Current evidence of irinotecan combination chemotherapy with TS-1 in patients with advanced colorectal cancer

A combination of irinotecan (CPT-11) with continuous intravenous infusions of (infusional) 5-fluorouracil (5-FU) and Leucovorin (LV) is one of the standard treatments for advanced colorectal cancer patients. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. TS-1, the oral fluoropyrimidine widely used in the treatment for gastric cancer, was approved for advanced colorectal cancer. Recently, several phase I/II studies assessed the efficacy and safety of combined treatment with TS-1 plus CPT-11 in patients with advanced colorectal cancer. These results showed that TS-1 plus CPT-11 was very effective. Toxicity was generally mild and manageable on an outpatient basis. Current evidence showed that a combination of CPT-11 plus TS-1 was more convenient and easier to administer than a combination of CPT-11 plus infusional 5-FU and LV. It is essential to prove that the combination of TS-1 plus CPT-11 can replace the combination of infusional 5-FU and LV plus CPT-11 without negatively affecting efficacy and toxicity.     

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.     

Progress in chemotherapy for colorectal cancer

Among colorectal cancer patients with recurrent or metastatic sites, survival was significantly prolonged for a group undergoing LV/5-FU therapy based on biochemical modulation compared with a group receiving no chemotherapy (best supportive care). LV/5-FU combination therapy is recognized as the standard therapy for colorectal cancer, but recently LV/5-FU plus oxaliplatin and LV/5-FU plus CPT-11 have appeared to be more effective than LV/5-FU in some randomized studies. Capecitabine, UFT/LV and S-1 are new oral drugs that are at least comparable to LV/5-FU in antitumor activity, but superior in tolerability, which benefits the patients' quality of life, especially elderly patients with colorectal cancer. Clinical combination studies using CDDP or CPT-11 with these oral drugs are now being performed. Much is expected of these drugs.     

Treatment of colorectal cancer metastasis: The role of chemotherapy

5-Fluorouracil (5-FU) has been the main chemotherapeutic agent for the treatment of colorectal cancer for four decades with modest efficacy. Modulation of 5-FU by leucovorin or continuous infusion improves the response rate, but overall survival duration remains approximately 12 months. Many oral fluoropyrimidines have been studied, including capecitabine, UFT, S-1, and Eniluracil. Capecitabine has demonstrated equivalent efficacy with 5-FU and has been approved as first line treatment. The combinations of capecitabine with CPT-11 or oxaliplatin are being developed. CPT-11 demonstrated non-crossover resistance with 5-FU and was proven to be effective treatment for patients who received prior 5-FU. CPT-11 in combination with 5-FU has demonstrated improved response rate and overall survival duration over 5-FU or CPT-11. Oxaliplatin plus 5-FU has offered another effective treatment option for colorectal cancer. Both 5-FU plus leucovorin in combination with CPT-11 or oxaliplatin are widely used first-line chemotherapies for advanced colorectal cancer. Optimal combinations and sequences of treatment are being studied, since several effective regimens have become available.     

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.     

Oxaliplatin plus oral fluoropyrimidines in colorectal cancer

The medical treatment of colorectal cancer (CRC) has rapidly evolved in recent years with the introduction of novel cytotoxic drugs into clinical practice such as irinotecan, oxaliplatin, and capecitabine. Combination regimens using infusional 5-fluorouracil (5-FU)/leucovorin (LV) plus either oxaliplatin or irinotecan have demonstrated clinically meaningful, high efficacy in advanced CRC. Based on the results of the Intergroup trial N9741, FOLFOX4, a combination of infusional plus bolus 5-FU/LV and oxaliplatin, has emerged as the standard first-line therapy in the palliative setting. However, infusional 5-FU-based regimens carry the need for use of central venous lines and implantable ports to allow treatment on an outpatient basis and are thus inconvenient and expensive. The use of oral fluoropyrimidines (capecitabine or uracil/tegafur [UFT] plus LV) as substitutes for infusional 5-FU in combination protocols with oxaliplatin offers greater convenience, at the same time conceivably maintaining the high efficacy and tolerability observed with intravenous protocols. Various phase I/II trials have recently been reported that investigated oxaliplatin in combination with either capecitabine or UFT/LV in patients with advanced CRC. This review will detail the results of these trials focused on capecitabine-based combinations.     

Combination chemotherapy with S-1 plus CPT-11 for patients with advanced or recurrent colorectal cancer

Various kinds of combination chemotherapies with 5-FU as a base agent have been performed for patients with advanced or recurrent colorectal cancer. S-1 was a newly developed 5-FU derivative and was orally administered. One of the combination therapies with S-1 plus irinotecan (CPT-11) has also been expected to have a better therapeutic value. Recently this combination therapy has been undertaken by our department, and its clinical use and toxicities are described in this article.     

Standard therapy of CPT-11 for colorectal cancer]

Irinotecan (CPT-11) is a potent inhibitor of topoisomerase I, and has demonstrated antitumor activity against metastatic colorectal cancer. In phase II studies, CPT-11 showed promising activity. Combining irinotecan with 5-fluorouracil (5-FU) and Leucovorin (LV) has shown benefits for patients with metastatic colorectal cancer CPT-11/5-FU/LV therapy is considered as a standard therapy. Weekly or biweekly administration of CPT-11 is most recommended.     

FOLFIRI方案对草酸铂治疗失败的晚期结直肠癌的疗效分析

背景与目的：依立替康（CFF-11）、草酸铂、氟尿嘧啶（5-FU）和卡培他滨是晚期结直肠癌的主要有效化疗药物。目前对于以5-Fu或卡培他滨与草酸铂组成的联合化疗方案治疗失败的晚期结直肠癌患者,推荐使用FOLFIRI方案,但国内研究报道的例数较少。本研究的目的是评价FOLFIRI方案治疗草酸铂化疗失败的结直肠癌患者的疗效和安全性,分析不同临床因素对疗效的影响。方法：FOLFOX6方案辅助化疗结束后12个月内进展或既往行FOLF0x6／capeox方案一线姑息化疗失败后的晚期结直肠癌患者90例患者纳入研究,接受FORFIRI方案治疗。观察疗效和不良反应。结果：90例患者中81例可评价疗效,其中完全缓解2例,部分缓解20例,稳定34例,总有效率27．2％,疾病控制率69．1％,中位疾病进展时间6．8个月（95％CI,4．9—8．8个月）,中位生存时间18．8个月（95％CI,17．5～20．2个月）。主要不良反应为恶心、呕吐、粒细胞下降、脱发、乏力、肝功能损害、口腔黏膜炎、腹泻等．Ⅲ度不良反应包括脱发15例（16．7％）、呕吐10例（11．1％）、恶心8例（8．9％）、粒细胞下降5例（5．6％）、肝功能损害2例（2．2％）和口腔黏膜炎2例（2．2％）。患者可耐受或经积极对症支持治疗可恢复。结论：FOLFIRI方案治疗FOLFOX6或CapeOX治疗失败的晚期结直肠癌可获得较高的临床获益率,患者耐受性良好,是一安全有效、值得广泛应用的方案。     

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.     

A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin.

BACKGROUND: Irinotecan (CPT-11) and 5-fluorouracil (5-FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN-38 followed by 5-FU/leucovorin in vitro led us to conduct a phase I trial of CPT-11 followed by 5-FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors. PATIENTS AND METHODS: Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT-11 (90 min infusion) on day 1, followed by leucovorin 20 mg/m(2) (intravenous push) and 5-FU (90 min infusion) on days 2-5 of each 21-day cycle. RESULTS: A total of 347 treatment cycles (median 4, range 1-25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy. CONCLUSIONS: CPT-11 and 5-FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT-11 275 mg/m(2) over 90 min on day 1, and 5-FU 400 mg/m(2) plus leucovorin 20 mg/m(2) on days 2-5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT-11 and 5-FU.     

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.     

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.     

Combination chemotherapy of biweekly irinotecan (CPT-11) plus tegafur/uracil (UFT) and leucovorin (LV) for patients with metastatic colorectal cancer: phase I/II study in Japanese patients

Purpose  We aimed to evaluate the safety and efficacy of combination chemotherapy with biweekly irinotecan (CPT-11) plus oral tegafur/uracil (UFT) and leucovorin (LV) in patients with previously untreated metastatic colorectal adenocarcinoma in phase I/II setting. Patients and methods  We recruited 37 patients with histologically proven metastatic colorectal adenocarcinoma. UFT (300 mg/m² per day) and LV (75 mg/day) were administered orally on days 1–21. CPT-11 was administered intravenously on day 1 and 15, at an initial dose of 60 mg/m², stepping up to 150 mg/m² in a traditional phase I fashion. The treatment was repeated every 4 weeks. After patients enrolled into a phase II portion, the efficacy and toxicity of this regimen were also assessed. Results  The recommended dose of CPT-11 was determined to be 150 mg/m². Although one patient had a pulmonary embolism after 60 mg/m² of CPT-11, the treatment was well tolerated in general. The overall objective response rate was 37.8% (14/37; 95% CI, 22.5–55.2) in all patients. Median progression-free survival was 226 days (95% CI, 133–276). Conclusions  Biweekly CPT-11 plus UFT and LV had a reasonable safety profile with manageable toxicity, and had a promising activity in patients with metastatic colorectal cancer. Further trials are indicated based on the promising results observed in this study.     

Chemotherapy for colorectal carcinoma

5-fluorouracil (5-FU) plus leucovorin (LV) therapy is the most widely used regimen with a high evidence as the first-line treatment for advanced colorectal cancer (CRC), as well as CPT-11 as the second-line. Recently, it is reported in several randomized prospective studies that convenient oral combination of UFT and LV has equal efficacy and less adverse effect. Intrahepatic arterial infusion (IHA) therapy shows high response rate in the treatment of liver metastasis. Survival benefit of IHA has to be disclosed by further clinical trials. Prospective studies showed that 6 months' administration of 5-FU and LV after curative resection of Dukes' C CRC contributes to a patients' better survival.     

A multicenter phase II study of irinotecan (CPT-11) alternated with 5-fluorouracil and leucovorin as first-line treatment of patients with metastatic colorectal cancer

Purpose In this multicenter phase II study the efficacy and safety of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) were assessed as first-line chemotherapy in patients with metastatic colorectal cancer (CRC).Patients and methods Enrolled in the study were 43 patients with advanced CRC. They received CPT-11 350 mg/m² i.v. on day 1, alternating with LV 20 mg/m² i.v. and 5-FU 425 mg/m² i.v. daily for five consecutive days, on days 22–26 (Mayo Clinic regimen). One cycle consisted of 6 weeks.Results A total of 179 cycles were administered with a median of four per patient (range one to nine). Efficacy was analyzed on an intention-to-treat basis. The overall objective response rate was 30% (95% CI 16–44), with four complete responses and nine partial responses, whereas 20 patients (4%) showed stable disease. The median time to disease progression was 9.0 months and median survival was 18.5 months. Grade 3/4 diarrhea was mainly related to CPT-11 rather than to 5-FU (9.3% vs 4.7% of patients), whereas grade 3/4 neutropenia was higher during 5-FU administration (16.3% vs 7.0% of patients).Conclusions The alternating schedule of CPT-11 with 5 days bolus of 5-FU and low-dose LV showed a clinical benefit in terms of tumor growth control as first-line treatment of patients with metastatic CRC. The overall safety data confirmed this alternating combination as a well-tolerated treatment.     

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.     

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.     

New combination therapies for gastrointestinal cancer

Recently, cisplation (CDDP) and CPT-11 have joined the other drugs used for gastrointestinal chemotherapy, and the combination of I-leucovorin (I-LV)/5-FU has become available for use in medical treatment in Japan. This enables doctors to make a variety of regimens for gastrointestinal cancers. In this paper, we explain the new combinations, especially LV/5-FU/platinum, CPT-11/CDDP, and LV/5-FU/CPT-11. The combination of 5-FU/LV/CPT-11 has shown a higher antitumor activity than 5-FU/LV alone, with increased progression free survival or time-to-treatment failure. This combination will be considered the new standard regimen for colorectal cancer. It is worthy of note that the combination of UFT/LV provided on equally effective but safe and more convenient oral alternative to the standard i.v. 5-FU/LV regimen for colorectal cancer.