0.87 to 1.48; P = .34), which gives no indication of an additional benefit of tamoxifen in these patients. CONCLUSION: This study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy.     

Less efficacy with alternating regimen as adjuvant chemotherapy in stage II node-positive breast cancer: results at 8 years (Pronacam 85).

A randomized trial to compare adjuvant treatment with an alternating regimen with conventional chemotherapy was performed. A total of 589 node-positive patients were included and stratified according to number of positive nodes (N1-3 and N > 4) and menopausal status. Premenopausal N1-3 patients were randomized to cyclophosphamide, methotrexate and fluorouracil (CMF) or CMF/4''-epirubicin, cyclophosphamide (EC), post-menopausal N1-3 patients to fluorouracil, 4 epirubicin, cyclophosphamide (FEC) or CMF/EC and pre- and post-menopausal patients with N > or = 4 to fluorouracil, 4'' epirubicin, cyclophosphamide, methotrexate, prednisone (FECMP) or CMF/EC. In premenopausal patients, CMF was superior to CMF/EC in terms of disease-free survival (DFS) (65% vs 45%, P = 0.0149) and survival (72.3% vs 50.2%, P = 0.0220) whereas, for N > or = 4 patients, differences between FECMP and CMF/EC did not achieve statistical significance (DFS 35% vs 26.2%; survival 50% vs 38.1%, P = NS). For post-menopausal patients, FEC was superior to CMF/EC in DFS (58.6% vs 36.8%, P = 0.0215) and survival (66.2% vs 46%, P = 0.0155). In post-menopausal patients with N > 4, differences favouring CMF/EC were significant in DFS (40.4% vs 22%, P = 0.0371) but not in survival (47.4% vs 32.2%, P = 0.1185). Alternating regimens did not offer better results in premenopausal and post-menopausal N1-3 patients. Results regarding post-menopausal N > 4 women require further confirmation.     

Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes

In the attempt to improve current adjuvant results in patients with one to three positive axillary lymph nodes, in November 1981 we activated a prospective randomized study to assess the effectiveness of intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) for 12 courses versus CMF for eight courses followed by Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) for four courses. The 5-year results were evaluated in a total of 486 patients entered into the study up to December 1987. CMF chemotherapy was delivered IV for a total of 12 courses when given alone and for eight courses when followed by four courses of Adriamycin. All drugs were recycled every 3 weeks. Rather than temporarily reducing doses, drug administration was delayed for 1 to 2 weeks in the face of myelosuppression on the planned day of treatment. After a median follow-up of 61 months, no significant differences were evident between the treatment groups in terms of relapse-free (CMF 74% v CMF followed by Adriamycin 72%) and total survival (CMF 89% v CMF followed by Adriamycin 86%). Drug treatments were fairly well tolerated and devoid of life-threatening toxicity. Present results, which were not influenced by menopausal status, indicate that Adriamycin given after CMF failed to improve treatment outcome over CMF alone. However, the role of Adriamycin in an adjuvant setting remains to be further clarified. Considering the good 5-year results achieved in this study at the expense of minimal toxicity, full-dose CMF remains, at present, the adjuvant chemotherapy of choice for patients with one to three positive nodes.     

CMF vs alternating CMF/EV in the adjuvant treatment of operable breast cancer. A single centre randomised clinical trial (Naples GUN-3 study).

The aim of this study was to test the hypothesis of Goldie and Coldman that the use of non-cross-resistant regimens of chemotherapy could lead to maximal anti-tumour effect. We compared standard CMF (cyclophosphamide, methotrexate, fluorouracil) with alternating CMF/EV (epirubicin, vincristine) in the adjuvant therapy of early breast cancer. Stage II premenopausal node-positive or post-menopausal node-positive oestrogen receptor-negative and stage III breast cancer patients were eligible for the study. From January 1985 to December 1990, 220 patients were randomised (115 to CMF and 105 to CMF/EV). Toxicity was mild; neurotoxicity, vomiting and hair loss were more frequent in the CMF/EV group, while permanent amenorrhoea, diarrhoea, stomach ache and minor infections occurred more often in the CMF arm. At a follow-up of 48 months, 113 patients (51.4%) had had recurrence (62 on CMF and 51 on CMF/EV) and 54 (24.5%) had died (30 on CMF and 24 on CMF/EV). There was no significant difference in disease-free and overall survival between the two arms. After adjusting for menopausal status and stage, the relative risk (RR) of recurrence for CMF/EV patients was 0.93 (95% CL 0.64-1.35), while the RR of death was 0.85 (95% CL 0.49-1.47). In conclusion, the Goldie-Coldman model of alternating therapy is not confirmed in this trial of adjuvant therapy of early breast cancer, although in view of its design a difference of less than 20% in 3 year disease-free survival could not be excluded.     

Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study.

PURPOSE: Current adjuvant therapies have improved survival for premenopausal patients with breast cancer but may have short-term toxic effects and long-term effects associated with premature menopause. PATIENTS AND METHODS: The Zoladex Early Breast Cancer Research Association study assessed the efficacy and tolerability of goserelin (3.6 mg every 28 days for 2 years; n = 817) versus cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (six 28-day cycles; n = 823) for adjuvant treatment in premenopausal patients with node-positive breast cancer. RESULTS: Analysis was performed when 684 events had been achieved, and the median follow-up was 6 years. A significant interaction between treatment and estrogen receptor (ER) status was found (P =.0016). In ER-positive patients (approximately 74%), goserelin was equivalent to CMF for disease-free survival (DFS) (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.84 to 1.20). In ER-negative patients, goserelin was inferior to CMF for DFS (HR, 1.76; 95% CI, 1.27 to 2.44). Amenorrhea occurred in more than 95% of goserelin patients by 6 months versus 58.6% of CMF patients. Menses returned in most goserelin patients after therapy stopped, whereas amenorrhea was generally permanent in CMF patients (22.6% v 76.9% amenorrheic at 3 years). Chemotherapy-related side effects such as nausea/vomiting, alopecia, and infection were higher with CMF than with goserelin during CMF treatment. Side effects related to estrogen suppression were initially higher with goserelin, but when goserelin treatment stopped, reduced to a level below that observed in the CMF group. CONCLUSION: Goserelin offers an effective, well-tolerated alternative to CMF in premenopausal patients with ER-positive and node-positive early breast cancer.     

Selection criteria for epirubicin-based adjuvant chemotherapy in node-negative breast cancer

The management of node-negative breast cancer is problematic due to the lack of reliable prognostic para-meters that distinguish patients who benefit from adjuvant chemotherapy. Since surgery alone is curative in approximately 70% of these patients, clinicians are faced with the dilemma of possible overtreatment or undertreatment. As a compromise, traditional cyclophosphamide/methotrexate/fluorouracil (CMF) is administered rather than newer, potentially more effective regimens containing anthracyclines or taxanes. Invasion and metastasis of solid tumors require tumor-biologic factors that promote the dissolution of the surrounding tumor matrix and the basement membranes, and the serine protease urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator-inhibitor type 1 (PAI-1), play major roles in these invasive processes. Our laboratory and others have reported that determinations by enzyme-linked immunosorbent assay (ELISA) of uPA and PAI-1 concentrations in tumor tissue extracts reliably separate patients with node-negative breast cancer at very low risk of relapse even without chemotherapy from high-risk patients who urgently need intensive effective treatment in order to reduce increased mortality. By eliminating low-risk patients from study entry, these markers permit unbiased evaluation of newer anthracycline-containing regimens in high-risk patients with node-negative disease. A multicenter, transnational European study is currently underway to compare the efficacy of a regimen combining epirubicin and cyclophosphamide with the traditional CMF regimen in these patients, whose risk of relapse and death is similar to that of many patients with node-positive disease.     

Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group.

BACKGROUND: The purpose of this study was to determine the relative efficacy of doxorubicin versus methotrexate in combination with intravenous cyclophosphamide and 5-fluorouracil (FAC versus CMF) as adjuvant chemotherapy for operable breast cancer. PATIENTS AND METHODS: Over a 4-year period, 985 women undergoing curative surgery for breast cancer (T1-3 N0-2 M0, stage I-IIIA, UICC) from nine hospitals were stratified with respect to axillary node involvement (node positive versus node negative) and randomized to receive either FAC (500/50/500/m(2)) every 3 weeks for six cycles or CMF (600/60/600/m(2)) every 3 weeks for six cycles. RESULTS: The relative dose intensities of FAC and CMF were 87% and 85% of planned doses, respectively. Unadjusted data indicated a non-significant trend towards better results with FAC. In the prospectively formed subset of node-negative patients, disease-free survival and overall survival were statistically superior in the FAC treatment arm (P = 0.041 and 0.034, respectively), but this advantage was not seen in the subset of node-positive patients, probably because of a difference in the percentage of patients with four or more positive nodes. Adjusting data for size of treatment effect and potential interactions (number of positive nodes, tumor size, treatment center), the overall relative risk (RR) of disease recurrence and death were significantly lower with FAC treatment (RR 1.2, P = 0.03, and RR 1.3, P = 0.05, respectively). This result was mainly due to the difference observed in the node-negative patient population. Toxicity was mild: FAC induced more alopecia, emesis, mucositis and cardiotoxicity; this last was of clinical concern, but was infrequent and manageable. CMF induced more conjunctivitis and weight gain. There were no toxic deaths. CONCLUSIONS: Doxorubicin in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil is superior to methotrexate in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil as adjuvant chemotherapy for operable breast cancer. A treatment effect is particularly evident in the node-negative patients. Although the clinical toxicity of FAC is greater than that of CMF, the levels were manageable and clinically acceptable.     

Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.     

Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Cyclophosphamide, epirubicin, and fluorouracil (CEF), compared with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. has lead to an improvement in relapse-free and overall survival in premenopausal women with node-positive breast cancer. We undertook this analysis to more accurately define the estimate of risk of secondary acute leukemia (sAL) following epirubicin-containing chemotherapy regimens. PATIENTS AND METHODS: We assessed the conditional probability of sAL among 1,545 women who received adjuvant (n = 1,477) or neoadjuvant (n = 68) chemotherapy in four National Cancer Institute of Canada Clinical Trials Group trials from 1990 to 1999. The risks associated with epirubicin-containing regimens (CEF or epirubicin and cyclophosphamide [EC]) and other regimens (doxorubicin and cyclophosphamide [AC] or CMF) were determined. RESULTS: A total of 10 cases of sAL were observed (eight acute myelogeneous leukemia, two acute lymphoblastic leukemia): seven among women treated with CEF, two who had received AC, and one following CMF. Using competing risk statistics, the conditional probability of sAL was 1.7% (95% confidence interval [CI], 0.5 to 3.6) among 539 women treated with CEF chemotherapy at a follow-up of 8 years, 0.4% (95% CI, 0% to 1.3%) among the 678 who received CMF, and 1.3% (95% CI, 0% to 4.7%) among the 231 treated with AC. The conditional probability of death from breast cancer at 8 years for the entire group of women treated with epirubicin-containing regimens in all four trials was approximately 34.9%. CONCLUSION: CEF chemotherapy for breast cancer carries a small increased risk of sAL compared with CMF. These estimates of acute leukemia risk are important in discussing treatment with women, especially patients with a lower risk of death from breast cancer, such as those with node-negative breast cancer.     

Timing of CMF chemotherapy in combination with tamoxifen in postmenopausal women with breast cancer: role of endocrine responsiveness of the tumor.

BACKGROUND: Controversy persists about whether chemotherapy benefits all breast cancer patients. PATIENTS AND METHODS: In the International Breast Cancer Study Group (IBCSG) trial VII, 1212 postmenopausal patients with node-positive disease were randomized to receive tamoxifen for 5 years or tamoxifen plus three concurrent courses of cyclophosphamide, methotrexate and 5-fluorouracil ('classical' CMF) chemotherapy, either early, delayed or both. In IBCSG trial IX, 1669 postmenopausal patients with node-negative disease were randomized to receive either tamoxifen alone or three courses of adjuvant classical CMF prior to tamoxifen. Results were assessed according to estrogen receptor (ER) content of the primary tumor. RESULTS: For patients with node-positive, ER-positive disease, adding CMF either early, delayed or both reduced the risk of relapse by 21% (P=0.06), 26% (P=0.02) and 25% (P=0.02), respectively, compared with tamoxifen alone. There was no difference in disease-free survival when CMF was given prior to tamoxifen in patients with node-negative, ER-positive tumors. CONCLUSIONS: CMF given concurrently (early, delayed or both) with tamoxifen was more effective than tamoxifen alone for patients with node-positive, endocrine-responsive breast cancer, supporting late administration of chemotherapy even after commencement of tamoxifen. In contrast, sequential CMF and tamoxifen for patients with node-negative, endocrine-responsive disease was ineffective.     

Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group.

PURPOSE: To evaluate the prognostic importance of immunocytochemically determined c-erbB-2 overexpression in the primary tumors of patients with breast cancer. PATIENTS AND METHODS: Primary tumors from 1,506 breast cancer patients (760 node-negative and 746 node-positive) who were treated in the International (Ludwig) Breast Cancer Study Group Trial V were studied. Node-negative patients were allocated randomly to either a single cycle of perioperative chemotherapy (PeCT) or no adjuvant treatment, and node-positive patients received either a prolonged chemotherapy (with tamoxifen for postmenopausal patients) or a single perioperative cycle. RESULTS: Tumors from 16% of the node-negative patients and 19% of the node-positive patients were found to be c-erbB-2-positive. In both groups c-erbB-2 positivity correlated with negative progesterone receptors (PR), negative estrogen receptors (ER), and high tumor grade. Lobular carcinomas were all negative, and, thus support the view that such tumors represent a defined subtype of breast carcinoma. The expression of c-erbB-2 was prognostically significant for node-positive but not for node-negative patients. However, in both subgroups, the prognostic significance was greater for patients who had received more adjuvant therapy. For node-positive patients, the effect of prolonged-duration therapy on disease-free survival (DFS) was greater for patients without c-erbB-2 overexpression (hazards ratio [HR], = 0.57; 95% confidence interval [CI], 0.46 to 0.72) than for those with c-erbB-2 overexpression (HR, 0.77; 95% CI, 0.51 to 1.16). Similarly, for node-negative patients, the effect of PeCT on DFS was greater for those without c-erbB-2 overexpression (HR, 0.82; 95% CI, 0.61 to 1.09) than for those with c-erbB-2 overexpression (HR, 1.22; 95% CI, 0.66 to 2.25). CONCLUSION: We conclude that tumors with overexpression of the c-erbB-2 oncogene are less responsive to cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant therapy regimens than those with a normal amount of gene product.     

Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials.

PURPOSE: This article reports the results of a pooled analysis of six randomized trials conducted to study the efficacy of uracil and tegafur (UFT) in the adjuvant treatment of node-negative breast cancer patients. PATIENTS AND METHODS: Six randomized controlled trials on node-negative breast cancer patients were conducted from 1992 through 1995 in Japan that included the three, three-arm trials (control [no adjuvant], UFT, and tamoxifen [TAM] groups) and the three, four-arm trials (control, UFT, TAM, and UFT plus TAM groups). Pooled analysis was performed on the data obtained from these six trials (involving 2,934 patients). RESULTS: Overall survival was compared between the UFT group (including both the UFT group and the TAM plus UFT group) and the non-UFT group (control group and TAM group). A significant difference (P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups. Overall survival was also compared between the TAM group (TAM group and TAM plus UFT group) and the non-TAM group (control group plus UFT group). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group, but the subset analysis showed a significant (P = .01) improvement in the estrogen receptor-positive subset. CONCLUSION: Adjuvant UFT improves the overall survival of node-negative breast cancer patients. Given that UFT has milder adverse effects, it is suggested that UFT can be a useful alternative to doxorubicin and cyclophosphamide, or cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment for node-negative breast cancer.