Phase II trial of fortnightly irinotecan (CPT-11) in the treatment of colorectal cancer patients resistant to previous fluoropyrimidine-based chemotherapy

Introduction This phase II study investigated the anti-tumour activity and toxicity of CPT-11 (250 mg/m2 i.v. infusion over 60 minutes) administered every 2 weeks as second-line chemotherapy in patients with advanced colorectal cancer (CRC). Material and methods Patients (n=63) with histology diagnosis of advanced CRC and proven resistance to previous fluoropyrimidine therapy were enrolled. Results A total of 510 CPT-11 cycles were administered, with a mean of 8 cycles per patient (range: 1–32). The median relative dose intensity was 93%. Partial response (PR) was obtained in 11 patients (17.5%; 95%CI: 8.1%–26.7%) and 29 patients (46.0%) showed stable disease (clinical benefit of 63.5%). The median duration of response was 6.8 months (95%CI: 6.1–7.5 months), median survival was 8.8 months (95%CI: 6.3–11.5 months) and median time to disease progression was 4.5 months (95%CI: 3.9–5.0 months). Overall, this schedule of CPT-11 chemotherapy was well tolerated by the patient. Neutropenia was the most frequent grade 3/4 haematological toxicity (20.6% of patients and 4.1% of cycles). Neutropenia with concurrent fever or infection occurred in 7 patients (11.1%). Late onset diarrhoea was the most frequent grade 3/4 non-haematological toxicity (19.0% of patients and 2.3% of cycles). Other, lower-incidence, toxicities were anaemia, fever, infection, mucositis, nausea and vomiting. There were no toxic deaths. Conclusions We found that CPT-11, administered as 250 mg/m² i.v. infusion over 60 minutes every 2 weeks, was active and well tolerated schedule in the second-line chemotherapy of advanced CRC patients. This bi-weekly scheme could be used as an alternative to the weekly or the every-three-week schedule as well as in combined therapies with other chemotherapeutic agents for the treatment of advanced, metastatic, CRC.     

Phase II study of UFT and oxaliplatin in first-line treatment of advanced colorectal cancer

The purpose of this study was to evaluate the efficacy, assessed as response rate, and toxicity of UFT (Tegafur-Uracil) in combination with oxaliplatin as first-line treatment of advanced colorectal cancer (CRC). In all, 84 patients with recurrent or metastatic CRC with measurable disease were included. Treatment consisted of oxaliplatin 85 mg m(-2) in 120-min intravenous (i.v.) infusion on days 1 and 15; i.v. l,leucovorin (l,LV) 250 mg m(-2) given in 2 h on day 1, followed by oral UFT 390 mg m(-2) on days 1-14, and oral l,LV 7.5 mg/12 h on days 2-14. Cycles were repeated every 28 days. A total of 492 cycles of chemotherapy were delivered with a median of six per patient (range 1-12). There was one complete response (1%) and 28 partial responses (34%) for an overall response rate of 35% (95% confidence interval (CI): 24-46%). A total of 36 patients (44%) had stable disease, whereas 17 (21%) had a progression. The median time to progression was 7.3 months and the median overall survival was 16.8 months. A prescheduled preliminary analysis was performed after inclusion of 16 patients who detected a high gastrointestinal toxicity, which led to a reduction of the UFT dose to 300 mg m(-2). With this new dosage, grade 3-4 diarrhoea and grade 3-4 nausea/vomiting dropped to 21 and 14% of patients, respectively. Other grade 3-4 toxicities were stomatitis in one (1%), anaemia in three (5%), neutropenia in two (3%), thrombocytopenia in one(1%), fatigue in six (9%), peripheral sensory neuropathy in nine (14%) and laryngopharyngeal dysesthesia in two patients (2%). The combination of oxaliplatin and UFT-l,LV is an active, easy-to-administer regimen with moderate toxicity. Hence, this regimen is worthy of further investigation.     

Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study

To evaluate the efficacy and toxicity of irinotecan (CPT-11) in combination with raltitrexed as first-line treatment of advanced colorectal cancer (CRC). A total of 91 previously untreated patients with advanced CRC and measurable disease were enrolled in this phase II study. The median age was 62 years (range 31-77); male/female 54/37; ECOG performance status was 0 in 50 patients (55%), one in 39 (43%) and two in two (2%). Treatment consisted of CPT-11 350 mg x m(-2) in a 30-min intravenous infusion on day 1, followed after 30 min by a 15-min infusion of raltitrexed 3 mg x m(-2). Measurements of efficacy included the following: response rate, time to disease progression and overall survival. Of the 83 evaluable patients valuable to objective response, there were five complete responses (6%) and 23 partial responses (28%), for an overall response rate of 34% (95% CI: 25.9-46.5%). In all, 36 patients (43%) had stable disease, whereas 19 (23%) had a progression. The median time to progression was 11.1 months and the median overall survival was 15.6 months. A total of 487 cycles of chemotherapy were delivered with a median of five per patient. Grade 3-4 WHO toxicities were as follows: diarrhoea in 13 patients (15%), nausea/vomiting in four (4%), transaminase increase in six (7%), stomatitis in two (2%), febrile neutropenia in three (3%), anaemia in five (6%) and asthenia in three (3%). The combination CPT-11-raltitrexed is an effective, well-tolerated and convenient regimen as front-line treatment of advanced CRC.     

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.     

Phase II study of weekly irinotecan (CPT-11) as second-line treatment of patients with advanced colorectal cancer

This phase II trial studied the antitumor effect and toxicity of weekly irinotecan (CPT-11, 125 mg/m² 60 min iv infusion, weekly for 4 wk plus 2 wk rest) as second-line chemotherapy in patients with advanced colorectal cancer (CRC) resistant or refractory to prior 5-fluorouracil (5-FU) therapy. Sixty-nine patients with adenocarcinoma (57% in the colon and 43% in the rectum) were enrolled. The median number of treatment cycles received per patient was 4 (range, 1–6). Overall response rate was 18% (95% CI, 9–26), with 4 complete responses (6%) and 8 partial responses (12%), and a median duration of response of 8.1 mo (95% CI, 4.2–12.1). Stable disease was observed in 19 patients (28%). The median time to disease progression was 5.2 mo (95% CI, 4.3–6.1), and the median overall survival was 13.3 mo (95% CI, 9.8–16.8 months). The toxicity profile was favorable: grade 3/4 delayed diarrhea was observed in 10 patients (14.5%) in one cycle each, and grade 3/4 neutropenia in 6 patients (8.7%) and 6 cycles (3.3%). No febrile neutropenia or infection was documented. Grade 3/4 nausea and vomiting were reported in 1 (1.4%) and 7 patients (10.1%), respectively. In conclusion, this phase II trial showed a response rate and a toxicity profile of weekly CPT-11 in line with the results of prior phase II studies.     

CPT-11联合5-FU/FA方案治疗局部晚期或转移性结直肠癌的临床研究

目的评价CPT-11(开普拓)联合5-FU/FA治疗局部晚期或转移性结直肠癌的临床疗效及不良反应.方法符合收治标准者19例,可评价疗效者17例,入组Arm A方案8例,Arm B方案9例,ArmA方案:CPT-11270mg/m2静滴d1;FA200mg/m2,5-FU 425mg/m2分别静滴,均d1～5,每3周重复,两次CPT-11(6周)评价疗效.ArmB方案:CPT-11 180mg/m2静滴d1,LA200mg/m2,静滴d1～2,5-FU 400mg/m2静推,然后5-FU 600mg/m2,d1～2,每2周重复,应用3次CPT-11(6周)为一个周期.结果17例患者,CR 1例,PR 5例,SD 9例,PD 2例,总缓解率35%,稳定率52.9%,中位缓解时间7.5个月,中位稳定时间5个月.主要剂量限制毒性为迟发性腹泻及中性粒细胞减少.结论CPT-11联合5-FU/FA两种方案治疗局部晚期或转移性结直肠癌有较高的疾病缓解率和稳定率,主要剂量限制毒性为迟发性腹泻及中性粒细胞减少.     

艾力联合5-Fu及CF治疗晚期大肠癌的临床研究

目的观察艾力(CPT-11)及5-氟脲嘧啶(5-Fu)治疗晚期大肠癌近期疗效及不良反应。方法艾力120mg/m2,静滴,第1天;CF 100mg天/,静滴,第1至5天;5-Fu 500mg/m2,静滴,第1至5天;3周为1周期,2个周期后评估疗效及毒性反应。结果24例患者可评估者22例,其中CR 1例,PR 7例,SD 8例,PD6例,有效率36.4%。主要不良反应为恶心、呕吐、迟发性腹泻和骨髓抑制等。结论艾力 5-Fu/CF治疗晚期大肠癌有较好的疗效,且毒副反应可以耐受。     

Concurrent irinotecan, oxaliplatin and UFT in first-line treatment of metastatic colorectal cancer: a phase I study

The feasibility of combining UFT plus leucovorin (LV) with alternating irinotecan and oxaliplatin was investigated in the first-line treatment of patients with advanced colorectal cancer. Twenty-five patients, median age 63 (range 24-79) years, World Health Organisation performance status 0-2 and median four marker lesions, received irinotecan 180 mg m(-2) on day 1, oxaliplatin 85-100 mg m(-2) on day 15 and UFT 200-300 mg m(-2) day(-1) with LV 90 mg day(-1), days 1-21 of a 28-day cycle. Patients were treated in cohorts of three. At the highest dose (irinotecan 180 mg m(-2), oxaliplatin 100 mg m(-2) and UFT 300 mg m(-2) day(-1)), three of four patients experienced grade 3 toxicity. Diarrhoea, lethargy and vomiting were dose-limiting. Three of nine patients had grade 2 toxicities at the maximum tolerated dose (irinotecan 180 mg m(-2), oxaliplatin 100 mg m(-2) and UFT 250 mg m(-2) day(-1)). There were no grade 3 toxicities in the first month of therapy. The overall response rate was 71% in 21 evaluable patients; progression-free survival was 8.8 months. Alternating irinotecan and oxaliplatin plus UFT is an effective and well-tolerated first-line treatment for patients with advanced colorectal cancer. We recommend a dose of irinotecan 180 mg m(-2) on day 1, oxaliplatin 100 mg m(-2) on day 15 and UFT 250 mg m(-2) day(-1) with LV 90 mg day(-1) on days 1-21 of a 28-day cycle for future studies.     

Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer

The aim of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly Irinotecan (CPT-11) plus UFT, and to assess the antitumour activity of this combination as second-line chemotherapy in patients with advanced colorectal carcinoma, 31 patients with measurable advanced colorectal carcinoma were treated. Cohorts of 3 patients received increasing dose levels of the combination. Levels 1 to 4 included a fixed dose of oral (p.o.) UFT (250 mg/m²/day) for 21 days of a 28-day cycle combined with increasing intravenous (i.v.) doses of CPT-11 (80, 100, 110 and 120 mg/m²) on days 1, 8 and 15. Levels 5 and 6 included a higher fixed dose of oral UFT (300 mg/m²) combined with increasing i.v. doses of CPT-11 (100 and 110 mg/m²) on days 1, 8 and 15. 147 courses were administered. MTD were reached at level 4 (2 cases of grade 4 diarrhoea and 1 grade 3 asthenia), and level 6 (1 grade 4 diarrhoea, 1 grade 3 diarrhoea and 1 grade 3 febrile neutropenia). Responses in 30 evaluable patients were: 3 partial responses (10%), 15 stable disease (50%) and progressive disease in 12 patients (40%). Median time to progression was 4.5 months (95% Confidence Interval (CI): 3.4–6.6 months) and median survival was 11 months (95% CI: 7.9–14.1 months). The recommended doses for phase II trials are: (a) CPT-11 110 mg/m² i.v. on days 1, 8 and 15 every 28 days plus UFT 250 mg/m² p.o. on days 1 through to 21 or (b) CPT-11 100 mg/m² and UFT 300 mg/m².     

Phase II study of oral S-1 plus irinotecan in patients with advanced colorectal cancer: Hokkaido Gastrointestinal Cancer Study Group HGCSG0302

We have previously reported on phase I/II studies of irinotecan plus S-1 therapy for advanced gastric cancer. Based on the safety and efficacy data that were obtained, this phase II study was planned to assess the efficacy of irinotecan plus S-1 for patients with advanced colorectral cancer. A total of 40 patients are enrolled at 13 medical institutions. The objective of this study was to establish a useful chemotherapy regimen for an out-patient setting.     

Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients

Background:To determine the dose-limiting toxicity of CPT-11 incombination with oxaliplatin, and the maximal tolerated dose (MTD) and therecommended dose (RD) of CPT-11 using an every two weeks schedule. Patients and methods:The study was designed to evaluate escalateddoses of CPT-11 starting at 100 mg/m² with a fixedclinically-relevant dose of 85 mg/m² oxaliplatin given every twoweeks. Results:Twenty-three patients and 186 cycles were evaluable fortoxicity (median per patient: 7, range: 1–13). Grade 3oxaliplatin-induced neurotoxicity was cumulative and limiting in 39%(9 of 23) of patients. The MTD of CPT-11 was 200 mg/m², withincomplete neutrophil recovery at day 15 as limiting toxicity. At the RD (175mg/m² of CPT-11): no grade 4 neutropenia was seen in the two firstcycles; 30% of patients experienced grade 3–4 diarrhea. Febrileneutropenia (3.2% of all cycles) was 3-fold more frequent inperformance status (PS) 2 than in PS 0–1 patients. Among elevencolorectal cancer (CRC) patients, three complete and four partial responseswere documented, including in three 5-fluorouracil (5-FU) refractory patients. Conclusion:To combine CPT-11 175 mg/m² and oxaliplatin85 mg/m² every two weeks is feasible in an outpatient setting, andvery active in 5-FU resistant CRC patients. A dose of 150 mg/m²CPT-11 is recommended in PS 2 patients.     

A randomised phase II multicentre trial of irinotecan (CPT-11) using four different schedules in patients with metastatic colorectal cancer

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of grade 3-4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.     

Phase II study of UFT with leucovorin and irinotecan (TEGAFIRI): first-line therapy for metastatic colorectal cancer

This phase II trial was performed to evaluate the efficacy and tolerability of oral tegafur-uracil (UFT) with leucovorin (LV) combined with intravenous (i.v.) irinotecan every 3 weeks (TEGAFIRI) as first-line treatment for patients with metastatic colorectal cancer (mCRC). Patients received oral UFT 250 mg m(-2) day(-1) and LV 90 mg day(-1) in three divided daily doses for 14 days followed by a 1-week rest and i.v. irinotecan 250 mg m(-2) as a 90-min infusion every 3 weeks. Tumour responses, assessed every two cycles using RECIST criteria, were reviewed by an independent review committee. In 52 evaluable patients, the best overall response rate was 33% (95% confidence intervals (CI) 20-47%; 1 complete and 16 partial responses). The median time to progression was 5.4 months (95% CI 3.02-7.52 months) and median overall survival was 14.9 months (11.73-17.97 months). A total of 307 cycles were administered, with a median number of five cycles per patient (range: 1-10). The most common grade 3/4 toxicities were neutropenia (25% of patients), diarrhoea (22%), vomiting (11%) and anaemia (11%). The TEGAFIRI regimen is a feasible, well-tolerated and convenient treatment option for patients with non-resectable mCRC.     

Uracil-tegafur/leucovorin and mitomycin C salvage therapy in patients with advanced colorectal cancer: a phase II study

Abstract

We investigated the efficacy and safety of oral Uracil/tegafur (UFT) with leucovorin and mitomycin C (MMC) as third-line treatment for patients with extensively pretreated metastatic colorectal cancer (mCRC). This was a multicenter, prospective phase II study. Patients received MMC 7 mg/m² on day 1 and UFT 300 mg/m² with leucovorin 90 mg, both divided into three daily doses, on days 1–28 every 5 weeks. All patients had failed prior treatment with irinotecan, oxaliplatin, fluoropyrimidine, bevacizumab, and cetuximab. The primary endpoint was tumor control rate evaluated after 2 cycles. Twenty-one patients were included: median age was 66 years (41·1–87·8 years). Tumor control rate was observed in 26·7% of the 15 patients evaluable for response. Median overall survival was 6·4 months. Grade 3 adverse events were asthenia, anorexia, and vomiting. In patients with mCRC who have progressed after as many as two prior therapies, the combination of UFT/leucovorin and MMC is safe and may produce a short stabilization of disease in approximately 25% of patients.     

CPT-11联合5-Fu/FA方案治疗34例晚期结直肠癌的疗效观察

目的评价CPT-11联合5-Fu／FA方案治疗晚期结直肠癌的临床疗效及毒副反应。方法全组34例,可评价疗效31例,其中3周方案14例,2周方案17例。3周方案：CPT-11 270mg／m^2静滴,d1,FA200mg／m。静滴,d1-5,5-Fu425mg／m^2静滴,d1-5,21d为1个周期,2个周期（6周）评价疗效;2周方案：CPT-11 180mg／m^2静滴,d1,FA200mg／m^2静滴,d1-2,5-Fu400mg／m^2静推,随后5-Fu600mg／m^2静滴22h,d1-2,14d为1个周期,3个周期（6周）评价疗效。结果CR1例,PR11例,SD14例,PD5例,总缓解率38．7％,总稳定率45．2％。中位缓解时间7．1个月,中位稳定时间8个月。主要毒副反应为迟发性腹泻（Ⅲ／Ⅳ度发生率为32．4％）及中性粒细胞减少（Ⅲ／Ⅳ度发生率为35．3％）。结论CPT-11联合5-Fu／FA两种方案治疗晚期结直肠癌有效率高,毒副反应可以耐受．可作为晚期结直肠癌的一线或二线化疗方案。     

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.     

Phase I study of S-1 combined with irinotecan (CPT-11) in patients with advanced gastric cancer (OGSG 0002)

OBJECTIVE: A dose-escalation study of irinotecan (CPT-11) combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLTs) in advanced gastric cancer. METHODS: S-1 was administered orally at 80 mg/m(2)/day for 21 consecutive days followed by a 2 week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 40 mg/m(2)/day, stepping up to 60, 80, 100 or 120 mg/m(2)/day depending on the DLT. Courses were repeated every 5 weeks, unless disease progression or severe toxicity was observed. At a level of the RD, five patients were added to conduct a pharmacokinetic (PK) study. RESULTS: A total of 24 patients were entered in this study. The MTD of CPT-11 was considered to be 100 mg/m(2), because 50% of the patients (3/6) developed DLTs, diarrhea and rash. Therefore, the RD of CPT-11 was set at the dose immediately below 80 mg/m(2). The overall response rate (RR) by the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24) and the RR at the RD was 66.7% (6/9), suggesting promising clinical efficacy. There were no significant differences between the PK parameters of S-1 on days 10 and 15. CONCLUSIONS: S-1 with CPT-11 can be combined safely without CPT-11 effect on S-1 PK data and holds promise as an effective regimen for advanced gastric cancer.     

Topoisomerase-I, thymidylate synthase primary tumour expression and clinical efficacy of 5-FU/CPT-11 chemotherapy in advanced colorectal cancer patients

While several studies have reported that thymidylate synthase (TS) tumour expression can be a reliable predictive marker of clinical response to 5-Fluorouracil (5-FU) for advanced colorectal cancer patients, only a few studies that searched for predictive factors of irinotecan (CPT-11) clinical response are available. The aim of the present study has been to verify the predictive value of immunohistochemical topoisomerase-I (Topo-I) and TS primary tumour expression in a consecutive series of 62 advanced colorectal cancer patients that received a first line 5-FU/CPT-11 chemotherapy. TS and Topo-I immunostaining was observed in 76% and 43% of tumours, respectively, resulting in a significant relationship within each tumour (r=0.365, p<0.004). Patients with different TS tumour expression showed a similar percentage of Objective Clinical Response, OR (40% vs. 28% of OR in low and high TS-expressing tumours, respectively, p=ns); also, patients with different Topo-I tumour expression did not show a different probability of OR (39% vs. 29% of OR in high and low Topo-I expressing tumours, respectively; p=ns).The tumour expression of these 2 biomarkers also did not impact on time to progression and overall survival of patients. Furthermore, the combined analysis of TS and Topo-I tumour status did not permit to individualize subgroups of patients with different probability of OR. With multivariate analysis, only patient Performance Status significantly impacted on OS (Hazard ratio 4.87; p=0.02) of these patients. We can conclude that high TS tumour expression seems not to preclude a clinical activity for 5-FU/CPT-11 polichemotherapy in advanced colorectal cancer patients; furthermore, clinical response and prognosis of colorectal cancer patients treated with 5-FU/CPT-11 regimen do not differ in tumours with different TS or Topo-I expression.     

A phase I/II study of oral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200-300 mg/m(2)) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1. RESULTS: A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m(2)) combined with UFT 250 mg/m(2)/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m(2) and three of six patients at the 300 mg/m(2) irinotecan dose level. Having defined the MTD, the 250 mg/m(2) dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients. CONCLUSION: UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1-14, with irinotecan 250 mg/m(2) administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.     

伊立替康联合5-Fu/CF治疗晚期结直肠癌的临床受益分析

背景与目的：伊立替康（CPT-11）是喜树碱类抗癌药物，为DNA拓扑异构酶Ⅰ抑制剂。它通过CyP3A酶氧化成无活性代谢物（包括APC），并通过羟酸酯酶-2（CES-2）活化成SN-38。CPT-11具有良好的抗结直肠癌的活性本文评价CPT-11联合5-FU／CF方案治疗晚期结直肠癌的临床受益、客观疗效和毒副反应。方法：用CFT-11联俞5-FU／CF方案治疗晚期结直肠癌患者32例，包括19例患者采用CPT-11联合5-FU／CF2周方案治疗；13例患者采用CPT-11联合5-FU／CF3剧厅案治疗。结果：可评价疗效者30例，其中完全缓解（CR）2例，部分缓解（PR）11例，RR占43．3％，稳定（SD）14例，占46．7％，进展（PD）3例。临床受益率为83．3％，疼痛缓解率83．3％。中位肿瘤进展时间7．2月，中位生存期13．8月。主要副反应为迟发性腹泻和中性粒细胞减少，未出现治疗相关性死亡结论：CPT-11联合5-FU／CF方案治疗晚期结直肠癌患者有效，临床缓解率高，明显减轻患者的痛苦，提高患者的生存质量，毒副作用患者能够耐受。因此，可作为晚期结直肠癌的一线或二线治疗方案。