Combination chemotherapy with navelbine and continuous infusion of 5-fluorouracil in metastatic, chemotherapy refractory breast cancer

Background:The protracted continuous infusion (PCI) of5-fluorouracil (5-FU) has proven in several studies an active and welltolerated treatment for advanced, pretreated breast cancer. Navelbine has alsoactivity in this setting. Patients and methods:Heavily pretreated patients with metastaticbreast carcinoma were eligible for the study. Treatment consisted of 5-FU 250mg/m² given as a PCI by an elastomeric pump and navelbine 20mg/m² on days 1 and 8, every four weeks. Eighty-three patients(median age 54 years; range 32–82 years) entered the study. The mediannumber of metastatic tumour sites was 2, with visceral involvement in 56patients. Apart from five patients with contraindications, all patients hadbeen pretreated with anthracyclines. Thirty-one patients had received taxanesand seventy-four bolus 5-FU. Results:A median of 5 cycles (range 1–14) per patient wasadministered. The median duration of 5-FU infusion was 17 weeks (range, 4-90).In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and24 partial remissions occurred (response rate, 45%). Median durationof response was 9 months. Toxicity was mild. Median survival was 20 months. Conclusions:PCI–5-FU combined with navelbine offers areasonable chance of tumour regression with modest side effects in patientswith heavily pretreated breast cancer.     

A phase II trial of weekly high dose continuous infusion 5-fluorouracil plus oral leucovorin in patients with advanced colorectal cancer

Background. In a previous Phase II trial, the authors showed that a weekly continuous infusion of 5-fluorouracil (5-FU) at a dose of 3.5 g/m² for 48 hours is an active treatment for advanced colorectal cancer. The overall response rate was 38.5%, and the median survival was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. To study the modulation of this weekly, high dose, continuous infusion 5-FU with oral leucovorin, a new Phase II trial was planned. Methods. From December 1991 to July 1992, 43 previously untreated patients with measurable advanced colorectal cancer were included in a multicenter study. They received on an outpatient basis 5-FU at a weekly dose of 3 g/m² by continuous infusion for 48 hours until progression or toxicity. Oral leucovorin (60 mg every 6 hours) also was given during the infusion of 5-FU. Results. Patients received a median dose intensity of 5-FU of 2.2 g/m²/week (range, 0.76-3 g/m²/week). One complete response and 11 partial responses were observed. The overall response rate was 29% (95% confidence interval [CI], 16–45%). Median time to progression was 7 months, and the median survival was 15 months. World Health Organization Grades 3 and 4 diarrhea were observed in 19 (45%) and 6 (14%) patients, respectively. Grade 3 mucositis also was observed in 10 (24%) patients, and Grade 4 mucositis was observed in 1. Grade 3 nausea and vomiting were reported in seven (17%) patients. Grade 3 hand–foot syndrome was detected in only two (2.5%) patients. No leukopenia or thrombocytopenia was observed. Conclusions. Oral leucovorin modulation of a weekly 48-hour infusion of 5-FU at a dose of 3 g/m² of leucovorin is a toxic regimen, always requiring dose reduction, with diarrhea and mucositis as the main limiting toxicities. Its antitumor activity does not seem superior to that observed with a weekly 48-hour infusion of 5-FU alone at a dose of 3.5 g/m². Cancer 1995; 76:559–63.     

Long-term ambulatory treatment of metastatic colorectal adenocarcinoma by continuous intravenous infusion of 5-fluorouracil

To delineate the efficacy of continuous intravenous 5-fluorouracil (5-FU) infusion therapy for advanced colorectal adenocarcinoma, a study of 36 patients with measurable metastatic disease was conducted. Patients received a daily intravenous infusion of 300 mg/m2 5-FU over a 24-h period utilizing portable infusion devices and central venous catheters. In a population characterized by substantial pretreatment exposure to radiotherapy, chemotherapy, and other indicators of poor prognosis, 13/36 (36%) patients achieved an objective response. An additional 10/36 (28%) patients manifested stable disease (no change) and experienced survival comparable to that of patients with objective response. Toxicity was minimal; patients were able to continue 5-FU infusions 95% of the total time on protocol. There were no adverse hematologic effects or catheter complications. Because previously untreated patients benefited more frequently (positive response, 50%), continuous intravenous infusion should be evaluated further as a primary modality option when 5-fluorouracil antitumor chemotherapy is contemplated.     

Mitoxantrone dose augmentation utilizing filgrastim support in combination with fixed-dose 5-fluorouracil and leucovorin in women with metastatic breast cancer

Based on reports of substantial antitumor efficacy of the combination of mitoxantrone (DHAD), 5-fluorouracil (FU) and leucovorin (LV), a clinical trial was performed to attempt augmentation of the dose of DHAD with filgrastim support. The doses and schedules, all intravenous, were DHAD (total dose divided over days 1 and 2), level I, 16 mg/m²; II, 20 mg/m²;III, 24 mg/m²; IV, 32 mg/m²;and LV, 300 mg, followed by FU, 350 mg/m²;,on days 1–3. Filgrastim was given at 5 g/kg/day subcutaneously on days 4–13. The planned cycle length was 21 days. Three or 4 patients were to be entered at each dose level and the maximum tolerated dose (MTD) was defined as thedose immediately below that which resulted in 2 patients with dose-limiting toxicity (DLT) in cycle 1. Once an apparent MTD was identified, an additional 6 patients were to be entered. Twenty patients (pts) were entered: level I: 3 pts; II: 3 pts; III: 10 pts; IV: 4 pts. The major toxicity was found to be cumulative thrombocytopenia with platelet counts 20,000/L occurring after cycle 1 at all levels beyond level I and five pts (25%) were removed from treatment solely because of platelet toxicity. Additional serious toxicities included grade 4 stomatitis in one patient (level IV) and cardiac toxicity in 2 patients with prior doxorubicin exposure. Ten pts had measurable and 8 had evaluable disease, and in 17 pts assessed, 5 (29%)achieved an objective response. The response rates in this study are lower than reported in the literature for the combination of DHAD, 5FU, LV and this may be related to the fact that only 40% of the patients were removed from protocol treatment because of disease progression. On the basis of limited DHAD-dose augmentation, toxicities observed, and modest response rate, the filgrastim-supported DHAD, 5FU, LV regimen as utilized in this study cannot be recommended for further development for treatment of women with metastatic breast cancer.     

Timed flat infusion of 5-fluorouracil increases the tolerability of 5-fluorouracil/docetaxel regimen in metastatic breast cancer: a dose-finding study

A dose-finding study was undertaken to determine the maximum-tolerated dose, and the recommended dose of docetaxel in combination with 12-h timed (22:00-10:00) flat infusion of 5-fluorouracil (5-FU) in metastatic breast cancer patients. This schedule seems to reduce the occurrence of stomatitis of the docetaxel and infusional 5-FU regimen.     

Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m(-2) on days 1 and 15, PTX 60 mg m(-2) on days 1, 8 and 15 and continuous infusion of 5-FU at 200 mg m(-2) every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable.     

Vinorelbine, cisplatin and continuous infusion of 5-fluorouracil (ViFuP) in metastatic breast cancer patients: A phase II study

Purpose:Chemotherapy regimens for patients with advanced breastcancer or large primary tumours (including locally advanced disease) usuallycontain anthracyclines, taxanes or both. We investigated a multi-agent regimenfor patients for whom anthracyclines and/or taxanes may not be suitable. Weassessed efficacy in terms of response rate and time to progression of acombination with continuous infusion 5-fluorouracil (5-FU), vinorelbine andcisplatin (ViFuP regimen), as a first or subsequent line treatment formetastatic breast cancer patients. Patients and methods:One hundred consecutive patients withadvanced breast cancer were treated with 5-FU 200 mg/m²administered continuously through a permanent central venous line; vinorelbinewas given on days 1 and 3 at a dose of 20 mg and cisplatin was administeredat 60 mg/m² on day one. Therapy was given every three weeks. Themedian age was 50 years (range 23–72). Fifty-two patients had receivedprior chemotherapy for metastatic breast cancer, and sixty-one percent hadpreviously received anthracyclines, thirty-five percent taxanes andtwenty-nine percent 5-FU as a bolus injection. All patients were assessablefor toxicity, four patients were not assessable for response. Results:There were four complete responses (4%).Forty-nine patients had a partial response (overall response rate, 55%;95% confidence interval (CI): 45%–65%). After amedian follow-up of 10.2 months, median duration of response is 5.2 months(range 1.5–20.7+ months), time to progression (TTP) is 6.8 months (range0.3–24.7 months). Acute toxicity, including myelosuppression, was mild:only 18% of patients had grade 4 granulocytopenia and one patientexperienced grade 4 diarrhea. Only 15% of patients had anynon-hematological grade 3 toxicity including nausea (4%), stomatitis(4%), diarrhea (2%), fatigue (1%), fever (1%),photosensitivity (1%), hand–foot syndrome (1%). Grade 2alopecia was observed only in six patients (6%). Eleven patientsdeveloped a right diaphragmatic supra elevation, while deep vein thrombosis,central venous catheter associated, occurred in eight patients. Conclusions:We identified a combination chemotherapy withnoteworthy efficacy and well tolerated subjectively as either a first- orsecond-line treatment for metastatic breast cancer patients. The regimenwarrants further development focusing on the comparison with either continuousadministration of oral fluoropyrimidine derivatives.     

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus ± LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m² per day and the l-LV dose being 5 mg/m² per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3–4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8–25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus ± LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin. Received: 22 September 1998 / Accepted: 5 January 1999     

Phase II multicentre study of docetaxel plus 5-fluorouracil in patients with anthracycline-pretreated metastatic breast cancer

The purpose of the study was to determine the efficacy and safety of docetaxel plus continuous infusion of 5-fluorouracil (5-FU) in patients with metastatic breast cancer previously treated with anthracyclines. A total of 41 patients with histologically proven metastatic breast cancer and performance status 0-2, who had received at least one anthracycline-containing regimen, received docetaxel 85 mg m(-2) followed by continuous infusion of 5-FU 750 mg m(-2) day(-1) for 5 days every 3 weeks for up to eight cycles. All patients received corticosteroid premedication, but there was no prophylactic colony-stimulating factor support. The most frequent metastatic sites were the liver (61%), bone (29%), and lung (29%). All 41 patients were assessable for toxicity and 30 were eligible and assessable for efficacy. The objective response rate was 70.0% (95% CI: 53.6-86.4%) for the per protocol group and 53.7% (95% CI: 38.4-68.9%) for the intent-to-treat (ITT) population. For the ITT population, median duration of response was 8.4 months (95% CI: 6.7-12.2 months), median time to progression was 6.7 months (95% CI 5.5-8.6 months), and median survival was 17 months (95% CI: 12.3-not recorded months). Grade 3/4 neutropenia occurred in 54% of patients, with febrile neutropenia in 24% of patients and 5% of cycles, but infections were rare. Stomatitis was frequent, grade 3 in 24% of patients and grade 4 in one patient (2%), but manageable. Diarrhoea was rare, grade 3 in 7% of patients and 1% of cycles. Other grade 3/4 nonhaematological toxicities were infrequent. In conclusion, this docetaxel/5-FU regimen is highly active and well tolerated in patients with anthracycline-pretreated metastatic breast cancer. The efficacy is particularly promising, as one-third of patients were either second-line and/or anthracycline-resistant/refractory.     

Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines

Purpose:To assess the antitumor efficacy and safety of avinorelbine and cisplatin combination in patients with metastatic breastcancer previously treated with anthracyclines. Patients and methods:Fifty-three patients with assessablemetastatic breast cancer with previous exposure to anthracyclines (adjuvantn= 6, palliative n= 47) were studied. Cisplatin 75mg/m² on day 1 was given followed by 25 mg/m²vinorelbine (VNR) on days 1 + 8, in a five-min i.v. infusion. Courses wererepeated every three weeks on an outpatient basis. Treatment continued untildisease progression, excess toxicity or patient refusal. Patients wereclassified according to their response to anthracyclines: anthracyclinerefractory patients were patients who had never responded under ananthracycline regimen. Anthracycline resistant patients were either metastaticpatients who progressed within four months of completing anthracycline-basedchemotherapy or patients who progressed within six months of completion of ananthracycline adjuvant treatment. Patients who progressed four months afterthe end of an anthracycline regimen in metastatic setting or six months afterthe end of an anthracycline regimen in adjuvant setting were considered aspatients previously treated with anthracyclines and were called `relapsed'. Results:Four patients (8%) achieved a complete response(CR) and twenty-two patients (41%) achieved a partial response (PR)with an overall response rate (OR) of 49% (95% confidenceinterval (CI): 35–63). Stable disease (SD) was observed infive patients (9%), twenty-two patients had progressive disease (PD).Responses according to previous sensitivity to anthracycline were as follow:5 refractory patients achieved a PR from 14 patients (36%). Seven ofsixteen resistant patients responded (44%), six with PR and one withCR. Among 23 `relapsed' patients, 14 responses were observed (61%),with 3 CR and 11 PR. There was no statistical difference in RR among the threegroups. The median duration of response for all patients was 7 months, themedian time to progression (TTP) 5 months and median overall survival 12months.All patients were assessed for toxicity. The main toxicity was neutropeniagrade 3 and 4 in 49% of patients. Febrile neutropenia requiringhospitalization was uncommon (2 patients). There were no treatment relateddeaths. Despite potential overlapping neurologic toxicities of the two drugs,only eight patients (15%) developed neuropathy, which was, however,mild (grades 1 and 2). Conclusions:This cisplatin–VNR regimen is well toleratedand active in patients who failed anthracyclines. The response rate, TTP andsurvival data are engouranging and indicate that cisplatin–VNR may havea place as second-line treatment alternative to taxanes or other less activeregimens. If these results can be verified in multi-institution trials, thiscombination of drugs would merit investigation as first-line therapy in thispatient population.     

Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: a phase II study.

BACKGROUND: The purpose of this study was to evaluate the efficacy and toxicity of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. PATIENTS AND METHODS: Fifty anthracycline- and taxane-pretreated MBC patients were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1, LV 200 mg/m(2)/day as a 2-h infusion followed by bolus 5-FU 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day for 2 consecutive days. Treatment was repeated every 3 weeks. Patients were evaluated for response every two cycles. RESULTS: The median age was 51 years (range 34-75). Twenty patients (40%) had received three or more chemotherapeutic regimens, 64% had three or four metastatic sites and 78% had visceral metastases. All patients had prior exposure to anthracyclines and taxanes. Based on an intention-to-treat analysis, one patient (2%) achieved a complete response and 16 (32%) a partial response, for a 34% overall response rate. Twenty-one patients (42%) had stable disease and 12 (24%) progressive disease. The median time to tumor progression was 5.3 months (range 0.5-12.8) and the median overall survival was 12.3 months (range 0.5-19.2). Toxicity was mild to moderate. Grade 3/4 neutropenia and thrombocytopenia occurred in 32% and 18%, respectively. Febrile neutropenia was experienced by three patients (6%), who were successfully treated. Grade 3/4 neurotoxicity was reported in 14% of the patients and gradually declined after treatment discontinuation. Cycle delays were reported in 28% of patients and dose reductions in 26%. Alopecia, nausea-vomiting, diarrhea and mucositis were not significant. There were no treatment-related deaths. CONCLUSION: The combination of oxaliplatin plus 5-FU/LV seems to be an active regimen in patients with MBC and prior exposure to anthracyclines and taxanes with a good safety profile. The incidence of severe toxicity was quite low and the compliance of patients to the treatment was satisfactory. The results obtained with this regimen could be considered encouraging in this heavily pretreated group of breast cancer patients with a high incidence of visceral metastases.     

Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure

This multicentre, randomised phase III study compared docetaxel with 5-fluorouracil+vinorelbine in patients with metastatic breast cancer after failure of neo/adjuvant or one line of palliative anthracycline-based chemotherapy. One hundred and seventy-six metastatic breast cancer patients were randomised to receive docetaxel (100 mg m(-2)) every 3 weeks or 5-fluorouracil+vinorelbine: 5-fluorouracil (750 mg m(-2) per day continuous infusion) D1-5 plus vinorelbine (25 mg m(-2)) D1 and D5 of each 3-week cycle. Eighty-six patients received 516 cycles of docetaxel; 90 patients received 476 cycles of 5-fluorouracil+vinorelbine. Median time to progression (6.5 vs 5.1 months) and overall survival (16.0 vs 15.0 months) did not differ significantly between the docetaxel and 5-fluorouracil+vinorelbine arms, respectively. Six (7%) complete responses and 31 (36%) partial responses occurred with docetaxel (overall response rate 43%, 95% confidence interval: 32-53%), while 4 (4.4%) complete responses and 31 (34.4%) partial responses occurred with 5-fluorouracil+vinorelbine (overall response rate 38.8%, 95% confidence interval: 29-49%). Main grade 3-4 toxicities were (docetaxel vs 5-fluorouracil+vinorelbine): neutropenia 82% vs 67%; stomatitis 5% vs 40%; febrile neutropenia 13% vs 22%; and infection 2% vs 7%. There was one possible treatment-related death in the docetaxel arm and five with 5-fluorouracil+vinorelbine. In anthracycline-pretreated metastatic breast cancer patients, docetaxel showed comparable efficacy to 5-fluorouracil+vinorelbine, but was less toxic.     

Salvage chemotherapy in metastatic breast cancer: An experience with the combination of mitoxantrone, 5-fluorouracil,and L-leucovorin

Summary From January 1992 to July 1993, 28 patients with metastatic breast cancer were entered in a phase II trial to assess the activity and toxicity of the combination of mitoxantrone, 5-fluoruracil, and leucovorin. Patients were eligible if they had progressive disease after either adjuvant (2 patients) or previous chemotherapy for metastatic disease (26 patients). Twenty-five patients (89.2%) had received previous anthracycline-based therapy. Predominant site of metastatic disease was visceral in 22 patients, bone in 2 patients, soft tissue in 4 patients, and the majority of patients (89.2%) had two or more sites of disease. The regimen was administered according to the following schedule: Mitoxantrone 9–12 mg/m² i.v. on day 1; L-Leucovorin 150 mg i.v. over 1 hour before 5-Fluorouracil 350 mg/m² i.v. push days, 1, 2 and 3. Courses were repeated every 21 days. Twenty-six patients were evaluable for response. We observed 2 complete responses, 5 partial responses with a median duration of 38 weeks (range 23–68). The objective response rate was 27% (95% C.I., 10% to 44%). Myelo-suppression was the most frequent toxicity, but it was mild in the majority of patients. Nine episodes of fever and neutropenia occurred in six patients but none of these episodes was fatal. No clinical evidence of cardiotoxicity was observed.At a median follow-up of 78 weeks, the median time to progression was 20.5 weeks and the median overall survival was 48 weeks.We conclude that this regimen is well tolerated and in our experience the objective response rate is similar to other salvage chemotherapy regimens.     

A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer

Purpose:To evaluate the safety and efficacy of a five-day regimenof oral 5-fluorouracil (5-FU) plus eniluracil (776C85) in patients withmetastatic colorectal cancer (CRC). Patients and methods:Seventy-five patients with metastatic CRCthat was previously untreated or refractory to 5-FU–leucovorin (LV) wereenrolled and divided into two strata based upon their treatment history.Twenty-four had not previously received chemotherapy or had received adjuvantchemotherapy that ended >6 months prior to enrollment on study (previouslyuntreated stratum). Fifty-one patients had disease refractory to intravenous(i.v.) 5-FU–LV (previously treated stratum). All patients received sevenconsecutive daily doses of eniluracil (20 mg/day) with once daily oral 5-FUgiven on days 2–6, repeated every four weeks. One-half of the patientsin each stratum also received 50 mg/day oral LV on days 2–6. The 5-FUdose was 25 mg/m² when administered without LV and 20mg/m² when administered with LV. Results:Partial response (PR) was noted in 2 of 12 patientsreceiving eniluracil–5-FU and in 3 of 12 patients receivingeniluracil–5-FU–LV in the previously untreated stratum. Noresponses were observed in the refractory disease stratum, however, 15patients (30%) demonstrated stable disease over 2–18+ courses oftherapy. Non-hematologic toxicities were mild; only 7% of patientsexperienced grade 3 diarrhea. Myelosuppression was frequent and dose limiting.Neutropenic sepsis was reported in 13.5% of patients. Conclusions:Eniluracil with 5-FU administered orally with orwithout LV on a five-day schedule is active and well tolerated when given asprimary therapy to patients with metastatic CRC.     

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.     

Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer

The purpose of the study was to evaluate the efficacy and safety of docetaxel plus epirubicin (ET) and of 5-fluorouracil plus epirubicin and cyclophosphamide (FEC) as first-line chemotherapy for metastatic breast cancer. A total of 142 patients (intent-to-treat (ITT)) with at least one measurable lesion were randomised to receive docetaxel 75 mg m(-2) plus epirubicin 75 mg m(-2) or 5-fluorouracil 500 mg m(-2) plus epirubicin 75 mg m(-2) and cyclophosphamide 500 mg m(-2) intravenously once every 3 weeks for up to eight cycles. Prophylactic granulocyte-colony-stimulating factor was only permitted after the first cycle, if required. Per-protocol analysis (n=132) gave an overall response rate for ET of 63.1% (95% confidence interval (CI), 50-78%) and for FEC 34.3% (95% CI, 23-47%) after a median seven and six cycles, respectively. Intent-to-treat population (n=142) gave an overall response rate for ET of 59% (95% CI, 47-70%) and for FEC 32% (95% CI, 21-43%) after a median seven and six cycles, respectively. The median response duration for ET was 8.6 months (95% CI, 7.2-9.6 months) and for FEC 7.8 months (95% CI, 6.5-10.4 months). The median time to progression (ITT) for ET was 7.8 months (95% CI, 5.8-9.6 months) and for FEC 5.9 months (95% CI, 4.6-7.8 months). After a median follow-up of 23.8 months, median survival (ITT) for ET and FEC were 34 and 28 months, respectively. Nonhaematologic grade 3-4 toxicities were infrequent in both arms. Haematologic toxicity was more common with ET and febrile neutropenia was reported in 13 patients (18.6%) in the ET group. Two deaths in the ET group were possibly related to study treatment. In conclusion, both ET and FEC were associated with acceptable toxicity. ET is a highly active first-line therapy for metastatic breast cancer.     

Continuous 5-fluorouracil infusion in refractory carcinoma of the breast

Twenty-five patients with refractory, metastatic carcinoma of the breast were treated with continuous ambulatory 5-fluorouracil (5 FU) infusion (200 to 300 mg/m²/day) through a chronic indwelling central venous catheter. All patients had had extensive previous treatment, including hormonal therapy in 20/25 patients (80%), radiation therapy in 18/25 patients (72%), and an average of 4.6 previous chemotherapy drugs per patient (range 1–10). Twenty-three of 25 patients (92%) had had previous bolus 5 FU. Seventeen of 25 patients (68%) had two or more metastatic sites of involvement and 17/25 patients (68%) had visceral involvement. Results: complete remission –1/25 (4%), partial remission –7/25 (28%), stable disease –6/25 (24%), and progressive disease –11/25 (44%), for an overall response rate of 8/25 (32%). Median duration of response was 6 months. Toxicities included hand-foot syndrome, mucositis, diarrhea, and nausea and vomiting, and required treatment interruption and/or dose attenuation in 9/25 patients (36%). No myelosuppression or serious catheter-related problems were seen. We conclude that continuous 5 FU infusion is a potentially effective salvage treatment that may provide meaningful palliation in some patients with carcinoma of the breast, in spite of extensive previous treatment.     

Intermittent low-dose cisplatin infusion as a possible modulator of 5-fluorouracil

Background This study was designed to determine whether 5-fluorouracil combined with intermittent low-dose cisplatin (cis-diaminedichloroplatinum, CDDP), a 5-fluorouracil modulator, would be an effective antitumor regimen. Methods Sarcoma 180 tumor (mouse sarcoma) was implanted in mice, and intravenous CDDP injections (0.5 mg/kg) were given at intervals of 12 hours. Tumors were removed on days 1, 3, and 5 of treatment for quantification of the tumor tetrahydrofolate and blood platinum levels. One group of mice was treated with a combination of CDDP and 5-fluorouracil (10 mg/kg), and another group was treated with 5-fluorouracil alone. Tumor thymidylate synthetase levels and tumor weights were compared between these 2 groups. Results Blood total platinum levels rose as the number of doses increased, while the tumor tetrahydrofolate levels did not change. Neither the levels of thymidylate synthetase, nor tumor reduction, differed between the CDDP/5-fluorouracil and the 5-fluorouracil treatment groups. Conclusion No significant effect of intermittent low-dose CDDP therapy was seen on folic acid or thymidylate synthetase levels, or on tumor growth. The results of this study do not endorse the efficacy of intermittent low-dose CDDP as a modulator of 5-fluorouracil.     

Salvage chemotherapy with high-dose leucovorin (LV) and 48-hour continuous infusion (CI) of 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) in patients with metastatic breast cancer (MBC) pretreated with anthracycline and taxanes

The purpose of this study was to evaluate the activity and tolerance of high-dose leucovorin (LV) and infusional 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) as salvage chemotherapy in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. 41 patients (median age 59 years) with MBC refractory or resistant to anthracyclines and taxanes were enrolled. The patients' performance status (WHO) was 0 in 10 patients (24%), 1 in 22 (54%), and 2 in 9 (22%). 30 (73%) patients had received 2 or more prior chemotherapy regimens. Cyclophosphamide (600 mg m(-2)) was given i.v. bolus on day 1 and LV (500 mg m(-2) d(-1)) as a 2-h infusion followed by 5-FU (1.5 g m(-2) d(-1)) over a 22 h c.i. for 2 consecutive days. Cyclophosphamide was administered every 28 days while 5-FU/LV every 14 days. In an intention-to-treat analysis, complete response (CR) was achieved in 2 (4.9%) patients and partial response (PR) in 9 (22%) (overall response rate 26.9%; 95% CI: 13.27-40.39%). Stable disease (SD) and progressive disease (PD) were observed in 9 (22%) and 21 (51%) patients, respectively. The overall response rate was 6% and 40% in patients with primary and secondary resistance to anthracyclines/taxanes, respectively (P = 0.047). The median duration of response and the median time to disease progression was 8 and 9.5 months, respectively. The median overall survival was 13 months and the probability for 1-year survival 51%. Grade 3/4 neutropenia occurred in 9 (22%) patients and 4 (9%) patients developed grade 3/4 thrombocytopenia. Non-haematological toxicity was mild. There were no cases of febrile neutropenia, toxic deaths or treatment-related hospital admissions due to toxicity. The combination of high-dose 5-FU/LV with conventional doses of cyclophosphamide is a well tolerated and effective salvage regimen in patients with MBC heavily pretreated with both anthracyclines and taxanes.