Cardiovascular disease prevention in eastern Europe

A phase II trial was conducted to evaluate the efficacy and toxicity of a modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) (with leucovorin (LV) rescue) as first-line chemotherapy in patients with locally advanced (inoperable) or metastatic gastric carcinoma. From July 1993 through August 1996, 36 patients with advanced gastric carcinoma received a regimen that consisted of: MTX 200 mg/m2 diluted in 250 ml normal saline by intravenous infusion over 20 minutes at hour 0; 5-FU 1,200 mg/m2 intravenous push injection at hour 20. Beginning 24 hours after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 hours for six doses. Cycles were repeated every 15 days. One patient was not assessable for response. Objective regression was observed in 15 of 37 patients (43%; 95% confidence interval, 26%-60%). One patient (3%) achieved complete response and 14 (40%) achieved partial response. No change was recorded in 14 patients (40%) and progressive disease was noted in six patients (17%). The median time to treatment failure was 7 months and the median survival was 12 months. Toxicity was within acceptable limits but one therapy-related death resulting from severe leukopenia occurred. The dose-limiting toxicity was mucositis. Five episodes of grade 3 or 4 stomatitis were observed and caused dosage modifications of MTX and 5-FU. Biochemical modulation of 5-FU by MTX appears as an attractive modality in patients with advanced gastric cancer. Further investigation both in experimental and clinical fields is needed to clearly define its role and to design the best modulatory strategy.     

Anosognosia and procedural learning in Alzheimer''s disease

Biochemical modulation of 5-fluorouracil (5-FU) by folinic acid (FA) increases the response rate in patients with metastatic colorectal cancer compared to 5-FU alone. Phase II trials also demonstrated increased efficacy when interferon was added to 5-FU. In two consecutive trials, 76 patients were treated on days 1-5 with FA 200 mg/m2 plus interferon 5 x 10(6) U/m2 and 5-FU 350 mg/m2 as intravenous bolus injection (n = 33, regimen A) or 5-FU 500 mg/m2 as 2-hour infusion (n = 43, regimen B), repeated every 3 weeks with individual 5-FU dose escalation in steps of 50 (regimen A) or 100 mg/m2 (regimen B). In regimen A 5-FU dose reduction to 300 mg/m2 due to toxicity was necessary in 49% of the patients; in regimen B a 5-FU dose of 600 mg/m2 or above was tolerated by 70% of the patients. Dose-limiting toxicity was severe mucositis and/or diarrhea. Objective responses were observed in 5 of 33 patients (15%) in regimen A (3-28%, 95% confidence interval) and 7 of 41 patients (17%) in regimen B (5-29%, 95% confidence interval). Median time to progression was 4.7 and 4.8 months, and median survival 9.9 and 11.4 months for regimens A and B, respectively. Prolonged 5-FU administration over 2 h allows the administration of a higher 5-FU dose compared to bolus injection with no apparent improvement in antineoplastic efficacy. The addition of interferon to the combination of 5-FU plus FA in this dose and schedule does not seem to improve the response rate but appears to increase treatment toxicity.     

Oxaliplatin, folinic acid and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD

Preliminary studies suggest synergy between oxaliplatin and fluorouracil (5-FU). To assess this issue, we performed a study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. Regimen consisted of oxaliplatin day 1, 130 mg/m2 every two cycles (folfox 1) or 100 mg/m2/cycle (folfox 2) or 85 mg/m2/cycle (folfox 3) and leucovorin 500 mg/m2 as a 2-hour infusion, followed by 5-FU 22 h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. One hundred and thirteen patients have been treated. One complete response (CR) and 32 partial responses (PRs) were observed for an overall response rate of 29.2%. Sixty-seven patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU than the one used in the folfox regimens, among them 18 had PRs (26.9%). The best response rate was observed in patients treated with the folfox 2 regimen: 41.7%. From start of folfox, median progression-free survival was 6 months and median survival 13 months. Limiting toxicities were peripheral neuropathy and neutropenia. Fifty-four percent of the patients experienced WHO toxicity > or = grade 3 with the folfox1 regimen, 45% with the folfox2 and 40% with the folfox3. The folfox regimens achieve a high response rate in pretreated patients with CRC. Further studies are needed to determine the best oxaliplatin dose-intensity.     

Comparison of 5-fluorouracil pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer

STUDY OBJECTIVE: To compare 5-fluorouracil (5-FU) pharmacokinetics in whole blood, plasma, and red blood cells in patients with colorectal cancer. DESIGN: Prospective, unblinded observational study in consecutive patients. SETTING: Large regional teaching hospital. PATIENTS: Five patients with colorectal cancer. INTERVENTIONS: Patients received folinic acid 200 mg/m2 intravenously over 2 hours, followed by 5-FU 600 mg/m2 intravenous bolus over 30 minutes, then 5-FU 600 mg/m2 intravenous infusion over 22 hours, administered on days 1 and 2. This 48-hour cycle was repeated every 14 days. MEASUREMENTS AND MAIN RESULTS: Concentrations of 5-FU in whole blood, plasma, and red blood cells were determined by high-performance liquid chromatography. ADAPT II was used for pharmacokinetic computations. The optimum model was determined for each matrix by calculating Akaike's information criteria values. Concentrations of 5-FU in whole blood were 106-115% of simultaneous plasma concentrations (median 112%), and packed red blood cell levels were 5-17% of plasma concentrations (median 11%). The drug's concentration-time profile was similar in the three matrices. The drug is reported to be unstable in whole blood, and red blood cell 5-FU concentrations were near the limit of detection (10 ng/ml), supporting plasma as the preferred matrix for therapeutic drug monitoring studies. Six pharmacokinetic models were fitted to the 5-FU individual data sets to determine the best curve fit. The optimal model for whole blood and plasma data sets was one compartment with both linear and nonlinear elimination models; a one-compartment model with nonlinear elimination provided the best curve fit for 5-FU in red blood cells. A two-compartment model with nonlinear elimination gave a similar degree of curve fit for plasma 5-FU as the one-compartment model with both linear and nonlinear elimination. CONCLUSIONS: These pharmacokinetic results provide the basis for further investigation into the ability to correlate 5-FU systemic exposure with clinical drug activity.     

Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin

PURPOSE: Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU. MATERIALS AND METHODS: Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient. RESULTS: TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02). CONCLUSION: For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.     

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen)

OBJECTIVE: To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA: Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS: Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS: The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION: According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.     

Treatment of advanced colorectal cancer with folinic acid and 5-fluorouracil in combination with cisplatinum

51 patients with metastatic colorectal cancer (stage Dukes D) were treated with intravenous (i.v.) infusion on days 1, 3, 5, 8 and 16 with folinic acid (200 mg/m2) and 5-fluorouracil (600 mg/m2), and on days 1, 8 and 16 with cisplatinum (25 mg/m2 i.v.); cycles were repeated every 4 weeks. All 51 patients were evaluable for toxicity and response criteria. 26 patients had objective responses (3 complete responses, 5.9%; 23 partial responses, 45.1%), relative risk 51% (95% confidence intervals 36.7-65.0%). Response duration ranged from 4 to 28.0 months (median 16.8). Overall median survival of all patients included was 14.7 months (range 3.0-33.0). Toxicity of WHO grade III, requiring dose reduction, occurred in 9 (18%) patients. The regimen described here appears to be active, safe and well tolerated for treatment of patients with advanced colorectal cancer.     

Sequential methotrexate/5-fluorouracil therapy with 5'-deoxy-5-fluorouridine against advanced gastric cancer: comparison between bolus injection and drip infusion of 5-fluorouracil administration. Hirosaki Cooperative Study Group for Cancer Chemotherapy

Forty-two patients with gastric cancer were entered in this study. Forty-one of them were eligible and administered sequential methotrexate (MTX)/5-fluorouracil (5-FU) with 5'-deoxy-5-fluorouridine (5'-DFUR). 5-FU was administered intravenously by drip infusion for 2 hours in 22 cases (group A), and was infused by bolus injection in 19 cases (group B). The treatment schedules were as follows: MTX 100 mg/m2 was given intravenously (i.v.) followed by 5-FU 600 mg/m2 i.v. 2 hours later and leucovorin 15 mg/body i.v. 8 and 20 hours later. This cycle was repeated once a week. 5'-DFUR 1,200 mg/body/day was given orally on 5 consecutive days per week. Three of 20 cases (15%) in group A showed PR, while 5 of 15 cases (33%) in group B showed PR. Median survival time was 2.8 months in group A and 3.7 months in group B. There was, however, no statistical difference. Gastrointestinal toxicity was commonly observed. Leukocytopenia was more severe in group B. Alopecia was more frequently observed in group B (p < 0.025). These results suggested bolus injection of 5-FU was a promising way of administration in sequential MTX/5-FU therapy.     

Risk factors for thrombotic events in giant cell arteritis and polymyalgia rheumatica

BACKGROUND: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV-5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%-60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen. PATIENTS AND METHODS: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV-5-FU (LV: 500 mg/m2, 5-FU: 1.5-2 g/m2/22 hours, days 1-2, every two weeks), were given the same LV-5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3). RESULTS: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%-39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks. CONCLUSIONS: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.     

5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer

The aim of this Phase III, balanced randomised trial was to compare continuous intravenous infusion (CVI) of 5-FU with bolus (B) administration for metastatic colorectal cancer (CRC). One hundred and fifty-five non-pretreated patients were randomised to receive CVI 5-FU at a dose of 750 mg/m2/day (d), 7 d every 21 d (n = 77), or bolus 5-FU 500 mg/m2/d x 5 d every 28 d (n = 78). Incremental dose escalation at 50 mg per step was recommended in the absence of toxicity. All the patients had measurable metastatic disease (M), particularly, liver and a good performance status (WHO grade 0-1). Dose intensity was significantly higher in CVI than in the bolus group: 1369 mg/m2/week versus 558 mg/m2/week (P = 0.0001). Grade II-IV stomatitis was more frequent in the CVI group (31% versus 9%; P < 0.0001) as was hand and foot syndrome (14% versus 3%; P < 0.001). Diarrhoea (22% versus 12%) and grade III granulocytopenia (2% versus 6%) were comparable. Responses were more frequent in the CVI (26%) than in the bolus group (13%) (P < 0.04); progression-free survival was higher for the CVI group (P = 0.04), but there was no statistical difference in overall survival (median: 10 months (m) compared to 9 m), and 1 year survival (SD) 42% (6%) versus 40% (6%). In the multivariate analysis, survival was better for patients with a good PS, well-differentiated adenocarcinomas and a primary tumour without serosal extension. In conclusion, with a higher dose intensity, CVI 5-FU improved tumour control, but not overall survival.     

A new complication of chemotherapy administered via permanent indwelling central venous catheter

BACKGROUND: The use of permanent intravenous access devices for chemotherapy administration has become a common practice in clinical oncology. Therefore, awareness of potential complications is important. The authors previously reported the use of high dose 5-fluorouracil (5-FU) (2600 mg/m2) and leucovorin (500 mg/m2) as a weekly 24-hour infusion for patients with colorectal carcinoma. In this report, a new complication of permanent indwelling catheters with high dose 5-fluorouracil (2600 mg/m2) and leucovorin (500 mg/m2) as a weekly 24-hour infusion for colorectal carcinoma is described. METHODS: Twenty-two patients in the previous Phase II trial on weekly high dose 5-FU and leucovorin were included in this study. All patients had either a single-lumen Port-o-cath (Pharmacia Deltec, St. Paul, MN) or Hickman catheter (Travenol Laboratories, Deerfield, IL). Occluded catheters were explanted, and the material found in their lumen was analyzed using infrared spectroscopy. RESULTS: Eleven of 22 patients had catheter blockage, and calcium carbonate formation (Calcite 100%) was identified within these catheters. CONCLUSION: Calcite formation causing catheter occlusion is a new and important complication resulting from using intravenous access devices for chemotherapy administration. Oncologists should be alerted to this phenomenon when high dose 5-FU and leucovorin are administered for 24 hours by continuous infusion using a single-port port-o-cath.     

A guinea pig''s view on prostate cancer screening trials

Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer.     

Chronic hypertrophic gastropathy in a child resembling adult Menetrier''s disease

N-(phosphonacetyl)-disodium L-aspartic acid (PALA) demonstrates a synergistic antitumor effect when combined with 5-Fluorouracil (5-FU) in in vitro studies. In a Phase II trial, 23 eligible patients with unresectable or metastatic adenocarcinoma of the stomach were treated with weekly i.v. bolus PALA (250 mg/M2) followed 24 hours later by a 24-hour infusion of 5-FU (2600 mg/M2) for an initial period of 8 weeks. No objective responses were noted. PALA and 5-FU is inactive against gastric adenocarcinoma at the doses and schedule used in this trial.     

Randomized phase II noncomparative trial of oral and intravenous doxifluridine plus levo-leucovorin in untreated patients with advanced colorectal carcinoma

BACKGROUND: Doxifluridine (5-dFUR) is a fluoropyrimidine derivative that has been shown to be active on a variety of solid tumors. The clinical use of intravenous (i.v.) 5-dFUR as a bolus injection or short term infusion has been limited because of its unpredictable severe neurotoxicity. Unlike fluorouracil (5-FU), 5-dFUR is effective when administered orally. METHODS: This randomized, parallel-group, Phase II trial of two schedules of 5-dFUR was conducted between April 1993 and September 1994. A total of 130 previously untreated patients with locally advanced or metastatic colorectal carcinoma were randomized to receive oral levo-leucovorin (1-leucovorin) 25 mg/dose followed by oral 5-dFUR 750 mg/m2 twice daily for 4 days every 12 days (arm A) or i.v. 1-leucovorin 25 mg/dose followed by i.v. 5-dFUR 3000 mg/m2 for 5 days every 21 days (arm B). RESULTS: The two treatment arms were well balanced in terms of age, sex, and disease extension. Metastases were present in more than 90% of the total population, with the liver being the most common site. A median of 7 oral courses (range, 1-15) and 5 intravenous courses (range, 1-9) were administered. Intent-to-treat analysis rate of the randomized patients revealed a response rate of 15% (95% confidence interval [CI], 7-26) in arm A and 41% (95% CI, 29-54) in arm B. However, 7 cases in arm A and 12 in arm B were inadequately treated, and the response rates, according to standard analysis, were respectively 17% (95% CI, 8-28) and 51% (95% CI, 37-65). The median time to treatment failure was 4 months (range, 1-23) and 7 months (range, 1-9), respectively, for the two groups; median survival was 11 months (range, 1-24) in both groups. National Cancer Institute Grade 3 and 4 diarrhea were observed in 25% of the orally treated patients and in 18% of those receiving i.v. treatment. Stomatitis was reported mainly in arm B (15%). Mild and moderate neurotoxicity was observed in 6% of the patients in both arms; no severe neurotoxicity was reported. CONCLUSIONS: 5-dFUR with l-leucovorin, administered either orally or intravenously, produces response rates that are similar to those offered by the regimens containing 5-FU that are usually used to treat advanced colorectal carcinoma. This study documents the good tolerance of the i.v. schedule administered as a 1-hour infusion; furthermore, oral administration seems to be promising and feasible as a home treatment.     

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.     

Abnormalities of CD45 isoform expression in HIV infection

Systemic chemotherapy with 5-fluorouracil (5-FU) has been the mainstay of treatment for patients with metastatic colorectal carcinoma. Administering the drug in a continuous low-dose schedule has produced better result than bolus therapy. Resistance to short-pulse treatment can also be overcome by prolonged exposure. Recent studies suggest the feasibility of biomodulation of 5-FU with recombinant interferon (rIFN alpha-2a) with improved response. Sixteen patients were treated with continuous 5-FU 250 mg/m2 and rIFN alpha-2a 10 x 10(6) u thrice weekly for a maximum of 24 weeks. Five of them had received bolus 5-FU previously. Nine (82%) of the chemonaive group and 1 (20%) previously treated patient had partial response. The median duration of response was 7 months. Grade II to III mucositis were seen in 44% of the patients and 2 patients developed neurological complications. Although the overall response appeared encouraging, the incidence of toxicity was high. In the absence of further phase III studies, rIFN alpha-2a biomodulation of 5-FU cannot be regarded as standard treatment for patients with metastatic colorectal carcinoma.     

Combination chemotherapy of continuous infusion 5-fluorouracil and daily low-dose cisplatin in advanced gastrointestinal and lung adenocarcinoma

Continuous intravenous infusion (c.v.i.) of 5-fluorouracil (5-FU) plus daily low-dose cisplatin (CDDP) was evaluated in 45 patients with advanced and recurrent unresected colorectal, lung, gastric and pancreatic adenocarcinoma. 5-FU was given at a dose of 320 mg/m2/day, c.v.i. for 4 weeks, and CDDP between 3.5 to 7 mg/m2/day, infused for one hour five times a week for 4 weeks. Patients received 1 to 3 cycles of treatment (average 1.5 cycle). Pancreatic cancer cases needed longer treatment periods (2.25 cycles). The response rate of colorectal cancer cases was 57.7% (15/26), pancreas cancer 40%, gastric cancer 62.5%, and lung cancer 66.7%. The overall response rate was 57.8%. No severe side effects occurred in any of these cases. These data indicate that this combination 5-FU + daily low-dose CDDP chemotherapy is effective in the treatment of advanced gastrointestinal and lung adenocarcinoma.     

Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma

BACKGROUND: Previous trials in patients with colorectal carcinoma have indicated that enhancement of 5-fluorouracil (5-FU) by leucovorin (LV) can result in an improved response rate and increased survival. METHODS: Phase II trials were performed with patients who had either gastric or papcreatic adenocarcinoma with inetastases. Forty-one gastric carcinoma patients and 31 pancreatic carcinoma patients with measurable disease were treated with 5-FU, 425 mg/m2 intraveneosly (i.v.) on Days 1-5 plus LV, 20 mg/m2 i.v., on Days 1-5, reported at 4 and 8 weeks, and then every 5 weeks thereafter. RESULTS: The patients with metastatic gastric carcinoma had a median survival of 4.8 months. There was a 22% objective response rate, including a 4.9% complete response rate and a 17.1% partial response rate. Among the 31 patients with pancreatic carcinoma, there was a median survival of 5.7 months. No patients in this group showed a response. CONCLUSIONS: The response rate for patients with metastatic gastric adenocarcinoma was modest and this regimen may provide temporary palliation for some patients. However, 5-FU and LV treatment is ineffective against metastatic pancreatic carcinoma.     

Treatment of advanced adenocarcinomas of the exocrine pancreas and the gallbladder with 5-fluorouracil, high dose levofolinic acid and oral hydroxyurea on a weekly schedule. Results of a multicenter study of the Southern Italy Oncology Group (G.O.I.M.)

BACKGROUND: To date there is no established chemotherapeutic treatment for patients with unresectable locally advanced and/or metastatic carcinomas of the exocrine pancreas or the gallbladder. A multicenter Phase II trial has been performed by the Southern Italy Oncology Group with the aim of evaluating the clinical effectiveness and tolerability of weekly 5-fluorouracil (5-FU) in modulation with intravenous (i.v.) high dose levofolinic acid and oral hydroxyurea. METHODS: A total of 70 patients fulfilling the standard eligibility for a Phase II study were enrolled in the trial. Forty patients had advanced pancreatic adenocarcinoma and 30 had advanced gallbladder carcinoma. The treatment schedule was: levofolinic acid, 100 mg/m2, in 500 mL of normal saline over 2-hour infusion followed by 5-FU, 600 mg/m2 i.v. bolus, and oral hydroxyurea, 1000 mg/m2, for 1 day every week for 6 consecutive weeks followed by 15 days of rest. RESULTS: Among the 40 patients with pancreatic adenocarcinoma, 5 (12.5%; 95% confidence level [CL], 8.5-16.5%) showed a partial response with a median duration of 5.6+ months, and 13 had stable disease. Twenty-two patients progressed. Median survival was 5.8 months. Among patients with advanced gallbladder carcinoma, 9 of 30 had a partial response (30%; 95% CL, 26-34%) with a median duration of 6.5 months, and 8 (27%) had stabilization of disease. Thirteen patients showed progressive disease. Median overall survival was 8 months. Toxicity was mild, with Grade 1 to 2 leukopenia and gastrointestinal toxicity the most frequent side effects. No chemotherapy-related deaths were observed. CONCLUSIONS: 5-FU in modulation with i.v. levofolinic acid and oral hydroxyurea on a weekly schedule is well tolerated by the vast majority of patients with locally advanced and/or metastatic carcinoma of the pancreas or the gallbladder. Although response rate and overall survival for patients with pancreatic adenocarcinoma are far from acceptable, the 30% overall response rate achieved in patients with advanced gallbladder carcinoma suggests that 5-FU in modulation with levofolinic acid and hydroxyurea is active in this neoplasm. The combination of modulated 5-FU with other antineoplastic drugs seems worthy of clinical testing in further controlled trials.     

In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.