Experimental study on intraperitoneal sequential MTX/5-FU therapy for peritoneal seeding in comparison with intravenous administration

Sequential MTX/5-FU therapy (intravenous route) is powerful chemotherapy especially for poorly differentiated adenocarcinoma of the stomach and its peritoneal metastases. The authors had proposed the idea of intraperitoneal sequential MTX/5-FU chemotherapy for potential peritoneal metastases and micrometastases from advanced gastric carcinoma. This experimental study was planned to confirm this experimentally. Peritoneal seeding model of nude mice was made by the intraperitoneal inoculation of human gastric cancer cell line MKN-45. Control group (n = 5) had no treatment. The intraperitoneal (i.p.) group and intravenous (i.v.) group underwent the treatments on the 7th, 14th, and 21st day after cell implantation. Experimental chemotherapies consisted of intraperitoneal injection of MTX (15 mg/kg, 1.5 ml saline) and 5-FU (50 mg/kg, 1.0 ml saline) for i.p. group and intravenous injection of MTX (15 mg/kg, 0.2 ml saline) and 5-FU (50 mg/kg, 0.2 ml saline) for i.v. group. Interval time between MTX and 5-FU administration was 2 hours. On the 35th day after the cell implantation necropsies were performed. Counting of peritoneal metastatic nodules revealed the number of nodules of control group. (14.2 +/- 6.7) > i.v. group (5.3 +/- 4.1) > i.p. group (0.41 +/- 0.7) (p < 0.05). Weight of omental tumors showed Control group (0.246 +/- 0.136 g) > i.v. group (0.140 +/- 0.068 g) > i.p. group (0.051 +/- 0.017 g) (i.v.-i.p., p < 0.01). The mouse body weight decrease less in the i.p. group than in the i.v. group (p < 0.05) throughout this experiment. The results of this experiment demonstrated intraperitoneal sequential MTX/5-FU therapy was more effective than intravenous sequential MTX/5-FU therapy for potential peritoneal seeding and peritoneal micrometastases from the gastric cancer. Moreover, the side effect of intraperitoneal administration was milder than by the intravenous route.     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate in patients with advanced colorectal cancer. Results of a phase II study

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity and efficacy of PALA/MTX and 5-FU in patients with metastatic colorectal cancer. 26 patients received PALA 250 mg/m2 as an intravenous 15-min infusion plus MTX 200 mg/m2 as a 30-min intravenous (i.v.) infusion on day 1 and 5-FU 600 mg/m2 as i.v. push on day 2. Cycles were repeated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m2 for the third, fifth and seventh cycle in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective responses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretreated), no change in 13 patients (50%) and tumour progression (6 patients) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months and median survival 13 months. Toxicity was mainly gastrointestinal with diarrhoea and mucositis, and severe or life threatening in only 3 patients. In 3 patients an increase in serum glucose levels occurred while being treated with PALA/MTX and 5-FU. 2 patients with insulin-dependent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA/MTX/5-FU in this dose and schedule is active in patients with colorectal cancer. Hyperglycaemia may be a potential side-effect of PALA-containing regimens especially in patients with diabetes. Careful monitoring of serum glucose levels in these patients is indicated.     

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.     

Is there a diagnostic role for bone scanning of patients with a high pretest probability for metastatic renal cell carcinoma?

A 66-year-old woman was admitted to our hospital complaining of abdominal pain and jaundice. Upper gastrointestinal series and computed tomography revealed pancreatic cancer. Pancreatectomy could not be performed because of portal invasion and multiple liver metastasis. Cholecystectomy, choledochojejunostomy and gastrojejunostomy were performed. The patient was treated with methotrexate (MTX) 100 mg/m2 i.v. followed one hour later with 5-fluorouracil (5-FU) 700 mg/m2. Leucovorin rescue of 10 mg po was given 24 hours after MTX administration. Treatment was repeated every 14 days. As a result, the size of a primary tumor of the pancreas was reduced (42%) on computed tomography, and the CEA level decreased to 27.8 ng/ml from 84 ng/ml. No side effects were observed. The patient continued to receive chemotherapy at our outpatient clinic for 20 months. She died of exacerbation of carcinomatous peritonitis 23 months after initial admission. Therefore, we conclude that MTX/5-FU sequential therapy seems beneficial to manage advanced pancreatic carcinoma from the viewpoint of antineoplastic activity as well as quality of life.     

A case report: multiple liver metastasis of gastric cancer responding to intraarterial infusion of MTX and 5-FU

In a 63-year-old male patient with gastric cancer having multiple liver metastases, the metastatic lesions responded well to postoperative staggered intraarterial infusion therapy with MTX and 5-FU. The intraarterial infusion therapy was administered once a week. A total of 5 courses of this therapy produced marked regression of liver metastases and remarkable necrosis. The effect was thus rated as PR. The patient is healthy and has been successfully rehabilitated. His dose is oral 5-FU (200 mg x 2).     

Successful treatment of recurrent multiple lung metastasis from colon cancer with combination chemotherapy using methotrexate, 5-fluorouracil, and high-dose leucovorin: a case report

A 66-year-old man, who had received sigmoidectomy for sigmoid cancer in 1985, was diagnosed as having multiple lung and liver tumors in September 1988. When celiac-angiography was performed, recurrent liver metastases from sigmoid cancer were suspected and he received a transarterial embolism with ADM 30 mg and MMC 20 mg. In addition, he was treated with a sequential chemotherapy with methotrexate (MTX), 1,200 mg intravenously (6 h-infusion) followed by 5-fluorouracil (5-FU), 600 mg/m2/day and leucovorin, 300 mg/body/day in continuous infusion for 5 days from day 2 with concomitant oral administration of dipyridamole (300 mg/day) over 14 days. Treatment was repeated every 28 days for two courses. For the third course, administration of only 5-FU, leucovorin and dipyridamole was performed. As a result, the size of pulmonary lesions was prominently reduced on computed tomography. Although mucositis, anal erosion, diarrhea and thrombocytopenia were noted, no severe side effects were observed. This sequential chemotherapy appears useful for metastatic lesions from colon cancer.     

Prolonged intraperitoneal infusion of 5-fluorouracil using a novel carrier solution

A novel peritoneal carrier solution, Icodextrin 20 (7.5%), has allowed exploration of prolonged, intraperitoneal (i.p.) infusion of the cytotoxic drug 5-fluorouracil (5-FU). A phase I and pharmacokinetic study was performed to determine the toxicities and maximum tolerated dose of prolonged and continuous intraperitoneal 5-FU in patients with peritoneal carcinomatosis. Seventeen patients were entered into this study. Each patient had a Tenckhoff catheter placed into the peritoneal cavity under general anaesthetic. After initial flushing and gradual increase in exchange volumes with Icodextrin 20, 5-FU was administered daily from Monday to Friday, 50% as a bolus in the exchange bag and 50% in an elastomeric infusor device delivering continuous 5-FU to the peritoneal cavity at 2 ml h-1. Treatment was continued for 12 weeks or until intolerable toxicity developed. Abdominal pain and infective peritonitis proved to be the main dose-limiting toxicities. Initial problems with infective peritonitis were overcome by redesign of the delivery system, and it proved possible to deliver 300 mg m-2 5-FU daily (5 days per week) for 12 weeks. Pharmacokinetic studies showed i.p. steady-state 5-FU concentrations (mean 47 500 ng ml-1) that were > 1000-fold higher than systemic venous levels (mean 30 ng ml-1).     

5-FU concentrations in the blood and tumor tissue after 5'-DFUR or UFT administration in the patients with uterine cervical cancer

In order to verify the antitumor activity of fluorinated pyrimidine drugs, we conducted an investigation of the clinical pharmacology with two drugs, 5'-DFUR and UFT. Total 21 cases of cervical cancer were alloted randomly into 5'-DFUR group (daily dose 800 mg for 3 days) consisting of 11 patients and UFT group (daily dose 600 mg for 3 days) consisting of 10 patients, the unchanged substances (5'-DFUR in the 5'-DFUR group and tegafur concentrations in the UFT group) and 5-FU concentrations in serum and tissues were measured 6 hours after administration of the drugs. The 5'-DFUR concentration in the 5'-DFUR group was not detected in serum and less than a detectable limit for all of cancerous tissues, normal cervical tissues, and lymph nodes. The tegafur concentrations in the UFT treated group was 13.8 +/- 7.0 micrograms/ml for serum, 10.4 +/- 6.4 micrograms/g for cancerous tissues, 14.1 +/- 7.3 micrograms/g for normal cervical tissues, and 4.5 +/- 4.2 micrograms/g for lymph nodes. The 5-FU concentrations in the 5'-DFUR treated group were 0.018 +/- 0.046 micrograms/g for cancerous tissues, but less than a detectable limit for serum and normal cervical tissues. On the other hand, in the UFT group, 0.271 +/- 0.247 micrograms/g for a cancerous tissue, 0.035 +/- 0.018 micrograms/ml for serum, 0.125 +/- 0.073 micrograms/g for normal cervical tissues, showing significantly high values (p < 0.01, p < 0.001, and p < 0.01, respectively) compared to those in the 5'-DFUR treated group. These results suggest that UFT is a promising drug for the treatment of cancer of the uterine cervix.     

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.     

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.     

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.     

Penetration kinetics of 5-fluorouracil into pancreatic fluid in post-pancreatoduodenectomy patients

Our aim was to investigate the pharmacokinetic behavior of 5-fluorouracil (5-FU) in pancreatic fluid and to evaluate its penetration characteristics in post-pancreatoduodenectomy patients. After completing the external drainage of the pancreatic duct during pancreatoduodenectomy surgery, eight patients were administered 1.0 g 5-FU i.v. by a 5 min infusion after the eighth day post-surgery on average. Blood and pancreatic fluid were collected, and the 5-FU concentrations were determined by HPLC assay. Their pharmacokinetic parameters were obtained by PCNONLIN and statistical analysis was performed. The Cmax was 20.03 +/- 18.25 mg/l in pancreatic fluid with a Tmax of 15.6 +/- 9.5 min following i.v. administration and 49.69 +/- 20.75 mg/l in plasma. 5-FU in plasma and pancreatic fluid were all in conformity with a non-linear model with a K(m) of 1098.08 +/- 1426.57 and 11.08 +/- 6.38 mg/l, respectively. The concentrations in pancreatic fluid were similar to that observed in plasma with an average penetration index up to 1.01 +/- 0.49. It is suggested therefore that 5-FU is capable of penetrating from blood into the pancreas as evidenced by the observed pancreatic concentrations.     

Randomized trial comparing two different modalities of administration of the same cytotoxic drugs in metastatic breast cancer

This protocol compare the efficacy of continuous infusion fluorouracil (5-FU) with weekly doxorubicin (DOX) and cyclophosphamide (CPM) to a "classical" monthly regimen of the same drugs, as a first line of treatment in metastatic breast carcinoma. The first arm of this protocol consisted of FAC: 5-FU 600 mg/m2 i.v. over 1 hour, day(d) 1, 2, 3, DOX 50 mg/m2 i.v. bolus, d1, and CPM, 400 mg/m2 i.v. bolus, d 1, 2, 3. The second arm consisted of FULON: 5-FU 250 mg/m2 per day continuously infused from d1 to d22, CPM 300 mg/m2 i.v. bolus, d1, 8, 15, 22, and DOX 15 mg/m2 i.v. bolus, day 1, 8, 15, 22. Between January 1990 and June 1993, 258 women with proven metastatic breast carcinoma were randomly assigned either to receive FAC or FULON chemotherapy regimen. Chemotherapy courses were administrated every 4 weeks for FAC regimen and every 6 weeks for FULON. Response rate (54 versus 53%), response duration (14 versus 12 months) and overall survival duration (23 versus 21 months) were not significantly different in the two regimens (FAC versus FULON). Preorative prognostic value of liver metastasis or high LDH level was slightly attenuated in patients treated by FULON. Efficacy of infusional 5-FU in metastatic breast cancer could have been lowered by weekly infusion of doxorubicin in the FULON regimen compared to monthly infusion. According to the modalities of delivery of the drugs, the two regimens seem equally effective.     

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 phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer

PURPOSE: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients with histologically proven metastatic colorectal cancer, and at least one bidimensionally measurable lesion, aged 18-70, with performance status < or = 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed > or = 6 months before study entry) were selected. Treatment was irinotecan 350 mg/m2, i.v., day 1, alternating with leucovorin 20 mg/m2 i.v. and 5-FU 425 mg/m2, i.v. daily for five consecutive days, day 22-26 (Mayo Clinic regimen). One alternating cycle was to be performed every six weeks. Patients were evaluated for efficacy every alternating cycle. Treatment was administered until five alternating cycles, disease progression, unacceptable toxicity or patient refusal. RESULTS: Thirty-three patients (28 chemotherapy-na?ve and five with prior adjuvant treatment completed > 1 year prior to accrual) were enrolled. The objective response rate (RR) was 30% (95% CI: 16-49; 10 patients/33; nine partial response and one complete response). All responses were reviewed by an independent external review committee. An additional 49% of patients had stable disease. The median survival was 16 months, the one year survival amounted to 58% and the median progression free survival was 7.2 months. Relative dose intensity was nearly 90% for both drugs. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, seen in 24% and 64% of patients, respectively. CONCLUSIONS: The alternating schedule of CPT-11 350 mg/m2 with five days bolus of 5-FU and low dose LV is an active and feasible regimen as front-line therapy for metastatic CRC. It is well tolerated, without evidence of overlapping toxicity. The response rate appears promising with regard to that expected with either single agent. This regimen warrants further assessment in randomized trials.     

Pharmacokinetics of a high dose of gentamicin administered intravenously or intramuscularly to horses

PURPOSE: The effect of uridine (UR) coadministration on the intestinal metabolism from 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU) was evaluated by a method of concentration difference between portal and systemic bloods in conscious rats (PS method). METHODS: 5'-DFUR (100 mg/kg) alone (Group A), or 5'-DFUR + UR (100 mg/kg each) (Group B) was orally administered to conscious rats. The portal and arterial bloods were simultaneously withdrawn from two canulas at appropriate time intervals, and blood concentrations of 5'-DFUR, 5-FU, UR and uracil (U) were assayed by HPLC. The concentration-time profiles of these drugs and its metabolites were analyzed by local moment analysis. RESULTS: UR coadministration made the local absorption ratio (Fa) of 5'-DFUR decrease significantly from 60.1 +/- 10.5% to 38.0 +/- 18.6% of dose. Though the local absorption ratios (Fm(a)) of the metabolite (5-FU) were the same between Group A and Group B (8.3 +/- 1.9 and 8.7 +/- 4.0% of 5'-DFUR, respectively), AUC of arterial 5-FU in Group B was 5 times greater than that in Group A. UR was not detected in the portal blood, and Fm(a) of U was estimated to be 41.9 +/- 26.8% of UR in Group B. CONCLUSIONS: It is predicted that a large portion of 5-FU generated from 5'-DFUR is further degraded in the intestine in Group A, and U generated from UR blocks 5-FU degradation in the intestine and the systemic circulation in Group B.     

5-fluorouracil and low-dose leucovorin as surgical adjuvant therapy from viewpoint of long-term outcome

Biochemical modulation of 5-FU by leucovorin (LV) has been demonstrated to increase the therapeutic effect compared to single agent 5-FU in the treatment of patients (pts) with advanced colorectal cancer. The purpose of this study was to determine the effectiveness of the 5-FU + LV combination as adjuvant therapy following surgery in pts with Dukes' B, C colon cancer. Pts were entered in a stratified clinical trial comparing two different combination chemotherapeutic regimens to single agent 5-FU, given orally as a control. This report summarized the result of treatment in 61 pts who were 5-FU oral alone and 32 pts who were 5-FU (375 mg/m2) and low-dose LV (20 mg/m2) intravenously for 5 days with 5-FU oral intake. 5-FU with LV regimen was associated with an improved survival compared with the single agent 5-FU oral intake (p < 0.05). 5-FU with LV regimen resulted in less recurrence in liver and lung compared with single-agent 5-FU oral intake.     

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.     

5-Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial

Leucovorin (LV) enhances the activity of 5-fluorouracil (5FU). Based on these data, we performed a randomized trial with 5FU, epirubicin (EPI), mitomycin C(MMC) with/ without LV in advanced gastric cancer (AGC). The purpose of our study was to investigate if the addition of LV improved the response rate of the combination 5FU EPI, MMC (FEM) over FEM. From January 1988 until April 1994, 88 patients with recurrent or metastatic AGC were randomly received 5FU, EPI, MMC with (group A) or without (group B) LV. Between the two arms of the study no difference was noticed in sex, performance status, primary site of tumor, and lymph node metastases. Therapy included group A (5FU 600 mg/m2/day, i.v. bolus, on days 1, 8, 29, 36, and EPI 45 mg/m2/day, i.v. bolus, on days 1 and 29, MMC 10 mg/m2/day, i.v. bolus, on day 1) and group B (the same as group A plus LV 200 mg/m2/day by 2 h intravenous infusion with 5FU intravenous push at midinfusion). No significant difference in response rate was noticed between the two treatment arms; there were two (5%) patients with complete response in group A, and five (12%) in A and 11 (26%) partial responders in group B (p < 0.1). A significantly higher number of patients achieving stable disease was observed in group B; 19 (44%) in comparison to group A 10 (24%) (p < 0.048). There were more patients with progressive disease in group A 25 (59%) than in group B 12 (28%) (p < 0.003) (Table 2). No difference was noted in mean duration of response: group A, 15.8 (6-31) weeks; and group B, 17.6 (6-28) weeks. The mean time to progression was for group A [11.4 (6-35) weeks] and for group B [17.6 (8-33) weeks]. Mean survival was for group A [27.4 (12-59) weeks] and for group B [30.6 (17-53) weeks], for 50% of patients. Causes of death were, for group A, 40 patients from disease progression and two sudden deaths; for group B, causes of death were for 41 patients disease progression and two sudden deaths. There were two patients in group A and one in group B that were not evaluable because they abandoned therapy after the first cycle. Toxicity was increased in group B; anemia, nausea and vomiting, and alopecia (p < 0.055) were more severe in group B, but not statistically different when compared to group A. Neutropenia, thrombocytopenia, mucositis, and fatigue of any grade were significantly more common and severe in group B. Significant dose reductions due to toxicity were required more commonly in group B. We conclude that the response rate was increased in the schedule with the addition of LV, at the cost of increased toxicity and with no difference in survival. A randomized trial comparing FEM-LV with new generation regimens would determine whether the addition of LV qualifies FAM equally active with these.     

Long-term complete response in two cases of liver metastases from rectal and gastric cancer treated with intra-arterial infusion chemotherapy of leucovorin and 5-fluorouracil

Intra-arterial infusion chemotherapy combined with leucovorin (LV) and 5-fluorouracil (5-FU) was performed in two patients with multiple metastases from rectal and gastric cancer. In each patient LV 45 mg was infused as a bolus just before and after 5-FU 1,000 mg/4 hrs administration. Thereafter 5-FU dose was decreased gradually. This regimen was principally repeated weekly on an outpatient basis. In both patients PR was detectable 3 and 4 months after the beginning of chemotherapy, and CR was obtained in 21 and 6 months, respectively. Neither patient showed any signs of recurrence and are in good health 35 and 30 months after initiation of chemotherapy. These findings suggest that our protocol has an excellent anti-tumor effect and improves the QOL in some patients for a long time.