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.     

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.     

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     

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.     

A case of irinotecan-resistant colon cancer responding to chronotherapy with oxaliplatin, 5-FU,l-LV

We report a case of irinotecan-resistant colon cancer responding to chronotherapy with oxaliplatin (L-OHP), 5-FU, l-LV (l-Leucovorin). A 72-year-old man was examined at a certain hospital because of constipation and appetite loss. Chest computed tomography (CT) revealed lung metastases, and abdominal CT revealed liver metastases. He was then referred to our hospital. A colonoscopy revealed type 2 tumor in the colon, at the hepatic flexure. We diagnosed adenocarcinoma of the colon with metastases to the liver and lung. Resection of the primary lesion was performed, and chemotherapy consisting of systemic administration of CPT-11, 5-FU and l-LV was performed. After 2 courses of combined treatment with CPT-11/5-FU/l-LV, CT revealed considerable reduction of the metastatic tumors. However, after 3 courses of combined treatment, progressive disease was observed and new brain and bone metastases were detected. We imported and used a non-approved/pending drug, oxaliplatin from the Remedy and Health Corporation, with informed consent from the patient and his family and our clinical ethics committee. Chronotherapeutic schedules have been performed, from which the safety and activity of oxaliplatin against advanced colorectal cancer was reported. Our patient received a 5-day course of chronomodulated 5-FU and l-LV (750 and 300 mg/body/day, respectively; peak delivery rate at AM 4:00 hours) with L-OHP on the first day of each course (100 mg/body, as a 6-hour infusion). Each course was again repeated every 21 days. A partial response was observed in the liver and lung metastases. These results indicate that chronomodulated 5-FU and LV with L-OHP therapy could be an effective regimen for cases of irinotecan-resistant colon cancer.     

Irinotecan, fluorouracil and folinic acid (FOLFIRI) as effective treatment combination for patients with advanced gastric cancer in poor clinical condition

AIMS AND BACKGROUND: Irinotecan (CPT-11) has been tested as a single agent in several studies, and response rates of 18-23% have been reported in first-line gastric cancer therapy. In the present study we report the safety and efficacy results combining CPT-11 with 5-fluorouracil (5-FU) and folinic acid (FA). PATIENTS AND METHODS: Thirty consecutive patients with metastatic gastric cancer, considered in poor clinical condition, were treated with CPT-11 and 5-FU/FA according to the FOLFIRI regimen. All enrolled cases were evaluable for toxicity and drug activity. RESULTS: The main grade 3-4 toxicity (according to the NCI-CTC criteria) was neutropenia (16%, grade 4 in 1 patient); non-hematological grade 3 toxicity consisted mainly in vomiting and diarrhea reported in 1 patient. No treatment-related serious adverse events were observed. Response was obtained in 12 patients (40%), stable disease in 2 patients (7%), while progression was documented in 16 patients (53%). CONCLUSIONS: These results are very promising, and suggest that the combination of CPT-11 plus 5-FU/FA is active and well tolerated and can be considered as useful treatment in patients with metastatic gastric cancer in poor clinical condition.     

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.     

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.     

Mitomycin-C and capecitabine as third-line chemotherapy in patients with advanced colorectal cancer: a phase II study

Purpose The aim of this study was to investigate the therapeutic value and safety of third-line treatment with mitomycin-C (MMC) and capecitabine (Xeloda) in patients with advanced colorectal cancer pretreated with combination regimens including 5-fluorouracil (5-FU), folinic acid (FA) and irinotecan (CPT-11) or 5-FU, FA and oxaliplatin (L-OHP).Patients and methods A total of 21 patients (M/F 16/5, median age 60.0 years) with advanced colorectal cancer, all of whom had developed progressive disease while receiving or within 6 months of discontinuing two sequential chemotherapy lines with 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP, were accrued to this study. At the time of their relapse or progression, cytotoxic chemotherapy, consisting of intravenous MMC 7 mg/m² on therapeutic day 1 plus oral capecitabine 1000 mg/m² twice daily on days 1–14, was initiated. After rest for 7 days, capecitabine 1000 mg/m² twice daily was administered on days 22–35 followed by 7 days rest. Treatment courses were repeated every 6 weeks unless there was evidence of progressive disease, unacceptable toxicity or patient refusal of treatment.Results All the patients were assessable for toxicity and 19 for response. The median number cycles of chemotherapy was two (range one to four). Only 1 patient (4.8%) had a partial response, 4 patients (19.0%) had stable disease, and 14 patients (66.7%) progressed. The median follow-up period was 7.3 months and median time to progression was 2.6 months. The median overall survival was 6.8 months. No toxic deaths occurred. Toxicities of third-line treatment were mild and manageable. As NCI/NIH common toxicity criteria, grade 3/4 anemia, neutropenia and thrombocytopenia occurred in two, one and one patients, respectively.Conclusion Our findings suggest that the combination of MMC and capecitabine in patients with advanced colorectal cancer pretreated with combination regimens including 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP is safe. However, this regimen had a poor response rate and no definitive contribution to increasing patients overall survival time. Further evaluation of other salvage regimens seems to be warranted.     

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.     

奥沙利铂联合甲酰四氢叶酸和氟尿嘧啶治疗晚期结直肠癌的临床观察

目的:评价奥沙利铂(LOHP)联合氟尿嘧啶(5FU)、甲酰四氢叶酸(CF)治疗晚期结直肠癌的近期疗效和不良反应。方法:采用LOHP85mg/m2,静脉滴入,持续2h,d1;CF300mg,静脉滴入,持续1h,d1～d5;5FU500mg,静脉滴入,持续4h,d1～d5。21d为1个周期,治疗3个周期后评价疗效。结果:共治32例,CR0例,PR12例,MR10例,SD6例,PD4例,总有效率37.5%(12/32)。不良反应主要为轻度的感觉神经毒性,轻度骨髓抑制及恶心、呕吐。结论:LOHP、5FU和CF联合应用治疗复治晚期结直肠癌患者有一定的疗效,不良反应较轻。     

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.     

Biochemical modulation of fluorouracil: comparison of methotrexate,folinic acid,and fluorouracil versus folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial

 Recent advances in biochemical pharmacology have revealed the basis for the biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in enhanced cell kill in vitro and in vivo. In addition, administration of FA prior to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary complex of thymidine synthase. In the present randomized study, two groups of patients with advanced colorectal cancer were treated as follows: 43 patients (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA + MTX. The dosage was as follows: group A received FA i. v. at 300 mg/m² per day, prior to i. v. 5-FU at 500 mg/m² per day on days 1 – 4; group B was given MTX i. v. at 130 mg/m² per day on day 0, followed 24 h later by FA at 15 mg q6h × 6, and 5-FU + FA was started on day 1 and given at the same doses and schedule described for group A. Objective responses were achieved by 8/43 pts in group A (1 complete response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15 partial responses), all occurring in the liver. There was no significant difference in the median time to progression (group A 6.1 months, group B 6.8 months) or the median survival (group A 9.2 months, group B 10.3 months). Toxicity was significantly greater in group B [grade 2 – 3 mucositis 20% versus only 2% in group A (P <0.0001); grade 3 diarrhea in group B 15% versus 3% in group A (P <0.001)]. According to our results, double biological modulation of 5-FU with MTX + FA led to an enhanced response rate with increased toxicity as compared with the 5-FU + FA regimen given at less than its maximally tolerated dose. Received: 8 May 1995 / Accepted: 25 January 1996     

Combined irinotecan,oxaliplatin and 5-fluorouracil in patients with advanced colorectal cancer. a feasibility pilot study

OBJECTIVES: To evaluate the feasibility and a possible activity range of combination irinotecan (CPT-11), oxaliplatin, and 5-FU in advanced colorectal cancer (ACC). PATIENTS AND METHODS: A total of 53 patients (51% chemoresistant) were treated. Twenty-eight received monthly intravenous oxaliplatin (120 mg/m2) and CPT-11 (250 mg/m2) on day 1 and a course of 5-FU; these constituted the IRI250 group. Twenty-five received monthly intravenous oxaliplatin (120 mg/m2), CPT-11 (300 mg/m2) on day 1, and a course of 5-FU (IRI300 group). 5-FU administration was carried out as follows. Those with predominant hepatic disease (n = 32) received an intra-arterial infusion of 5-FU (2,500 mg/day on days 1-4); these were the IA-FU group. The remaining 21 patients received intravenous 5-FU (2,600 mg/m2 plus leucovorin 500 mg/m2 on days 1 and 15); these constituted the IV-FUFOL group. RESULTS: Intention-to-treat response rate was 54.7% (4 CR, 7.5%). Twelve patients (22.5%) had stable disease; only 4 (7.5%) progressed. Median progression-free and overall survivals were 10 and 18 months, respectively. One-year progression-free and overall survival rates were 44.3 and 67.4%, respectively. Grade 3-4 toxicities included diarrhea (45.3% of patients), neutropenia (52.8%), mucositis (13.2%), and emesis (11.3%). There were 3 treatment-related deaths (5.7%), all in the IA-FU/IRI300 subgroup. Severe adverse effects requiring chemotherapy dose adjustment were observed in 67.9% of the patients, with odds ratios 9.04-fold higher in the IA-FU/IRI300 group (95% CI: 1.07-76.20) and 0.23-fold lower in the IV-FUFOL/IRI250 group (95% CI: 0.05-0.97). Conclusion: This combination seems to have substantial activity in ACC. Overall toxicity was unacceptable in the IA-FU and IRI300 groups, with diarrhea and cytopenia constituting the dose-limiting side effects. Tolerance and efficacy profiles achieved with IV oxaliplatin (120 mg/m2 day 1), IV CPT-11 (250 mg/m2 day 1) and IV 5-FU 2.6 g/m2 with IV leucovorin (500 mg/m2 days 1 and 15) was favorable and deserves further investigation.     

Multicenter phase II study of fractionated bimonthly oxaliplatin with leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer,pre-treated with chemotherapy

In vitro and in vivo studies have shown that oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and leucovorin (L) have a synergistic activity on metastatic colorectal cancer (MCC). In order to better exploit the synergism of action between the three drugs, L-OHP was administered over 2 days, together with 5-FU-L, in a cohort of patients with MCC that had been pre-treated with chemotherapy. Forty-six patients were entered into the trial. All had been pre-treated with chemotherapy for metastatic disease: 14 with the 'de Gramont' regimen alone, and 32 with the same regimen combined with irinotecan (CPT-11). The outpatient treatment consisted of L-OHP 50 mg/m(2), followed immediately by the 'de Gramont' regimen. All drugs were administered on days 1 and 2, every 14 days. Median patient age was 65 years (range: 46-78), male/female ratio was 29/17. All 46 patients were evaluated for response and toxicity. We observed 1 complete response (2.2%) and 14 partial responses (30.4%), giving an overall response rate of 32.6% (95% CI: 19.5-48.06%); 22 patients had stable disease (47.8%) and 9 patients progressed (19.6%). After a median follow-up of 13 months, median time to progression was 6.4 months (range: 3.1-31.2+), while overall median survival was 12.2 months (range: 3.7-31.2+). Toxicity was manageable: grade 3 or 4 neutropenia was observed in 33% of patients, while only 6% of patients had grade 1-2 neurotoxicity. The fractionated bimonthly schedule of L-OHP plus 5-FU-L, showed activity, with an acceptable toxicity profile, both in patients with MCC pre-treated with the 'de Gramont' regimen alone, or with this regimen associated with CPT-11.     

Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial

Background:

We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases.

Methods:

This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2–6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m⁻², 5-FU to 550 mg m⁻² per day and L-OHP to 15 mg m⁻² per day.

Results:

Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3–15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21–53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction.

Conclusion:

Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases.     

Increased tolerability of bimonthly 12-hour timed flat infusion 5-fluorouracil/irinotecan regimen in advanced colorectal cancer: A dose-finding study

A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.     

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。     

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.     

Colorectal cancer metastasis resectability after treatment with the combination of oxaliplatin, irinotecan and 5-fluorouracil. Final results of a phase II study

Purpose. To investigate the response rate of the triple combination of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) and 5-fluorouracil (5-FU) and to assess its impact on secondary resectability of previously non-resectable liver metastasis (LM). Patients and methods. Patients≥18 with MCRC, ECOG grade 0-2, and no prior treatment received L-OHP (85 mg/m²), CPT-11 (150 mg/m²) and 5-FU (2 250 mg/m² in 48 h CI) on D1 every 15 days. Results. Forty-seven patients with initially non-resectable metastatic disease were included. Median age 62 years (38-76); 28 males; 26 patients with 0 performance status (ECOG) 40 patients had prior surgery and four adjuvant chemotherapy. All patients were evaluable for toxicity and 42 for response. Main grade 3-4 toxicities were neutropenia (40%), febrile neutropenia (4%), diarrhea (21%), nausea/vomiting (11%/15%), fatigue (11%), anemia and alopecia (9% each); grade 3-4 neurotoxicity was observed in 28% patients. Secondary surgery was possible in 15 of 47 (31.9%) patients and 12/30 (40%) patients with only LM: in this cohort, median OS has not been reached at 22 months median follow-up, with 2/12 patients having died. Overall response rate was 69% (95% CI, 53-82%); 13 (31%) had stable disease. Median time to progression and overall survival (OS) were 10.9 (95% CI, 9.9-13.2) and 19.9 (95% CI, 11.7-TBD) months, respectively. Conclusion. This combination has shown promising activity with manageable toxicity as front-line treatment in MCRC, and has allowed the resectability of LM in a considerable number of patients, offering them the possibility of long-term survival.