CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR

CPT-11 (irinotecan) has shown activity in patients with advanced colorectal cancer resistant to leucovorin (LV) and 5-fluorouracil (5-FU). In this study, the simplified bimonthly LV-5-FU regimen was combined with CPT-11 (FOLFIRI) as third-line therapy for patients with advanced colorectal cancer. Continuous infusion of 5-FU was administered with disposable pumps as outpatient therapy. FOLFIRI consisted of CPT-11 180 mg/m2 as a 90-min infusion day 1; LV 400 mg/m2 as a 2-h infusion during CPT-11, immediately followed by 5-FU bolus 400 mg/m2 and 46-h continuous infusion of 2.4-3 g/m2 every 2 weeks. Among the 33 patients treated, 2 had partial responses for an overall response rate of 6%; 20 patients were stabilised (61%) and 11 had disease progression (33%). From the start of FOLFIRI, median progression-free survival was 18 weeks and median survival was 43 weeks. For the 242 cycles analysed, NCI-CTC toxicities grade 3-4 per patient were nausea 15%, diarrhoea 12% and neutropenia 15%. Overall, 10 patients (30%) experienced grade 3-4 toxicity. 7 patients (21%) had grade 2 alopecia. FOLFIRI generated activity and acceptable toxicity, in heavily pretreated patients, with limited diarrhoea, mostly asymptomatic neutropenia and manageable nausea and relatively uncommon alopecia. This regimen is suitable for studies in chemotherapy-na?ve patients.     

Irinotecan combined with bolus fluorouracil, continuous infusion fluorouracil, and high-dose leucovorin every two weeks (LV5FU2 regimen): a clinical dose-finding and pharmacokinetic study in patients with pretreated metastatic colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and recommended dose of irinotecan (CPT-11) in combination with fluorouracil (5-FU) and leucovorin (LV), using a biweekly LV5FU2 regimen and increasing doses of CPT-11, and to assess the efficacy of this combination in pretreated patients with colorectal cancer (CRC). PATIENTS AND METHODS: All patients had metastatic CRC and a World Health Organization performance status of 0 or 1. CPT-11 was administered over a 90-minute infusion every 2 weeks at a range of dose levels (100, 120, 150, 180, 200, 220, and 260 mg/m(2)). LV5FU2 was started 1 hour after the end of the biweekly CPT-11 infusion and was also administered on day 2. RESULTS: Fifty-five patients were entered onto this trial; 549 cycles were administered. The MTD was not reached at 260 mg/m(2), and a dose level of 300 mg/m(2) was added. The MTD as defined in the protocol was not reached at this dose level either, but all patients had cycles delayed and/or required a dose reduction. This dose was deemed to be the MTD. To take into account both the toxicity of and compliance with the biweekly schedule, the recommended CPT-11 dose was established at 180 to 200 mg/m(2). Antitumor activity was observed at almost all dose levels, with an objective response rate of 22%. Median time to progression was 6.3 months and overall survival was 15 months. CONCLUSION: The biweekly CPT-11/LV5FU2 combination is feasible and safe, without overlapping toxicity. CPT-11 at 180 to 200 mg/m(2) in combination with LV5FU2 has been selected as the recommended dose for further studies.     

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.     

Multicenter phase II study of gemcitabine and oxaliplatin (GEMOX) as second-line chemotherapy in colorectal cancer patients pretreated with 5-fluorouracil plus irinotecan

PURPOSE: To evaluate the efficacy and tolerance of the gemcitabine/oxaliplatin (GEMOX) combination as second-line chemotherapy for patients with advanced colorectal cancer (CRC) pretreated with an irinotecan (CPT-11)/5-fluorouracil (5-FU)/leucovorin (LV) regimen. PATIENTS AND METHODS: Patients with documented disease progression during or after first-line treatment with CPT-11 and 5-FU/LV were enrolled. Gemcitabine (1,000 mg/m(2) days 1 and 8) and oxaliplatin (100 mg/m(2) day 1) were administered every 3 weeks. RESULTS: Partial responses were observed in 6 of the 34 (17.7%) patients enrolled (intention-to-treat analysis; overall response rate: 17.7%; 95% confidence interval 4.8-30.5%). Eight (23.5%) patients experienced disease stabilization and 20 (59%) disease progression (tumor growth control rate = 41.2%). The median duration of response was 5.5 months, and the median time to tumor progression 2.7 months. The median overall survival was 9.1 months (1-year survival rate: 44.0%). Grade 3 neutropenia and thrombocytopenia occurred in 18 and 15% of the patients, respectively. Other severe non-hematologic toxicities were rare. CONCLUSION: The interesting tumor growth control rate and the favorable toxicity profile of the GEMOX regimen in pretreated patients with advanced CRC strongly suggest that this regimen may provide an alternative therapeutic option for this group of patients.     

三种方案治疗晚期大肠癌近期疗效比较

目的 :比较 5 FU/LV、L OHP 5 FU/LV及CPT 11 5 FU/LV治疗晚期大肠癌的疗效和毒副反应。方法 :采用三种方案对 6 5例患者进行研究 ,3周为一个疗程。 5 FU/LV方案为LV 2 0 0mg/d ,iv 2小时 ,第 1～ 5天 ;5 FU5 0 0mg/d ,iv第 1～ 5天 ;L OHP 5 FU/LV方案为L OHP 130mg/m2 iv第 1天 ,5 FU/LV用法同上 ;CPT 11 5 FU/LV方案为CPT 11180mg/m2 30分钟第 1天 ,5 FU/LV用法同上。至少化疗 2个疗程后进行评价。结果 :三种方案总体疗效分别为 13.33%、2 1.2 1%、11.76 % ;总体恶心、呕吐发生率分别为 4 0 .0 0 %、39.39%、17.6 5 % ;腹泻发生率分别为 13.33%、6 .0 6 %、2 9.4 1% ;骨髓抑制发生率分别为 2 6 .6 7%、2 4 .2 4 %、35 .2 9% ;神经毒性发生率分别为 0、15 .15 %、0 ;三种方案间均无显著性差异 (P >0 .0 5 )。结论 :三种方案治疗晚期大肠癌的近期疗效无明显差别 ,毒副反应发生率低 ,耐受好 ,均适合临床应用     

FOLFIRI regimen for metastatic or recurrent colorectal cancer

Irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and Leucovorin (LV) became the standard first-line chemotherapy for colorectal cancer in the U.S. and Europe in 2000, largely owing to the results of controlled randomized phase III trials of 5-FU/LV with or without CPT-11. One of the regimens for CPT-11 plus infusional 5-FU/LV therapy is the FOLFIRI regimen. This regimen consists of CPT-11 180 mg/m(2) as a 90-min infusion on day 1 and l-LV 200 mg/m(2) as a 2-h infusion during CPT-11, immediately followed by a bolus dose of 5-FU 400 mg/m(2) and a 46-h continuous infusion of 2,400 mg/m(2) every 2 weeks. FOLFIRI, as well as oxaliplatin/5-FU/LV therapy (FOLFOX), is an internationally accepted standard chemotherapy for metastatic colorectal cancer. Safe use of this effective regimen requires adequate supportive therapy in Japan, as well as in Western countries.     

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

PURPOSE: To evaluate the activity and safety of an alternating schedule of irinotecan (CPT-11) with high-dose 5-fluorouracil (5-FU) given as a weekly 48-hour infusion in combination with leucovorin (LV) in the first-line treatment of metastatic colorectal cancer (MCRC) patients. PATIENTS AND METHODS: We tested the activity of a regimen consisting of a four times per week schedule of high-dose LV (150 mg/m2) followed by a 48-hour 5-FU infusion (2,600 mg/m2) alternated with CPT-11 (350 mg/m2). An alternating cycle was to be performed every 8 weeks. Treatment was administered until disease progression, unacceptable toxicity or patient refusal occurred. Thirty-five consecutive patients with measurable MCRC, aged 18-80, with a performance status < or =2, were entered into our study from May 1998 to January 2000. RESULTS: Four complete and 9 partial responses were observed (objective response rate was 37%; 95% confidence interval, CI: 21.5-55.1%); an additional 46% of the patients had stable disease. The median duration of response was 6.2 months, median time to progression 8 months (95% CI: 5.9-10.1%), and overall survival was 18.5 months (95% CI: 15.1-21.9%). The 1-year survival was 68%. No toxic deaths occurred. The incidence of grade 3-4 toxicity per patient in any cycle was: mucositis 9% and diarrhea 11% for the infusional 5-FU part, nausea/vomiting 3%, diarrhea 14%, and neutropenia 43% for the CPT-11 part of regimen. CONCLUSIONS: Our alternating schedule of 5-FU/LV and CPT-11 is a well-tolerated outpatient treatment as front-line therapy for MCRC with comparable efficacy to regimens with both drugs given together.     

Phase I study of CPT-11 and continuous 5-FU / l-leucovorin combination therapy(modified AIO regimen)in patients with metastatic colorectal cancer

A combination of CPT-11, continuous 5-fluorouracil(5-FU)and leucovorin(LV), the Arbeitsgemeinschaft für Internistische Onkologie(AIO)regimen, is widely used for the treatment of metastatic CRC. The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC. Our objective was to evaluate the safety of the AIO regimen plus CPT-11 in Japanese colorectal carcinoma(CRC)patients. We investigated the maximum tolerated dose(MTD), dose-limiting toxicity(DLT), and recommended dose(RD)for CPT-11 and continuous 5-FU. CPT-11, 5-FU, and l-LV were administered on days 1, 8, and 15 of a 28-day cycle. The dose of CPT- 11 was escalated from 40 mg/m2 (level 1)to 80 mg/m2 (level 3). The 5-FU dose was then escalated from 1,000 mg/m2 (level 4)to 2,000 mg/m2 (level 5). If neither level met the criteria for the MTD, the recommended dose was defined as level 5, and the dose escalation was discontinued, because the maximum approved weekly dose of CPT-11 alone in Japan is 80 mg/m2 and the dose of 5-FU in the original AIO regimen was 2,000 mg/m2. A total of 18 patients were enrolled in this study. Hematological and non-hematological toxicity were infrequent and mild. There were no toxicities greater than grade 2 at each dose level. Level 5 did not meet the MTD criteria. Our results confirm that the modified AIO plus CPT-11 regimen is safe for Japanese patients. The recommended doses in the present study were CPT-11 80 mg/m2, 5-FU 2,000 mg/m2, and l-LV 250 mg/m2.     

Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.     

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.     

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 with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m² (7 patients) or 70 mg/m² (48 patients). After completion of CPT-11 infusion, LV 200 mg/m² was administered over 2 hr followed immediately by 5-FU 450 mg/m², IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m² weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m². Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m². Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.     

Multiple-target chemotherapy (LV-modulated 5-FU bolus and continuous infusion, oxaliplatin, CPT- 11) in advanced 5-FU-refractory colorectal cancer: MTD definition and efficacy evaluation. A phase I-II study

AIMS AND BACKGROUND: To identify the maximum tolerated doses and to define the activity of a regimen incorporating leucovorin (LV)-modulated 5-fluorouracil (5-FU) bolus and continuous infusion, oxaliplatin (I-OHP) and irinotecan (CPT-11) in patients with advanced, 5-FU-refractory colorectal cancer (CRC). PATIENTS AND METHODS: Starting doses: LV 100 mg/m2 as a 2-hour infusion followed by 5-FU 300 mg/m2 bolus administration followed by 5-FU 500 mg/m2 as a 22-hour infusion on days 1 and 2; I-OHP 65 mg/m2 as a 2-hour infusion concomitantly with LV on day 1; CPT-11 90 mg/m2 concomitantly with LV on day 2. Planned cycle interval: 2 weeks. RESULTS: Two hundred twenty-six cycles were administered to 27 patients. Recommended doses were 5-FU bolus 300 mg/m2, 5-FU protracted infusion 500 mg/m2, I-OHP 75 mg/m2, and CPT-11 150 mg/m2. Among 25 patients evaluable for response we observed 13 disease stabilizations (52%; 95% CI: 33-71%), 6 instances of disease progression and 6 responses (24%; 95% CI: 7-41%). Median time to progression and overall survival were 24 and 60 weeks, respectively. A cycle delay > 3 days was observed in 134/199 cycles (67%). CONCLUSIONS: This study confirms the feasibility of triplet chemotherapy in patients with advanced 5-FU-refractory CRC.     

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

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

Phase II trial of a biweekly regimen of fluorouracil and leucovorin plus irinotecan in patients with previously untreated advanced gastric cancer

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

Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR

For patients resistant to leucovorin (LV) and 5-fluorouracil (5-FU), the addition of oxaliplatin (85 or 100 mg/m2) to bimonthly LV-5-FU has given a response rate of 20-46%. The highest response rate has been observed with oxaliplatin 100 mg/m2 (FOLFOX2). The present phase II study (FOLFOX6) infused oxaliplatin (100 mg/m2) with LV (400 mg/m2) as a 2-h infusion on day 1, followed by bolus 400 mg/m2 and a 46-h infusion (2.4-3 g/m2) of 5-FU, every 2 weeks. Among the 60 patients treated, 16 (27%) had partial responses (95% confidence interval: 15-38), 27 (45%) had stable disease, 15 (25%) experienced disease progression and 2 (3%) had non-measurable disease. From the start of FOLFOX6, median progression-free survival was 5.3 months and median survival 10.8 months. From the 448 cycles analysed, NCI-CTC grade 3-4 toxicities per patient were: peripheral neuropathy 16%, nausea 7%, diarrhoea 7%, mucositis 5%, neutropenia 24%, thrombocytopenia 2%. Overall 26 (46%) patients experienced grade 3-4 toxicities. Because of toxicity, only 36% of the patients received > or = 90% of the scheduled oxaliplatin dose intensity. FOLFOX6 was active in pretreated patients resistant to LV-5-FU and is being investigated as first-line therapy. We are now investigating FOLFOX7, a regimen with a higher oxaliplatin dose intensity and a lower 5-FU dose.     

Biweekly chemotherapy with oxaliplatin, irinotecan, infusional Fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer.

PURPOSE: To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients. PATIENTS AND METHODS: Patients received CPT-11 followed by L-OHP and LV 200 mg/m(2) and followed by 5-FU 3,800 mg/m(2) as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses. RESULTS: Forty-two patients entered the study. CPT-11 175 mg/m(2) and L-OHP 100 mg/m(2) in combination with LV 200 mg/m(2) and 5-FU 3,800 mg/m(2) could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively. CONCLUSION: This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.     

Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen.

PURPOSE: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m(2)) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone. PATIENTS AND METHODS: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m(2) and continuous 5-FU infusion 1.5 to 2 g/m(2)/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m(2), bolus 5-FU 400 mg/m(2), and continuous 5-FU infusion 600 mg/m(2)/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX4). RESULTS: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P =.02). From the start of treatment, median progression-free survival was 4. 7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively. CONCLUSION: This phase II study of oxaliplatin at 85 mg/m(2) in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.     

5-Fluorouracil and folinic acid with or without CPT-11 in advanced colorectal cancer patients: A multicenter randomised phase II study of the Southern Italy Oncology Group

Purpose:The combination regimen CPT-11 plus bolus and infusion5-fluorouracil (5-FU) with high-dose leucovorin (hybrid regimen LV5FU2) hasbeen tested for activity and toxicity against advanced colorectal carcinomain a randomised, multicenter phase II trial. Patients and methods:A total of 102 chemotherapy-naïvepatients were randomised in a 1 : 2 fashion to receive: leucovorin 100mg/m² administered as a two-hour infusion before 5-FU 400mg/m² as an intravenous bolus, and FU 600 mg/m² as a22-hour infusion immediately after 5-FU bolus injection repeated on days 1 and2 (LV5FU2 regimen, arm A, 34 patients) or CPT-11 at 180 mg/m² (150mg/m² for patients of age 70 and <75 years) only on day 1immediately before LV5FU2 therapy (LV5FU2 + CPT-11 regimen, arm B 68patients). Both treatments were repeated every two weeks. The presence of acalibration arm assured consistency and more realistic evaluation of resultsachieved with the LV5FU2 + CTP-11 regimen. Results:Thirty-three and sixty-four patients were evaluable inarm A and B, respectively. The overall response rate was 18% in arm A(95% CI: 7%–34%) and 40% in arm B(95% CI: 28%–52%). Median time to progression,median duration of response and survival were similar in both groups.Responders (CR + PR) survived statistically longer than non-responders onlyin arm B (20 vs. 10 months, P = 0.0016). All patients were evaluablefor toxicity which was mild in both groups; gastrointestinal disturbances werethe most common. There were no treatment-related deaths. Grade 3–4toxicity was uncommon in both arms. Conclusions:The addition of CPT-11 to the hybrid LV5FU2 regimenprovided a significant overall response rate (40%) with relatively mildtoxicity. The overall response rate was 18% in patients treated withLV5FU2 alone in the calibration arm. Thus, considering other encouraging datafrom the literature, the CPT-11 + FU–LV combination therapy can beregarded as a new, very effective treatment option for first-line treatmentof advanced colorectal cancer patients.     

Oxaliplatin combined with irinotecan and 5-fluorouracil/leucovorin (OCFL) in metastatic colorectal cancer: a phase I-II study.

BACKGROUND: A phase I-II multicenter trial was conducted to define the maximal tolerated dose and describe the activity of an OCFL combination using oxaliplatin (OHP), irinotecan (CPT-11) and 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (CRC). PATIENTS AND METHODS: CRC patients not pretreated with palliative chemotherapy, with performance status < or =1 and adequate haematological, kidney and liver function, were eligible. Treatment consisted in weekly 24-h infusion 5-FU (2300 mg/m(2))/LV (30 mg) and alternating OHP (70-85 mg/m(2), days 1 and 15) and CPT-11 (80-140 mg/m(2), days 8 and 22) repeated every 5 weeks. OHP and CPT-11 were escalated in cohorts of three to six patients. RESULTS: Thirty patients received a median of five cycles. Dose-limiting toxicity occurred at dose level 3, and the recommended dose was OHP 70 mg/m(2), CPT-11 100 mg/m(2), LV 30 mg and 5-FU 2300 mg/m(2)/24 h. Grade > or =3 toxicities were diarrhea 23%, neutropenia 20%, fatigue 7%, and neurologic 7%. Two febrile neutropenia episodes (one fatal) were recorded. Among 28 patients with measurable disease (90%), we observed two complete and 20 partial responses; overall RR was 78% (95% CI, 59% to 92%). Median time to progression and overall survival were 9.5 and 25.4 months, respectively. Seven patients underwent liver metastases resection. CONCLUSION: OCFL is an overall well tolerated regimen with very high efficacy, which makes it most suitable for tumour control before surgery of metastatic disease.