Phase II study of biweekly irinotecan and mitomycin C combination therapy in patients with fluoropyrimidine-resistant advanced colorectal cancer

PURPOSE: Experimental studies have shown that mitomycin C (MMC) acts synergistically with irinotecan. We evaluated the antitumor activity and toxicity of a combination of irinotecan and MMC in patients with metastatic colorectal cancer resistant to fluoropyrimidines. METHODS: Eligible patients had evidence of tumor progression while receiving fluoropyrimidine-based regimens or had disease recurrence within 6 months after the completion of adjuvant treatment with fluoropyrimidines. Irinotecan (150 mg/m(2)) and MMC (5 mg/m(2)) were administered on days 1 and 15 of a 28-day cycle. Treatment was repeated every 4 weeks. RESULTS: Among the 41 patients enrolled, 37 (90%) had received previous chemotherapy for metastatic disease, and 4 had received adjuvant chemotherapy alone. Objective responses were observed in 14 patients (34%, 95% confidence interval 20-49%). The median time to progression was 4.2 months, and the median survival time was 11.9 months. The study treatment was well tolerated; the median number of cycles received was four. Grade 3 or 4 neutropenia, the most common toxic effect, occurred in 20 patients (49%). Grade 3 or 4 thrombocytopenia occurred in four patients (10%) and grade 3 diarrhea in one patient. CONCLUSIONS: Our results suggest that irinotecan and MMC combination therapy is effective and well tolerated in patients with fluoropyrimidine-resistant metastatic colorectal cancer. Further clinical investigation of this regimen is warranted.     

Clinical study of irinotecan plus infusional fluorouracil/l-leucovorin (FOLFIRI) in patients with fluoropyrimidine-resistant metastatic colorectal cancer

The clinical efficacy and safety of irinotecan plus infusional fluorouracil/l-leucovorin (FOLFIRI) in patients with fluoropyrimidine-resistant metastatic colorectal cancer were studied retrospectively. 20 patients were treated with FOLFIRI at our hospital between October 2003 and November 2005. The objective overall response rate was 28% (5/18; 95% confidence interval, 9.7-54%). The disease control rate (CR+PR+SD) was 61%. The most frequent grade 3 to 4 adverse event was neutropenia, and it was seen in 50%. Non-hematological toxicities were mild. The median survival time was 11 months. The 1-year survival rate was 34%. This study showed the activity and safety of FOLFIRI in practice.     

依立替康(Irinotecan,CPT-11)治疗晚期大肠癌临床研究

目的：评价ＣＰＴ－１１（商标名：开普拓）单药治疗晚期大肠癌的临床疗效及其不良反应。材料与方法：从１９９７年１１月至１９９９年３月入选晚期大肠癌６９例,符合收治标准者６１例,可评价闻效者５０例,其中,以前未接受过任何化疗的病人２５例,经过一个５ＦＵ为主方案化疗后耐药的病人２５例。ＣＰＴ－１１３０－３００mg/m^2,静肪点滴,每３周为一疗程。除ＰＤ病人外,至少用药３周期。结果：在可评价病例中,８例（１６．     

Preliminary study of fortnightly irinotecan hydrochloride plus cisplatin therapy in patients with advanced gastric and colorectal cancer

PURPOSE: Irinotecan hydrochloride shows a strong activity against gastric cancer and colorectal cancer, while combined therapy with irinotecan and cisplatin is useful for gastric cancer. However, myelosuppression and diarrhea are still dose-limiting factors. To reduce such toxicities to enable therapy to be performed on an outpatient basis, we tested the effect of divided administration of cisplatin. METHODS: Irinotecan (60 mg/m2) plus cisplatin (30 mg/m2) were administered on days 1 and 15 every 4 weeks to 13 patients with advanced gastric cancer and 13 with advanced colorectal cancer. Treatment was continued if a leukocyte count > or = 3000/mm3, a platelet count > or = 100,000/mm3, and grade 0 diarrhea were confirmed. Doses were reduced if grade 3-4 hematological toxicity and grade 2 or higher nonhematological toxicity occurred. RESULTS: The major toxicity was leukopenia (neutropenia), but grade 3-4 nonhematological toxicity was not observed. The response rate was 41.7% for gastric cancer (5/12 evaluable patients) and 36.7% for colorectal cancer (4/11 evaluable patients). The median survival time was 313 days (range 29-920 days) for gastric cancer patients and 490 days (range 83-1184 + days) for colorectal cancer patients. CONCLUSION: Fortnightly administration of irinotecan and cisplatin (with a divided cisplatin dose) seems to be a useful regimen for gastrointestinal cancer. It reduces toxicity while maintaining a good antitumor effect.     

Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: A combination of irinotecan with continuous intravenous infusions of 5-fluorouracil (5-FU) and leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. This phase II study evaluated the efficacy and safety of the oral fluoropyrimidine S-1 plus irinotecan in patients with previously untreated advanced or recurrent colorectal cancer. PATIENTS AND METHODS: Forty eligible patients with histologically confirmed colorectal adenocarcinoma received this treatment. S-1 was administered orally on days 1 to 14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg (BSA < 1.25 m(2)), 50 mg (BSA > or = 1.25 to < 1.50 m(2)), or 60 mg (BSA > or = 1.50 m(2)). Irinotecan (150 mg/m(2)) was administered by intravenous infusion on day 1. RESULTS: A total of 327 courses of treatment were administered to 40 patients. Five patients had complete responses, and 20 had partial responses. The overall response rate was 62.5% (95% confidential interval, 47.5%-77.5%). Median progression-free survival was 8.0 months (95% confidential interval, 5.2-11.4 months). The rates of grade 3 or 4 toxicity were as follows: neutropenia, 15%; anemia, 7.5%; anorexia, 12.5%; and diarrhea, 7.5%. CONCLUSIONS: Combined treatment with S-1 and irinotecan is an effective, well tolerated, and convenient regimen in patients with advanced colorectal cancer. Our findings suggest that combined treatment with S-1 and irinotecan is a promising regimen, offering benefits in terms of safety and survival as compared with conventional regimens in patients with advanced colorectal cancer.     

FOLFIRI方案二线治疗晚期大肠癌临床疗效观察

目的观察FOLFIRI方案二线治疗晚期大肠癌的临床疗效和不良反应。方法病理确诊的44例晚期大肠癌患者接受FOLFIRI方案化疗：伊立替康（CPT．11）150nlg／m^2,静脉滴注,第1天;亚叶酸钙（CF）200mg／m^2,静脉滴注2h,第1、2天;5-氟尿嘧啶（5-Fu）400mg／／112,静脉注射,第1、2天后予5-Fu600mg／m。持续静脉滴注22h,第1、2天;每2周重复,化疗2次为1个周期。治疗4～6个周期后按实体瘤疗效评定标准评价疗效及不良反应。结果全组病例均可评价疗效,其中完全缓解2例,部分缓解16例,有效率为40．9％;中位生存期11．3个月,中位疾病进展时间6．5个月。主要的不良反应为乙酰胆碱能综合征和迟发性腹泻及骨髓抑制。结论FOLFIRI方案作为二线方案治疗晚期大肠癌疗效肯定,可使大部分患者临床受益,不良反应可以耐受,值得临床进一步试用、研究。     

不同剂量密度伊立替康联合LD—FP持续灌注治疗晚期大肠癌的临床研究

目的观察不同剂量密度伊立替康(CPT-11)联合LD-FP持续灌注治疗晚期大肠癌的近期疗效、生存期和毒副作用。方法采用两种方法对38例患者进行研究。每周剂量(A组)21例,3周剂量(B组)17例。A组:CPT-1160 mg/m2,iv,d1、8、15;B组:CPT-11 150 mg/m2iv,d1。两组分别联合5-Fu 300 mg/(m2.d),d1~14,微量泵持续静脉给药;DDP5 mg/d,d1~5,d8~14,iv;CF100 mg/(m2.d),d1~14,iv。28 d为1周期。结果A、B两组总有效率分别为20.0%和23.5%,中位肿瘤进展期(mTTP)均为5个月,中位生存期(MST)分别为15和14.5个月,临床获益率分别为75.0%和76.4%。胆碱能症状、黏膜炎均表现轻微。Ⅲ/Ⅳ度迟发性腹泻发生率分别为9.5%和23.5%,Ⅲ/Ⅳ度粒细胞减少发生率分别为14.3%和35.2%。结论两种方案治疗晚期大肠癌疗效无差别,每周方案毒性反应更低,均可作为晚期大肠癌的一线、二线化疗方案。     

A phase II study of combination therapy with irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer

Purpose

A combination of irinotecan with continuous infusional 5-fluorouracil (5-FU) is the standard treatment for advanced colorectal cancer. The aim of this study was to determine the efficacy and safety of combining irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer.

Methods

Irinotecan was administered as an intravenous infusion at a dose of 120 mg/m² on day 1 and 15. And S-1 was administered orally on days 1–14 of a 28-day cycle. S-1 was given orally at a dose that did not exceed 40 mg/m² based BSA: BSA < 1.25 m², 40 mg twice daily; 1.25–1.5 m², 50 mg twice daily, and BSA > 1.5 m², 60 mg twice daily, for 14 consecutive days.

Results

A total of 38 patients were enrolled. An intent-to-treat analysis showed a complete response and partial response to occur in 13.2% and 50.0%, respectively. The disease control rate was 84.2%. The median progression-free survival and overall survival were 10.0 months and 29.1 months, respectively. The rates of grade 3/4 toxicity over 4 cycles were the following: neutropenia, 15.8%; leucopenia, 7.9%; anorexia, 15.8%; diarrhea, 10.5%. Conclusion: IRIS is an effective, well tolerated and convenient treatment regimen for patients with advanced colorectal cancer.     

Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer

Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250-350 mg/m(2) as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m(2) as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3-4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m(2)) and raltitrexed (3 mg/m(2)) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.     

Pharmacokinetics and metabolism of irinotecan combined with capecitabine in patients with advanced colorectal cancer

BACKGROUND: Irinotecan (CPT-11) in combination with 5-fluorouracil/folinic acid is used successfully for first-line treatment of metastatic colorectal cancer. Capecitabine (CCB) represents a very convenient alternative to 5-fluorouracil, either as single agent or in a combination of regimens acting synergistically and with the potential to further improve efficacy. Both CPT-11 and CCB need to be activated by human carboxyl esterases, therefore a probable pharmacokinetic drug interaction was checked. PATIENTS AND METHODS: Ten patients suffering from advanced colorectal cancer were enrolled in this trial. CPT-11 was administered as a 30-min i.v.-infusion (70 mg/m2) weekly. CCB was given p.o. twice daily for two weeks (2,000 mg/m2 daily) starting the day after the first CPT-11 infusion. Plasma samples were analysed during/after the first (MONO) and third (CAPIRI) CPT-11 infusion. RESULTS: CCB did not alter CPT-11 plasma disposition, and no significant changes in c(max), AUC(last), Vdss and Cl(tot) during CAPIRI treatment could be observed. However, co-administration of CCB appeared to decrease SN-38 (the cytotoxic CPT-11 metabolite) plasma concentrations during the first three hours after initiation of CPT-11 infusion, with strongly time-dependent plasma percentage differences between control and CAPIRI treatment (p < 0.005, R = 0.981). Co-administration of CCB also had a similar impact on the initial plasma disposition of SN-38gluc, but not on that of the APC metabolite. CONCLUSION: Overall, our findings indicate that, while the administration of CCB resulted in reversible lower formation rates of SN-38 and SN-38gluc, it did not have a significant impact on CPT-11 pharmacokinetics.     

Cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil

Cetuximab (Erbitux®) in combination with irinotecan is the most promising combination in heavily pretreated patients with advanced colorectal cancer. Efficacy of this combination was confirmed in the pivotal BOND I study. The aim of the present study was to evaluate efficacy and toxicity of a combination regimen of cetuximab and irinotecan but in contrast to the BOND I study all patients had previously received 5-FU, oxaliplatin and irinotecan and all had progressed during or shortly after completion of treatment. Before January 2005 salvage therapy with cetuximab and irinotecan was not used in Denmark. The Danish government had initiated a national programme for patients with advanced cancer and according to this programme the National Board of Health may approve and finance experimental treatment. From January 2005 to September 2005, 65 consecutive patients were treated with cetuximab (weekly) and irinotecan (each 2 or 3 weeks) at three university hospitals. Median age was 57 years (23-78), and median performance status was 1 (0-3). Response rate was 20%, median TTP was 5.5 months and median OS was 10.4 months. Response and survival was significantly correlated with severity of skin toxicity. Toxicity grade 3 was rare (skin toxicity 8%, diarrhoea 10%, nausea 3%, vomiting 3%, fatigue 8%). Salvage therapy with cetuximab and irinotecan is effective in patients pretreated with irinotecan, and oxaliplatin and in a general population the results from the BOND I study was confirmed.     

Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan,oxaliplatin and 5-fluorouracil

BackgroundStandard weekly cetuximab and irinotecan (CetIri) is an effective regimen in heavily pretreated patients with advanced colorectal cancer (ACRC). Inspired by a pharmacokinetic study demonstrating no differences between weekly and biweekly cetuximab, we present the results of 74 consecutive patients treated with biweekly CetIri.MethodsBiweekly CetIri schedule: cetuximab 500 mg/m², first course was given as a 120-min infusion followed 1 h later by irinotecan 180 mg/m² as a 30-min infusion. Subsequent courses of cetuximab were given in 60 min, immediately followed by irinotecan—resulting in an overall treatment time of 90 min.ResultsAll patients had ACRC resistant to 5-fluorouracil and irinotecan and 95% to oxaliplatin. Median age was 63 years, median performance status was 0. Median duration of therapy was 4.3 months. Response rate was 25%. Median progression-free survival and overall survival were 5.4 months and 8.9 months, respectively, comparable to own historical controls receiving weekly CetIri. Grade 3–4 toxicity was rare (skin 7%, nail 3%, diarrhoea 10%, fatigue 3%, neutropenia 9%). One patient experienced severe allergic reaction.ConclusionSalvage therapy with simplified biweekly CetIri is a convenient, effective and well-tolerated regimen in heavily pretreated patients with ACRC. A confirmatory phase II study is ongoing.     

Single-agent irinotecan as second-line weekly chemotherapy in elderly patients with advanced colorectal cancer

AIMS AND BACKGROUND: Irinotecan is a standard option for relapsed/refractory advanced colorectal cancer. Although in a recently reported, randomized trial it was found that a regimen of irinotecan once every 3 weeks was associated with a lower incidence of severe diarrhea than with weekly treatment with similar efficacy, there is no evidence in the literature that suggests the optimal dosing strategy for the drug, along with treatment efficacy and safety, following 5-fluorouracil/oxaliplatin-based chemotherapy in elderly patients. A phase II study has reported significantly reduced toxicity when irinotecan was administered once a week for 2 weeks, followed by a week rest. PATIENTS AND METHODS: From January 2004 to April 2005, we analyzed, retrospectively, our data on single-agent irinotecan as a second-line chemotherapy in elderly patients (> or =70 years) with advanced colorectal cancer. Twenty-three patients were evaluated. CPT-11 (80 mg/m2) was given as a 60-min intravenous infusion in repeated 21-day courses comprising weekly treatment for 2 consecutive weeks followed by a 1-week rest. Tumor measurements were obtained after every third course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria, version 2. RESULTS: The median number of treatment courses received per patient was 4 (range, 1-8). All patients were assessable for toxicity and 21 for response. The most frequently observed severe toxicities were diarrhea (grade 3, 13%) and neutropenia (grade 3, 30.4%; grade 4, 8.6%). Only 1 case of neutropenic fever occurred. Other hematological and non-hematological toxicities were mild and manageable. Objective partial responses were observed in 3 patients (13%). An additional 10 patients (43%) had stable disease as their best response. To date, 12 patients have progressed with a median time-to-progression of 4.3 months and a median survival of 8.3 months. CONCLUSIONS: A weekly irinotecan administration can induce tumor control in elderly patients with advanced colorectal cancer that has progressed during or shortly after 5-fluorouracil/oxaliplatin-based chemotherapy. However, a careful monitoring of hematological toxicity and special instructions to prevent and manage diarrhea are mandatory in this setting of patients.     

A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil

This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.     

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.     

TOPO-1在转移性结直肠癌组织中的表达及与伊立替康化疗的相关性研究

目的　探讨拓扑异构酶1（topoisomerase1,TOPO-1）在转移性结直肠癌组织中的表达,并分析其与伊立替康（CPT-11）化疗疗效的相关性。方法 经病理活检证实为转移性结直肠癌初诊者98例,均接受FOLFIRI方案一线化疗,化疗前检测肿瘤组织TOPO-1的表达水平,分析TOPO-1表达水平与近期疗效的关系,并观察远期疗效。结果 TOPO-1 表达水平与转移性结直肠癌的临床特征无明显相关性（P＞0.05）。高表达组患者RR为52.2%（24/46）,低表达组RR为28.8%（15/52）,差异有统计学意义（P<0.05）。TOPO-1高表达组中位PFS为9.5个月（8~12个月）,低表达组为8.0个月（7~9个月）,差异有统计学意义（P=0.002）。结论 TOPO-1高表达转移性结直肠癌患者可从伊立替康化疗中获得更高的近期疗效和更长的无疾病进展生存时间,可能对伊立替康化疗更敏感。     

Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients

Purpose  This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients. Methods  Five dose level combinations with irinotecan (from 180 to 240 mg/m², day 1, q21), capecitabine (1,500–2,000 mg/m² per day, days 2–15, q21) and erlotinib (50–150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. Results  Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed. Conclusions  The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m² and capecitabine 1,500 mg/m² per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.     

Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer

The aim of this phase II study was to investigate the tolerance and efficacy of a second-line irinotecan/mitomycin C combination in patients with advanced gastric or colorectal cancer, pretreated with 5-fluorouracil. Forty patients who had received 5-fluorouracil-based chemotherapy for advanced disease or adjuvant 5-fluorouracil treatment were enrolled. Chemotherapy consisted of irinotecan 125 mg/m2 and mitomycin C 5 mg/m2, given every 2 weeks. Treatment was continued until progression or limiting toxicity occurred. Five partial responses (12.5%), 22 cases of stable disease (55%) and 13 of progression (32.5%) were registered, giving an overall response rate of 12.5% [95% confidence interval (CI), 4.2-26.8%] and an overall control of tumor growth in 67.5% (95% CI, 50.8-81.4%) of patients. Median progression-free survival was 5 months, median survival time 8 months, and 1-year probability of survival was 21.6%. Diarrhea and neutropenia affected 25% and 12.5% of patients respectively, with only 7.5% experiencing grade 3-4 toxicity. There were no chemotherapy-related deaths or hospitalizations. This combination regimen was shown to be moderately effective with substantially lower toxicity than irinotecan monotherapy in 5-fluorouracil-pretreated patients with advanced gastric or colorectal cancer. It may represent an attractive option in patients at high risk for developing specific irinotecan toxicity.