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 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used a relatively new trial methodology, the group sequential design, to prospectively evaluate two dose levels of bolus/infusional 5-fluorouracil (5-FU) and folinic acid in 192 consecutive-patients with advanced colorectal carcinoma. On day 1, all patients received 200 mg m(-2) of folinic acid infusion over 2 h. Cohort A (n = 102 patients) received 500 mg m(-2) 5-FU by i.v. 15-min infusion followed by an infusion of 500 mg m(-2) 5-FU over 22 h. Treatment was repeated on day 2 and further cycles given 2-weekly. After sequential analysis excluded a response rate of over 40%, cohort B (n = 90 patients) received an increased dose of 600 mg m(-2) 5-FU bolus and infusion. Patients had received no prior 5-FU therapy and the two cohorts had similar demographic features. In 179 evaluable patients, the overall response rate was 18% (95% CI 12-24%) with CR of 6% and PR of 12%, with no difference between the two cohorts. Overall median survival was 34 weeks (95% CI 30-39) with no significant difference between cohorts (median survival 32 and 37 weeks in cohort A and B respectively; P = 0.27). On multivariate analysis, poor performance status, elevated initial WBC and alkaline phosphatase and low serum albumin were associated with reduced survival (P < 0.05), and initial raised WBC showed an association with reduced likelihood of response (P = 0.002). Overall toxicity was low with CTC grade 3 mucositis, diarrhoea, nausea or vomiting in < or = 6% of patients and no treatment-related deaths. Significant (grade 3 or above) leucopenia was more common in cohort B than in cohort A (9% and 1% respectively); there were more dose reductions, and the median administered dose intensity was lower in cohort B than in cohort A (89% and 97% respectively; P = 0.006). In this group of relatively unselected patients, we have confirmed a relatively low objective response rate and median survival of 7.8 months with this regimen. There was no significant difference in outcome between the two dose levels but the higher dose of 5-FU was associated with more dose reductions and greater toxicity.
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PMID:Bolus/infusional 5-fluorouracil and folinic acid. A report on two prospective, consecutive phase II studies with 5-fluorouracil dose escalation. 965 65

The aim of this study was to evaluate the efficacy and tolerance of second-line continuous 5-fluorouracil (5FU) chemotherapy combined with folinic acid and mitomycin C in patients with advanced colorectal cancer who progressed on first-line chemotherapy. From June 1992 to April 1994, 24 consecutive patients, median age 59.7 years (range 41-73), performance status (PS) 0 to 2, were treated as second-line chemotherapy with mitomycin C, 7 mg/m2 every 4 weeks, folinic acid 200 mg/m2/day as a 2 h infusion followed by 400 mg/m2 of 5FU bolus and 600 mg/m2 continuous 5FU infusion for 22 h on days 1 and 2 and every 14 days; 19 patients did not respond to folinic acid and 5FU bolus regimen (in 2 patients, this was associated with pirarubicin in a continuous hepatic artery infusion) and 3 did not respond to irinotecan; 2 patients had disease progression during adjuvant chemotherapy with folinic acid and 5FU bolus. Tumor response was assessed every 12 weeks. One patient died before evaluation and 1 was lost to follow-up after 3 cycles; 7/24 patients had an objective response (29.2%, 95% confidence interval (CI): 11.0-47.4) including 2 complete responses; 7 additional patients had stable disease or minor response. Mean duration of response was 7.5 months. Median survival was 10 months and survival at 1 year was 39.4% (95% CI: 4-59.4). One patient who had a disease progression under irinotecan presented an objective response. No iatrogenic deaths occurred, nor was any grade 3 or 4 myelotoxicity seen. No hand-foot syndrome nor any cardiotoxicity arose but 2 grade II alopecia were seen. Digestive toxicities were the most frequent but with only 4 grade III toxicities (1 vomiting, 1 mucositis and 2 diarrhea) and no grade IV. With nearly 30% objective response and acceptable toxicity this treatment seems to offer a good alternative in the treatment of advanced colorectal cancers after the failure of first-line chemotherapy.
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PMID:5-Fluorouracil, high-dose folinic acid and mitomycin C combination chemotherapy in previously treated patients with advanced colorectal carcinoma. 966 54

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.
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PMID:Treatment of refractory metastatic breast cancer with 5-fluorouracil and levofolinic acid as 48 hours continuous venous infusion. 1047 46

Oxaliplatin is the first clinically available diaminocyclohexane platinum coordination complex. The drug is non-cross-resistant with cisplatin or carboplatin and is one of the few active drugs against human colorectal cancer. Its cytotoxicity is synergistic with fluorouracil and folinic acid (leucovorin), the reference treatment for this disease. The main cumulative dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy. The drug can also produce diarrhoea, vomiting and haematological suppression. Unlike cisplatin, no renal failure or peripheral motor neuropathy have been reported and the sensory neuropathy is partly reversible. Unlike carboplatin, oxaliplatin produces only mild to moderate haematological toxicity. Oxaliplatin undergoes biotransformation into aquated forms in the blood, where 3 species can be found: total platinum, ultrafilterable or 'free' platinum and erythrocyte platinum. Flameless atomic absorption (FAAS) is used for assaying platinum concentration in various tissues. Inductively-coupled plasma mass spectrometry (ICP-MS), with a >10-fold lower sensitivity threshold than FAAS, was also used for the determination of oxaliplatin pharmacokinetics. The pharmacokinetics of oxaliplatin are described by a 3-compartment model. The drug rapidly crosses the cellular membrane as a result of its lipophilicity. Hence, at the end of a 2-hour infusion, approximately 40% of the blood platinum is found in erythrocytes. The distribution half-life of ultrafiltrated plasma platinum ranges from 10 to 25 minutes and its terminal elimination half-life is 26 hours (determined with FAAS) or 270 hours (ICP-MS). The elimination half-life of erythrocytic platinum is 12 to 50 days, close to that of erythrocytes. 30 to 50% of the platinum is recovered in the urine within 2 to 5 days, with renal clearance accounting for half of the total clearance of ultrafiltrated platinum. The total clearance of this species is correlated with the glomerular filtration rate. No pharmacokinetic-pharmacodynamic relationship has been established for oxaliplatin. Pharmacokinetic alterations produced by fluorouracil + folinic acid or irinotecan were minimal if any. The prolonged stability of oxaliplatin makes it suitable for continuous infusions over 4 to 5 days, with a delivery rate which can be either constant or chronomodulated (peak rate at 1600h), using programmable ambulatory pumps. Chronomodulation significantly reduces toxicity and improves antitumour activity as compared with constant rate infusion. These differences in pharmacodynamic properties were paralleled by differences in plasma concentration time courses. The different drug concentration profiles achieved with different infusional modalities may be useful tools for understanding the relationship between the pharmacokinetics and pharmacodynamics of oxaliplatin and may lead to further optimisation of its administration schedule and its combination with other drugs.
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PMID:Oxaliplatin: pharmacokinetics and chronopharmacological aspects. 1066 56

The aim of this study was to develop a phase II study gauging the contribution of a daily low-dose of carboplatin combined with 5-fluorouracil (5-FU) and folinic acid (FOL) in a chronotherapy schedule for advanced colorectal cancer patients. 60 patients with metastatic colorectal cancer were included in a phase II trial in which 50% of patients had received prior chemotherapy of up to three regimens. Treatment consisted of a combination of 5-FU (700 mg/m(2)/day) and FOL (300 mg/m(2)/day) infused from 10.00 pm to 10. 00 am peaking at 4.00 am with carboplatin infused from 10.00 am to 10.00 pm at 40 mg/m(2)/day with a peak at 4.00 pm. 4-day courses were repeated every 2 weeks in an ambulatory setting with a programmable pump. Patients experienced excellent tolerance (grades III-IV%): diarrhoea, 8.1; nausea/vomiting, 4.8; mucositis, 3.2; skin or neurological 1.7; granulocytes 29.0; platelets and haemoglobin (Hb) 9.7. Major tumour responses were observed in 47% of cases, 4 complete response (CR), 24 partial response (PR); 3 CR and 6 PR (69%) were recorded in 13 previously untreated patients; 11 (18%) underwent subsequent surgical resection of residual metastases. Median survival was 14.6 months with 22% patients surviving over 2 years (35% survival for responders versus 0 for non-responders). In conclusion, this chronotherapy determined administration of 5-FU/FOL and carboplatin yielded an excellent therapeutic index for the combination and warrants further evaluation in the first-line treatment of metastatic colorectal cancer.
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PMID:Chronotherapy with 5-fluorouracil, folinic acid and carboplatin for metastatic colorectal cancer; an interesting therapeutic index in a phase II trial. 1070 35

The efficacy of oxaliplatin combined with high-dose 5-fluorouracil (5-FU) and folinic acid (FA) as an outpatient salvage treatment for patients with metastasized colorectal cancer was retrospectively analyzed in one center. Tumor progression had occurred for the majority of patients during two regimens (n = 11) otherwise during one (n = 1) regimen of prior 5-FU-based chemotherapy, which had been applied in a standardized sequential fashion. As third-line therapy oxaliplatin was infused intravenously over 2 h at a dose of 60 mg/m2 prior to a 2-h infusion of FA (500 mg/m2). 5-FU (2,600 mg/m2) was subsequently given over 24 h. A favorable response was observed in 9/12 (75%) of the heavily pretreated patients, including partial remissions in 3/12, minor responses in 2/12 and stable disease in 4/12 patients. The median progression free time was 23 weeks (interquartile range i. r. 0-28) for all patients, the median survival time from start of third-line therapy 55 weeks (i. r. 40-86). The median survival time from the beginning of first-line palliative chemotherapy was 34 months (i. r. 25-45 months). The highest toxicity was WHO grade III and was observed in six patients: Nausea (2), diarrhea (3), vomiting (2) and peripheral neuropathy (1). The quality of life was not adversely affected by the oxaliplatin/5-FU/FA-regimen as assessed by the EORTC QLQ-C30 questionnaire. Thus, the results show the efficiency and low toxicity of oxaliplatin/high-dose 5-FU/FA as palliative third-line therapy of patients with metastasized colorectal cancer and emphasize that sequential palliative chemotherapy may lead to extended survival of these patients.
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PMID:Weekly oxaliplatin, high-dose infusional 5-fluorouracil and folinic acid as palliative third-line therapy of advanced colorectal carcinoma. 1072 Nov 70

Three active antitumor agents, i.e. 5-fluorouracil (5-FU), oxaliplatin and CPT-11, are available for the treatment of advanced colorectal cancer (CRC) patients and have been successfully combined in two-drug regimens. Hence, CRC has become a chemosensitive disease, but the optimal combination of these agents in first-line treatment remains to be determined. We report the first case of the combination of CPT-11 with oxaliplatin, 5-FU and folinic acid (FA) as first-line chemotherapy for a patient with a pre-occlusive sigmoid adenocarcinoma and synchronous bulky liver metastases. CPT-11 was given at 125 mg/m2, prior to the start of a chronomodulated 4-day infusion of oxaliplatin 25 mg/m2/day, 5-FU 800 mg/m2/day and FA 300 mg/m2/day repeated every 2 weeks. The doses could be escalated to 150 mg/m2 for CPT-11 and 900 mg/m2/day for 5-FU. After six cycles of chemotherapy 70% reduction in tumor size was documented in the liver. The primary tumor was no longer detectable by barium enema. The toxicity included three episodes of grade 4 neutropenic fever, and two episodes of severe diarrhea and vomiting with dehydration. A cumulative grade 2 neurosensory toxicity was observed after six cycles. Following surgery of the primary tumor, because of the major hepatic tumor response and of the absence of extra-hepatic metastases, the patient might be registered for a liver transplantation program. This first report of combining the three active agents in CRC every 2 weeks led to a high dose intensity of each agent and was associated with a dramatic tumor response of a very advanced disease in a patient with already altered performance status. The antitumor activity in this patient suggests that a three-drug intensified regimen might be feasible and active. A prospective study appears warranted to further examine the efficacy and toxicity of this therapeutic approach, and to determine whether it may increase the fraction of advanced CRC patients becoming resectable. This aggressive chemotherapy program may contribute to a re-examination of the usefulness of liver transplantation in patients with metastatic CRC confined to the liver.
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PMID:Dramatic tumor response of bulky liver metastases following treatment with CPT-11 and a chronomodulated 4-day infusion of 5-fluorouracil, folinic acid and oxaliplatin every 2 weeks in a colorectal cancer patient. 1089 41

The objective of this phase II prospective study was to determine the efficacy and the toxicity of a new schedule of neoadjuvant chemotherapy in locally advanced squamous cell carcinomas of the head and neck (SCCHN). Thirty-three patients were included in this study (13 stage III and 20 stage IV). Cisplatin (CDDP: 35 mg/m2), 5-fluorouracil (FU: 2 g/m2) and folinic acid (FA: 500 mg/m2) were administered by continuous i.v. infusion for 24 h, once every 7 days. Six cycles of neoadjuvant chemotherapy were planned before definitive locoregional treatment. A total of 195 cycles were analysed for toxicity: mucositis was observed in 11/195 cycles; 12/195 showed diarrhea and vomiting occurred in 10/195. The myelosuppression was low (neutropenia: 4/195, thrombopenia: 3/195). One treatment-related death was observed after grade IV neutropenia at the fourth cycle. Thirty-two patients were evaluated for response. The objective response rate was 87%, with 50% complete response (CR) and 37% partial response. Failure rate was 13% (stable disease). There was no progressive disease. Survival and DFS duration were significantly higher in cases of CR or in laryngeal localization. The average peak plasma levels for the 6 courses of CDDP, 5-FU, dl-FA and mTHF were 4.9+/-0.76 microM, 4.1+/-0.54 microM, 29.1+/-2.4 microM and 4.8+/-0.31 microM respectively. Therefore, the administration of the 3 drugs by a 24 h continuous i.v. infusion reached an efficient level for drug modulation. This new weekly schedule is as active as other standard therapy in the disease but significantly less toxic as neoadjuvant chemotherapy in advanced untreated SCCHN. With the low toxicities observed with this schedule, additional treatment (surgery and/or radiotherapy) is warranted to evaluate the impact on overall survival of SCCHN.
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PMID:Phase II trial of cisplatin, 5-fluorouracil and folinic acid using a weekly 24-h infusion schedule for locally advanced head and neck cancer: a pharmacokinetic and clinical survey. 1093 96

To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel, cisplatin and 24 h continuous infusion of 5-FU/folinic acid in patients (pts) with unresectable, locally advanced or metastatic gastric adenocarcinoma. Forty-five chemotherapy-naive pts (28 male and 17 female) with a median age of 60 years (range 35-74) were enrolled. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2 h infusion. Paclitaxel 175 mg/m2 was administered as a 3 h-infusion on days 1 and 22 and cisplatin 50 mg/m2 as 1 h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29, 36) followed by 2 weeks rest were considered one cycle. A median of 3 cycles (range 1-4) were administered to 45 pts assessable for response, survival and toxicity. Five pts (11%) obtained a CR and 18 pts (40%) a PR (ORR 51%; 95% CI: 35.8-66.3%). Responses were achieved in the liver, lymph nodes, lungs and at the site of the primary tumour. Nine pts (20%) had stable disease. Thirteen pts (29%) were considered to have failed treatment, 8 pts (18%) due to progressive disease and 5 pts (11%) who did not receive one complete cycle of therapy due to acute non-haematologic toxicity. The median progression-free and overall survival times were 9 months (range 1-36+) and 14 months (range 2-36+), respectively. Neutropenia WHO III(o)/IV(o) occurred in 7 pts (15%) with only 1 pt having grade IV. Additional non-haematologic WHO III(o)/IV(o) toxicities included nausea/vomiting in 5 (11%), alopecia in 22 (49%), and diarrhoea in 1 patient each (2%). Dose reductions or treatment delays were necessary in 8 pts (17%), mainly due to neutropenia. All pts were treated on an outpatient basis. The combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of pts with advanced gastric cancer. While the overall acceptable toxicity allows its use in the palliative setting, it may also be an attractive option to be tested for neoadjuvant or adjuvant treatment.
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PMID:A phase II study of paclitaxel, weekly, 24-hour continous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer. 1094 91

After a long period in which the only therapeutic approach for the management of colorectal cancer was the optimization of fluoropyrimidine-based chemotherapy, the last few years have seen the emergence of newly active chemotherapeutic agents endowed with novel mechanisms of action, such as oxaliplatin (OHP), irinotecan (CPT11), raltitrexed and oral 5-fluorouracil (5-FU) pro-drugs which can offer new therapeutic possibilities. The availability of these different classes of cytotoxic agents has introduced the possibility of combination chemotherapy. The most widely studied combinations are 5-FU/folinic acid (FA)/CPT11 and 5-FU/FA/OHP, both of which have been tested in two randomized studies. These trials consistently demonstrated that the addition of CPT11 or OHP to widely accepted infusional/bolus 5-FU/FA regimens is superior to the same 5-FU/FA schedule alone in term of response rate (rate of about > 50%) and time to progression. It's worth nothing that both trials with the combination of 5-FU/FA/CPT11 showed a significant survival benefit. Toxicity profiles were more pronounced with the combination therapies but the quality of life evaluation showed that the combinations had no negative impact on the evolution of the global health status over time. A current ongoing randomized study compares 5-FU/FA/CPT11 with 5-FU/FA/OHP in order to identify the best first-line chemotherapy. Preliminary results in terms of objective response and toxicity are similar for both treatments. Raltitrexed is a thymidilate synthase inhibitor with activity comparable to 5-FU and a convenient administration schedule. In our institution, we performed a phase II single center trial to assess the efficacy of the combination of raltitrexed and CPT11. The principal aim of the study was the overall response rate. We observed a very promising 51% overall response rate. Most relevant side effects were diarrhea in about 20% of patients, asthenia and vomiting. Two recent studies have assessed the efficacy and tolerability of raltitrexed-OHP combination therapy. The results showed that the combination is active (ORR: 46-62%) and tolerable. Promising results have also been obtained in phase I studies with the OHP/CPT11 combination. All these data need to be confirmed in phase II-III clinical trials. In conclusion, combination therapy with CPT11 plus 5-FU/FA produces a 2-3 month survival advantage over 5-FU/FA alone and represents the new reference in the first-line chemotherapy of colorectal cancer. The association of 5-FU/FA and OHP improves response rates and progression-free survival. The increase in toxicity of these combinations is predictable and reversible and does not compromise quality of life. These important data suggest that there is now a limited role for single-agent first-line chemotherapy of metastatic colorectal cancer.
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PMID:[Combination of 5-Fluorouracil and folinic acid--is it still the standard therapy for advanced colorectal carcinoma?]. 1119 98


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