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.     

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.     

草酸铂联合氟尿嘧啶和醛氢叶酸双周疗法治疗晚期大肠癌46例临床观察

目的:评价草酸铂(L-OHP)联合5-氟尿嘧啶(5-FU)/醛氢叶酸(LV)双周疗法治疗晚期大肠癌的疗效。方法:采用L-OHP联合5-FU/LV双周疗法治疗经病理检查确诊的晚期大肠癌46例,所有患者均有可评价病灶。治疗方案为L-OHP85mg/m2,静脉滴入2h;LV200mg/m2,静脉滴入2h;5-FU500mg,静脉推注10min;5-FU3·0g/m2,静脉持续灌注46h。以上方案每2周重复1次,每2次为1个疗程,所有患者至少接受2个疗程的治疗。结果:46例可评价疗效:CR6例,PR16例,NC18例,PD6例,CR+PR为47·8%(22/46)。不良反应主要为周围神经毒性、恶心和呕吐、骨髓抑制和腹泻。结论:L-OHP联合5-FU/LV双周疗法治疗晚期大肠癌患者,疗效好,不良反应轻。     

Adjuvant therapy for colon cancer 2005: new options in the twenty-first century

The most effective current regimen for adjuvant treatment of surgically resected stage III colon cancer is the FOLFOX regimen of oxaliplatin, 5-FU and LV for 12 weeks, with a proportional risk reduction of 45% compared with approximately 36% for 5-FU/LV regimens. Infusion regimens of 5-FU with and without LV have been shown to confer equivalent benefit to bolus regimens in reducing the risk of cancer recurrence, but with lesser toxicity profiles. Oral 5-FU prodrug regimens have similarly shown equivalent benefit to bolus regimens, and toxicity comparable to infusional regimens, but with the added convenience over 5-FU infusion therapy. The addition of irinotecan to 5-FU and LV regimens has not demonstrated an advantage compared with 5-FU/LV treatments in the adjuvant setting.     

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.     

Advances in the treatment of metastatic colorectal cancer

The overall 5-year survival rate for patients with metastatic colorectal cancer (CRC) is less than 10%. Median survival with 5-fluorouracil (5-FU)/leucovorin (LV) therapy is approximately 12 months. Recent additions to the chemotherapy armamentarium for this disease have begun to prolong median survival times. In trials in which patients are exposed to all three approved chemotherapy agents, oxaliplatin, irinotecan, and 5-FU/LV, or capecitabine during the course of their disease, median survival has reached 20 months. The addition of oxaliplatin and irinotecan to 5-FU/LV regimens has also led to the maintenance of quality of life for longer intervals than were traditionally observed with 5-FU/LV alone. Current standard first-line regimens for metastatic CRC are FOLFOX (infusional 5-FU/LV with oxaliplatin) and FOLFIRI (infusional 5-FU/LV with irinotecan). The addition of bevacizumab to a two-drug regimen (irinotecan with 5-FU/LV) prolongs median survival to 20 months, with a modest amount of additional toxicity. Improvements in this median survival have not yet been realized with modifications to the current standard regimens; however, the oral agent capecitabine appears to be a reasonable substitute for infusional 5-FU/LV in combination regimens or as a single agent, with the advantage of reducing the inconvenience of the long infusion time. Ongoing investigations will identify a place for capecitabine, epidermal growth factor inhibitors, and new cytotoxics in the treatment of metastatic CRC.     

Phase II study of oxaliplatin in japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines

BACKGROUND: Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m2 every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines. METHODS: Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m2 every 3 weeks. RESULTS: Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1-6). The overall response rate was 9% (5/57, 95% CI: 4-19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living. CONCLUSIONS: The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients.     

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.     

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     

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.     

晚期结直肠癌内科治疗进展

晚期转移性结直肠癌的5年生存率低于10％。5-FU／LV方案治疗的中位生存期大约12个月。最近化疗方案的更新延长了患者的中位生存期。研究发现奥沙利铂、伊立替康联合5-FU／LV或者卡培他滨等化疗方案使中位生存期延长到20个月。奥沙利铂，伊立替康联合5-FU／LV比传统的单药5-FU／LV使生活质量改善时间延长。目前转移性结直肠癌标准的一线治疗方案为FOLFOX和FOLFIRI。正在进行的研究关注新的分子靶向药物（molecular targeted therapy）联合化疗治疗转移性结直肠癌，且部分试验取得了较好的疗效。本文将对5-FU、新一代化疗药物以及分子靶向药物在转移性结肠癌治疗的演进及新进展作一综述。     

Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX

This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m2 administered over 90 min, followed by LV, 200 mg m2 administered over 2 h plus 5-FU 400 mg m2 as a bolus and 600 mg m2 as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3-4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.     

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.     

Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients.

PURPOSE: To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD). PATIENTS AND METHODS: Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle. RESULTS: Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU. CONCLUSION: The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.     

奥沙利铂联合氟尿嘧啶及甲酰四氢叶酸治疗晚期大肠癌近期疗效分析

目的 :评价国产奥沙利铂 (oxaliplatin ,L OHP)联合氟尿嘧啶及甲酰四氢叶酸 (CF)治疗大肠癌的疗效和毒副反应。方法 :2 8例晚期大肠癌患者 ,予国产L OHP 12 0mg/m2 ,静脉滴入 ,持续 2h ;CF 15 0mg/m2 ,静脉滴入 ,持续 2h ;5 -氟尿嘧啶 ( 5 FU ) 5 0 0mg/m2 ,静脉滴入 ,持续 >4h ,于CF滴完后用。每 3周重复 1次 ,用药 2个周期后评价疗效。结果 :2 8例患者中 ,无完全缓解 (CR) ,部分缓解 (PR) 9例 ,稳定 (SD) 12例 ,进展 (PD) 7例 ,总有效率(RR ,CR PR) 3 2 1% ( 9/2 8) ,中位无进展生存期 6 7个月 ,中位生存期 9 8个月。毒副反应主要是末梢神经毒性、恶心呕吐、骨髓抑制及静脉炎等 ,患者均可耐受。结论 :国产L OHP联合 5 FU /CF治疗晚期大肠癌具有较好的疗效     

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.     

New systemic frontline treatment for metastatic colorectal carcinoma

Options for first-line chemotherapy in patients with metastatic colorectal carcinoma have broadened considerably with the introduction of irinotecan and oxaliplatin. Furthermore, the oral fluoropyrimidine capecitabine has demonstrated efficacy in Phase III trials and recently was approved for first-line treatment in Europe and the United States. Capecitabine yielded similar median times to disease progression and median survival rates compared with bolus 5-fluorouracil (5-FU)/leucovorin (LV) (Mayo Clinic/North Central Cancer Treatment Group regimen), with superior and similar response rates, respectively. However, its role as a first-line, single-agent substitute for intermittent infusional 5-FU/LV remains to be defined. The addition of irinotecan or oxaliplatin to 5-FU/LV resulted in improved response rates and progression-free survival in large, randomized trials; moreover, irinotecan-containing regimens resulted in improved overall survival. Prevalent regimens of irinotecan/5-FU/LV and oxaliplatin/5-FU/LV have been compared in two randomized Phase III trials. One study demonstrated the statistical superiority of oxaliplatin/infusional 5-FU/LV over irinotecan/bolus 5-FU/LV in terms of response, time to disease progression, and median survival; however, those advantages may have been attributable to infusional administration or to major differences in second-line therapy. A randomized Phase III study comparing irinotecan and oxaliplatin in combination with the same infusional 5-FU/LV regimens and crossover in case of disease progression showed equivalent efficacy for both schedules in the first-line setting, but the irinotecan combination proved beneficial in terms of safety. New molecular targeted agents, such as angiogenesis-modulating compounds (e.g., bevacizumab) and epidermal growth factor receptor inhibitors (e.g., cetuximab), are under clinical investigation. This review updates current systemic frontline treatments and future perspectives for patients with advanced colorectal carcinoma.     

Weekly high-dose 5-fluorouracil (5-FU), leucovorin (LV) and bimonthly cisplatin in patients with advanced gastric cancer

BACKGROUND: A phase II clinical trial was performed to evaluate the activity and toxicity of bimonthly cisplatin and weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin in patients with advanced gastric cancer. PATIENTS AND METHODS: From September 1997 to March 1998, 23 chemo-naive patients of advanced gastric cancer were enrolled in this study. The regimen consisted of weekly 24-h infusion of 5-FU (2,600 mg/m2) and LV 150 mg and bimonthly cisplatin (25-50 mg/m2) bolus for 12 weeks followed by a 2-week break. RESULTS: There were 10 male and 13 female patients with a median age of 52 years. A total of 428 chemotherapy treatments were given with a mean of 11. Seventeen patients were evaluable for response. There were 41% (7/17) partial response, 18% (3/17) stable disease and 41% (7/17) progressive disease. The grade III or IV toxicity included anorexia 35% (8/23), fatigue 26% (6/23), vomiting 17% (4/23) and mucositis 9% (2/23). One patient developed perforated duodenal stump after chemotherapy. One patient died of hyperammonemia-related coma. The median times to disease progression and overall survival were 3.5 and 7 months, respectively. CONCLUSIONS: This regimen showed modest activity against gastric cancer. However, there was no survival advantage and there was greater toxicity than with weekly high-dose 5-FU-LV alone.     

Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741

BACKGROUND: Intergroup Trial N9741 evaluated 5-fluorouracil (5-FU)/leucovorin (LV) administered in conjunction with either irinotecan or oxaliplatin in the first-line treatment of advanced colorectal carcinoma (CRC). The current report describes two treatment arms that were withdrawn from the protocol due to unexpected treatment-related toxicities and a high mortality rate. The complications observed in these arms highlight the importance of aggressive and immediate supportive care in the management of digestive toxicity. METHODS: In Trial N9741, patients were randomly assigned to receive one of the following six regimens: 1) irinotecan plus bolus 5-FU/LV (Arm A); 2) sequential irinotecan plus bolus 5-FU/LV (Arm B); 3) bolus 5-FU/LV only (Mayo Clinic regimen; Arm D); 4) oxaliplatin plus bolus 5-FU/LV (Arm E); 5) oxaliplatin plus infusional 5-FU/LV (Arm F); or 6) oxaliplatin plus irinotecan (Arm G). In the current study, the authors investigated treatment-related toxicity in patients who received either of the two combination regimens containing daily bolus 5-FU (i.e., patients in Arm B or Arm E). RESULTS: Sixty-one and 47 patients were enrolled in Arm B and Arm E, respectively. Diarrhea and neutropenia were the most common toxicities in both groups. Five patients in Arm B (8.2%) and 4 patients in Arm E (8.5%) died within 60 days of study entry. All fatal toxicities occurred within 15 days of treatment administration, and all deaths were associated with the simultaneous occurrence of multiple symptoms, which were dominated by Grade > or = 3 diarrhea. CONCLUSIONS: Combination regimens containing daily bolus 5-FU/LV and oxaliplatin or irinotecan can be associated with severe gastrointestinal toxicity and high mortality rates. Therefore, the authors recommend the use of more tolerable infusional 5-FU-based regimens in the treatment of metastatic CRC.     

Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial).

BACKGROUND: The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m(2) on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter. RESULTS: The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months. CONCLUSION: The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.