A phase II study of irinotecan alternated with a weekly schedule of oxaliplatin, high-dose leucovorin and 48-hour infusion 5-fluorouracil in patients with advanced colorectal cancer

OBJECTIVES: To evaluate the safety and efficacy of irinotecan (CPT-11) alternated with a weekly treatment for 4 weeks of oxaliplatin (L-OHP), high-dose leucovorin (LV) and a 48-hour 5-fluorouracil infusion (5-FU 48 h) as first-line chemotherapy for patients with advanced colorectal cancer (ACC). Patients and METHODS: Previously untreated patients with ACC received chemotherapy consisting of a weekly treatment for 4 weeks of L-OHP (65 mg/m2), high-dose LV (150 mg/m2) followed by a 5-FU 48 h infusion (2,300 or 1,800 mg/m2) alternated with CPT-11 (350 mg/m2). A cycle was to be performed every 8 weeks. Treatment was continued up to tolerance, disease progression or patient refusal. Forty consecutive patients with measurable ACC, aged 26-70, performance status < or =2, entered our study. RESULTS: Six complete and 17 partial responses were observed (overall response rate, 57.5%; 95% confidence interval, CI: 38.8-71.1%); an additional 35% of the patients had stable disease. The median duration of response was 10.9 months (range, 6.5-30+ months). The median time to progression and the median overall survival time were 11.4 (95% CI: 10.4-12.3) and 20.3 (95% CI: 16.4-23.7) months, respectively. At the median follow-up period of 24 months, 17 patients (42.5%) are still alive. After a median number of 4 cycles, one toxic death occurred. The incidence of grade 3-4 toxicity per patient in any cycle was: stomatitis 7.5%, nausea/vomiting 2.5% and diarrhea 45% for the infusional part, neutropenia 37.5%, anemia 2.5%, thrombocytopenia 5%, alopecia 5% and diarrhea 10% for the CPT-11 part of the regimen. Gastrointestinal toxicity was different according to the dose of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2,300 mg/m2 with a high incidence of grade 3-4 diarrhea (72.2%) and stomatitis (16.6%), and led to dose reduction of 5-FU in 13 of 18 patients (72.2%). For 22 patients who started 5-FU at a dose of 1,800 mg/m2, a dose reduction of 5-FU was necessary only 5 times (22.7%). No patient discontinued treatment because of severe neurotoxicity. CONCLUSIONS: The activity of our alternating regimen of L-OHP/LV/5-FU 48 h and CPT-11 for not previously treated ACC patients is counterbalanced by a high toxicity and a inconvenient schedule.     

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 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed 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-naïve 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.     

A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma

Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2,600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range, 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study, in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2,600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five), stomatitis (three), hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR), with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months, and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity, with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.     

5-fluorouracil administered as a 48-hour chronomodulated infusion in combination with leucovorin and cisplatin: a randomized phase II study in metastatic colorectal cancer

OBJECTIVE: The primary objective of this trial was to determine the objective response of two regimens with CDDP administered every 2 weeks immediately before or after an 'optimal' 48-hour chronomodulated infusion of 5-fluorouracil (5-FU) modulated with leucovorin (LV) in metastatic colorectal cancer patients. Secondary endpoints were toxicity, 5-FU and its metabolites, plasma pharmacokinetics and progression-free and overall survival. METHODS: Metastatic colorectal cancer patients with measurable disease who were chemotherapy-naive or pretreated only with a 5-FU-bolus-based chemotherapy were eligible for this study. The study was designed as a randomized phase II clinical trial. RESULTS: Eighty-three patients were entered into the study. Forty-two were randomized to CDDP given before 5-FU and 41 to CDDP given after 5-FU. Patient characteristics were similar among the two groups. Toxicities were also similar among the two arms and the most frequent WHO grade III-IV toxicities were stomatitis (14%) and neutropenia (39-50%). Plasma pharmacokinetic profiles of 5-FU and 5-FUH2 were not significantly affected by the sequence of CDDP and 5-FU administration. Antitumor activity was similar in the two arms and was very promising both in pretreated patients (response rate 29%; 95% confidence interval 15-46%) and in chemotherapy-naive patients (response rate 56%, complete response 9%, 95% confidence interval 40-71%). Median survival of the patients with and without pretreatment was 12 and 16 months, respectively. CONCLUSIONS: These results do not suggest a sequence dependence of the synergism between CDDP and 5-FU. However, they challenge the need of oxaliplatin to improve 5-FU/LV activity in advanced colorectal cancer. In fact, our results with an 'optimal' 5-FU dose and scheduling are very similar to those obtained with oxaliplatin plus 5-FU/LV. However, only a randomized phase III study will be able to give an answer to the hypotheses raised by this study.     

A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer

Purpose In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC).Patients and methods Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m² i.v. on day 1, alternating with LV 20 mg/m² i.v. and 5-FU 425 mg/m² i.v. daily for five consecutive days, on days 22–26 (Mayo Clinic regimen). One cycle consisted of 6 weeks.Results A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16–44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients).Conclusions The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.     

A phase II study of Tomudex alternated with methotrexate, 5-fluorouracil, 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 tomudex with methotrexate (MTX)/5-fluorouracil (5-FU)/leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer.Patients and methods: Patients with histologically proven metastatic colorectal cancer and at least one bidimensionally measurable lesion, aged 18–70, with performance status 2, normal baseline biological values, and no prior chemotherapy, were selected. Treatment was tomudex 3 mg/m² and, after two weeks, MTX, 200 mg/m² by 30 infusion after hydration with 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m² and leucovorin, orally, 15 mg for six times every 6 hours, beginning 24 hours after MTX. Cycles were repeated every four weeks. Tumor response assessment was performed after three cycles.Results: Thirty-four patients were enrolled in this study, of whom twenty-four had liver metastases, nine local relapse, five lymph node involvement, four lung metastases, and three peritoneal carcinomatosis. Four patients achieved objective responses (one complete and three partial), for an overall response rate of 12% (95% CI: 0%–22%). Twelve patients had stable disease and 18 progressed on therapy. Median survival for all patients was 13 months. Two patients experienced grade 3 WHO neutropenia while hepatotoxicity was reported in 13 patients (6 grade 1, 3 grade 2, 3 grade 3, 1 grade 4), suggesting that this combination could increase hepatic toxicity in comparison to tomudex or MTX/5-FU alone.Conclusions: Our results suggest that this regimen does not warrant further investigation in advanced colorectal cancer patients, at least not with this schedule and doses.     

Whole-body hyperthermia (41.8 degrees C) combined with bimonthly oxaliplatin, high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer: a phase II study.

BACKGROUND: Second- and third-line treatments remain a challenge in advanced colorectal cancer. Studies of bimonthly regimens of high-dose leucovorin (LV) and 5-fluorouracil (5-FU) by continuous infusion combined with oxaliplatin (L-OHP) have shown encouraging response rates in patients not responding to a bimonthly LV/5-FU regimen. Hyperthermic enhancement of L-OHP efficiency by increased DNA adduct formation has been demonstrated in vitro. This study was designed to address feasibility, toxicity and efficacy issues of whole-body hyperthermia (WBH) as an adjunct to L-OHP/LV/5-FU in pretreated patients after progression to first- and second-line treatments with LV/5-FU by continuous infusion and irinotecan. PATIENTS AND METHODS: Forty-four patients with advanced colorectal cancer, who had progressed during or within 3 months after completion of chemotherapy with LV/5-FU 24-h infusion (LV/5-FU(24h)) (eight patients) or irinotecan combined with or after LV/5-FU(24h )(36 patients), were treated with L-OHP 85 mg/m(2), 2-h intravenous (i.v.) infusion, followed by LV 200 mg/m(2), 1-h i.v. infusion, and 5-FU 3 g/m(2), 48-h continuous infusion. Every second cycle of the biweekly regimen was combined with WBH, thus allowing a comparison of toxicity with and without WBH in the same patient. Whole-body hyperthermia was administered by a humidified radiant heat device. The target temperature of 41.8 degrees C was maintained for 60 min. L-OHP (2-h infusion) was started at a core body temperature of 39 degrees C. RESULTS: All patients could be evaluated for toxicity, and 41 patients were evaluable for response. A total of 273 L-OHP-containing regimens were administered, 130 with and 143 without WBH. Hyperthermic treatment combined with L-OHP/LV/5-FU showed no unexpected toxicities. WHO grade 3 toxicities were rare and evenly balanced between cycles given with or without WBH. One early death occurred due to sepsis and tumor lysis. The overall response rate was 20%, with two complete and six partial responses. Twenty-three patients (56%) had stable disease and nine patients (22%) progressive disease. With a median observation time of 70 weeks, the median time to progression was 21 weeks [95% confidence interval (CI) 17-25 weeks] and the median survival was 50 weeks (95% CI 39-61 weeks) from the start of therapy. CONCLUSIONS: This trial suggests some advantage of combining L-OHP/LV/5-FU with WBH. Results compare favorably with the activity of similar regimens without WBH in less extensively pretreated patients. These data support further evaluation and warrant phase III studies.     

Phase II study of weekly paclitaxel and 24-hour infusion of high-dose 5-fluorouracil and leucovorin in the treatment of recurrent or metastatic gastric cancer

To investigate the efficacy and safety of combining weekly paclitaxel with weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV, folinic acid) in the treatment of patients with advanced gastric cancer. Patients with histologically confirmed recurrent or metastatic gastric cancer were studied. Paclitaxel 80 mg/m2 3-hour intravenous infusion was given on days 1, 8, and 15, and high-dose 5-FU 2,600 mg/m2 plus LV 300 mg/m2 24-hour intravenous infusion (HDFL) was given on days 2, 9, and 16, repeated every 4 weeks. Between August 1997 and August 2003, 30 patients were enrolled. The median age was 58 years (range: 37-70). Eighteen patients (60.0%) had recurrent or metastatic disease and 12 patients had de novo metastatic disease. Among the 27 patients evaluable for tumor response, 2 achieved complete response and 9 achieved partial response, with an overall response rate of 40.7% (95% confidence interval, CI: 22-61%). Eleven of the 21 patients without prior exposure to HDFL-containing regimens responded (response rate: 52.4%, 95% CI: 29-74%), while none of the 6 patients who had previously failed HDFL-containing regimens responded (p value = 0.054 by Fisher's exact test). All 30 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 6 and 10 months, respectively. Major grade 3-4 toxicities were neutropenia in 12 patients (40.0%), diarrhea in 10 patients (33.3%), and stomatitis in 3 patients (10.0%). Grade 1-2 and 3-4 paclitaxel-related neuropathy developed in 16 (53.3%) and 2 (6.7%) patients, respectively. None of the patients discontinued protocol treatment because of paclitaxel-related neuropathy or developed HDFL-related hyperammonemic encephalopathy. This paclitaxel-HDFL regimen is effective and well tolerated in the treatment of advanced gastric cancer.     

Outpatient weekly high-dose continuous-infusion 5-fluorouracil plus oral leucovorin in advanced colorectal cancer. A phase II trial

BACKGROUND:: Background: In a previous phase I–II trial we showed thatmaximum tolerable dose (MTD) of 5-fluorouracil (5-FU) a weekly48-hour continuous infusion (CI) was 3.5 g/m². In a subsequentconfirmative phase II trial with 85 evaluable patients, a 38.5%response rate was obtained, and a median survival of 12 months.These data were comparable to those achieved by biochemicalmodulation of 5-FU with leucovorin. On this basis we attemptedto modulate high-dose 5-FU (3 g/m²) with oral leucovorin (LV)but the regimen too toxic and the dose had to be reduced. Anew phase II trial with 2 g/m²/week plus oral leucovorin wasplanned. PATIENTS AND METHODS:: From July 1992 to June 1994, 110 previously untreated patientswith advanced, measurable colorectal cancer were included ina multicenter study. The patients received, on an outpatientbasis, 5-FU 2 g/m² by continuous infusion for 48 hours oncea week until progression or the appearance of toxic effects.Oral leucovorin (60 mg every six hours) was also given duringthe 5-FU infusion. RESULTS:: Patients received a median dose intensity of 5-FU of 1.6 g/m²/week(range 0.9–2). Three complete responses and 36 partialresponses were observed. The overall response rate was 37.5%(95% CI, 28% to 46.8%), the median time to progression 7.4 monthsand median survival 14.5 months. W.H.O. grade 3 diarrhea occurredin 27 patients (24.5%); grade 3 mucositis was observed in 9(8.1%) patients and grade 4 in one. Grade 3 nausea and vomitingwas reported in 13 (11.7%) patients, while grade 3 hand-footsyndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurredin one patient and grade 3–4 thrombocytopenia in two. CONCLUSION:: Oral leucovorin modulation of weekly 48-hour continuous infusionof 5-FU at 2 g/m² is an active regimen, with diarrhea and mucositisas the main limiting toxic effects. Its antitumor activity doesnot seem superior to that obtained with a weekly 48-hour continuousinfusion of 5-FU alone at a dose of 3.5 g/m². advanced colorectal cancer, biochemical modulation, continuous infusion, fluorouracil, phase II trial     

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.     

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus ± LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m² per day and the l-LV dose being 5 mg/m² per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3–4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8–25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus ± LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin. Received: 22 September 1998 / Accepted: 5 January 1999     

Weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin in patients with advanced colorectal cancer: Taiwan experience

Between January 1994 and November 1995, 41 patients with metastatic colorectal carcinoma were enrolled in this study. All these patients had recurrent disease after a prior 5-fluorouracil based adjuvant chemotherapy or failed to achieve response by prior chemotherapy that included 5-fluorouracil. 5-Fluorouracil, 2600 mg/m2, was administered concurrently with 100 mg/m2 leucovorin over 24 hours of continuous intravenous infusion. The treatment was repeated every week until progressive disease was documented. Forty-one patients received a total of 810 courses of treatment. The overall response rate was 17.1% (95% confidence interval 5.6-28.6%). In two patients who achieved complete response, the liver was the metastatic site. The median survival was 18.4 months for responders and 12.6 months for non-responders. Gastrointestinal toxicities including diarrhea, stomatitis, nausea and vomiting were the major side-effects. Sixteen incidences (39.0%) of grade 2-3 gastrointestinal toxicities were observed. One patient (2.4%) developed a grade 3 cardiac toxicity, and another one (2.4%) had a grade 2 neurotoxicity. Hematological toxicities were minimal with no evidence of severe (grade 2 or more) leukopenia or thrombocytopenia. We conclude that in patients with pretreated metastatic colorectal cancer, weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin is associated with higher efficacy and tolerable toxicity. This regimen is a good option as a second-line treatment for those whose diseases are recurrent from or refractory to prior 5-fluorouracil, and deserves a longer period of follow-up.      

A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer

Inhibition of epidermal growth factor receptor (EGFR) signalling contributes to the therapy of colorectal cancer. Gefitinib, an oral EGFR tyrosine kinase inhibitor, shows supra-additive growth inhibition with irinotecan and fluoropyrimidines in xenograft models. We designed a study to determine the tolerability and efficacy of gefitinib in combination with irinotecan, infusional 5-fluorouracil (5-FU) and leucovorin (LV), on a 2-week schedule. Among 13 patients with advanced colorectal cancer, 10 required dose reductions of irinotecan and 5-FU because of dehydration, diarrhoea, and neutropenia, seven of whom required hospitalisation, three with neutropenic fever. One patient achieved partial response and seven had disease stabilisation. The combination of this standard chemotherapy regimen with gefitinib is associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level.     

Phase II study of a weekly 8-hour 5-fluorouracil and leucovorin infusion for patients with advanced colorectal cancer: dose adjusted according to its toxicity

BACKGROUND: 5-fluorouracil (5-FU) clearly behaves as two different drugs according to the schedules for its administration. A weekly, 8-h 5-FU continuous infusion (CI) regimen may produce a dual effect, because it elicits both a high plasma 5-FU level and also a durable exposure to 5-FU, which may have the advantage of inhibiting both DNA synthesis and RNA activities. The plasma 5-FU level, however, cannot be monitored in most hospitals, so we initiated a pragmatic clinical trial with this weekly 8-h 5-FU Cl regimen and adjusted the drug's dose according to the detected toxicity. METHODS: The initial dose of 5-FU was 1200 mg/m2 and this was escalated by 200 mg/m2 weekly, provided that no evidence of significant (grade 2 or greater) toxicity became apparent. Twenty-six patients entered the study from June 1998 to March 1999. RESULTS: The median dose of 5-FU delivered was 1600 mg/m2. The major symptoms precluding dose escalation were nausea and vomiting. Seven patients demonstrated a partial response (26.9%), 11 patients revealed stable disease (42.3%) and eight exhibited progressive disease (30.8%). CONCLUSION: This weekly 8-h CI 5-FU protocol with the adjustment of dose according to toxicity was not able to achieve the same 5-FU dose and response rate as in previous studies with pharmacokinetic monitoring of 5-FU levels. However, with the concurrent administration of intensive anti-emetic premedication, it is still possible to achieve adequate plasma 5-FU levels by adjusting the 5-FU dose according to elicited toxicity.     

Two consecutive phase II trials of biweekly oxaliplatin plus weekly 48-hour continuous infusion of nonmodulated high-dose 5-fluorouracil as first-line treatment for advanced colorectal cancer

The combination of 5-fluorouracil (5-FU) plus leucovorin (LV) with oxaliplatin has become one of the standard treatments for advanced colorectal cancer (CRC). Two consecutive phase II trials assessed the efficacy and safety of combined therapy with oxaliplatin and high-dose 5-FU without LV for patients with advanced CRC. A total of 89 patients were enrolled in both trials. Fifty-nine patients in trial A underwent a scheduled regimen of biweekly oxaliplatin 85 mg/m(2) and weekly nonmodulated 5-FU 3.0 g/m(2). Increased incidence of toxicity led to a 25% reduction in the starting dose of 5-FU (2.25 g/m(2)) for trial B. Patients treated in trial B showed a higher cumulative dose and relative dose intensity for oxaliplatin and 5-FU than those treated in trial A. Response to treatment, time to progression (TTP), overall survival (OS), and duration of response were evaluated as efficacy variables. Overall response rate was preserved despite the reduction in 5-FU dose (55.9% and 63.0%, respectively). Median durations of responses were 10.6 and 10.4 months, median TTPs were 7.7 and 7.3 months, and OS times were 21.7 and 13.1 months, respectively. Reduction in the starting 5-FU dose from 3.0 to 2.25 g/m(2) resulted in a decrease in the main grade 3/4 hematologic toxicities (neutropenia, 22.0% to 10.0%) and nonhematologic toxicities (diarrhea, 52.5% to 23.3%; nausea/vomiting, 18.6% to 3.3%). Neurosensory toxicity was similar in both trials (16.9% and 16.7%). Biweekly oxaliplatin in combination with nonmodulated high-dose 5-FU is an active, well-tolerated treatment that offers a lower cost than a modulated schedule for patients with advanced, metastatic CRC.     

Continuous-infusion high-dose leucovorin with 5-fluorouracil and cisplatin for relapsed metastatic breast cancer: a phase II study

Twelve women with metastatic breast cancer were treated with continuous infusion high dose leucovorin, 5-fluorouracil and cisplatin. Toxicity was severe although the dose was lower than previously described for the treatment of other cancers, and there was little anti-tumor activity. Many other regimens are more effective and less toxic.     

5-fluorouracil administered as a 48-hour semiintermittent infusion in combination with leucovorin, cisplatin and epirubicin: phase II study in advanced gastric cancer patients

The main objective of this study was to determine the feasibility and the antitumor activity of a chemotherapy regimen with a 48-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), cisplatin (CDDP), and epirubicin (EPIDX) administered every 3 weeks in patients with locally advanced or metastatic gastric cancer. Thirty-three patients received CDDP 60 mg/m2 over 30 minutes followed by 1-LV 250 mg/m2 over 2 hours followed by EPIDX 60 mg/m2 over 5 minutes (bolus) and followed by 5-FU 3,800 mg/m2 as a 48-hour semiintermittent continuous infusion, with 67% of total daily dose administered between 4 pm and midnight. Four patients had a locally advanced disease and 29 had metastatic disease. A total of 171 cycles were administered. Most relevant toxicities were stomatitis (grade III in 2% of cycles and 12% of patients) and neutropenia (grade III-IV in 8% of cycles and 28% of patients) with 3 (9%) patients experiencing 1 episode of febrile neutropenia. No toxic deaths occurred. Thirty-one patients were evaluable for response. In 3 patients (9.6%) a complete response and in 11 patients (35.4%) a partial response was observed, for an objective response rate of 45% (95% C.I. 27-64%). Median progression-free and overall survival were 5.9 and 9.8 months, respectively. In conclusion, this regimen is feasible in an outpatient setting with acceptable and manageable toxicities, and it is associated with promising antitumor activity, time to progression, and survival.     

Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer

Purpose To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer. Experimental Design Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m² as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m² bolus i.v. and leucovorin 20 mg/m² i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m² and 5-FU to 500 mg/m². Results Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3–4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU. Conclusions Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer.     

UFT/leucovorin and oxaliplatin alternated with UFT/leucovorin and irinotecan in metastatic colorectal cancer

A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC.