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

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

Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: Results of a phase II study

Purpose: To evaluate the antitumor activity in terms of response rate (RR), time to progression (TTP) and survival of paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic breast cancer (MBC).Patients and methods: Fifty-four patients with bidimensionally measureable disease were included during phase II. Thirty-two had anthracycline resistant disease. Treatment consisted of 5-FU (24-hour i.v. infusion) 2.0 g/m², leucovorin (two-hour i.v. infusion prior to 5-FU) 500 mg/m², weekly for six weeks (day 1, 8, 15, 22, 29, 36) and paclitaxel (three-hour i.v. infusion) 175 mg/m² was administered additionally on days 1 and 22, q 50 days.Results: We observed complete remissions in 4% of patients (2 of 54), partial remissions in 55% (30 of 54), stable disease in 37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%–72%). The RR in 32 patients with anthracycline resistant disease was 59% (19 of 32). The median duration of response was 12 months (3–22), median TTP eight months (2–22) and median survival time 15 months (2–28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, mucosits, nausea and vomiting.Conclusions: Paclitaxel combined with weekly 24-hour infusional 5-FU/leucovorin is well tolerated in the second line treatment of MBC. High efficacy was documented even in the treatment of anthracycline resistant disease, which warrants further evaluation.     

Phase II trial of 5-fluorouracil, leucovorin and cisplatin for treatment of advanced pancreatic adenocarcinoma

Background. Advanced pancreatic adenocarcinoma is a rapidlyfatal disease for which an active chemotherapy regimen is sought.Here we report the outcome of a phase II trial to assess thetoxicity and efficacy of a combination of 5-flu-orouracil (5-FU),leucovorin and cisplatin (CDDP). Methods. A regimen combining leucovorin (200 mg/m²/d x 5d),5-FU (375 mg/m²/d x 5d in a 2-hour infusion) and CDDP (15 mg/m²/dx 5d) was given to 52 patients with histologically-proven, previouslyuntreated, locally advanced (n = 13) and/or metastatic (n =39) pancreatic adenocarcinoma. Results. Of 48 patients evaluable for response, 10 achievedpartial responses, for an overall response rate of 21% (95%CI 9.5%–32.5%), and a palliative effect was observed in52%. The median survival was 9.5 months (18 months for locally-advancedand 5 months for metastatic disease) with a 1-year survivalof 34.6% and a median progression-free survival of 4.5 months.Chemotherapy was well tolerated with grades 3 or 4 nausea/vomitingin 12%, diarrhea in 6%, anaemia in 17%, neutropenia in 12%,and thrombocytopenia in 10%. Eleven patients (21%) had Grade2 peripheral neuropathy. Conclusion. The combination of leucovorin, 5-FU and CDDP seemsto be an effective palliative treatment, with moderate toxiceffects, in advanced pancreatic adenocarcinoma. advanced pancreatic adenocarcinoma, cisplatin, 5-fluorouracil, leucovorin     

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study

Purpose: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer.Patients and methods: A total of 306 patients were randomized to receive either 5-FU 425 mg/m² given by bolus injection on days 1–5 plus intravenous (i.v.) LV 20 mg/m² every four to five weeks or 5-FU 3.5 g/m²/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms.Results: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3–4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm.Conclusions: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3–4 toxicity.     

Diagnosis and Treatment of Chronic Prostatitis Caused by Chlamydia trachomatis

Abstract

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m² (2-hour i.v. infusion) followed by 5-FU 400 mg/m² (bolus) and 5-FU 600 mg/m² (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m² (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients <70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged ≤70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.     

A phase II study of modified deGramont 5-fluorouracil, leucovorin, and oxaliplatin in previously treated patients with metastatic colorectal cancer

Purpose: To evaluate the toxicity and efficacy of a modified deGramont regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with advanced colorectal cancer who have progressed on at least one but not more than two prior chemotherapy regimens. Patients and Methods: Patients with stage 4 colorectal cancer were treated with oxaliplatin 85 mg/m² by a 2-hour intravenous infusion, followed by leucovorin 500 mg/m² by a 2-hour intravenous infusion, followed by 5-FU 400 mg/m² by bolus injection, followed by 5-FU 2.4 g/m² administered by a 46-hour continuous infusion. Cycles were administered every 2 weeks. Results: Seventy patients were treated and 68 patients had previously received irinotecan. Eleven percent of patients had a partial response, 33% of CEA-evaluable patients had a ≥50% drop in their CEA level. The median time to progression was 6.2 months, and the median overall survival was 8.7 months. Toxicity was mild to moderate, as 14% of patients experienced grade 3 or 4 neutropenia and 3% of patients experienced grade 3 neuropathy. Conclusion: The modified deGramont regimen of 5-FU, leucovorin, and oxaliplatin is tolerable and is associated with a modest degree of antitumor activity in patients who have progressed on both 5-FU and irinotecan.     

5-Fluorouracil, leucovorin and interferon alpha 2b in advanced pancreatic cancer: A pilot study

Background: On the basis of data suggesting the possibilityof maximizing the efficacy of 5-FU by LV and IFN, a pilot clinicaltrial was initiated in advanced pancreatic cancer. Patients and methods: Twenty-four patients received weekly 5-FU600 mg/m² bolus 1 hour after the initiation of a 2-hour infusionof 500 mg/m² of leucovorin. Three MU of interferon alpha 2bwas administered subcutaneously three times a week. Results: Two of 22 evaluable patients obtained partial responses(8%, confidence interval 3%–33%). Toxicity was severe.Diarrhea and stomatitis were the most common side effects, occuringin 50% and 25% of patients, respectively. Conclusion: Because of the presence of severe toxicity we suggestthat further clinical trials in pancreatic cancer be attemptedonly after a better definition in preclinical studies of interactionsamong 5-FU, leucovorin and interferon. pancreatic cancer, 5-fluorouracil, modulation     

A phase I study of weekly docetaxel, 24-hour infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer

OBJECTIVES: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of both docetaxel and 5-fluorouracil (5-FU) when administered weekly in a regimen of docetaxel, 5-FU/leucovorin and cisplatin (DFLP) for 2 consecutive weeks every 3 weeks. PATIENTS AND METHODS: A total of 31 patients with chemo-naive, advanced adenocarcinoma of the stomach were enrolled in the study. Cisplatin and leucovorin dosages were fixed throughout the study at 30 and 300 mg/m2, respectively. 5-FU dosage was fixed at 1,600 mg/m2 while docetaxel was evaluated at weekly 1-hour infusion dosages of 30, 40 and 50 mg/m2 to determine the MTD. Cisplatin, 5-FU and leucovorin were administered together as a 24-hour continuous infusion following docetaxel. Weekly 5-FU dosages of 1,600, 2,000 and 2,400 mg/m2 were then evaluated after setting the docetaxel dosage at the MTD. RESULTS: A total of 95 chemotherapy cycles were administered, with a median of three cycles per patient. The MTD of docetaxel was defined at 40 mg/m2. At a docetaxel dosage of 50 mg/m2 per week, the dose-limiting events of grade 4 febrile neutropenia and grade 3 hypomagnesemia occurred. With fixation of docetaxel to 40 mg/m2, the DLT for 5-FU was found at 2,400 mg/m2 per week. This incurred grade 4 neutropenia such that the MTD of 5-FU was defined at 2,000 mg/m2. Grade 3/4 neutropenia occurred in 14 patients (45%), with 2 patients developing febrile neutropenia. Grade 2 and 3 hypomagnesemia and hypokalemia occurred in 9 (41%) and 4 (18%) patients, respectively, of the first 22 patients treated with a 24-hour infusion of cisplatin and 5-FU/leucovorin immediately following docetaxel. Following a change in the cisplatin administration schedule to a 3-hour infusion after 5-FU/leucovorin infusion, no such complications were observed in 9 subsequently treated patients. Grade 2 diarrhea was recorded in 11 patients (35%). Grade 2/3 asthenia occurred in 9 patients (30%), which resolved after correction of electrolyte disorders. Twenty-six patients were assessable for response analysis. There were 2 (7.8%) complete and 14 (53.8%) partial responses, with the overall response rate being 61.5% (95% confidence interval, 41.5-81.6%). Responses were observed at all dose levels. CONCLUSION: Two consecutive weeks of DFLP infusions every 3 weeks appear to be an active regimen with a tolerable toxicity profile in advanced gastric cancer. For further phase II studies, the recommended dose for this combination is 40 mg/m2 of docetaxel and 2,000 mg/m2 of 5-FU per week.     

Phase I/II study with a weekly 24-hour infusion of 5-fluorouracil plus high-dose folinic acid (HD-FU/FA) in intensively pretreated patients with metastatic breast cancer

BACKGROUND: In metastatic breast cancer patients who have had prior exposureto anthracyclines, single agents induce less than 15% and combinationchemotherapy less than 20%–30% of objective responses.Therefore more active and tolerable salvage regimens are needed. PATIENTS AND METHODS: Forty-three patients with advanced breast cancer pretreatedwith 1–5 (median 2) different chemotherapy regimens wereentered into this phase I/II trial. Treatment consisted of folinicacid (FA) (500 mg/m² i.v., 2-hour infusion) followed by a 24-hourinfusion of 5-fluorouradil (FU) which was escalated from 1.5g/m² (dose level (dll)), to 1.8 g/m² (dl 2) to 2.1 g/m² (dl3). Therapy was given as outpatient treament once weekly times6 followed by a 2-week rest. RESULTS: HD-FU/FA was well tolerated. No dose-limiting toxicity occurredat dl 1 or 2. Only 3/32 (9%) patients had WHO grade 3%4 toxicities(gastrointestinal toxicities, hand-foot-syndrome) at dl 3. Theresponse rate for all 32 of the patients treated at dl 3 was41% (13/32). In the 24 patients with anthracycline-refractorydisease, a response rate of 41% (10/24) was achieved. The medianremission duration was ii months and the median survival time19 months. CONCLUSIONS: This schedule of FU/FA is a safe outpatient treatment with substantialactivity in intensively pretreated breast cancer patients. phase I/II trial, folinic acid/5-fluorouracil, pretreated breast cancer     

Five-day continuous infusion of 5-fluorouracil and pulsed folinic acid in patients with metastatic colorectal carcinoma: An effective second-line regimen

Objective: A previous phase I trial in 14 pretreated patients with progressive advanced colorectal cancer demonstrated 750 mg/m² to be the maximum tolerable dose of 5-fluorouracil (5-FU) administered as a 5-day continuous infusion modulated by short infusions of 100 mg/m² folinic acid twice daily. The dose-limiting toxicities were hand-foot syndrome and severe mucositis. A response rate of 21% and 50% stable disease could be achieved. In order to determine the effectiveness and tolerability, we initiated a multicenter phase II trial applying a 650 mg/m² recommended dose of 5-FU and 100 mg/m² folinic acid twice daily every three weeks.Patients and methods: From January 1994 to July 1996, 88 advanced and progressive colorectal cancer patients either previously treated with a bolus schedule of 5-FU and folinic acid (34 patients) or without (54 patients) previous chemotherapy were included in this trial.Results: In the group of previously treated patients, therapy led to 6% (2 of 34 patients) remissions while stable disease could be observed in 68% (23 of 34 patients) of the patients. The median survival time was 14 months. The main toxicity was mucositis grade 3 in 15% of the previously treated patients and 10% in the nonpretreated patients. In the population of nonpretreated patients, the overall response rate was 15% (eight of 54 patients) and stable disease could be induced in 67% (36 of 54 patients). The median survival time was 13.7 months.Conclusion: This regimen is an active second-line therapy in advanced colorectal cancer with minimal toxicity, thus preserving the quality of life during palliative chemotherapy. Antitumor activity in previously untreated patients does not seem superior to that obtained with weekly regimens applying 24- or 48-hour continuous infusions of 5-FU and folinic acid.     

Phase II trial of cyclophosphamide, leucovorin, 5-fluorouracil 24-hour infusion and tamoxifen in pancreatic cancer

Leucovorin modulates the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. 24-hour infusion of 5-FU has been shown to enhance antitumor activity in colorectal cancer compared to bolus infusion. According to experimental data cyclophosphamide and tamoxifen may enhance the effectiveness of leucovorin and 5-FU. A phase II trial was initiated to evaluate the effect of a combination of low-dose cyclophosphamide (C), leucovorin (L), 5-FU (F) and tamoxifen (T) (CLFT) in advanced pancreatic cancer. Fifty patients were treated monthly with 300 mg/m2 cyclophosphamide and weekly with 500 mg/m2 leucovorin followed by a 24-hour infusion of 2000 mg/m2 5-FU and tamoxifen 20 mg bid. Three patients had a partial response (6%), two a minor response (4%) and 32 (64%) no change of disease. The median survival time was 8.5 months for all patients, the median time to progression of disease was 4.6 months and the 1-year survival rate was 28%. CLFT was fairly well tolerated. These data suggest that biochemical modulation of 24-hour infusional 5-FU with leucovorin together with cyclophosphamide and tamoxifen has some positive effects in the treatment of pancreatic cancer.     

Phase II study of weekly 24-hour intra-arterial high-dose infusion of 5-fluorouracil and folinic acid for liver metastases from colorectal carcinomas

Background:A multicenter phase II trial was initiated inorder to evaluate the weekly, high-dose 24-hour infusion of5-fluorouracil (5-FU) plus folinic acid (FA) in patients with unresectablecolorectal cancer hepatic metastases. Patients and methods:A weekly hepatic arterial infusion (HAI) ofFA 500 mg/m² followed by a 24-hour infusion of 5-FU 2,600mg/m² (later reduced to 2,200 mg/m²) was given via asurgically implanted intra-arterial port system. One treatment cycle consistedof six weekly applications followed by a two-week rest period. Toxicity wasassessed according to the WHO criteria. Chemotherapy was continued untildisease progression or complete response occured. Results:A total of 50 patients (40 chemonaive, 10 pretreated)entered this trial. An objective tumor response occurred in 28 patients(56%), while 13 patients (26%) had stable disease. The medianprogression free survival was 12 months, and the median survival 22.3 months.Due to a high rate of gastrointestinal side-effects in the initial phase ofthe trial, the dosage of 5-FU was reduced to 2,200 mg/m² for allsubsequent patients. Diarrhea and nausea led to a dose reduction in 40%of applications and 24% of patients, respectively. One patient died ofcardiac insufficiency unrelated to chemotherapy before responseevaluation. Conclusions:This HAI approach using high-dose 5-FU was relativelywell tolerated when 2,200 mg/m² instead of 2,600 mg/m²was used. The activity of this regimen is promising and warrants furtherevaluation and modification.     

A weekly 24-h infusion of high-dose 5-fluorouracil (5-FU)+leucovorin and bi-weekly cisplatin (CDDP) was active and well tolerated in patients with non-colon digestive carcinomas

In patients with non-colon digestive carcinomas, various schedules and doses of 5-fluorouracil (5-FU) and leucovorin combined with cisplatin (CDDP) have been used extensively. The present study explored the toxicity and activity of a weekly 24-h infusion of high dose 5-FU modulated by high dose leucovorin with bi-weekly CDDP. 59 patients with measurable disease were treated with a weekly infusion of high dose 5-FU (2 or 2.6 g/m2)+leucovorin 500 mg/m2 for 6 weeks and a bi-weekly dose of CDDP (50 mg/m2). All patients had metastatic or locoregionally advanced disease and had a performance status < or =3. All patients were evaluable for toxicity and 58 for response. Toxicity was different according to the schedule of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2.6 g/m2 with a high incidence of grade 3/4 neutropenia (16%) and febrile neutropenia (13%), and led to dose reductions in both CDDP and 5-FU in 13 patients (34%). For patients who started 5-FU at a dose of 2 g/m2, no reduction in 5-FU was required, and only 4 patients required a dose reduction of CDDP (19%). Grade 3/4 neutropenia was seen in 10% of patients of this group and only 1 patient required hospitalisation for febrile neutropenia. Other grade 3/4 toxicities were rare in both groups. Renal toxicity was infrequent and mild and did not require dose adjustments. The overall response rate was 33%; 19 patients achieved a partial responses (PR). No patient had a complete response (CR). The median duration of response was 5.7 months (range 2-24 months) and the median survival was 7.9 months ( range: 1-30, 95% confidence interval (CI): 7-9). The combination of weekly 24-h infusion of high dose 5-FU with leucovorin and bi-weekly cisplatin seems a well-tolerated and active treatment in non-colon digestive carcinomas. A dose of 2 g/m2 of 5-FU seems to be recommended.     

Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study

Background: Irinotecan plus infusional 5-fluorouracil/leucovorin(FOLFIRI) is accepted as a reference treatment for the first-linetreatment of patients with metastatic colorectal cancer (MCRC).The aim of this study was to demonstrate that a regimen withoutleucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI(response rate). Patients and methods: Chemotherapy-naive patients with MCRCwere randomized to receive either irinotecan (180 mg/m² on day1) + 5-fluorouracil (5-FU) (400 mg/m² bolus and 600 mg/m² 22-hinfusion) + LV (200 mg/m² on days 1–2) (FOLFIRI) every2 weeks or irinotecan (80 mg/m²) + 5-FU (2.250 mg/m² 48-h infusion)(FUIRI) weekly. Results: In all, 346 patients were included, 173 in each arm.In the intention-to-treat analysis, the response rates for FOLFIRIand FUIRI were 57% [95% confidence interval (CI) 49% to 64%]and 51% (95% CI 43% to 59%), respectively (P = 0.2809). No statisticallysignificant differences were observed between FOLFIRI and FUIRIregarding median progression-free survival (8.3 versus 8.4 months;P = 0.4339) nor median overall survival (21.6 versus 19.2 months;log-rank test P = 0.2941). Grade 3/4 neutropenia was significantlymore frequent on FOLFIRI arm (27% versus 9%), while the proportionof diarrhea was higher on FUIRI arm (21% versus 42%). Conclusion: FUIRI represents a valid alternative without LVto the FOLFIRI regimen as MCRC first-line treatment. Key words: colorectal cancer, 5-fluorouracil, irinotecan Received for publication May 7, 2008. Revision received July 11, 2008. Accepted for publication July 14, 2008.     

Combination chemotherapy with tauromustine (TCNU), 5-fluorouracil and leucovorin in advanced colorectal carcinoma: A dose-finding study

Background: In preparation for a phase II trial we performeda dose-finding study involving tauromustine (TCNU), fluorouracil(5-FU) and leucovorin (LV), applied in patients with colon cancer.To prevent TCNU/5-FU antagonism, a phenomenon recently demonstratedin vitro, special attention was paid to the sequencing of theseagents. Patients and methods: In 25 patients with advanced colorectalcarcinoma (13 M, 12 F, median age 51 yrs), four dose levelsof TCNU (25, 30, 35 or 40 mg/m²) were investigated. The agentwas administered orally once per week in weeks 1 through 4,in combination with fixed i.v. doses of 400 mg/m² 5-FU and 80mg/m² LV, once a week, weeks 1 through 8. Unless progressionoccurred, two 8-week cycles were applied. TCNU was administeredat least 24 hours prior to 5-FU, because recent in vitro studiessuggested that such an interval is required to obtain additivecytotoxicity. Results: All 25 patients were evaluable for toxicity; 23 patientsreceived at least one full 8-week course, and 13 were eligiblefor second cycles. Significant haematologic toxicity, predominantlythrombocytopenia WHO grade 3 or 4, was mainly encountered atthe 35 and 40 mg/m² dose levels. Although occasionally severe,myelosuppression did not result in toxic deaths; spontaneoushaemorrhage was never observed, and platelet transfusions werenot required. Additional toxicity, also related to the two higherdose levels, consisted of diarrhea (WHO grade 3) and the ‘handand foot syndrome’, both occurring in a single patient;two patients developed fever of undetermined origin, but onlyone of them required hospitalization and antibiotic treatment.The overall response rate was 20% (7 partial responses in 25evaluable patients). Conclusions: For phase IL studies, we recommend a weekly oraldose of 40 mg/m² TCNU, weeks 1 through 4, in combination with400 mg/m² 5-FU and 80 mg/m² LV (IV), once a week, weeks 1 through8. chemotherapy, colorectal carcinoma, TCNU     

Oxaliplatin with high-dose leucovorin and infusional 5-fluorouracil in irinotecan-pretreated patients with advanced colorectal cancer (ACC)

The purpose of this study was to evaluate the efficacy and tolerance of the bimonthly administration of oxaliplatin in combination with high-dose leucovorin and infusional 5-fluorouracil (5-FU) (FOLFOX2 regimen) in patients with advanced colorectal cancer (ACC) who did not respond or whose disease progressed within 3 months after front-line treatment with CPT-11-containing regimens. Forty-one patients with ACC who did not respond or whose disease progressed after front-line treatment with CPT-11 + 5-FU/leucovorin were enrolled. Oxaliplatin was administered at the dose of 100 mg/m2 on day 1 as a 2-hour infusion simultaneously but through different lines with leucovorin (500 mg/m2 on days 1 and 2); 5-FU was given at the dose of 1,750 mg/m2/d as a 22-hour continuous intravenous infusion on days 1 and 2. The regimen was repeated every 2 weeks. In an intention-to-treat analysis, complete response was achieved in one (2.4%) and partial response in six (14.6%) patients (overall response rate: 17%; 95% CI: 5.56-28.59%); stable disease and progressive disease were observed in 15 (36.6%) and in 19 (46.31%) patients, respectively. The median duration of response and the median time to tumor progression were 6 and 8.5 months, respectively. The median overall survival was 12 months and the probability for 1-year survival was 42.9%. Grade III/IV neutropenia occurred in 17 (41%) patients and febrile neutropenia developed in one of them (2%). There was no treatment-related death. Peripheral neuropathy greater than or equal to grade II occurred in 24 (58%) patients. Other toxicities were relatively mild. The bimonthly administration of oxaliplatin in combination with high-dose leucovorin and 48-hour continuous infusion of 5-FU is a relatively active and well-tolerated regimen for patients with ACC resistant or refractory to CPT-11 + 5-FU (continuous infusion)/leucovorin.     

Phase II study of cisplatin and 120-hour continuous infusion of 5-fluorouracil in patients with advanced pancreatic adenocarcinoma

BACKGROUND:: Advanced pancreatic carcinoma (APC) is a rapidly fatal diseaseand an active chemotherapy with palliative effects and impacton patient survival is needed. 5 fluorouracil (5-FU) combinedwith cisplatin (CDDP) has a recognized synergjstic activity,but its activity in APC has never been well established. METHODS:: Forty eligible patients (pts) with measurable APC were treatedin a phase II trial with 5-FU 1000 mg/m²/ day from day 1 today 5 by continuous intravenous infusion and CDDP 100 mg/m²on day 2. Eighty percent of the pts (36/40) had metastatic disease,32.5% (13/40) were previously treated and 65% (26/40) had performancestates of 2 or 3. RESULTS:: Of 38 evaluable pts, one had a complete response and 9 achievedpartial responses; the overall response rate (RR) was 26.5%(95% CI: 12% to 40%). The median duration of responses was 10months (range 4-18). The RR in non-pretreated pts was 32% Apalliative effect was seen in 45% of pts (17/38). The mediansurvival was 7 months and 12 pts (29%) were alive at 1 year.Leukopenia was the most important toxicity; 11 pts (27%) hada grade 4 leukopenia and 3 had neutropenic fever. CONCLUSIONS:: The combination of CDDP and 5-FU in continuous infusion seemsan active and well tolerated treatment in APC and will be comparedto standard therapy in a multicentric randomized trial. pancreatic cancer, chemotherapy, 5-fluorouracilcisplatin combination     

Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma: A multicenter study by the Association of Medical Oncology of the German Cancer Society (AIO)

BACKGROUND: No effective salvage therapy is known for patients with metastaticcolorectal carcinoma progressive after chemotherapy with 5-fluorouracil(5-FU)/folinic acid (FA) or 5-FU/alpha interferon (IFN) combinations.The aim of the study was to test whether weekly FA/high-dose5-FU is an effective therapy in pretreated patients with progressivemetastatic colorectal carcinoma. PATIENTS AND METHODS: Between January and December 1992, 57 patients with metastaticcolorectal carcinoma were treated with weekly infusions of high-dose5-fluorouracil (5-FU) (2600 mg/m² as 24-hour infusion) and folinicacid (FA) (500 mg/m² as 1-hour infusion prior to 5-FU). Allpatients were pretreated with chemotherapy, most of them withregimens containing 5-FU i.v. bolus/FA or 5-FU/alfa interferon(IFN), and all had documented progressive disease at the timeof entering the study. In patients with partial remission (PR)or stable disease (SD) with improvement of their clinical condition,therapy was continued until progressive disease (PD) was documented.In all other patients therapy was stopped after one course (6infusions). RESULTS: 5/57 patients (9%) achieved PR, 32/57 (56%) SD, in 19/57 (33%)disease was progressive and one toxic death occured. 26/32 patients(81%) with SD or PR after the first chemotherapy again obtainedSD or PR on high-dose 5-FU/FA but only 8/18 (44%) of those withPD after first chemotherapy did so. The median duration of SD/PRwas 3 months and the median survival for all patients 8 months(range 3–17+). Apart from one toxic death, toxicity consistingfor the most part of mucositis (n = 24), nausea (n = 23), diarrhoea(n – 18) and hand-foot syndrome (n = 12) was moderate. CONCLUSION: Pretreated patients with metastatic colorectal carcinoma, notablythose with a primary PR or SD, can probably benefit from weeklyhigh-dose 5-FU/FA. metastatic colorectal carcinoma, high-dose 5-FU/FA     

Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer.

BACKGROUND: Oxaliplatin shows preclinical activity in many cancer cell lines that are resistant to cisplatin, and also has synergism with 5-fluorouracil (5-FU). We undertook this study to evaluate the efficacy and toxicities of a combined oxaliplatin, 5-FU and leucovorin (LV) continuous infusion regimen in patients with advanced gastric cancer who progressed during or after treatment with 5-FU and platinum compounds. PATIENTS AND METHODS: Twenty-six patients with advanced gastric cancer, whose disease progressed while receiving, or after discontinuing, chemotherapy with a 5-FU and platinum regimen, were enrolled in this study. Treatment comprised oxaliplatin (85 mg/m2 on day 1) as a 2-h infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 48-h infusion of 5-FU 2.4-3.0 g/m2 concurrently with LV 150 mg/m2. Cycles were repeated at 2-week intervals. RESULTS: Of the 23 evaluable patients, there were six partial responses (response rate 26%). All responding patients were among those who entered into this trial immediately after failure of previous chemotherapy with 5-FU and cisplatin. The median time to progression was 4.3 months and the median overall survival was 7.3 months. The most common hematologic toxicity was grade 1-2 anemia in 39 cycles (39%). No grade 4 leukopenia or thrombocytopenia were observed. The most common non-hematologic toxicity was nausea/vomiting (33%). Peripheral neuropathy of grade 1 or 2 was noted (27%), but there was no grade 3 or 4 neurotoxicity. CONCLUSIONS: This phase II study of oxaliplatin, 5-FU and LV continuous infusion showed activity in previously platinum-treated patients with advanced gastric cancer, with acceptable toxicities.     

Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy

To evaluate toxicity and efficacy of chemotherapy in elderly patients (≥65 years of age) with advanced colorectal cancer, data from two consecutive trials conducted between 1984 and 1995 at the National Institute for Cancer Research were analysed comparing the results of treatment in those 65 years of age or older and in those younger than 65 years. Of 215 patients recruited, 82 elderly patients (median age 70 years, median performance status 1) received one of the following regimens based on 5-fluorouracil (5-FU): (1) weekly 5-FU 600 mg/m² i.v. bolus (30 patients); (2) weekly 5-FU 600 mg/m² bolus plus leucovorin (LV) 500 mg/m² 2-h i.v. infusion (28 patients); (3) Weekly 5-FU 2600 mg/m² 24-h continuous i.v. infusion plus LV 100 mg 4-h i.v. infusion and 50 mg orally every 4 h for five doses (24 patients). Overall, 1071 chemotherapy cycles were administered with a median number of 12 courses per patient. The main side effects were diarrhoea, observed in 38% of patients, stomatitis in 24% of patients and hand-foot syndrome in 13% of patients, and haematological toxicity affected only 15% of patients. No patient suffered grade IV toxicity. In three patients chemotherapy was discontinued because of toxicity (two patients suffered grade III diarrhoea, one patient grade III hand-foot syndrome). No significant difference in toxicity was evident between patients older than or younger than 65 years. Analysis of median dose intensity demonstrated no difference between the two groups. Overall objective response was observed in 18% (95% confidence limits 11–29) of elderly patients (15/82) in comparison with 23% (95% CL 17–32) of patients <65 years of age (31/133 pts). In conclusion, chemotherapy in elderly patients with advanced colorectal cancer is a safe and effective treatment with acceptable toxicity and comparable objective response rates. Received: 6 January 1998 / Accepted: 27 February 1998