Biweekly irinotecan plus bolus 5-fluorouracil and folinic acid in patients with advanced stage colorectal cancer

OBJECTIVE: In this study, we evaluated the efficacy and tolerability of biweekly irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and folinic acid (FA) regimen (IFL) in patients with advanced stage colorectal cancer. METHODS: A total of 28 patients were examined. The median age was 51 years (range, 30-74 years). One treatment cycle consisted of CPT-11 180 mg/m(2) on days 1 and 15; 5-FU 425 mg/m(2) on days 1, 2, 15 and 16; and FA 20 mg/m(2) on days 1, 2, 15 and 16, every 4 weeks. A total of 119 cycles (median, 4.0 cycles) were administered. Of the 28 patients, 18 received the chemotherapy as first line treatment, seven received it as second line and three received it as third line. RESULTS: An overall objective response rate of 21.5% was achieved in the patient group. However, the overall response rate for the 18 patients receiving first line treatment was 27.7%. The median response duration was 10.5 months (range, 3-19 months). An additional 28.6% of the patients had stable disease for a median duration of 6.5 months (range, 3-8 months). Median time to disease progression was 4.5 months (range, 1-22+ months) and median overall survival time was 11+ months (95% confidence interval, 9-15 months). Toxicities were mild and manageable. CONCLUSIONS: We conclude that biweekly IFL is a practical and tolerable treatment option with a disease control rate of 50.1% in patients with advanced stage colorectal cancer.     

Retrospective comparison of single-agent chemotherapy with weekly 5-fluorouracil or weekly irinotecan in previously treated patients with metastatic colorectal cancer

This study is a retrospective analysis of response, toxicity and freedom from progression of two single-agent chemotherapy regimens in patients with previously treated metastatic colorectal cancer. Thirty-five patients with histologically confirmed measurable metastatic colorectal cancer received chemotherapy after failure of first-line 5-fluorouracil (5-FU) and leucovorin treatment. The median age was 61 years. Twenty-seven patients had liver metastases, 6 had local recurrence, 1 had retroperitoneal lymph node metastases and 1 had lung metastases. Eighteen patients received weekly 2600 mg/m2 5-FU and 17 patients received weekly 125 mg/m2 irinotecan (CPT-11). Treatment was given until disease progression. Total number of cycles was 202 for 5-FU and 248 for CPT-11. The relative dose intensity was 1.0 for 5-FU and 0.84 for CPT-11. No grade 3-4 toxicity was registered in patients who received 5-FU. Grade 3-4 toxicity rates were as follows in those who received CPT-11: vomiting 1 (5.9%) patient in 1 cycle, diarrhea 3 (17.7%) patients in 3 cycles and neutropenia in 3 (17.7%) patients in 3 cycles. No patients manifested febrile neutropenia. Two patients (11.8%) needed hospital admission because of toxicity: 1 for vomiting and 1 for diarrhea. No objective responses were observed in the 5-FU group of patients. Three patients (17.6%) who received CPT-11, achieved partial response with a median duration of 8 months. Stable disease was registered in 3 (17.6%) and 9 (52.9%) patients in 5-FU and CPT-11 groups respectively (p=0.05). Median time to progression was 3.3 months for patients who received 5-FU and 4.2 months for those treated with CPT-11 (not significant). One-year survival was 22.2% and 54.3% respectively (p=0.05). Conclusion: Weekly chemotherapy with CPT-11 is tolerated with acceptable toxicity and leads to a better response rate than weekly high dose 5-FU. It also significantly improves survival but does not prolong freedom from progression.     

Outpatient 5-fluorouracil, folinic acid and cisplatin in patients with advanced esophageal carcinoma

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m²/d, 5-FU 300 mg/m²/d, and cisplatin 20 mg/m²/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57+months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.     

A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients

The combination of irinotecan (CPT-11), oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and folinic acid (FA) is one of the possibilities to overcome chemoresistance in advanced colorectal cancer (ACRC) patients. The aim of this study was to determine the tolerability and activity of CPT-11 plus chronomodulated infusion of L-OHP, 5-FU and FA in ACRC patients. A total of 35 patients (91% pretreated, 77% with CPT-11, 54% with L-OHP, 42% with both) were treated every 3 weeks with CPT-11, 180 mg m(-2) day 1 i.v., plus L-OHP, 20 mg m(-2) day(-1), 5-FU, 700 mg m(-2) day(-1) and FA, 150 mg m(-2) day(-1), all three drugs from day 2 to day 5 by chronomodulated infusion. The patients' (pt) data were as follows: male/female 21/14; median age 58 years (range: 38-70); PS 0: 26 pts (74%), PS 1: 8 pts (23%), PS 2: 1 pt (3%); primary tumour colon/rectum 26/9; involved organs: 1, 14 pts (40%); 2, 17 pts (48%); >or=3: 4 pts (11%); previous chemotherapy lines 1: 12 pts (34%), 2: 10 pts (28%), >or=3: 10 pts (28%). A total of 221 courses (c) were performed; no grade 4 toxicity was observed with only one grade 3 (G3) neutropenia and thrombocytopenia (3%) in one out of 221 courses (<1%). Maximal toxicity (G3) was nausea and diarrhoea in 10 pts (28%), occurring in 14 out of 221 c (6%) and 12 out of 221 c (5%) respectively. Seven patients achieved a partial response (20%, confidence interval (c.i.) 6.8-33.3) and one patient a complete response (2.9%, c.i. 0-8.4), for a total overall response rate of 22.9% (c.i. 9-36.8); 15 out of 35 (42.9%, c.i. 26.5-59.3) had stable disease and 12 out of 35 (34.3%, c.i. 18.6-50) patients underwent a progression. In conclusion, this four-drug regimen is feasible in advanced pretreated ACRC patients with no significant haematological toxicity and acceptable diarrhoea. The activity of this combination is currently studied in EORTC 05011 study.     

High-dose folinic acid and 5-fluorouracil in advanced colorectal cancer

Twenty-three patients with advanced colorectal cancer were treated with folinic acid (200 mg/m2/day 1-5 IV bolus injection) and 5-fluorouracil (400 mg/m2/day 1-5 IV in 15 minutes) every 28 days. Only three patients were pretreated. Objective response was observed in 6 (30%) of 20 evaluable patients (three complete and three partial responses). The median duration of response was 9 months (range 5-15) and time to disease progression ranged from 2 to 12 months (median 6 months). Median survival was 21 months (range 12-23+) for responders. Another 6 (30%) patients had stabilization of disease. Toxicity was generally gastrointestinal (mucositis, diarrhea, nausea); moderate leukopenia was noted. The response rate found in this study indicates that folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly in colorectal cancer.     

Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases

The main objectives of this study were to assess the use of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FA) as neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases and to determine the response rate and proportion of patients that could be down-staged to resectable tumors. Forty patients were treated with irinotecan (180 mg/m2 over 30 min) on d 1, FA (200 mg/m2 over 30 min) followed by 5-FU (400 mg/m2 bolus and continuous infusion of 600 mg/m2 over 22 h) on d 1 and 2 every 2 wk. The overall response rate was 55% (95% CI: 39.5-70.4%). The progression-free survival was 12.1 mo (95% CI: 11.4-14.8 mo). The median overall survival was 20 mo (95% CI: 17.7-26.6 mo). Four patients (10%) have undergone liver resection after a median of eight cycles. Those patients remained alive with a median follow up period of 33 mo. The principal grade 3-4 toxicity was neutropenia in 20 patients (50%). We conclude that the regimen of irinotecan/5-FU/FA was highly active in patients with colorectal cancer and liver metastases with limited toxicity. In a subgroup of patients with initial inoperable liver metastases, this regimen was able to down-stage the disease to an operable stage.     

A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.     

Oxaliplatin, folinic acid and 5-fluorouracil (FOLFOX-4) combination chemotherapy as second-line treatment in advanced colorectal cancer patients with irinotecan failure: a Korean single-center experience

OBJECTIVE: This study was designed to determine the effectiveness and tolerance of oxaliplatin, folinic acid (FA) and infusional 5-fluorouracil (5-FU) (FOLFOX-4) chemotherapy when used as a second-line treatment in patients with advanced colorectal cancer for whom an irinotecan-containing regimen failed. METHODS: Thirty-eight patients with measurable colorectal cancer, progressive after previous irinotecan-containing chemotherapy for metastatic disease, were registered in this trial. Oxaliplatin was administered on day 1 at the dose of 85 mg/m(2) as a 2 h infusion, concurrently with FA 200 mg/m(2)/day, followed by bolus 5-FU 400 mg/m(2) and a 22 h infusion of 5-FU 600 mg/m(2) for two consecutive days. The treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue the treatment. RESULTS: For 34 patients treated, a total of 183 chemotherapy cycles were administered. In an intent-to-treat analysis, six patients (16%) achieved a partial response that they maintained for 5.4 months. The median progression-free and overall survivals were 2 and 5 months, respectively. Frequently encountered toxicities were peripheral neuropathy and gastrointestinal side effects including diarrhea. Although there was one early death, toxicity profiles were generally predictable and manageable. CONCLUSION: Second-line FOLFOX-4 is a feasible regimen with modest activity for colorectal cancer patients with irinotecan failure. Further clinical trials incorporating novel biological agents are warranted.     

A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil

This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.     

An alternating regimen of irinotecan/ 5-fluorouracil/folinic acid and oxaliplatin/ 5-fluorouracil/folinic acid in metastatic colorectal cancer: a Phase II trial

OBJECTIVE: To assess the feasibility and activity of a combination schedule with irinotecan (CPT-11), oxaliplatin (L-OHP), brief infusional fluorouracil (5-FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer (MCC) patients. METHODS: Fifty consecutive patients were treated with CPT-11 125 mg/m2 as a 90-min intravenous infusion, followed by FA 20 mg/m2 as an intravenous bolus, and 5-FU 500 mg/m2 over a 2-hour intravenous infusion on days 1 and 8. L-OHP was administered at 85 mg/m2 over 2 h on day 15, in combination with a FA 60 mg/m2 intravenous bolus and 5-FU 600 mg/m2 as a 2-hour intravenous infusion on days 15-16. The treatment was repeated every 4 weeks for a maximum of 9 cycles. RESULTS: Twenty-five of 50 assessable patients achieved a complete (n=5) or partial (n=20) response, leading to a response rate of 50% (95% CI 35-64%). Eighteen (36%) patients showed stable disease. The median time to tumor progression was 10.3 months (95% CI 9.6-10.9 months). After a median follow-up of 16.4 months, the median survival was not reached. Grade 3 neutropenia (8%), grade 3 nausea/vomiting (6%) and grade 3 diarrhea (2%) were the major adverse events. CONCLUSION: This alternating three-drug regimen is very well tolerated, manageable and effective in terms of activity and time to progression.     

Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study

Purpose To evaluate the efficacy and safety of irinotecan as second-line treatment in patients with advanced colorectal cancer (ACC) failing or relapsing after 5-fluorouracil (5-FU) plus leucovorin (LV) standard chemotherapy.Patients and methods Irinotecan was randomly administered in two different schedules (once every 3 weeks, and every 10 days) in patients failing prior 5-FU plus LV. Patients were randomized to two treatment groups: group A received irinotecan 350 mg/m² every 21 days and group B received irinotecan 175 mg/m² days 1 and 10 every 21 days.Results Group A comprised 60 patients: 34 male/26 female, median age 64 years (range 48–70 years), and median Karnofsky performance status (PS) 90. Their metastatic sites included liver (n=47), lymph nodes (n=27), lung (n=14), abdomen (n=14), pelvis (n=8), "other" (n=2), and local recurrence (n=12). Group B comprised 60 patients: 36 male/24 female, median age 62 years (46–70 years), and median PS 90. Their metastatic sites included liver (n=49), lymph nodes (n=29), lung (n=17), abdomen (n=16), pelvis (n=11), "other" (n=2), and local recurrence (n=13). Group A showed the following responses: complete response (CR) 2, partial response (PR) 12, stable disease (SD) 21, progressive disease (PD) 26, overall response rate (ORR) 23%, tumor growth control 58%. Group B showed the following responses: CR 1, PR 14, SD 22, PD 23; ORR 25%; tumor growth control 62%. Toxicities included acute cholinergic syndrome (group A 53%, group B 19%; P<0.0001), late-onset diarrhea grade 1/2 (group A 21%, group B 46%) and grade 3/4 (group A 41%, group B 66%; P<0.0001), nausea and vomiting grade 1/2 (group A 34%, group B 59%) and grade 3/4 (group A 30%, group B 12%; P<0.0001), neutropenia grade 3/4 (group A 27%, group B 28%; P<0.03), with febrile neutropenia seen in only four patients in group A, anemia grade more than 2 (group A 28%, group B 12%; P<0.05), asthenia grade more than 3 (group A 24%, group B 18%; P<0.001), and alopecia grade more than 3 (group A 40%, group B 34%; P<0.2).Conclusions The present study indicates that, in patients with ACC who have relapsed after 5-FU plus LV, the administration of irinotecan fractionated into two doses every 21 days yields a similar efficacy to, but a much lower incidence of toxicity than, the same total dose of irinotecan administered once every 21 days.     

Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer

Background  

This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer.     

Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients.

BACKGROUND: The aim of this study was to observe the effects of neoadjuvant therapy with irinotecan and 5-fluorouracil (5-FU)/folinic acid (FA) on the resection rate and survival of colorectal cancer patients with initially unresectable hepatic metastases. PATIENTS AND METHODS: Forty patients received neoadjuvant chemotherapy comprising irinotecan 180 mg/m(2) administered intravenously (i.v.) on day 1, FA 200 mg/m(2) i.v. on days 1 and 2, 5-FU 400 mg/m(2) i.v. bolus on days 1 and 2, and 5-FU 1200 mg/m(2) as a continuous 48-h i.v. infusion on day 1. The treatment was repeated every 2 weeks and response was assessed every 12 weeks (six cycles). RESULTS: The objective response rate to chemotherapy was 47.5% (n = 19), with two complete responses and disease stabilization in 11 (27.5.%) patients. Responses were unconfirmed for 11 patients undergoing surgery within 2 weeks. Treatment was well tolerated and adverse events were typical of the chemotherapy agents used. Twenty-seven (67.5%) patients reported hematological toxicity (35.0% grade 3/4) and 14 (35.0%) reported gastrointestinal toxicity (12.5% grade 3/4). Thirteen patients (32.5%) underwent potentially curative liver resection following chemotherapy. Chemotherapy was particularly effective in patients with large metastases on entry to the study. The median time to progression is 14.3 months and, at a median follow-up of 19 months, all patients are alive. CONCLUSIONS: Neoadjuvant therapy with irinotecan combined with 5-FU/FA enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. The effects of treatment on survival have yet to be determined.     

High-dose continuous infusion folinic acid and bolus 5-fluorouracil in patients with advanced colorectal cancer: a phase II study

Encouraging results have recently been reported for studies using folinic acid in combination with 5-fluorouracil (5-FU) in the treatment of patients with gastrointestinal (GI) malignancies. Thirty-six patients with advanced colorectal cancer with unequivocal evidence of progression while treated with fluoropyrimidines were treated with a six-day continuous infusion of 500 mg/m2/d of folinic acid initiated 24 hours before a five-day course of 5-FU administered as an intravenous (IV) bolus of 370 mg/m2/d. An initial dose of 250 mg/m2/d of 5-FU was used in patients previously treated with ionizing radiation and/or a nitrosourea. Three objective partial responses were observed. The overall median duration of survival was 8.1 months. Toxicity was acceptable and not in excess of that expected for 5-FU alone.     

Irinotecan and chronomodulated infusion of 5-fluorouracil and folinic acid in the treatment of patients with advanced colorectal carcinoma: a phase I study

BACKGROUND: Irinotecan (CPT-11) is an active drug in the treatment of patients with advanced colorectal carcinoma. The infusion of 5-fluorouracil (5-FU) according to circadian rhythms was used previously to decrease toxicity and to increase its therapeutic efficacy. The objective of this study was to establish the maximum tolerated dose (MTD) of CPT-11 together with a chronomodulated infusion of 5-FU and the l-form of folinic acid (FA). Secondary end points were the assessment of activity and quality of life (QoL). METHODS: Twenty-six patients with advanced colorectal carcinoma who had received previous treatment with 5-FU were entered on this Phase I study. At least three patients were recruited at each dose level. The CPT-11 starting dose was 175 mg/m(2) on Day 1 with an increase of 50 mg/m2 per dose level. A daily administration of chronomodulated 5-FU (900 mg/m2; peak delivery rate at 04:00) and FA (175 mg/m2; peak delivery rate at 04:00) for 5 days every 3 weeks was given with CPT-11. After the first three patients, the 5-FU dose was reduced to 700 mg/m2 per day due to toxicity. No intrapatient dose escalation was allowed. RESULTS: One hundred sixty-one courses were delivered. Dose-limiting toxicity was observed during the first course in seven patients (27%). Four patients developed neutropenia, with one patient reporting febrile neutropenia, two patients reporting severe stomatitis, and six patients reporting severe diarrhea. CPT-11 MTD was reached at 350 mg/m2 when a toxic death was observed with a recommended dose of 325 mg/m2. Six partial responses were observed (23%). The median duration of response and the progression free and overall survival rates were 199 days, 175 days, and 359 days, respectively. QoL was not affected by the treatment. CONCLUSIONS: The recommended dose for Phase II trials is 325 mg/m2 CPT-11 on Day 1, which is similar to the dose given as a single agent, together with a 5-day chronomodulated infusion of 700 mg/m2 5-FU and 175 mg/m2 FA. Intensification of this schedule every 2 weeks should be achievable.     

Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid

We report the results of an expanded trial of 5-fluorouracil (FUra) combined with high-dose folinic acid for treatment of patients with advanced colorectal or gastric adenocarcinoma. In each treatment course, the patients received both FUra (340-400 mg/m2/day by iv infusion over 15 minutes) and folinic acid (200 mg/m2/day by iv bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete response (CR) and partial response (PR) rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to FUra attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates above 10(-5) M were achieved after a rapid single iv injection of 200 mg/m2 of folinic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

Purpose

To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC).

Patients and methods

A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m², 5-fluorouracil 2000 mg/m², folinic acid 500 mg/m² weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m² applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS).

Results

A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio = 1.14; 95% confidence interval (CI) 0.94-1.37; P = 0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio = 1.08, P = 0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P = 0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P = 0.006)

Conclusion

mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.     

A randomized phase II trial of irinotecan in combination with infusional or two different bolus 5-fluorouracil and folinic acid regimens as first-line therapy for advanced colorectal cancer.

BACKGROUND: Three different therapeutic regimens of irinotecan (CPT-11) in combination with 5-fluorouracil (5-FU) and folinic acid (FA) were evaluated for efficacy and safety in the first-line therapy of advanced colorectal cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive intravenously either: CPT-11 125 mg/m(2), FA 20 mg/m(2) followed by 5-FU 500 mg/m(2) bolus, weekly for 4 weeks (arm A, Saltz regimen); or CPT-11 180 mg/m(2) day 1 then FA 200 mg/m(2) over 2 h and 5-FU 400 mg/m(2) bolus and 5-FU 600 mg/m(2) 22-h infusion on days 1 and 2, every 2 weeks (arm B, Douillard regimen); or CPT-11 350 mg/m(2) (days 1 and 43) alternating with FA 20 mg/m(2)/day followed by 5-FU bolus 425 mg/m(2)/day during 5 days (days 22-26) (arm C, Mayo Clinic regimen). RESULTS: A total of 154 patients were included in the study (arm A, 51 patients; arm B, 53; arm C, 50). Overall response rates for the intention-to-treat populations were 33% [95% confidence interval (CI) 21% to 48%], 42% (95% CI 28% to 56%) and 30% (95% CI 18% to 45%) for arms A, B and C, respectively. Median times to progression were 6, 8 and 7 months for arms A, B and C, respectively. Median survival times were 15, 12 and 17 months for arms A, B and C, respectively. Overall response rates for the evaluable patient populations were 40% (95% CI 24% to 58%) in arm A, 44% (95% CI 29% to 60%) in arm B and 31% (95% CI 17% to 47%) in arm C. Neutropenia was the main serious adverse event in arms A (30% of patients) and C (22% of patients) but occurred in only 8% of patients in arm B. Delayed diarrhea was the main severe adverse event for the three regimens, from 15% to 22%. CONCLUSION: All three regimens were highly active. The biweekly combination of CPT-11 and 5-FU/FA (arm B) was notable for its low incidence of grade 3/4 neutropenia. The incidence of grade 3/4 delayed diarrhea was equivalent for the three treatment arms.     

Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid

We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.