Cyclophosphamide, adriamycin, and cis-platinum (CAP) in metastatic and locally advanced breast cancer

A combination of cyclophosphamide, adriamycin, and cis-platinum (CAP) was tested in 20 previously untreated patients with locally advanced or metastatic breast cancer with the aim of assessing the ability of this platinum-containing regimen to induce a high complete remission rate. The drug regimen was given on a 3/week schedule at the following doses: cyclophosphamide 200 mg/m2 i.v. on days 1, 2, 3; adriamycin 40 mg/m2 i.v. or day 1 and cis-platinum 20 mg/m2 i.v. plus hydration on days 1, 2, 3. In the absence of progression, six cycles of CAP were planned and response was evaluated at that time. Thirteen of 20 patients achieved partial remission (65%) but only one obtained complete remission (5%). Overall median duration of response was 9 months (range 4-20 + months). Tumor response was mainly documented in soft tissues (primary tumor: 14 of 16; other sites: 19 of 20). Grade II leukopenia was documented in 60% of patients. All patients experienced moderate to severe gastrointestinal toxicity and alopecia was universal. No renal toxicity was observed. Although CAP regimen at the given dose schedule induced a high overall response rate (70%), the complete remission rate in this limited number of patients was lower than expected. These results do not appear superior to those achieved with conventional drug regimens.     

Antiemetic effects of combinations of metoclopramide, droperidol and dexamethasone for the prevention of cisplatin-induced gastro-intestinal toxicity: a randomized crossover trial

Thirty-two patients with primary lung cancer receiving combination chemotherapy including cisplatin at a dosage of 80-120 mg/m2 were entered into an antiemetic randomized crossover trial. Patients received metoclopramide (2 mg/kg i.v. every 2 h X 5), droperidol (0.5 mg/kg i.v.) and dexamethasone (30 mg i.v.) on day 1, and metoclopramide (1mg/kg i.v. every 8 h X 3) (Regimen A) or metoclopramide and droperidol (2.5 mg i.v. every 8 h X 3) (Regimen B) on days 2 to 5. No vomiting occurred within the first 24 hours after cisplatin administration in 75% of patients. Regimen B was found to be more effective than regimen A with respect to the mean duration of vomiting (p less than 0.1), the mean duration of nausea (p less than 0.05), the mean duration of anorexia (p less than 0.05), and the mean score of the patients' opinions (p less than 0.1). When the patients were asked for their opinion of the two regimens, 39% preferred regimen B (p less than 0.05). There were no major side effects with either regimen.     

A randomised comparative trial of mitozantrone/methotrexate/mitomycin C (MMM) and cyclophosphamide/methotrexate/5 FU (CMF) in the treatment of advanced breast cancer

Mitozantrone (Novantrone) has recently been incorporated into a new combination chemotherapy regimen with mitomycin-C and methotrexate (MMM) against advanced breast cancer. We have compared MMM (mitozantrone 8 mg m-2 i.v. q 3 weekly, methotrexate 35 mg m-2 i.v. q 3 weekly, mitomycin-C 8 mg m-2 i.v. q 6 weekly) with CMF (cyclophosphamide 100 mg orally, days 1-14, methotrexate 35 mg m-2 i.v., days 1 and 8, 5-FU 1,000 mg i.v., days 1 and 8, q 4 weekly), each regimen with folinic acid rescue, in a randomised trial, 29/57 evaluable patients treatment with MMM achieved an objective response (51%) compared with 33/55 treated with CMF (60%). Overall median survival was 16 months for MMM and 12 months for CMF. Subjective toxicity was low for both regimens and the only significant difference was in incidence of diarrhoea (50% for CMF vs 21% for MMM). Haematological toxicity was similar, leading to treatment delays and/or dose reductions in 35% patients with CMF vs 43% with MMM. Thrombocytopenia was significantly increased in MMM (34% vs 14%). No clinical cardiotoxicity was seen, but a significant reduction in left ventricular ejection fraction occurred in four patients on CMF vs 2 on MMM. MMM is an active, well tolerated new chemotherapy regimen for advanced/metastatic breast carcinoma with an efficacy and toxicity spectrum very similar to CMF.     

A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer

This paper describes a randomised clinical trial in patients with advanced breast cancer, comparing the regimen 3M, mitomycin C 7-8 mg m-2 (day 1), mitozantrone 7-8 mg m-2 (day 1 and 21), methotrexate 35 mg m-2 (day 1 and 21) given on a 42 day cycle with a standard anthracycline containing regimen, VAC, vincristine 1.4 mg m-2 (day 1), anthracycline (adriamycin or epirubicin) 30 mg m-2 (day 1), cyclophosphamide 400 mg m-2 (day 1) given on a 21 day cycle. Of a total of 217 patients, 107 were randomised to 3M and 110 to VAC and a mean of 5.5 courses was given per patient. The overall response rate (complete and partial) was 53% (95% Confidence Limits (CL): 43-62%) for 3M and 49% (CL; 39-58%) for VAC. The response according to sites of metastases was the same for both treatment groups. Symptomatic toxicity including alopecia, neuropathy, vomiting (P less than 0.001) and nausea (P less than 0.01) were significantly less for 3M. Myelosuppression including leucopenia (P less than 0.001) and thrombocytopenia (P less than 0.001) was significantly greater with 3M at day 21, although there was no difference in nadir counts in patients at special risk of myelosuppression and there was no evidence of an increase in infective or bleeding complications. There was no significant difference in the duration of response to 3M (10 months, CL 6-15) and VAC (11 months, CL 7-12), nor in survival (3M, 8 months, CL 6-12; VAC, 10 months, CL 8-12). These results indicate that 3M is as effective as, but has significantly less symptomatic toxicity than, an anthracycline containing regimen for the treatment of advanced breast cancer.     

Adriamycin, cyclophosphamide, ftorafur and tamoxifen (ACFT) in patients with advanced breast cancer

One hundred and six patients with advanced breast cancer were treated with chemoendocrine therapy consisting of adriamycin (40 mg/m2) i.v. on day 1 and cyclophosphamide (130 mg/m2) i.v. daily for 5 days every 3 weeks, ftorafur (500 mg/m2) and tamoxifen (40 mg) orally daily. Of 82 evaluable patients, 16 showed complete response (20%), 32 partial response (39%), 32 no change (39%), and two progressive disease (2%). The overall response rate was 59%, and the median duration of response was 16.3 (3.5-67+) months with a median survival time from the start of chemoendocrine therapy of 25.5 (3.5-67+) months. The median survival time of responders (32.5 months) was significantly longer than that of non-responders (15.3 months). The major toxicities were hair loss, G1 symptoms, and hematological toxicity, but these were clinically well tolerated. No serious cardiac, renal or liver damage was seen. These results indicated that the addition of tamoxifen to the ACF regimen increased the number of complete responses and prolonged the survival time of responders.     

Combination of cyclophosphamide, adriamycin and platinum (CAP) versus 5-fluorouracil, adriamycin and cyclophosphamide (FAC) as primary treatment in metastatic breast cancer: results of a prospective randomized study

Based on favorable results we reported earlier with the CAP regimen in breast cancer (CAP vs CMFVP), the present study compared the CAP with the FAC regimen, which is so far one of the most active adriamycin containing chemotherapy regimens in breast cancer. The aim of the study was to find the optimal first line treatment and possibly evaluate the role of cis platinum in breast cancer chemotherapy. The CAP schedule consisted of cyclophosphamide 200 mg/m2 i.v. days 1, 3 and 5, adriamycin 40 mg/m2 i.v. day 1, and platinum 30 mg/m2 i.v. day 1, 3 and 5. The FAC schedule included 5-FU 500 mg/m2 days 1 and 8, adriamycin 50 mg/m2 day 1, and cyclophosphamide 500 mg/m2 day 1. One hundred and twenty-six previously untreated patients received greater than 2 cycles and were evaluated. In the CAP arm 15 complete (26%) and 24 partial remissions were observed, resulting in a 67% overall response rate (39/58). The response in soft tissue and visceral organs was notable (78% - 22/28, 71% - 15/21) with an important complete response rate (32%). In the FAC arm there was an overall response in 41% (28/68) of patients, with 8 complete (12%) and 20 partial responses. The difference in overall response, complete response, and response in soft tissue and visceral organs, was statistically significant in favor of the CAP arm (P less than 0.005). Concerning bone metastases there was no difference between the two schedules in response rate, nor in the median remission duration (CAP 11, FAC 10 months). In spite of a somewhat longer median survival in the CAP group, the difference (13 months vs 9 months) was not statistically significant (P = 0.10). Toxicity was moderate and tolerable in both regimens with more pronounced myelosuppression and vomiting in the CAP group. Compared with the FAC schedule the platinum containing combination chemotherapy (CAP) showed higher antitumor activity with no reflection on remission duration and survival.     

Comparison of response to 5'-deoxy-5-fluorouridine therapy alone and in combination with tamoxifen or medroxyprogesterone acetate in advanced and recurrent breast-cancer

We studied the therapeutic usefulness of low dose 5'-deoxy-5-fluorouridine (5'-DFUR) alone and in combination with medroxyprogesterone acetate (MPA) or tamoxifen (TAM). As first line therapy, 58 patients with advanced and recurrent breast cancer were assigned to receive Regimen A (5'-DFUR 600 mg/body/day daily + TAM 30 mg/body/day daily), Regimen B (5'-DFUR 600 mg/body/day daily + MPA 600 mg/body/day daily), or Regimen C (5'-DFUR 600 mg/body/day daily). In 48 evaluable patients, the response rates to treatment were 22.2% (4/18 cases) with Regimen A, 62.5% (10/16 cases) with Regimen B, and 21.4% (3/14 cases) with Regimen C. Regimen B was significantly superior to the other two regimens. The incidence of adverse reactions was low in all three groups, being 10.5% (2/19 cases) with Regimen A, 12.5% (2/16 cases) with Regimen B, and 21.4% (3/14 cases) with Regimen C. In addition, the degree of all adverse reactions was mild (WHO grade 1). Low dose 5'-DFUR therapy in combination with low dose MPA was evaluated to be a useful treatment regimen, emphasizing the quality of life of patients, based on its high effectiveness and safety in advanced and recurrent breast cancer patients.     

Laevofolinic acid, 5-fluorouracil, cyclophosphamide and escalating doses of epirubicin with granulocyte colony-stimulating factor support in locally advanced and/or metastatic breast carcinoma: a phase I-II study of the Southern Italy Oncology Group (GOIM).

Sixty-four consecutive patients with locally advanced (n = 7) or metastatic breast cancer (n = 57), were treated with a combination of laevofolinic acid 100 mg m-2 plus 5-fluorouracil 340 mg m-2 i.v. on days 1-3, cyclophosphamide 600 mg m-2 i.v. on day 1 and epirubicin 90 mg m-2 i.v. on day 1. Epirubicin dose was progressively escalated by 10 mg m-2 per cycle up to 120 mg m-2 in the absence of dose-limiting toxicities. Granulocyte colony-stimulating factor (G-CSF) was given subcutaneously in order to prevent neutropenia. Epirubicin dosage could be increased to 100 mg m-2 in 53 patients (87%), to 110 mg m-2 in 31 patients (51%) and to 120 mg m-2 in 18 cases (30%). In most patients the dose-limiting toxicity was represented by myelosuppression. A statistically significant correlation was found between median white blood count (WBC) or absolute neutrophil count (ANC) nadir and epirubicin dose level (P = 0.009; P = 0.008). Moreover, a statistically significant correlation was observed between the number of chemotherapeutic cycles, nadir ANC and WBC and the occurrence of anaemia and thrombocytopenia of increasing severity. These data suggest the occurrence of progressive cumulative bone marrow toxicity. Although patients who reached different epirubicin levels showed differences in mean dose intensity, such differences were not statistically significant. No correlation was found between the increase in dose intensity and type, rate or duration of objective responses. In patients with metastatic breast cancer the overall response rate was 72% (95% CL 66-78%) with a 25% complete response rate. Median duration of response was 10 and 13 months respectively for complete and partial responses. All patients with locally advanced breast cancer had an objective response and underwent radical mastectomy. Projected median survival of the whole series of patients with metastatic breast cancer was 20 + months. These data demonstrate that the combination of 5-fluorouracil with laevofolinic acid, cyclophosphamide and epirubicin is very active against metastatic breast cancer. Use of G-CSF allows epirubicin dosage to be increased up to 120 mg m-2 cycle-1, but its use may be linked to the occurrence of sometimes severe cumulative haematological toxicity.     

Phase II study of continuous infusional 5-fluorouracil with epirubicin and carboplatin (instead of cisplatin) in patients with metastatic/locally advanced breast cancer (infusional ECarboF): a very active and well-tolerated outpatient regimen.

Infusional 5-fluorouracil (F) with cisplatin (C) and epirubicin (E), so-called infusional ECF, is a highly active new schedule against locally advanced or metastatic breast cancer. Cisplatin, however, is a major contributor to toxicity and usually requires inpatient treatment. In an attempt to overcome this, we have investigated the effect of substituting carboplatin for cisplatin in our original infusional ECF regimen. Fifty-two patients with metastatic (n = 36) or locally advanced/inflammatory (n = 16) breast cancer were treated with 5-fluorouracil 200 mg m-2 day-1 via a Hickman line using an ambulatory pump for for 6 months, with epirubicin 50 mg m-2 intravenously (i.v.) and carboplatin AUC5 i.v. every 4 weeks, for six courses (infusional ECarboF). The overall response rate (complete plus partial) was 81% (95% CI 67%-90%), with a complete response rate of 17% (95% CI 6-33%) in patients with metastatic disease and 56% (95% CI 30-80%) in patients with locally advanced disease. Median response duration and survival for metastatic disease was 8 and 14 months respectively, and two patients with locally advanced disease have relapsed. These results are very similar to those previously achieved with infusional ECF. Severe grade 3/4 toxicity was low. Infusional ECarboF is a highly active, well-tolerated, outpatient regimen effective against advanced/metastatic breast cancer and now warrants evaluation against conventional chemotherapy in high-risk early breast cancer.     

Combined modality treatment of locally advanced breast cancer: Adjuvant combination chemotherapy with and without doxorubicin

Forty-one women with non-metastatic but locally advanced breast cancer were treated by modified radical or radical mastectomy, and were then randomized to receive one of two adjuvant chemotherapy regimens. Regimen A consisted of 6 months of cyclophosphamide, adriamycin, and fluorouracil (CAF) followed by 6 months of cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP). Regimen B was 12 months of CMFVP. Patients were stratified for estrogen-receptor status, and all patients with a positive estrogen receptor value received tamoxifen 20 mg bid in addition to the chemotherapy. Eight of 21 patients randomized to Regimen A are alive and free of disease, whereas only 1 of 20 patients on Regimen B is well. A trend toward improved disease-free survival favoring Regimen A was observed (P = .05), although a significant difference in overall survival has not been demonstrated. Our findings support the continued study of adriamycin-containing regimens in the adjuvant setting and in combined modality therapy of locally advanced breast cancer.     

Dose-intense weekly cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisolone (CMFP) in advanced breast cancer

Weekly chemotherapy with cyclophosphamide 80 mg m-2 day-1 p.o. continuously, methotrexate 35 mg m-2 week-1 i.v., 5-fluorouracil 500 mg m-2 week-1 i.v., vincristine 1.4 mg m-2 i.v. every two weeks and prednisolone 20 mg m-2 day-1 p.o. continuously (CMFVP) was prospectively studied in 45 previously untreated outpatients with advanced breast cancer to determine the feasibility of delivering a dose-intense regimen. Of 40 evaluable patients, complete response (CR) occurred in one patient, partial response (PR) in 20 (CR + PR 53%), stable in eight, progression in 11 and five were unevaluable for response. The median relapse-free survival for responders was 25 weeks and median survival for all patients was 31 weeks. The mean dose intensity relative to the Cooper regimen fell from 1.02 to 0.6 within the first 4 weeks of treatment and the median dose intensity achieved for all patients on study was only 0.52. Eighty-seven per cent of patients had treatment delays with a mean of 3.9 delays per patient and 71% had dose reductions. Neutropenia was the major toxicity with WHO grade 3 or 4 neutropenia (less than 1.0 x 10(9) l-1) in 62% of patients and three septic deaths while neutropenic. Dose-intense weekly CMFVP in this schedule cannot be delivered to previously untreated outpatients with advanced breast cancer.     

Etoposide and adriamycin containing combination chemotherapy (HOPE-Bleo) for relapsed Hodgkin's disease.

Forty-four patients with relapsed or resistant Hodgkin's disease were treated with adriamycin 40 mg m-2 i.v. on day 1, vincristine 1.4 mg m-2 i.v. on days 1 and 8, prednisolone 40 mg m-2 orally daily for 8 days, etoposide 200 mg m-2 orally daily for 4 days according to the nadir white cell count, and bleomycin 10 mg m-2 i.v. days 1 and 8 (HOPE-Bleo). Median age was 27 (range 12-71). When stage was considered according to all sites currently or previously involved by Hodgkin's disease (cumulative stage) 26 patients (59%) had stage IV, 13 (29%) stage III and five (11%) stage II disease; 33 (75%) had B symptoms. All patients had received previous chemotherapy and 18 (41%) had received two or more regimens. Twenty-six patients (59%) achieved CR and 10 (23%) PR; the median duration of CR was 22 months and median survival for all patients was 48 months. Eight patients remain in continuous CR; none of these had received extensive previous chemotherapy. Among the 19 patients who had relapsed from CR achieved by a single previous chemotherapy regimen, six (32%) achieved long CR on HOPE-Bleo. The regimen was generally well tolerated but the principal toxicity was myelosuppression. There were two toxic deaths, one due to neutropenic sepsis and the other due to acute peritonitis. The HOPE-Bleo regimen is an effective treatment for relapsed or resistant Hodgkin's disease, with a low probability of carcinogenesis and infertility. These factors suggest that HOPE-Bleo deserves further evaluation as primary treatment for Hodgkin's disease and very careful selection of relapsed patients for high dose salvage chemotherapy with bone marrow transplants must be exercised.     

Adriamycin, vincristine and mitomycin C as first and second line therapy for advanced breast carcinoma

Forty-three patients with advanced breast cancer were treated with adriamycin, vincristine and mitomycin C at 6 week intervals. Adriamycin 40 mg m-2 and vincristine 1 mg m-2 were given on days 1 and 22: patients treated early in the study received 10 mg m-2 mitomycin C, but in view of repeated treatment delays the dose was reduced to 6 mg m-2. Thirty-two women had received prior hormone therapy and 24 previous chemotherapy. Responses were seen in 15 of 38 evaluable patients (40%) with a further 9 (24%) achieving disease stabilization. Median duration of response was 10 months and of disease stabilization was 5 months. Overall median survival for the whole group was 8 months, but 16 months for the 15 responding patients, five of whom survived beyond 2 yr. Responses were seen more frequently in patients who had received no prior chemotherapy. Myelosuppression may have contributed to three of the five early deaths in the non-pretreated group. Other significant side effects were alopecia, gastrointestinal toxicity and malaise.     

Therapeutic efficacy of pirarubicin cyclophosphamide and doxifluridine in advanced and metastatic breast cancer

Twenty-four eligible patients (23 of whom were evaluated) with advanced and metastatic breast cancer were treated at the Saitama Cancer Center every 4 weeks with pirarubicin (30 mg/m2 i.v., day 1 and 8), cyclophosphamide (200 mg/m2 div, day 1 and 8) and doxifluridine (800 mg/day po, day 1-14). The 23 evaluable patients had a median age of 49.7 years (range 35.3-72.1) and underwent a median number of 3 cycles (range 2-5). Grade 4 leukopenia (10/24 patients) was the dose-limiting factor and led to infection in one patient. Four complete responses and 7 partial responses with a median duration of 12.1 months (range 2.6-61.0) were achieved, resulting in an overall response rate of 47.8%. The 50% survival duration was 22.9 months.     

High dose medroxyprogesterone acetate (MPA) treatment in metastatic carcinoma of the breast: a dose-response evaluation.

The results of controlled clinical trial that used high doses of medroxyprogesterone acetate (MPA) in the treatment of metastatic breast cancer are reported. Two treatment reigmens were used: regimen A, 500 mg daily with a total dose of 30 g; regimen B, 1,000 mg daily with a total dose of 60 g. The overall response rates were similar, with no statistically significant difference between the two treated groups. Regimen A (lower dosage group) reached a remission rate of 44%, whereas regimen B (higher dosage group) had a remission rate of 41%. The mean duration of response was 8 months with regimen A and 9 months with regimen B. The advantages of the lower dosage regimen as opposed to the higher dosage regimen of MPA in the treatment of advanced breast cancer are discussed.     

Randomized comparative study of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and UFT-tamoxifen regimens as adjuvant chemotherapy after surgery for breast cancer: Tochigi Prefectural Study Group for Post-Breast Cancer Adjuvant Chemotherapy

This prospective randomized study aimed at establishing the optimal postoperative adjuvant chemotherapy regimen for premenopausal n+ breast cancer patients. The treatments were Regimen A, comprising 6 courses of CMF (cyclophosphamide, 100 mg/body on days 1-14; methotrexate, 40 mg/m2 on days 1 and 8; and 5-fluorouracil, 500 mg/m2 on days 1 and 8), and Regimen B, consisting of UFT (300 mg/day) and tamoxifen (30 mg/day) administered orally each day for 2 years. Telephone registration allocated the patients to the treatment groups by the minimization method in relation to the T category, number of n+ lesions and estrogen receptor status. Forty-five patients were registered, and 44 of them were eligible (22 cases each to Regimen A and Regimen B). The principal background factors showed no biases between the groups. The adverse reaction incidence was significantly higher with Regimen A (90.9% vs 22.7%). The 5-year survival rate was 89.8% with Regimen A and 100% with Regimen B, while the 5-year disease-free rates were 64.5% and 76.3%, showing no statistical significance. Regimen B showed a better QOL rating after 6 months of therapy in relation to nausea-vomiting and hair loss, and after 24 months in relation to appetite, sleep, performance status, happiness, anorexia and hair loss.     

Sequential methotrexate-5-fluorouracil (MTX-5-FU) treatment of patients with advanced gastric and colorectal cancer. Sequential Methotrexate-5-FU Study Group

A multicenter cooperative study was conducted from July 1984 to March 1986 to evaluate the clinical efficacy of sequential MTX-5-FU treatment in 96 cases of advanced gastric cancer and 39 cases of colorectal cancer. 5-FU 600 mg/m2 i.v. was given and MTX 30 mg/m2 (A), 100 mg/m2 (B) and 300 mg/m2 (C) i.v. were given, and the administration interval between MTX and 5-FU was 1 to 3 h for the gastric cancer group, and 7 h for the colorectal cancer group. Leucovorin rescue of 10 mg/m2 p.o. was given 24 h after MTX administration. In the gastric cancer group, the response rate for Regimen A was 23.2% (CR 1 and PR 12) out of 56 evaluable cases, and for Regimen B, 40.5% (CR 1 and PR 14) out of 37 evaluable cases. In the colorectal cancer group, the response rate for Regimen A was 28.6% (PR 6) out of 21 evaluable cases and for Regimen B, 20.0% (PR 3) out of 15 cases. Median survival time for the gastric cancer group was 5.5 months with Regimen A and 7.6 months with Regimen B, and for the colorectal cancer group 10.9 months with Regimen A and 7.9 months with Regimen B. Main adverse effects were marrow impairment and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In this study Regimen B showed relatively good results. In order to evaluate the biochemical modulation occurring with sequential MTX-5-FU treatment, a further phase III study in gastric cancer patients should be conducted.     

A multicentre phase II pilot study of epirubicin and Taxol (paclitaxel) in patients with advanced breast cancer

Anthracyclines are the gold standard monotherapy for metastatic breast cancer. Higher response rates are seen with drug combinations, especially with newer agents such as taxanes. The purpose of this study was to evaluate the toxicity and activity of the combination of paclitaxel and epirubicin in patients with advanced breast cancer. Thirty-five women with locally advanced or metastatic breast cancer (first and second relapse) were treated with epirubicin 75 mg/m2 and paclitaxel 200 mg/m2 3-weekly. Six centres recruited 35 patients; 34 (97%) were assessable for response. Eighteen had undergone prior chemotherapy, including six (17%) with anthracycline-containing regimens. Grade 4 neutropenia was found in 33 patients (94%), which was of 4 days' average duration; however, infective complications were rare, with only nine cycles (6%) complicated by neutropenic sepsis. There were two sepsis-related deaths. Symptomatic cardiotoxicity was infrequent, although a >15% decline in cardiac function was recorded in five patients (14%). Grade 3 peripheral neuropathy occurred in three patients (9%). The overall response rate was 50% (95% confidence interval 33-67) (complete response 12%; partial response 38%), with a median duration of response of 31 weeks. The median time to progression was 27 weeks, with a median survival of 48 weeks. This regimen appears to be a relatively safe, tolerable and effective treatment for advanced breast cancer. A United Kingdom Co-ordinating Committee for Cancer Research Phase III trial (AB-01) comparing this combination of epirubicin and paclitaxel with cyclophosphamide and paclitaxel completed accrual in November 1999.     

Prospective randomized trial in advanced malignant melanoma with cis-platinum, vindesine, and etoposide vs. cis-platinum, vindesine, and lomustine

Thirty-seven consecutive patients with disseminated malignant melanoma and previously untreated with chemotherapy were randomly allocated to receive vindesine, cis-platinum, and etoposide (Regimen A) or vindesine, cis-platinum, and lomustine (Regimen B). In 31 evaluable patients, Regimen A induced an overall response rate of 31% and a complete response rate of 6%; with Regimen B the corresponding findings were 20% and 20%, respectively. The median duration of complete response was 12 months with both regimens and the comparative median total survivals were 8 and 6 months, respectively. In no case was toxicity so severe to require treatment discontinuation, and the major dose-limiting side effect was myelosuppression, especially in the patients treated with Regimen B. Present results confirm once more the limited activity of drugs and regimens presently utilized in the treatment of advanced malignant melanoma.     

Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90).

Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m(-2) intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m(-2) i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m(-2) i.v. bolus on days 1, 2 and 3 or ''FULON'' consisting of 5-fluorouracil 250 mg m(-2) day(-1) continuously infused from day 1 to day 22, doxorubicin 15 mg m(-2) i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m(-2) i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < or = 0.01). We conclude that the two regimens appeared equally effective but have different toxicities.