[A double-blind randomized comparative study of oral 5-fluorouracil (5-FU), cyclophosphamide (CPA), and 5-FU + CPA in advanced breast cancer]. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). A double blind comparative study of tegafur (FT) and UFT (a combination of Tegafur and uracil) in advanced breast cancer. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. Refractory breast cancer: a comparison of two different chemotherapy regimens. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Evaluation of single-drug versus multiple-drug chemotherapy in the treatment of advanced breast cancer. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. The French Epirubicin Study Group. Single-drug vs combination cytotoxic chemotherapy in advanced breast cancer: a randomized study. Combination or mild single agent chemotherapy for advanced breast cancer? CMF vs epirubicin measuring quality of life. Controlled evaluation of adriamycin (NSC-123127) in patients with disseminated breast cancer. Doxorubicin versus mitomycin versus doxorubicin plus mitomycin in advanced breast cancer: a randomized study. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. Combination chemotherapy and adriamycin in patients with advanced breast cancer. A Southwest Oncology Group study. Phase II clinical trial of isophosphamide (NSC-109724) in patients with advances breast cancer. Evaluation of VP-16 and the combination of adriamycin and vincristine in advanced breast cancer. Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies. Chemotherapy of advanced breast cancer: a controlled randomized trial of cyclophosphamide versus a four-drug combination. VP-16 + adriamycin vs. adriamycin alone in advanced adenocarcinoma of the breast, phase II, a randomized trial: a Southwest Oncology Group Study. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. Randomized clinical trial of doxorubicin alone or combined with mitolactol in women with advanced breast cancer and prior chemotherapy exposure. Combination chemotherapy for metastatic breast carcinoma. Prospective comparison of multiple drug therapy with L-phenylalanine mustard. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. Randomized trial of doxorubicin alone or combined with vincristine and mitomycin C in women with metastatic breast cancer. Epirubicin or epirubicin and vindesine in advanced breast cancer. A phase III study. 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).
A randomized trial was performed comparing the effects of oral 5-fluorouracil (5-FU), 300 mg/day, cyclophosphamide (CPA), 150 mg/day and 5-FU + CPA in advanced breast cancer. Some 181 patients were entered in the trial, with 1 ineligible, and 14 incomplete cases. Then 166 were evaluated for their rates of response in the treatment groups: 14.0% (8/57) in 5-FU, 23.6% (13/55) in CPA, and 37.0% (20/54) in 5-FU + CPA, with a P value of 0.019. The difference in response rates between 5-FU and 5-FU + CPA was shown to be significant (p = 0.005). When long NC was included in the comparison, there was a significant difference (p = 0.006) between the groups. A higher incidence of adverse effects was noted in the combination group. A significant difference was noted in TTP (time to progression) among the 3 groups (p = 0.0144), and between 5-FU and 5-FU + CPA (p = 0.0061). There were no significant differences in the overall survival among the groups (p = 0.6808). In conclusion, the combination oral treatment of 5-FU and CPA appears effective as a first line therapy for advanced breast cancer, and also in the postoperative adjuvant setting. Between February 1993 and September 1995, 739 patients with metastatic breast cancer were entered on an Intergroup trial (E1193) comparing doxorubicin (60 mg/m(2)), paclitaxel (175 mg/m(2)/24 h), and the combination of doxorubicin and paclitaxel (AT, 50 mg/m(2) and 150 mg/m(2)/24 h, plus granulocyte colony-stimulating factor 5 mg/kg) as first-line therapy. Patients receiving single-agent doxorubicin or paclitaxel were crossed over to the other agent at time of progression.
                Patients were well balanced for on-study characteristics.
                Responses (complete response and partial response) were seen in 36% of doxorubicin, 34% of paclitaxel, and 47% of AT patients (P =.84 for doxorubicin v paclitaxel, P =.007 for v AT, P =.004 for paclitaxel v AT). Median time to treatment failure (TTF) is 5.8, 6.0, and 8.0 months for doxorubicin, paclitaxel, and AT, respectively (P =.68 for doxorubicin v paclitaxel, P =.003 for doxorubicin v AT, P =.009 for paclitaxel v AT). Median survivals are 18.9 months for patients taking doxorubicin, 22.2 months for patients taking paclitaxel, and 22.0 months for patients taking AT (P = not significant). Responses were seen in 20% of patients crossing from doxorubicin --> paclitaxel and 22% of patients crossing from paclitaxel --> doxorubicin (P = not significant). Changes in global quality-of-life measurements from on-study to week 16 were similar in all three groups.
                (1) doxorubicin and paclitaxel, in the doses used here, have equivalent activity; (2) the combination of AT results in superior overall response rates and time to TTF; and (3) despite these results, combination therapy with AT did not improve either survival or quality of life compared to sequential single-agent therapy. A double blind study to compare the efficacy of oral UFT (400 mg Tegafur (FT) plus 896 mg uracil/day) with that of oral FT (800 mg/day) on advanced breast cancer was performed between November, 1986, and November, 1989. Sixty patients were registered for the trial and fifty-six cases were evaluated (28 for UFT and 28 for FT). The primary end points in the study were response rate and time to relapse. There were no significant differences in patients' characteristics in either group. The objective response rates were 39% (11/28; 95% confidence interval (C.I.), 22-59%) in UFT and 21% (6/28; 95% C.I., 8-41%) in FT, without statistical significance (P = 0.25). For time to relapse, a trend was seen in favor of UFT, but this effect did not achieve statistical significance (P = 0.09). Both subjective and objective adverse effects were similar between the two treatments. The overall survivals were similar in both parts of the study. The size of the trial was too small for a definite conclusion to be drawn although, for both response rate and time to relapse, a trend was seen in favor of UFT. A large scale randomized study will be necessary to compare the drugs in the management of patients with advanced breast cancer. This phase III study compared docetaxel with mitomycin plus vinblastine (MV) in patients with metastatic breast cancer (MBC) progressing despite previous anthracycline-containing chemotherapy.
                Patients (n=392) were randomized to receive either docetaxel 100 mg/m2 intravenously (i.v.) every 3 weeks (n=203) or mitomycin 12 mg/m2 i.v. every 6 weeks plus vinblastine 6 mg/m2 i.v. every 3 weeks (n=189), for a maximum of 10 3-week cycles.
                In an intention-to-treat analysis, docetaxel produced significantly higher response rates than MV overall (30.0% v 11.6%; P < .0001), as well as in patients with visceral involvement (30% v 11%), liver metastases (33% v 7%), or resistance to previous anthracycline agents (30% v 7%). Median time to progression (TTP) and overall survival were significantly longer with docetaxel than MV (19 v 1 weeks, P=.001, and 1 1.4 v 8.7 months, P=.0097, respectively). Neutropenia grade 3/4 was more frequent with docetaxel (93.1 % v62.5%; P < .05); thrombocytopenia grade 3/4 was more frequent with MV (12.0% v 4.1%; P < .05). Severe acute or chronic nonhematologic adverse events were infrequent in both groups. Withdrawal rates because of adverse events (MV, 10.1%; docetaxel, 13.8%) or toxic death (MV, 1.6%; docetaxel, 2.0%) were similar in both groups. Quality-of-life analysis was limited by a number of factors, but results were similar in both groups.
                Docetaxel is significantly superior to MV in terms of response, TTP, and survival. The safety profiles of both therapies are manageable and tolerable. Docetaxel represents a clear treatment option for patients with MBC progressing despite previous anthracycline-containing chemotherapy. Sixty metastatic and recurrent breast cancer patients who had been given cyclophosphamide, methotrexate and fluorouracil (CMF) therapy previously and were treated at the Oncology Departments of Cukurova and Ege University Medical Schools between March 1992-94, were randomized into 2 groups for the chemotherapy program. The 30 patients in the 1st group were given etoposide: 200 mg x day x 5 days orally every 3 weeks. The 30 patients of the 2nd group were given fluorouracil: 500 mg x m2, doxorubicin: 5O mg/m2, cyclophosphamide: 500 mg/m2 intravenously every 3 weeks. The response rates were 21/30 in group 1 and 17/30 in group 2. The median duration of responses was 11 months (8-21) in the 1st and 9 months (4-18) in the 2nd group. Severe myelotoxicity was observed in 2 of the patients in the 1st group and in 5 of the patients in the 2nd group. The aim of this study was to compare the efficacy and tolerability of docetaxel to methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure. A randomised multicentre trial was conducted in 283 patients with advanced breast cancer who had failed previous anthracycline treatment. Docetaxel at a dose of 100 mg/m2 every 3 weeks (n = 143) was compared with sequential methotrexate and 5-fluorouracil (MF; n = 139) given at day 1 and 8 every 3 weeks at dosages of 200 mg/ m2 and 600 mg/m2, respectively. After progression, crossover to the alternative treatment group was recommended. There was a significantly higher overall response rate in the docetaxel 42% (CR 8% + PR 34%) than in the MF arm 21% (CR 3% + PR 18%) (P < 0.001). The median time to progression (TTP) was 6.3 months in the docetaxel arm and 3.0 months in the MF arm (P < 0.001). Docetaxel also had a significantly higher response rate of 27% following crossover compared with MF (12%). Significantly more side-effects (leucopenia, infections, neuropathy, oedema, asthenia, skin, nail changes, alopecia) were seen in the docetaxel than in the MF group. However, grade 3 and 4 side-effects were infrequent with both drugs, with the exception of fatigue, alopecia and infections. Median overall survival (OS) including crossover phase was 10.4 months in the docetaxel and 11.1 months in the MF arm (P = 0.79). Based on the response rate and the primary endpoint of TTP, docetaxel is superior to sequential methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure. Fifty-one postmenopausal patients with advanced breast cancer were randomized to receive either cyclophosphamide given continuously or cyclophosphamide given continuously with methotrexate, 5-fluorouracil, vincristine, and prednisone given intermittently. The results with the multiple-drug therapy were significantly better than with the single-drug therapy, both with regard to percentage (63% versus 25%) and median duration (400 versus 210 days) of objective response. Toxicity was moderately increased with the combination as compared to the single-drug treatment. The French Epirubicin Study Group carried out a randomized trial comparing epirubicin alone 75 mg/m2 with fluorouracil (5FU) 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 50 mg/m2 (FEC 50) and 5FU 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 75 mg/m2 (FEC 75) as first treatment for advanced breast cancer patients. Patients were stratified according to whether or not there were bone metastases only. Four hundred twelve patients entered this trial; 378 were assessable for tolerability and 365 for efficacy. The overall response rates were comparable between FEC 50 (44.6%) and FEC 75 (44.7%), but both were better than the epirubicin alone (30.6%) (P = .04 and P = .0006, respectively). The complete response rate was better in FEC 75 (15.5%) than in FEC 50 (7%) (P = .025) or epirubicin (4%) (P = .002). Similar results were obtained in the group of patients without bone-only metastases. No difference in the three treatments was observed in the patients with bone metastases only. Mean durations of response were similar in the three groups, being 412 days, 440 days, and 350 days for FEC 50, FEC 75, and epirubicin, respectively. Patients without previous adjuvant chemotherapy fared better than those with previous treatment (without anthracyclines). Tolerability was fair in the three groups. Overall, the epirubicin-alone group showed better tolerance than the two other groups, which did not differ significantly. Time to progression and survival were not different among the three groups, but more early relapses occurred in the epirubicin and FEC 50 groups; survival seemed to be better during the first 8 months in the FEC 75 group, and the survival difference between the epirubicin group and the FEC 75 group was of borderline significance. No difference in survival was observed between epirubicin- and FEC 50-group patients, even though the response rate was significantly worse in the monochemotherapy group. nan Forty patients with advanced breast cancer, randomised to receive CMF or weekly low dose Epirubicin, were evaluated by UICC criteria of response and WHO toxicity criteria, in addition to three QoL instruments: the 'Qualitator' daily diary card, 4 weekly Nottingham Health Profile (NHP) and Linear Analogue Self-Assessment (LASA). Response rates were 58% for CMF and 29% for epirubicin (chi 2 = 3.51, 1 d.f., P > 0.05). Median time to treatment failure was 24 weeks for CMF, 7 weeks for epirubicin (P < 0.05) but survival was similar in both groups. Survival was better for responders than for non-responders (medians 87 and 30 weeks, P = 0.02). CMF caused more objective alopecia (P < 0.001), nausea and vomiting (P < 0.001) and haematological toxicity (P < 0.02). However, QoL measures only recorded a significant difference in energy and pain, influenced primarily by the non-responders in each treatment group but with no difference in overall global scores. Scores for responders, irrespective of treatment, were better to start with (LASA P = 0.001); at 12 weeks, scores had improved (Qualitator P < 0.05; NHP P < 0.05). Scores in non-responders showed no change. In this small study aggressive chemotherapy gave better response and similar survival without impairing Quality of life overall. Detailed QoL measurement should be integral to all cancer chemotherapy trials. nan In a randomized trial the antineoplastic and toxic effects of doxorubicin (ADR), mitomycin (MMC), and the combination of the two were evaluated in postmenopausal patients with advanced breast cancer using the following treatment regimens: ADR (75 mg/m2 by iv bolus every 3 weeks); MMC (20 mg/m2 by iv bolus every 6 weeks); and ADR (45 mg/m2 by iv bolus every 3 weeks) and MMC (10 mg/m2 by iv bolus every 6 weeks). One hundred one patients were entered in the study. Entrance to single-agent MMC therapy was stopped after allocation of 12 patients because of unacceptable side effects, especially nausea and vomiting, and the suggestion of minor efficacy. One of these patients had partial response, eight had no change, and three had progressive disease. The patients in the ADR and ADR plus MMC group were similar as to the following: age (median, 60 years); menopausal age; disease-free interval; performance status, extent of previous cytotoxic therapy (approximately 90% were pretreated) and radiation therapy; and dominant site of disease but with significantly more involved organ sites in the ADR plus MMC group. Among evaluable patients (42 in the ADR group and 39 in the ADR plus MMC group), response rates were as follows: complete response--21 versus five; partial response--26 versus 44; no change--40 versus 38; and progressive disease--12 versus 13 (P greater than 0.10). Median times to disease progression were 5.2 and 7.8 months, respectively (log-rank test, P = 0.03), but survival times were similar, 9.3 and 10.2 months, respectively (log-rank test, P greater than 0.40). For the two treatment groups suppression of wbc count was similar, while anemia, thrombopenia, and nausea and vomiting were significantly more common among the ADR plus MMC-treated group. Five treatment-induced deaths were observed in the ADR plus MMC group (one from sepsis; two from diffuse hemorrhage; and two from cardiomyopathy), compared to none in the ADR group. In conclusion, this study disclosed no major advantage of the combination of ADR plus MMC compared to ADR alone as second-line treatment of advanced breast cancer, but results from other studies may imply a possible role of MMC as part of second-line combination chemotherapy regimens. To determine the place of single-agent paclitaxel compared with nonanthracycline combination chemotherapy as front-line therapy in metastatic breast cancer.
                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.
                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).
                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. In January, 1972, the Southwest Oncology Group initiated two randomized studies for patients with advanced breast cancer. The study for patients with prior chemotherapy showed a 33% response rate with adriamycin. The study for patients without previous chemotherapy consisted of three treatment regimens; a weekly repeated combination of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone; these same five drugs given in courses of 5 days repeated every 4 weeks; and adriamycin as a single agent every 3 weeks. For the 283 evaluable patients, the response rates were: weekly combination 63/106 (59%); intermittent combination 39/98 (40%); and adriamycin 31/79 (39%). The median duration of response was 8 months for weekly combination, 10 months for intermittent therapy and only 4 months for adriamycin. Leukopenia was the dose-limiting toxicity with all three regimens. The weekly combination is the most effective therapy for patients with advanced disease. Extensive trails of combinations that include adriamycin are underway. nan 39 previously treated patients with metastatic breast cancer were treated in a partially randomized study evaluating VP-16 and the combination of Vincristine (VCR) and Adriamycin (ADR). Of the 19 patients treated with VP-16 initially, two had partial remissions. No responses were noted in eleven patients who corssed-over after failing VCR plus ADR. Of the 20 patients treated with VCR plus ADR initially, four patients had partial responses. An additional 2/15 patients responded on crossover after failing initially on VP-16. No significant differences in time to last follow-up or death could be detected between the two treatment programs. To determine whether patients with high-risk metastatic breast cancer draw benefit from combination chemotherapy as first-line treatment.
                A total of 260 women with measurable metastatic breast cancer fulfilling high-risk criteria, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either mitoxantrone 12 mg/m(2) or the combination of fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2) and cyclophosphamide 500 mg/m(2) (FEC) every 3 weeks. Treatment was continued until complete remission plus two cycles, or until disease progression. In the case of partial remission or stable disease, treatment was stopped after 12 cycles. Second-line treatment was vindesine, mitomycin and prednisolone. Gain from treatment was estimated using a modified Brunner's score composed of time to progression, patients' rating of the treatment benefit, alopecia, vomiting and performance status.
                After recruitment from 1992 to 1997 and observation from 1997 to 1999, the final evaluation showed that single-agent treatment with mitoxantrone does not differ significantly from combination treatment with FEC in terms of response, objective remission rate, remission duration, time to response, time to best response, time to progression or overall survival. There was, however, a significant difference in gain from treatment using a modified Brunner's score favoring the single-agent treatment arm. There was no evidence that any subgroup would fare better with combination treatment.
                No significant difference was detected between the treatment with mitoxantrone as a single agent and the combination of low-dose FEC in terms of response or survival; therefore, the imperative of the necessity of first-line combination chemotherapy for patients with high-risk metastatic breast cancer may be questioned. Since toxicity and quality of life score favored the single-agent mitoxantrone treatment arm, this treatment may be offered to patients preferring quality of life to a potential small prolongation of survival. In premenopausal women with metastatic breast cancer, differences in survival curves early during follow-up can be misleading. The authors therefore analyzed long-term survival in 378 patients, entered in three randomized trials, started between 1973 and 1978. Combined data from the three trials were used to increase the power for identifying prognostic variables. Cancer and Leukemia Group B (CALGB) trial 7382 randomized patients to oophorectomy plus either cyclophosphamide or combination chemotherapy or observation. Eastern Cooperative Oncology Group (ECOG) 2174 randomized patients who had not progressed 3 months after oophorectomy to combination chemotherapy or combination chemotherapy or observation. Trial ECOG 2177 randomized estrogen receptor (ER) positive or ER-unknown patients to oophorectomy plus combination chemotherapy or immediate combination chemotherapy, and ER-negative patients were directly assigned to combination chemotherapy. Hence ER-negative patients need not have been healthy enough to be randomized to oophorectomy. With only 14% of the patients still alive, median survival on the three studies was 30, 24, and 28 months. The median survival of individual treatments changed noticeably in ECOG 2174 and ECOG 2177 with long-term follow-up. At this time there are no differences in survival between randomized regimens in any of the three trials. In a multivariate model, factors associated with significantly poorer survival were visceral-dominant disease, nodal metastases, breast metastases, age younger than 45 years, ER negativity, and not receiving chemotherapy immediately after oophorectomy. This treatment difference was thus not due to imbalances in the prognostic variables used in the model, but it may be due to imbalances of unknown prognostic factors or differences in patient selection. Ninety-nine patients with advanced breast cancer were randomized to receive either cyclophosphamide continuously or a combination of cyclophosphamide, methotrexate, 5-fluorouracil and vinblastine given intermittently. The number and duration of objective responses were greater in patients receiving the combination but the differences between the two treatments did not achieve formal significance. The combination was logistically easier to manage and produced less toxicity. One hundred twenty-two patients with advanced adenocarcinoma of the breast were randomized to receive adriamycin (AD) alone or a combination of VP-16 plus lower dose adriamycin (VAD). The patients were stratified to good and poor risk. The starting dose (day 1) of AD was 60 mg/m2 for good risk and 45 mg/m2 for poor risk. The starting dose of the VAD combination for the good-risk patient was VP-16, 75 mg/m2 daily x 5 plus adriamycin 35 mg/m2. The poor-risk dose for VAD was VP-16, 50 mg/m2 daily x 5 plus adriamycin, 30 mg/m2 on day 1. The total dose of AD was 450 mg/m2 on both arms. The patients who were on the VAD arm continued on VP-16 maintenance. Both arms were repeated every 21 days. There were 54 evaluable patients on the adriamycin arm and 52 evaluable patients on the VAD arm. Both arms were similar with regard to age, menopausal status, performance status, and prior hormonal therapy. More hematologic toxicity was seen in the adriamycin arm. Complete responses were observed on both arms, three (5%) with adriamycin and three (5%) with combination. Eleven (19%) and ten (18%) partial responses were observed with the adriamycin and VP-16 plus adriamycin, respectively. AD produced more stable disease than VAD (41% vs. 29%). Complete responses were seen only in the good-risk patients. Time to progression was delayed on the combination arm (P = 0.02). The survival in both arms was similar. The addition of VP-16 to adriamycin does not offer an important clinical advantage. In a prospective randomised study 128 patients with advanced breast cancer were treated either with Adriamycin (20 mg/week) or vincristine, Adriamycin and cyclophosphamide (VAC). An objective response was obtained in 31 and 35% of patients in the two groups. There was no significant difference with regard to duration of response or survival. Weekly low dose Adriamycin was well tolerated. When subjective side effects occurred, they were usually slight and transient. In approx. 40% of the patients no side-effects at all were observed. Eight per cent had alopecia requiring a wig. Only slight myelosuppression could be seen in a few patients and this had no practical implications. Most or all of VAC patients experienced severe toxicity with regard to nausea, vomiting and alopecia. Also myelosuppression was more pronounced among VAC patients. It is concluded that weekly doses of Adriamycin as single agent therapy for advanced breast cancer is as effective as the VAC combination delivered every third week, with considerably less toxicity. Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC.
                Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256).
                Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination).
                The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC. One hundred fifty-one women with advanced breast cancer who had failed prior chemotherapy were randomized to monthly courses of doxorubicin (60 mg/m2 I.V. day 1, observation after 500 mg/m2) or doxorubicin (40 mg/m2 I.V. day 1; maximum 500 mg/m2) and mitolactol (135 mg/m2 orally, days 1-10; 180 mg/m2 after maximum doxorubicin). Median survival times were 232 days for doxorubicin and 225 days for doxorubicin + mitolactol, and median times to progression were 112 days and 97 days, respectively. Results are inconsistent with a 25% improvement in survival or time to progression for doxorubicin + mitolactol (p = 0.04 and 0.02, respectively, adjusted for stratification factors but not multiple testing). Regression rates for all patients, both measurable and evaluable, were 30% for doxorubicin alone and 26% for doxorubicin + mitolactol. Regression rates were significantly higher in patients with measurable indicator lesions. Cardiac toxicity was seen in four patients, all of whom were receiving doxorubicin alone. It appears that the combination of doxorubicin + mitolactol is not substantially more effective than doxorubicin alone in women with advanced breast cancer and prior chemotherapy exposure. A prospective randomized clinical trial was undertaken in 184 patients with metastatic breast carcinoma to compare single drug chemotherapy with L-phenylalanine mustard (L-PAM) and intermittent combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluourouracil (CMF). All patients had not been previously treated with cytotoxic drugs and all had objectively measurable visceral of soft tissue disease. Of the 93 patients who received CMF, 49 (53%) achieved a complete (14 patients) or partial (35 patients) regression of measurable tumor, for a median duration of 25 weeks. Eighteen of the 91 patients (20%) treated with L-PAM responded, for a median duration of 13 weeks. The toxicity was primarily hematologic, and greater in the CMF group, which also received more cycles of therapy because of the higher rate and duration of response. The overall survival of CMF-treated patients was superior to that of the single drug group. The differences were even greater when the patients were subclassified according to the presence of liver involvement or nonambulatory performance status. The superior antitumor effect of CMF over L-PAM suggests that it may be a more effective drug regimen to be used as an adjuvant to primary therapy. To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer.
                Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m(2) on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m(2) on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study.
                The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P =.10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P =.47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P =.08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue.
                Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug's tolerability. A randomized clinical trial was performed to determine if combination therapy with doxorubicin, vincristine, and mitomycin C (DVM) was superior to doxorubicin alone in women with metastatic breast cancer for whom prior chemotherapy had failed. A total of 185 women were randomized to monthly courses of D (60 mg/m2, observation after 500 mg/m2); or D (50 mg/m2, maximum cumulative dose 500 mg/m2), V (1 mg/m2), and M (10 mg/m2, given every other cycle). Patients failing after D alone could receive V (1 mg weekly for 5 weeks, then 1.2 mg/m2 every 5 weeks) plus M (12 mg/m2 every 5 weeks). Objective responses were seen in 24 of 95 patients (25%) on D alone and 39 of 90 patients (43%) on DVM (two-sided p = 0.01). The time to disease progression distribution was significantly better for DVM (two-sided p = 0.02), but the magnitude of the advantage was small with the medians being 2.7 months for D and 4.2 months for DVM. There was no significant difference in survival between the two regimens. The degree of leukopenia was greater for DVM both in terms of median white blood cell nadir (1,300/microL versus 1,700/microL) and percentage of patients with a nadir less than 1,000/microL (33% versus 16%). A total of 45 patients received VM following D alone, and only seven (16%) achieved an objective response. We conclude that, despite a significantly higher response rate and longer time to progression, the degree of clinical benefit is not sufficient to recommend the combination of DVM over D alone as second-line therapy for women with metastatic breast cancer. The level of efficacy seen with VM as tertiary therapy is low and is of such a magnitude to suggest that V adds little but toxicity to M. 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. To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer.
                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.
                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.
                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.
Combination chemotherapy regimens show a statistically significant advantage for survival, tumor response and time to progression in women with metastatic breast cancer but they also produce more toxicity. An unresolved question is whether combination regimens are more effective than single agents given sequentially.