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.     

Palliative second-line treatment with weekly high-dose 5-fluorouracil as 24-hour infusion and folinic acid (AIO) plus oxaliplatin after pre-treatment with the AIO-regimen in colorectal cancer (CRC)

BACKGROUND AND AIMS: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-Fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) and folinic acid (FA) (AIO-regimen) plus Oxaliplatin (L-OHP) after pre-treatment with the AIO regimen, focusing in particular on the efficacy of palliative first- and second-line treatment in colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous palliative first-line treatment in accordance with the AIO regimen. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m2 L-OHP in the form of a 2-hour intravenous (i.v.) infusion and 500 mg/m2 FA as a 1 to 2-hour i.v. infusion, followed by 2,600 mg/m2 5-FU administered as a 24-h inf. i.v. once weekly. A single treatment cycle comprised 6 weekly infusions followed by 2 weeks of rest. RESULTS: During second-line treatment, a total of 26 patients received 340 chemotherapy applications. As the main symptom of toxicity, diarrhoea (NCI-CTC toxicity grade 3+4) presented in 5 patients (19%; 95% CI: 4-34), followed by nausea (CTC grade 3) in one patient (4%; 95% CI: 0-11). Twenty-three patients were evaluable for treatment response. The remission data can be summarised as follows: Complete remission (CR): n=1 (4%; 95% CI: 0-13); partial remission (PR): n=3 (13%; 95% CI: 0-27); stable disease (SD): n=11 (48%; 95% CI: 27-68) and progressive disease (PD): n=8 (35%; 95% CI: 15-54). The median progression-free survival (PFS) rate (n=26) was 3.3 months (range 0-11.5), the median survival time counted from the start of second-line treatment (n=26) 11.6 months (range 2.1-33.0) and the median survival time counted from the start of first-line treatment (n=26) 19.9 months (range 7.7-49.8). CONCLUSION: Palliative second-line treatment according to the AIO regimen plus L-OHP is feasible in an outpatient setting and well tolerated by the patients. Tumour control (CR + PR + SD) was achieved in 65% of the patients, the median survival time being 11.6 months. The AIO regimen followed by the 'AIO regimen plus L-OHP' therapy sequence led to a promising median survival time of 19.9 months (range 7.7-49.8).     

Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordic schedule as first-line therapy in advanced colorectal cancer.

BACKGROUND: This multicentre phase II study evaluated the efficacy and safety of irinotecan combined with the Nordic schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line therapy in patients with advanced colorectal cancer. PATIENTS AND METHODS: Seventy-four patients with measurable disease and a WHO performance status of 2 or less were treated with irinotecan 210 mg/m(2) as a 30-90 min intravenous infusion on day 1, followed by 5-FU 500 mg/m(2) and FA 60 mg/m(2) bolus on days 1 and 2, every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was the objective response rate. RESULTS: Twenty-nine out of 68 evaluable patients achieved a complete (n = 7) or partial (n = 22) response, leading to an overall response rate of 43% [95% confidence interval (CI) 31% to 55%]. The median duration of response was 10 months. The estimated median time to progression and survival were 6.4 months (95% CI 5.4-9.0) and 15.6 months (95% CI 13.3-19.0), respectively, in the intention-to-treat population. A total of 860 cycles were administered to 74 patients. Neutropenia was the main adverse event with grade 3-4 toxicity in 66% of patients and 17.5% of cycles. Grade 3-4 non-haematological toxicities were infrequent and included diarrhoea in 16% of patients and 2% of cycles and nausea/vomiting in 10% of patients and 1% of cycles. CONCLUSIONS: Irinotecan combined with the bolus Nordic schedule of 5-FU/FA is active in advanced colorectal cancer with an easily managed safety profile which ensures good schedule compliance. The low incidence of grade 3-4 non-haematological toxicity justifies the further evaluation of this combination in the context of randomised clinical trials.     

Retrospective comparison of two different schedules of irinotecan, 5-fluorouracil and folinic acid in previously untreated patients with advanced colorectal carcinoma: a single institution experience

PURPOSE: To compare efficacy and tolerability of weekly irinotecan combined with 5-fluorouracil (5-FU) bolus and folinic acid (FA) regimen (IFL) versus biweekly irinotecan with infusional 5-FU and FA (FOLFIRI) in patients (pts) with advanced stage colorectal cancer. PATIENTS AND METHODS: Treatments outcome of 86 pts (IFL - 38 pts, FOLFIRI - 48 pts) was evaluated. Chemotherapy regimens were as follows: IFL - intravenous (i.v.) infusion irinotecan 125 mg/m(2) over 90 min and 5-FU 500 mg/m(2) preceded by FA 20 mg/m(2) both given by i.v. bolus injection, all repeated on days 1, 8, 15 and 22 every 6 weeks; FOLFIRI - i.v. irinotecan 180 mg/ m(2) on days 1 and 15 with subsequent FA 200 mg/m(2) administered as a 2-hour infusion and i.v. bolus injection of 400 mg/m(2) 5-FU immediately followed by 22-hour i.v. infusion of 600 mg/m(2) 5-FU on days 1, 2, 15 and 16 every 4 weeks. Treatment continued until disease progression or unacceptable toxicity. RESULTS: A total of 152 (mean - 4) IFL cycles and 328 (mean - 6) FOLFIRI cycles were administered. Average dose intensity was 0.8 and 0.78 respectively. Toxicities were mild and manageable for both regimens evaluated. Overall response rate was 36.8% in IFL arm and 44.7% in FOLFIRI arm. At the median follow-up of 16 months in IFL arm and 14 months in FOPFIRI arm the two year survival was 38% and 45%, the median survival was 18 months and 21.5 months, and the median progression free survival was 6 months and 9.4 months respectively. CONCLUSIONS: In our experience, both IFL and FOLFIRI regimens have acceptable toxicity at a similar level of dose intensity. Compared to IFL, FOLFIRI seems to improve progression-free survival.     

High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study

BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur.     

Neoadjuvant treatment with weekly high-dose 5-Fluorouracil as 24-hour infusion,folinic acid and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer

PURPOSE: To evaluate the efficacy and safety of neoadjuvant treatment comprising weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion, folinic acid (FA) and biweekly oxaliplatin (L-OHP), followed by metastatic resection in patients with primarily resectable liver metastases of colorectal cancer (CRC). PATIENTS AND METHODS: 20 patients with primarily resectable liver metastases of CRC were enrolled in a prospective phase II study. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m(2) L-OHP in the form of a 2-hour intravenous infusion and 500 mg/m(2) FA as a 1- to 2-hour intravenous infusion, followed by 2,600 mg/m(2 ) 5-FU administered as a 24-hour intravenous infusion once weekly. A single treatment cycle comprised one infusion per week during a period of 6 weeks followed by a 2-week rest. Two cycles were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted, and the patients were followed up. RESULTS: After neoadjuvant therapy, 2 of the original 20 patients showed complete remission (CR; 10%) and 18 patients partial remission (PR; 90%). As the main symptom of toxicity, diarrhea (CTC toxicity grade 3-4) was observed in 6 patients (30%), followed by vomiting in 3 patients (15%). The curative resectability rate was 80% (16 of 20). In 9 of 18 patients (50%) undergoing surgical intervention, mild postoperative complications, mainly wound healing disturbances (n = 5), occurred. No postoperative mortality was observed. Over a median follow-up of 23 months (12-38) 6 of 16 curatively resected patients developed distant metastases and 1 patient a local pelvic recurrence. The 2-year disease-free survival rate was 52% and the 2-year cancer-related survival rate 80%. CONCLUSION: The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24-hour infusion combined with FA and L-OHP is very effective and well tolerated. Surgical morbidity does not appear to be increased by the neoadjuvant treatment.     

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.     

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.     

Bolus/infusional 5-fluorouracil and folinic acid for metastatic colorectal carcinoma: are suboptimal dosages being used in the UK?

Bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA) is reported to be highly active [partial response (PR) = 54%, median survival 18 months] in patients with metastatic colorectal carcinoma (MCCa). To confirm this level of activity, we conducted a retrospective analysis of 95 previously untreated patients with MCCa treated with FA by 2 h i.v. infusion (200 mg m-2) followed by 5-FU bolus/22 h i.v. infusion (300-500 mg m-2) on days 1 and 2 every 2 weeks. Thirty patients also received N-(phosphonacetyl)-L-aspartate (PALA), 250 mg m-2, 24 h prior to 5-FU/FA. In 81 evaluable patients, the response rate was low: PR = 11%, stable disease (SD) = 36% and median survival = 8 months. There was an improvement in survival with increased 5-FU dosage (500 mg m-2) [relative hazard (RH) = 0.38, 95% CI 0.21-0.70], controlled for age, primary site, PALA, liver function and performance status. Good performance status (PS 0 or 1) was also associated with improved survival (RH = 0.21, 95% CI 0.10-0.46). Response, survival and toxicity were not altered by the co-administration of PALA. Bolus/infusional 5-FU (500 mg m-2) and FA was well tolerated. WHO toxicities (grade 3) were: mucositis, 2%; diarrhoea, 14%; nausea and vomiting, 5%. In light of the apparent dose effect, poor response and low toxicity, we recommend that regimes incorporating higher 5-FU dosages are explored and prospectively validated before bolus/infusional 5-FU becomes accepted standard practice.     

Randomised phase II study of standard versus chronomodulated CPT-11 plus chronomodulated 5-fluorouracil and folinic acid in advanced colorectal cancer patients

In this study, a randomised phase II trial explored the effects of 6-h chronomodulated CPT-11 infusion in advanced colorectal cancer patients. Sixty-eight pre-treated patients were randomly assigned to CPT-11 administered at 180 mg/m2 on day 1, by 1-h infusion (Arm A) or 6-h sinusoidal infusion with peak timing at 5:00 a.m. (Arm B). All patients also received chronomodulated folinic acid/5-fluorouracil (FA/5-FU). Patients in Arm B obtained a 25.7% response rate for 7.0 months duration, a progression-free survival for 8.0 months and a median survival of 28 months. The same data in Arm A were 18.2%, 4.5, 6.0 and 18 months, respectively. No differences in drugs dose-intensity or increased toxicity with prolonged chronomodulated infusion were detected. Major grade 3-4 toxicity was diarrhoea: 10 patients in Arm A and 13 in Arm B. In conclusion, this study has shown that chronomodulated infusion of CPT-11 and FA/5-FU is safe, active and can be integrated with oxaliplatin (EORTC 05011) for the treatment of advanced colorectal cancer.     

Oxaliplatin in combination with infusional 5-fluorouracil and leucovorin every 2 weeks as first-line treatment in patients with advanced colorectal cancer: a phase II study

PURPOSE: To evaluate the efficacy and safety of oxaliplatin (L-OHP) in combination with leucovorin (LV)-modulated bolus plus infusional 5-fluorouracil (5-FU; de Gramont schedule) every 2 weeks in chemotherapy-naive patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Thirty-two patients (median age: 69 years) with histologically confirmed and two-dimensionally measurable metastatic CRC were enrolled. The patients' performance status (WHO) was 0 in 14 (44%), 1 in 15 (47%), and 2 in 3 (9%) patients. Twenty (62.5%) patients had at least two metastatic sites. LV was administered at a dose of 200 mg/m2/day as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at the dose of 400 mg/m2 and then, as a 22-hour continuous infusion at the dose of 600 mg/m2/day for 2 consecutive days. L-OHP was administered on day 1 at the dose of 85 mg/m2 as a 2-hour infusion in parallel with LV but using different infusion lines. Treatment was administered every 2 weeks. RESULTS: In an intention-to-treat analysis, 2 (6.2%) complete and 9 (28%) partial responses (28%; odds ratio 34.2%; 95% confidence interval 17.92-50.83%) were achieved while 8 (25%) patients had stable disease and 13 (41%) progressive disease. The median duration of response was 5 months, but the median time to progression has not yet been reached. After a median follow-up period of 11 months, the median survival has not yet been attained, but the projected probability for 1-year survival was 72%. Grade 3/4 neutropenia occurred in 16 (50%) patients while 1 (3%) of them developed febrile neutropenia. There was no treatment-related death. Peripheral neuropathy grade 2 and > or =3 occurred in 5 (16%) and 7 (21%) patients, respectively. CONCLUSIONS: The bimonthly administration of L-OHP in association with LV-modulated bolus plus infusional 5-FU ('de Gramont' regimen) is a well-tolerated and effective front-line treatment for metastatic CRC.     

Triplet combination with irinotecan plus oxaliplatin plus continuous-infusion fluorouracil and leucovorin as first-line treatment in metastatic colorectal cancer: a multicenter phase II trial.

PURPOSE: To evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) plus fluorouracil (5-FU)/leucovorin (LV) (de Gramont regimen) as first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: Thirty-one patients with MCC who had not received prior therapy for metastatic disease were enrolled. Their median age was 60 years; performance status (World Health Organization) was 0 in 12, 1 in 14, and 2 in five patients; 19 patients (61%) had prior surgery, and 14 (45%) had adjuvant chemotherapy. CPT-11 was administered on day 1 at 150 mg/m(2) as a 90-minute intravenous (IV) infusion; L-OHP was administered on day 2 at 65 mg/m(2) as a 2-hour IV infusion; and on days 2 and 3, LV 200 mg/m(2) preceded 5-FU administration of 400 mg/m(2)/d initial IV bolus dose followed by 600 mg/m(2)/d 22-hour IV continuous infusion. The regimen was repeated every 2 weeks. RESULTS: All patients were assessable for toxicity and 30 for response to treatment. Complete response was achieved in two patients (6.5%) and partial response in 16 (51.6%) (overall response rate, 58.1%; 95% confidence interval, 40.7% to 75.4%); eight patients (25.8%) had stable disease, and five (16.1%) had disease progression. The median duration of response was 9 months, and the median time to disease progression was 13 months. Neutropenia grade 3 to 4 occurred in 14 patients (45%) and febrile neutropenia in two (6%). Diarrhea grade 3 to 4 was observed in 10 patients (32%), neurotoxicity grade 3 to 4 in three (9%), and asthenia grade 3 in two (10%). No treatment-related death has occurred. CONCLUSION: The triplet combination of 5-FU/LV + CPT-11 + L-OHP is a highly active regimen with manageable toxicity as front-line treatment in MCC.     

奥沙利铂联合5-氟尿嘧啶和醛氢叶酸钙时辰治疗晚期胃癌的初步临床研究

目的观察奥沙利铂(L-OHP)联合5-氟尿嘧啶(5-Fu)、醛氢叶酸钙(FA)方案(FFL方案)时辰输注法治疗晚期胃癌的疗效和不良反应。方法FFL方案时辰输注法治疗26例晚期胃癌患者,L-OHP 25 mg.m-2.d-1,5-Fu 600 mg.m-2.d-1,FA 300 mg.m-2.d-1,多通道程控时辰输液泵连续给药4 d,每14 d为1个周期,至少用2个周期。结果26例晚期胃癌患者中,完全缓解(CR)2例(7.7%),部分缓解(PR)13例(50.0%),稳定(SD)6例(23.1%),进展(PD)5例(19.2%),总有效率为57.7%。在共80个周期的化疗中,最常见的不良反应为血液学毒性、胃肠道毒性、外周神经毒性,但均以Ⅰ度为主,Ⅲ度中性粒细胞减少发生2例次,血小板减少、呕吐和口腔黏膜炎分别发生1例次,未出现Ⅳ度不良反应。中位缓解时间为3.5个月,中位肿瘤进展时间为4.5个月,全组患者中位生存期为8个月。结论FFL方案时辰输注法是治疗晚期胃癌安全有效的化疗方案。     

5-fluorouracil plus folinic acid with or without ifosfamide in advanced colorectal cancer: a phase II randomized trial

AIM: This phase II trial evaluated the biomodulation of 5-fluorouracil (5-FU) plus folinic acid (FA) with or without ifosfamide (IFO) in chemotherapy-naive patients with colorectal cancer. PATIENTS AND METHODS: Forty-eight patients were randomized to receive: FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3), arm A; or FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3) plus IFO (2,000 mg/m2 in 1000 mL 5% dextrose in a 2-hr infusion, days 1 to 3), arm B. Mesna was added during and after IFO to prevent hemorrhagic cystitis. Treatment was repeated every 21 days in both arms. RESULTS: Forty-five patients were assessable for response: in arm A, 5 patients achieved a partial response (overall response, 25%), and in arm B, 2 patients achieved a complete and 1 a partial response (overall response, 12%). Time to failure was 3.5 months (range, 1-38) in patients treated with 5-FU plus FA, and 3 months (range, 1-21) in patients treated with the IFO combination. The median survival time was 13.5 months (range, 1-49 months) in arm A and 16 months (range, 1-43 months) in arm B. Diarrhea, stomatitis and vomiting were the most common nonhematologic toxicities in both arms. The most notable hematologic toxicity was leukopenia; 15% and 20% of patients experienced grade 4 in arm A and arm B, respectively. CONCLUSIONS: IFO does not increase the activity of the 5-FU plus FA combination in advanced colorectal cancer.     

FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG)

To compare the efficacy and toxicity of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFOXIRI) vs irinotecan and 5-FU/LV (FOLFIRI) as first-line treatment of patients with metastatic colorectal cancer (MCC). A total of 283 chemotherapy-na?ve patients with MCC were enrolled (FOLFIRI arm: n=146; FOLFOXIRI arm: n=137). In the FOLFOXIRI arm, CPT-11 (150 mg m(-2)) was given on d1, L-OHP (65 mg m(-2)) on d2, LV (200 mg m(-2)) on days 2 and 3 and 5-FU (400 mg m(-2) as i.v. bolus and 600 mg m(-2) as 22 h i.v. continuous infusion) on days 2 and 3. In the FOLFIRI arm, CPT-11 (180 mg m(-2)) was given on d1 whereas LV and 5-FU were administered in the same way as in the FOLFOXIRI regimen. Both regimens were administered every 2 weeks. There was no difference in terms of overall survival (median OS: 19.5 and 21.5 months, for FOLFIRI and FOLFOXIRI, respectively; P=0.337), median time to disease progression (FOLFIRI: 6.9 and FOLFOXIRI: 8.4 months; P=0.17), response rates (33.6 and 43% for FOLFIRI and FOLFOXIRI, respectively; P=0.168). Patients treated with FOLFOXIRI had a significantly higher incidence of alopecia (P=0.0001), diarrhoea (P=0.0001) and neurosensory toxicity (P=0.001) compared with patients treated with FOLFIRI. The present study failed to demonstrate any superiority of the FOLFOXIRI combination compared with the FOLFIRI regimen, although the observed median OS is one of the best ever reported in the literature.     

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.     

Irinotecan (CPT-11) in combination with infusional 5-fluorouracil and leucovorin (de Gramont regimen) as first-line treatment in patients with advanced colorectal cancer: a multicenter phase II study

The combination of CPT-11 with 5-fluorouracil (5-FU) in advanced colorectal cancer (ACC) represents an attractive approach. A phase II study was conducted to assess the tolerance and efficacy of CPT-11 in combination with leucovorin-modulated bolus plus infusional 5-FU given according to the de Gramont regimen in chemonaive patients with ACC. Fifty-four patients with histologically confirmed ACC were enrolled. The patients' median age was 65 years; 30 (55.5%) patients were men; performance status (World Health Organization) was 0 in 27 (50%) patients, 1 in 22 (41%), and 2 in 5 (9%). Patients received leucovorin (200 mg/m2/d) as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at 400 mg/m2/d, and then as a 22-hour continuous infusion at 600 mg/m2/d, repeated on 2 consecutive days. CPT-11 (180 mg/m2; 30-minute intravenous infusion) was administered on day 1, simultaneously with leucovorin administration. This cycle was repeated every 2 weeks. Complete response was achieved in 4 patients (8%) and partial response in 19 (37%) (overall response rate: 45%; 95% CI: 24-50.5%). Stable disease was achieved in 16 (31%) patients and progressive disease in 13 (25%). The median duration of response and the median TTP were 5 and 8 months, respectively. After a median follow-up period of 11 months, 33 (61%) patients are still alive; the median overall survival has not yet been reached. Thrombocytopenia and anemia were very rare. Grade III/IV neutropenia developed in 19 patients (36%); febrile neutropenia developed in 4 patients, and 1 of them died of sepsis. Grade IV diarrhea was seen in 7 (13%) patients, and 4 of them required hospitalization. Grade III and IV mucositis was observed in two (4%) and one (2%) patients, respectively. Other toxicities were mild. The combination of CPT-11 and bolus plus infusional 5-FU is a relatively well-tolerated and effective first-line treatment in ACC. Final results from large phase III trials are awaited to clarify whether the CPT-11/5-FU combinations should be considered as "standard" first-line treatment in ACC.     

Phase I study of 5-fluorouracil with folinic acid combined with recombinant human granulocyte-macrophage colony-stimulating factor.

A Phase I study was conducted to determine whether the addition of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to a combined 5-fluorouracil (5-FU) and folinic acid (FA) regimen would allow an escalated starting dose of 5-FU. FA (500 mg/m2) was administered as a 2-hour infusion on days 1 through 5, with 5-FU administered as a bolus injection 1 hour after the initiation of FA. Fifteen patients were enrolled in the trial; six were entered at a dose level of 375 mg/m2 of 5-FU, six at 450 mg/m2, and three at 540 mg/m2. rhGM-CSF was administered subcutaneously on days 6 through 15. A course of therapy was repeated every 28 days. Serious toxicity was observed at 450 mg/m2, with two patients developing grade 3 mucositis and one, grade 4 mucositis. Dose-limiting toxicity occurred at 540 mg/m2, at which point three patients developed grade 4 mucositis. One patient with metastatic colon cancer who received 5-FU at 540 mg/m2 achieved a partial response. Because of this persistent mucositis, the addition of rhGM-CSF used in this schedule would not allow an increased starting dose of 5-FU.     

Weekly 24-hour infusion of high-dose 5-fluorouracil plus folinic acid in combination with mitomycin C for the treatment of advanced gastric cancer

PURPOSE: This study was performed to investigate the activity and safety of high dose 5-fluorouracil (5-FU) given as a weekly 24-hour infusion in combination with folinic acid plus mitomycin C in patients with advanced gastric cancer. PATIENTS AND METHODS: Chemonaive patients with locally advanced inoperable, recurrent or metastatic gastric cancer were treated with 15 mg/m(2) i.v. mitomycin C as bolus on day 1 of a 7-week cycle followed by a 2-hour infusion of folinic acid (500 mg/m(2)) and a 24-hour infusion of 5-FU (2,600 mg/m(2)) given on days 1, 8, 15, 22, 29, and 36 as outpatient treatment. RESULTS: Thirty evaluable patients (median age 58 years and median ECOG performance status 1) received 1-4 cycles (median 3). 53% of the patients had liver metastases. Treatment-related toxicity was low with 10% of patients experiencing diarrhea >/=grade 3, 3% mucositis grade 3 and 3% nausea grade 3 (CTC). Hematological toxicity was mild with 13% thrombopenia grade 3 and no leukopenia grade 4. Eleven patients achieved a partial remission (major response rate 37%; 95% confidence interval 22-53%). Median time to progression was 5 months and median overall survival time was 7 months. CONCLUSION: This regimen is a well-tolerated outpatient treatment for patients with advanced gastric cancer with efficacy being comparable to other chemotherapy protocols.     

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.