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Background: This retrospective study evaluated the activity and toxicity profile of a regimen of vinorelbine and 5-fluorouracil with levofolinic acid, given to a large series of patients with recurrent or refractory metastatic breast cancer after first-line chemotherapy., Patients and Methods: Overall, 286 evaluable patients were included in the analysis. Two chemotherapy schedules were reviewed: a) the bolus regimen consisted of levofolinic acid 100 mg/m2 and 5-fluorouracil 375 mg/m2, both administered i.v. on days 1,2 and 3, plus vinorelbine 25 mg/m2 i.v. bolus on days 1 and 8 every 3 weeks; b) the infusional regimen of levofolinic acid 100 mg/m2 given as a 2-hour infusion, followed by 5-fluorouracil 400 mg/m2 i.v. bolus and by 5-fluorouracil 600 mg/m2 administered as 22-hour continuous venous infusion (c.v.i) for 2 days, plus vinorelbine i.v. bolus on days 1 and 8., Results: Overall, twelve patients achieved a complete response (4%; 95%CL 2%-7%) and 115 patients showed a partial response (40%, 95%CL 34%-46%), for an overall response rate of 44% (95CL 39%-50%). Sixty-one patients had stable disease (21%) and 98 patients progressive disease (34%). The tumor growth control rate was 63% (95%CL 60%-71%). Patients with soft tissue metastases as the dominant disease showed the highest response rate (56%), followed by viscera (48%) and bone (33%). The difference in response rate between patients with dominant visceral disease versus those with dominant bone disease was statistically significant (p=0.038). Patients treated with the bolus schedule achieved a 40% overall response rate with a 5% complete response rate, while those who received the infusional regimen had a 48% overall response rate with a 5% complete response rate. This difference was not statistically significant (p=0.164). The overall median duration of objective responses was 8.3 months (range 4-14 months), median time to progression of the all series was 6.1 months (range 2-24 months) and the median overall survival was 14.6 months (range 3-32). There was a statistically significant difference in survival among responder and non-responder patients (p=0.0009)., Conclusion: The results of this large off-trial analysis confirmed the clinical activity and adverse-event profile reported in controlled clinical trials of the vinorelbine/ 5-fluorouracil with levofolinic acid regimen in clinical practice. This combination regimen was active with a low toxicity burden and, therefore, represents a good therapeutic choice for patients who require second-line chemotherapy.

Purpose: we carried out a phase III randomized trial to compare vinorelbine-cisplatin regimen to gemcitabine-cisplatin regimen, and to a sequential administration of gemcitabine-ifosfamide followed by vinorelbine-cisplatin or the opposite sequence of vinorelbine-cisplatin followed by ifosfamide-gemcitabine according to the 'worst drug rule' hypothesis in patients with locally advanced unresectable stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoint was survival parameters, while secondary endpoints included analysis of response rates and toxicity., Patients and Methods: patients were randomized to receive: (a) gemcitabine 1000 mg/m(2) on days 1, 8 and 15 plus ifosfamide 1500 mg/m(2) on days 8-12 with mesna uroprotection (GI regimen) followed by vinorelbine 25 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 (GI --> VC regimen); (b) the opposite sequence (VC --> GI); (c) vinorelbine plus cisplatin as above described (VC regimen); or (d) gemcitabine 1400 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 8 (GC regimen). All regimens were given every 4 weeks. All patients were chemotherapy naive and had a ECOG PS 0-2., Results: 400 patients were enrolled into the trial. Interim analysis after inclusion of 243 patients showed that ORR were 19% in the GI --> VC arm, 32% in the inverse sequence arm (CV --> GI), 42% in the VC arm, and 30% in the GC arm. The VC arm was statistically superior over the GI --> VC arm (p = 0.0074), but not over the other regimens. Median TTP was 3.1 months in the GI --> VC arm versus 5.0 months in the VC --> GI arm (p = 0.014). For these reasons the GI --> VC and VC --> GI arm were closed since the 'worst drug rule' hypothesis was rejected. Accrual in the VC and GC arms continued up to 140 and 138 patients respectively. Final ORR were 44% for the VC regimen (4 CR), and 34% for the GC regimen (1 CR). This difference was statistically significant (p = 0.032). OS was 9.0 and 8.2 months, respectively, with no statistically significant difference. The 1-year survival rate was 24 and 20%, respectively for VC and GC regimens. As expected the incidence of phlebitis was higher in the VC arm, while thrombocytopenia, flu-like syndrome and asthenia were more frequent in the GC arm., Conclusions: the results of this trial indicate that the combination of vinorelbine and cisplatin and that of gemcitabine and cisplatin are equivalent in terms of median TTP and OS, although the vinorelbine-cisplatin regimen is associated with a higher ORR. Both regimens may be considered as reference treatments for future studies. Moreover, our data reject the 'worst drug rule' hypothesis of sequential treatments in NSCCL at least with the combination used in this study., (Copyright 2002 Elsevier Science Ireland Ltd.)

A multicenter phase I-II trial was carried out with the aim of identifying the dose-limiting toxicity and the maximum tolerated dose of vinorelbine (VNR) in combination with pegylated liposomal doxorubicin at a dose of 20 mg/m(2) every 15 days in patients with metastatic breast carcinoma. In the phase I part of the trial, VNR was given at a dose of 20 mg/m(2) every 15 days to a group of 3 patients. In absence of unacceptable toxicity, VNR was escalated to 25, 30, and 35 mg/m(2) for subsequent groups of 3 patients, until the dose-limiting toxicity was reached. No case of palmar-plantar erythrodysesthesia was recorded in these patients. Grade 4 neutropenia, grade 3 thrombocytopenia, and grade 3 mucositis were the dose-limiting toxicities recorded in patients treated with VNR 35 mg/m(2). These side effects caused a substantial decrease in programmed dose intensity. Therefore 30 mg/m(2) was considered the maximum tolerated dose of VNR in combination with pegylated liposomal doxorubicin 20 mg/m(2), both given every 15 days. These dosages were employed for the treatment of further 18 patients included in phase II of the study. The overall response rate, calculated according to an intention to treat analysis, was 63% (95% CI: 44-80%), with 2 patients achieving a complete response. The median time to progression was 7.0 months or more (range 2-14 months). Median duration of objective responses was 8.4 months or more. The duration of the 2 complete responses was 9 and 14 months, respectively. Median duration of survival was 16.0 months or more (range from 4.0 to >or=24.0). Toxicity was generally mild and easily manageable. Neutropenia and mucositis were the most frequently recorded side effects. A case of palmar-plantar erythrodysesthesia was recorded in phase II of the study. In conclusion, the maximum tolerated dose of VNR in association with pegylated liposomal doxorubicin is 30 mg/m(2) on a bimonthly schedule. Moreover, the combination of VNR and pegylated liposomal doxorubicin is active against metastatic breast carcinoma and is associated with a good toxicity profile. Further studies with this combination regimen are warranted., (Copyright 2002 S. Karger AG, Basel)

Effective palliation of metastatic breast carcinoma (MBC) after the failure of front-line chemotherapy for advanced disease, often based on the use of anthracyclines and taxanes, is quite difficult to achieve due to the development of dominant neoplastic cellular clones highly resistant to further therapy. Therefore the therapeutic index of second and third line chemotherapeutic treatments is usually quite low. Thirty patients with MBC with progressive disease after anthracycline-based chemotherapy as first line therapy were treated with l-FA 100 mg/m2/day and 5FU 1000 mg/m2/day ad continuous venous infusion for 96 hours every 4 weeks. Most patients (60%) had multiple sites of disease at entry and had visceral lesions as the dominant site of disease. Twenty-eight patients were evaluated for objective response: two patients had clinically progressive disease before restaging after the third cycle of chemotherapy. These patients were considered progressive disease since all patients were included in an intent-to-treat analysis. Nine patients achieved partial response for an overall response rate of 30% (intent-to-treat analysis) with a median duration of 9.5+ months (range 4.0/14.0 months), and disease stability was obtained in 10 cases (33%) with a median duration of 5.5 months (5-11). Progressive disease was recorded in 9 patients. After a median follow-up of 11 months, the overall median survival time of the whole series of patients was 14.0+ months. Objective responses were recorded both at visceral and bone sites. Chemotherapeutic treatment was generally quite well tolerated. No toxic deaths were recorded. Among gastrointestinal side-effects grade 3 stomatitis was noted in 30% of patients, and grade 3 diarrhea in 10% of cases. Grade 3-4 leukopenia was observed in 23% of patients, but significant episodes of febrile neutropenia were limited (2 patients). Grade 3 thrombocytopenia was seen only occasionally in 1 patient. Grade 1 anemia was recorded in 10% of patients. Hand-foot syndrome was noted in 2 patients (7%). Cardiotoxicity was minimal. The combination of 5FU and high-dose I-FA given as 96 hour continuous venous infusion was active, at least in terms of the overall response rate, against anthracycline refractory metastatic breast carcinoma. These results compare favourably with bolus 5FU/FA or other salvage regimens in terms of antineoplastic activity, and is well tolerated both subjectively and objectively by most patients.

Twenty-four consecutive patients with metastatic breast carcinoma (MBC) refractory to first line chemotherapy were treated with high-dose folinic acid (FA) 100 mg/m2 diluted in 250 cc of normal saline as 2 hour infusion followed by 5-fluorouracil (5FU) 400 mg/m2 bolus then 5FU 600 mg/m2 as continuous infusion for 22 hours. This therapy was repeated for 2 consecutive days. Chemotherapy was repeated every 15 days. All enrolled patients were evaluable for objective response. A complete response was achieved in 1 patient (4%) and a partial response in 6 cases (25%) for an overall response rate of 29% (confidence limits 18%-39%). The median duration of objective responses was 8.4+ months (range 3.0+/12.8). Six patients showed no change (25%) with a median duration of 4.0 months 11 patients progressed (46%). A subjective improvement in tumor-related symptoms was reported by all responding patients and in 3 patients with no change. Most patients (7/10) with symptomatic bone lesions had a subjective improvement with reduction in analgesic drugs consumption. Objective responses were observed at all sites of disease. In fact, responses were seen in the skin liver lung bore and rodal metastases. The median overall survival was 13.0+ months (range 4.0/16.2+). Over a total of 160 cycles (a mean of 6.6 cycles/patient) grade 1-2 leukopenia was seen in 9 patients (37%) grade 1 thrombocytopenia in 4 patients (17%) and grade 1 anemia in only 2 cases (8%). Grade 3-4 leukopenia or thrombocytopenia were not seen. Phlebitis at the injection vein occurred in 3/10 patients (30%) which refused to implant a central line. In patients with a central line or a port-a-cath no cases of vascular, toxicity were seen. Gastrointestinal toxicity was very mild with 9 patients (37%) suffering from grade 1-2 nausea/vomiting 6 patients (25%) complaining of grade 1-2 diarrhea and 6 patients with grade 1-2 stomatitis. Hand-foot syndrome was observed in only 1 patient. No cases of grade 3-4 gastrointestinal toxicities have been, observed. No cases of cardiotoxicity and/or neurotoxicity were recorded. The combination of high-dose FA and 5FU given as 48 hour continuous venous infusion every 2 weeks is active, at least in terms of objective response rate and tumor-related symptoms palliation against anthracycline-refractory MBC. These results compare favorably with bolus administration of FA and 5FU or other salvage regimens.

Purpose: To evaluate the therapeutic activity and toxicity of gemcitabine in the treatment of metastatic urothelial carcinoma., Patients and Methods: Twenty-four consecutive patients with recurrent- and/or metastatic urothelial carcinoma pretreated with first line cisplatin-based chemotherapy were treated with gemcitabine 1000 mg/m2/week intravenously diluted in 250 cc of normal saline as 20 minutes infusion for 3 consecutive weeks followed by a 1 week rest period. Chemotherapy was repeated every 28 days., Results: All enrolled patients were evaluable for objective response accordingly to an intent-to-treat analysis. A complete response was achieved in 1 patient (4%) and a partial response in 6 cases (25%) for an overall response rate of 29% (confidence limits 18%-39%). The median duration of objective responses was 7.4+ months (range 3.0+/12.8). Six patients showed no changes (25%) with a median duration of 4.0 months. A subjective improvement in tumor-related symptoms was reported by all responding patients, and in 3 patients with no change. Six out of 9 patients with symptomatic bone lesions had a subjective improvement with reduction in analgesic drugs consumption. Objective responses were observed at all sites of disease. The median overall survival was 13.0+ months (range 4.0/16.2+). Over a total of 76 cycles (a mean of 3.1 cycles/patient), grade 1-2 leukopenia was seen in 9 patients (37%), grade 1-2 thrombocytopenia in 4 patients (17%), and grade 1 anemia in only 2 cases (8%). Grade 3 leukopenia was seen in 3 cases (12.5%). Grade 4 leukopenia or grade 3-4 thrombocytopenia were not seen. Gastrointestinal toxicity was very mild., Conclusions: Single agent gemcitabine at the dose of 1000 mg/m2 on a weekly schedule is active, at least in terms of objective response rate and tumor-related symptoms palliation, against pretreated urothelial carcinoma with good tolerability. These results compare favorably with those achieved with the most active drugs such as cisplatin and methotrexate.

CD1 female mice were treated with doxorubicin (DXR, 5 mg/Kg i.v.) once a week for eight weeks or with lonidamine (LND, 100 mg/Kg i.p.) once a week for eight weeks. Other mice received lonidamine (100 mg/Kg i.p.) immediately before doxorubicin (5 mg/Kg i.v.) administration. The animals were sacrificed four weeks after the last administration and their cardiac morphology was evaluated by means of light microscopy. Lonidamine slightly reduced the extent of the atrial but not of the ventricular alterations caused by DXR. The results seem to indicate that, in this experimental model, lonidamine does not substantially modify the cardiotoxicity induced by doxorubicin.