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.     

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.     

Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer.

PURPOSE: To compare a full-dose epirubicin-cyclophosphamide (HEC) regimen with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy and with a moderate-dose epirubicin-cyclophosphamide regimen (EC) in the adjuvant therapy of node-positive breast cancer. PATIENTS AND METHODS: Node-positive breast cancer patients who were aged 70 years or younger were randomly allocated to one of the following treatments: CMF for six cycles (oral cyclophosphamide); EC for eight cycles (epirubicin 60 mg/m(2), cyclophosphamide 500 mg/m(2); day 1 every 3 weeks); and HEC for eight cycles (epirubicin 100 mg/m(2), cyclophosphamide 830 mg/m(2); day 1 every 3 weeks). RESULTS: Two hundred fifty-five, 267, and 255 eligible patients were treated with CMF, EC, and HEC, respectively. Patient characteristics were well balanced among the three arms. One and three cases of congestive heart failure were reported in the EC and HEC arms, respectively. Three cases of acute myeloid leukemia were reported in the HEC arm. After 4 years of median follow-up, no statistically significant differences were observed between HEC and CMF (event-free survival [EFS]: hazards ratio [HR] = 0.96, 95% confidence interval [CI], 0.70 to 1.31, P =.80; distant-EFS: HR = 0.97, 95% CI, 0.70 to 1.34, P =.87; overall survival [OS]: HR = 0.97, 95% CI, 0.65 to 1.44, P =.87). HEC is more effective than EC (EFS: HR = 0.73, 95% CI, 0.54 to 0.99, P =.04; distant-EFS: HR = 0.75, 95% CI, 0.55 to 1.02, P =.06; OS HR = 0.69, 95% CI, 0.47 to 1.00, P =.05). CONCLUSION: This three-arm study does not show an advantage in favor of an adequately dosed epirubicin-based regimen over classical CMF in the adjuvant therapy of node-positive pre- and postmenopausal women with breast cancer. Moreover, this study confirms that there is a dose-response curve for epirubicin in breast cancer adjuvant therapy.     

Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study.

PURPOSE: To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer. PATIENTS AND METHODS: Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to 14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen. RESULTS: A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P =.94). CONCLUSION: Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients.     

Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial.

PURPOSE: This randomized, multicenter, phase III study compared doxorubicin and docetaxel (AT) with doxorubicin and cyclophosphamide (AC) as first-line chemotherapy (CT) in metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients (n = 429) were randomly assigned to receive doxorubicin 50 mg/m(2) plus docetaxel 75 mg/m(2) (n = 214) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (n = 215) on day 1, every 3 weeks for up to eight cycles. RESULTS: Time to progression (TTP; primary end point) and time to treatment failure (TTF) were significantly longer with AT than AC (median TTP, 37.3 v 31.9 weeks; log-rank P =.014; median TTF, 25.6 v 23.7 weeks; log-rank P =.048). The overall response rate (ORR) was significantly greater for patients taking AT (59%, with 10% complete response [CR], 49% partial response [PR]) than for those taking AC (47%, with 7% CR, 39% PR) (P =.009). The ORR was also higher with AT in patients with visceral involvement (58% v 41%; liver, 62% v 42%; lung, 58% v 35%), three or more organs involved (59% v 40%), or prior adjuvant CT (53% v 41%). Overall survival (OS) was comparable in both arms. Grade 3/4 neutropenia was frequent in both groups, although febrile neutropenia and infections were more frequent for patients taking AT (respectively, 33% v 10%, P <.001; 8% v 2%, P =.01). Severe nonhematologic toxicity was infrequent in both groups, including grade 3/4 cardiac events (AT, 3%; AC, 4%). CONCLUSION: AT significantly improves TTP and ORR compared with AC in patients with MBC, but there is no difference in OS. AT represents a valid option for the treatment of MBC.     

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.     

Adjuvant CMF for node-negative and estrogen receptor-negative breast cancer patients.

From December 1980 to September 1985, a total of 90 eligible patients with stage T1-3a, node-negative, and estrogen receptor-negative (less than or equal to 10 fmol/mg of cytosol protein) tumors were entered into a randomized study to assess the effectiveness of adjuvant intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) in a subset of patients at high risk of early disease relapse. High values of [3H]thymidine labeling index were documented in two thirds of 62 assessed specimens from the patient population, and one half of the patients had histologically undifferentiated tumors. Patients were allocated to either local-regional modality alone (control group, 45 women) or to CMF (45 patients) after surgery. A full dose of CMF (600 mg/m2 each of cyclophosphamide and fluorouracil, and 40 mg/m2 of methotrexate) was administered IV on day 1, and then repeated every 3 weeks for a total of 12 treatments. After a median follow-up of 80 months, the 7-year results confirmed the superiority of adjuvant CMF compared to local-regional modality alone (relapse-free survival 85% vs 42%, P = .0001; total survival 86% vs 58%, P = .006). A benefit from adjuvant CMF was observed in all subgroups, and the rates of both local-regional and distant failure were decreased. Treatment was fairly well tolerated and devoid of life-threatening toxicity. Present results confirm our previous observation concerning the dismal prognosis of node-negative and estrogen receptor-negative breast cancer patients as well as the beneficial effect of adjuvant chemotherapy in this selected subset.     

Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer

We compared the efficacy of CEF (cyclophosphamide, epirubicin, and fluorouracil) against CMF (cyclophosphamide, methotrexate, and fluorouracil) in moderate or high risk breast cancer patients. We randomly assigned 1224 patients with completely resected unilateral breast cancer to receive nine cycles of three-weekly intravenous CMF or CEF. Patients were encouraged to take part in a parallel trial comparing oral pamidronate 150 mg twice daily for 4 years versus control (data not shown). Substitution of methotrexate with epirubicin significantly reduced the unadjusted hazard for disease-free survival (DFS) by 16% (hazard ratio 0.84; 95% CI; 0.71-0.99) and for overall survival by 21% (hazard ratio 0.79; 95% CI; 0.66-0.94). The risk of secondary leukaemia and congestive heart failure was similar in the two groups. Overall CEF was superior over CMF in terms of DFS and OS in patients with operable breast cancer without subsequent increase in late toxicities.     

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.     

Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial

To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.     

Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer.

PURPOSE: To determine the place of single-agent paclitaxel compared with nonanthracycline combination chemotherapy as front-line therapy in metastatic breast cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic breast cancer were randomized to receive either paclitaxel 200 mg/m(2) intravenously (IV) over 3 hours for eight cycles (24 weeks) or standard cyclophosphamide 100 mg/m(2)/d orally on days 1 to 14, methotrexate 40 mg/m(2) IV on days 1 and 8, fluorouracil 600 mg/m(2) IV on days 1 and 8, and prednisone 40 mg/m(2)/d orally on days 1 to 14 (CMFP) for six cycles (24 weeks) with epirubicin recommended as second-line therapy. RESULTS: A total of 209 eligible patients were randomized with a median survival duration of 17.3 months for paclitaxel and 13.9 months for CMFP. Multivariate analysis showed that patients who received paclitaxel survived significantly longer than those who received CMFP (P =.025). Paclitaxel produced significantly less severe leukopenia, thrombocytopenia, mucositis, documented infections (all P <.001), nausea or vomiting (P =.003), and fever without documented infection (P =.007), and less hospitalization for febrile neutropenia than did CMFP (P =.001). Alopecia, peripheral neuropathy, and myalgia or arthralgia were more severe with paclitaxel (all P <.0001). Overall, quality of life was similar for both treatments (P > = .07). CONCLUSION: Initial paclitaxel was associated with significantly less myelosuppression and fewer infections, with longer survival and similar quality of life and control of metastatic breast cancer compared with CMFP.     

Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen.

PURPOSE: To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen. PATIENTS AND METHODS: Five hundred sixty-two estrogen receptor-positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu. RESULTS: For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P =.008), clinical benefit (CB; 57% v 45%; P =.016), time to progression (TTP; median, 12.2 v 8.5 months; P =.0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P =.0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P =.45) or CB (33% v 26%; P =.31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P =.0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P =.0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP. CONCLUSION: Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.     

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.     

Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403).

PURPOSE: To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. PATIENTS AND METHODS: A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m(2) on day 1 and vinorelbine 25 mg/m(2) on days 1 and 8, or epirubicin 90 mg/m(2) IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1000 mg/m(2) (950 mg/m(2) from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. RESULTS: Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P =.15). The complete response rate was significantly superior in the combination arm (17% v 10%; P =.048) as was median duration of progression-free survival (10.1 months v 8.2 months; P =.019). Median survival was similar in the two arms (19.1 months v 18.0 months; P =.50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. CONCLUSION: Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.     

Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group Study--NCIC CTG MA.5.

PURPOSE: To investigate the therapeutic impact of chemotherapy-induced amenorrhea in premenopausal patients with breast cancer. PATIENTS AND METHODS: We conducted a retrospective cohort study of a National Cancer Institute of Canada Clinical Trials Group phase III trial involving premenopausal patients randomized to receive cyclophosphamide, methotrexate, and fluorouracil (CMF), versus intensive cyclophosphamide, epirubicin, and fluorouracil (CEF). The objectives of our study were to describe the incidence of amenorrhea at 6 and 12 months post-random assignment and to determine the association of amenorrhea with relapse-free and overall survival. RESULTS: Data on 442 patients were used in our analyses. Despite the higher cumulative dose of cyclophosphamide in the CMF treatment arm, at 6 months post-random assignment, the rate of amenorrhea was higher in the CEF group (relative risk, 1.2; 95% CI, 1.0 to 1.3), with no difference at 12 months. In the receptor-positive subgroup, 6-month amenorrhea rates were not associated with prognosis. In contrast, amenorrhea at 12 months was significantly associated with relapse-free survival (hazard ratio, 0.51; 95% CI, 0.32 to 0.82; P = .005) and overall survival (hazard ratio, 0.40; 95% CI, 0.22 to 0.72; P = .002). CONCLUSION: Late chemotherapy-induced amenorrhea seems to be associated with improved outcome in patients with premenopausal, receptor-positive breast cancer.     

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.     

Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre.

PURPOSE: To compare the efficacy and safety of doxorubicin and docetaxel (AT) with fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients (n = 216) were randomly assigned to either AT (doxorubicin 50 mg/m(2) and docetaxel 75 mg/m2) or FAC (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); both regimens were administered on day 1, every 3 weeks. RESULTS: A median number of six cycles was delivered in both arms, with a median relative dose-intensity of more than 98%. Median time to progression (TTP) and median overall survival (OS) were significantly longer for patients on AT compared with FAC (TTP: 8.0 v 6.6 months, respectively; P = .004; and OS: 22.6 v 16.2 months, respectively; P = .019). The overall response rate (ORR) was significantly higher in patients on AT compared with FAC (58% v 37%, respectively; P = .003). The ORR on AT was also higher in patients with visceral disease compared with FAC patients with visceral disease (59% v 36%, respectively; P = .003). There were no differences in grade 3 to 4 neutropenia and infections (AT 89% v FAC 84% and AT 12% v FAC 9%, respectively). Neutropenic fever was more common in AT-treated patients than FAC-treated patients (33% v 9%, respectively; P < .001). Grade 3 to 4 nonhematologic toxicity was infrequent in both arms. Congestive heart failure was observed in 3% and 6% of patients on AT and FAC, respectively. CONCLUSION: In this phase II to III study, AT resulted in a significantly longer TTP and OS and a higher objective ORR than FAC. First-line AT is a valid treatment option for patients with MBC.     

Epirubicin or epirubicin and vindesine in advanced breast cancer. A phase III study

One hundred thirty-three evaluable patients with advanced breast cancer entered a randomized trial comparing epirubicin 60 mg/m2 with a combination of epirubicin 45 mg/m2 and vindesine 3 mg/m2 day 1 and 8 every 4 weeks. In all 10 premenopausal women an oophorectomy was performed. Seventy-five patients had previously received cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for advanced disease and 68 had received adjuvant chemotherapy (cyclophosphamide or CMF). Among evaluable patients (72 in the epirubicin group and 61 in the epirubicin + vindesine group) response rates were as follows: complete response--seven versus six; partial response--31 versus 22; no change--16 versus 17 (p greater than 0.40). Median time to disease progression was 6 months in both groups and median survival times were identical (12 months). Thrombocytopenia was less frequent in the epirubicin + vindesine group (p less than 0.01). In the epirubicin + vindesine group, mild to moderate peripheral neuropathy was observed in 40% of the patients. Congestive heart failure developed in one patient with a cumulative dose of epirubicin less than 1000 mg/m2 and in 7 of 15 patients who had greater than 1000 mg/m2. Four died of this cause. In conclusion, epirubicin is effective as a single agent for advanced breast cancer. The combination with vindesine does not increase its efficacy.     

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.     

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.