开普拓（CPT—11）治疗中国人晚期大肠癌初步结果

目的 评价开普拓（ＣＰＴ－１１）治疗中国晚期大肠癌患者的疗效及安全性。方法 ＣＰＴ－１１ ３００ｍｇ／ｍ＾２加生理盐水２００ｍｌ,静脉点滴３０ｍｉｎ,每３周１次,３周为１个周期,至少治疗３个周期。结果 收治１４例,初汉７例,二线治疗７例。在１３例可评价疗效的患者中,ＰＲ３例,Ｓ４例,Ｐ６例,有效率为２３．１％,缓解期为３￣７个月。３例ＰＲ患者均为初治者,治疗后中位生存期为９个月（６￣２２个月）。治     

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。     

A Phase II Study of Advanced Colorectal Cancer Patients Treated with Combination 5-Fluorouracil Plus Leucovorin and Subcutaneous Interleukin-2 Plus Alpha Interferon

Summary

Twenty-one patients with advanced, pretreated colorectal cancer in disease progression were entered in a phase II study to investigate the use of 5-fluorouracil (5FU) + leucovorin with subcutaneous Interleukin-2 + alpha interferon (α-IFN). Eighteen of these patients were evaluable for response to treatment: 1 partial response (PR) (duration 8 months), 9 stable disease (SD) (median duration of 6.5 months, range 2-15) and 8 progressive disease (PD). The PR patient survived for 15 months, the SD patients for a median of 11 months and 8 months for PD patients. Toxicity evaluated in the 21 patients reached grade 4 for mucositis in two cases. Grade 3 toxicity was observed more frequently for fever (52.3%) and diarrhea (33.3%) and was most probably the result of the combined side-effect of chemotherapy and the biological response modifiers (BRMs). Treatment was, for the most part, carried out on an out-patient basis as originally planned.

In 15 patients tests were carried out to verify whether any immuno-activation had taken place. Significant increases were found during the course of therapy regarding cluster of differentiation activation (HLA-DR, CD71, CS25). Different curves were observed during the course of treatment with respect to the CD8 value, which proved higher in SD patients than in PD patients.

Our study would seem to suggest that the addition of BRMs to 5FU + leucovorin could increase survival. The next step, however, must be to determine lower doses of IL-2 for subcutaneous administration in order to reduce toxicity but maintain the same immunostimulation.     

Etoposide,Leucovorin (LV) and 5-Fluorouracil (5-FU) in 5-FU+LV Pre-Treated Patients with Advanced Colorectal Cancer

Abstract

In the present study, we evaluated the efficacy and safety of the weekly combination of etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer (ACC), previously treated with weekly LV+5-FU. Etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m², DL-II: etoposide 120 mg/m², and DL-III: etoposide 180 mg/m², in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m² i.v. over 1 hour and 5-FU 500 mg/m² i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n=19) compared to DL-II (n=10) and DL-III (n=8) (p<0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neu-tropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation.     

奥沙利铂联合亚叶酸钙与5-氟脲嘧啶治疗老年晚期结直肠癌的临床研究

目的评价国产奥沙利铂（L-OHP）联合亚叶酸钙（CF）、5-氟脲嘧啶（5-Fu）治疗局部晚期或转移性老年结直肠癌患者（≥70岁）的临床疗效及毒副反应。方法入组30例患者，方案L-OHP130mg／m^2静脉滴注2h，第1天；CF200mg／m^2静脉滴注2h，第1～5天；5一Fu425mg／m^2静脉滴注6h，第1-5天。每3周重复，两周期后评价疗效。结果30例患者均可评价疗效，无CR病例，PR15例，SD8例，PD7例，有效率为50％，中位生存期18个月，中位无进展生存9．5个月，1年生存率为66.7％。主要毒副反应为神经毒性，中性粒细胞减少，消化道反应及腹泻。结论L-OHP联合5-Fu／FA方案治疗局部晚期或转移性老年结直肠癌患者疗效较高，耐受性较好，值得进一步研究。     

奥沙利铂联合亚叶酸钙与5-氟脲嘧啶治疗老年晚期结直肠癌的临床研究

目的评价国产奥沙利铂(L-OHP)联合亚叶酸钙(CF)、5-氟脲嘧啶(5-Fu)治疗局部晚期或转移性老年结直肠癌患者(≥70岁)的临床疗效及毒副反应。方法入组30例患者,方案L-OHP 130mg/m2静脉滴注2h,第1天;CF 200mg/m2静脉滴注2h,第1~5天;5-Fu 425mg/m2静脉滴注6h,第1~5天。每3周重复,两周期后评价疗效。结果30例患者均可评价疗效,无CR病例,PR 15例,SD8例,PD 7例,有效率为50%,中位生存期18个月,中位无进展生存9.5个月,1年生存率为66.7%。主要毒副反应为神经毒性,中性粒细胞减少,消化道反应及腹泻。结论L-OHP联合5-Fu/FA方案治疗局部晚期或转移性老年结直肠癌患者疗效较高,耐受性较好,值得进一步研究。     

Clinical Study of Combining Chemotherapy of Oxaliplatin or 5-Fluorouracil/Leucovorin with Hydroxycamptothecine for Advanced Colorectal Cancer

OBJECTIVE To estimate the short-time efficacy, side effects, survival rate after the treatment of combining chemotherapy of oxaliplatin or 5-fluorouracil/leucovorin with hydroxycamptothecine (HCPT) for the patients with advanced colorectal cancer.METHODS From January 2002 to November 2005, 59 patients with advanced colorectal cancer confirmed by pathology were enrolled into this study in the department of medical oncology,in the Sixth People's Hospital of Shanghai Jiaotong University,Shanghai. Patients' characteristics in two groups were similarly confirmed by statistic. All 37 patients in OH group received oxaliplatin (130 mg/m2 dl) plus hydroxycamptothecine (6mg/m2 d1-4), and all 22 patients in the HLF group received hydroxycamptothecine (6 mg/m2 d1-4) plus leucovorin (300 mg d1-5) and 5-fluorouracil (0.375 g/m2 d1-5). The regimens in both groups were 21-day cycle that was repeated three weeks. The side effects were evaluated. The efficacy was estimated after two cycles of chemotherapy for each patient.RESULTS The efficacy of the treatment in the OH group with 37 patients and in the HLF group with 22 patients was estimated.The overall response rate (CR + PR) was 32.4% in the OH group and 22.7% in the HLF group. There was no complete response (CR) and there was no statistical significantly difference (x2= 0.876,P = 0.704) in two groups. The 1-year survival rate was 30.98%in the OH group and 15.02% in the HLF group, and it had no significant difference between the two groups. The median PSF and OS were 5.83 months and 11.17 months in the OH group vs.7.40 months and 10.48 months in the HLF group, and it had no significant differences between the two groups (P > 0.05). The major side effects of grade Ⅲ and Ⅳ in the two groups were myelosuppression and gastrointestinal reactions. The statistically significant difference in side effects appeared in leukoperda (x2=17.173, P = 0.001), nausea/vomiting (x2 = 6.426, P = 0.039), diarrhea (x2 = 16.245, P = 0.000) and peripheral neuropathy.CONCLUSION The efficacy was almost equal between the OH and the HLF groups, and the two regimens can be used as the second-line treatments for the patients with colorectal cancer. Leucopenia, nausea, diarrhea and peripheral neuropathy appeared more in OH group, and anemia and thrombocytopenia were almost equal between the OH and the HLF groups.     

奥沙利铂联用氟脲嘧啶、亚叶酸钙治疗晚期大肠癌的临床研究

目的　观察奥沙利铂联用氟脲嘧啶、亚叶酸钙治疗晚期大肠癌 (ACRC)的疗效和安全性。方法　收治晚期大肠癌患者 3 0例 ,采用L_OHP 13 0mg/m2 静脉滴注 4hd1 ;CF 2 0 0mg/m2 静脉滴注半小时后 5_Fu 5 0 0mg/m2 静脉滴注 6hd1～ 5,每 3周重复。结果　部分缓解 (PR) 9例 ,稳定 (SD) 8例 ,进展 (PD) 8例 ,总有效率 3 6%。毒性反应主要为感觉神经毒性 ( 90 %) ,其次为恶心呕吐 ( 60 %)和腹泻 ( 4 6 7%)。骨髓抑制毒性小。结论　L_OHP联合 5_Fu、CF治疗大肠癌疗效肯定 ,耐受性良好 ,值得临床进一步研究     

羟基喜树碱联用氟脲嘧啶／醛氢叶酸治疗晚期大肠癌的临床研究

目的：观察羟基喜树碱（hydroxycamptothecin,HCPT）与醛氢叶酸（leucovorin,LV）、氟脲嘧啶（fluorouracil,5-FU)组成的HLF方案对晚期大肠癌的疗效及不良反应。方法：治疗组27例予HLF方案化疗,HCPT6-8mg/m^2,第1-5天静滴;LV20mg/m^2,第1-5天静注：5-FU425mg/m^2,第1-5天静注。对照组35例予Mayo方案化疗,LV及5-FU用法同治疗组。以上方案每4周重复。结果：HLF方案和Mayo方案有效率、疾病进展时间（time to progression,TTP）分别为29.6%vs22.9%（P=0.546）和29.0周vs22.0周（P=0.0238）。主要不良反应为消化系统、血液系统毒性,多为Ⅰ-Ⅱ度,患者耐受良好。结论：HLF方案治疗晚期大肠癌,可能有助于提高有效率、延缓疾病进展,值得临床进一步观察研究。     

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.     

雷替曲塞联合L-OHP与5-Fu/LV联合L-OHP方案治疗晚期结直肠癌的临床疗效比较

 目的 评价雷替曲塞联合奥沙利铂（L-OHP）治疗晚期大肠癌的疗效和安全性。方法 40例晚期复治大肠癌患者分为两组,A组20例,予雷替曲塞3mg/m^2,d1,静脉注射15min,奥沙利铂130mg/m^2,d1静脉滴注3h,每3周重复1次。B组20例,奥沙利铂130mg/m^2,d1静脉滴注3h,甲酰四氢叶酸200mg/m^2,静脉滴注2h,续以5-Fu400mg/m^2静脉滴注6～8h,连用5d,每3周重复1次,每次计为1治疗周期。结果 A、B两组分别有19例和18例可评价,RR分别为36.8%和22.2%,中位TTP分别为7.8个月和5.0个月,两组结果比较差异有统计学意义（P〈0.05）。结论 雷替曲塞联合L-OHP方案在临床疗效优于5-Fu/LV联合L-OHP方案。     

Weekly irinotecan (CPT-11) in 5-FU heavily pretreated and poor-performance-status patients with advanced colorectal cancer

Irinotecan (CPT-11) is an effective drug in patients with advanced colorectal cancer (CRC). Little is known about its efficacy and safety in previously treated patients with poor performance status. We prospectively evaluated the antitumor efficacy and safety of CPT-11 monotherapy in this setting. Thirty-four patients with poor performance status (Karnofsky score between 60 and 80) and/or progressing on one or more previous 5-FU-based chemotherapy lines for advanced colorectal adenocarcinoma were enrolled in this study. Treatment consisted of irinotecan (CPT-11) at 100 mg/m² administered as a 60-min iv infusion every week for four consecutive weeks followed by a 2-wk rest period until disease progression or unacceptable toxicity. The overall objective response rate (WHO criteria) for the 34 patients included was 20.6% [95% confidence interval (CI): 6.3%–34.9%]. Stable disease was obtained in 13 patients (38.2%) and 14 patients (41.2%) progressed. The median time to disease progression was 5.5 mo (range: 0.9–17.5) and the median survival was 8.3 mo (95% CI: 1.7–16.9). Overall, weekly CPT-11 was well tolerated with grade 3/4 neutropenia as the main hematological toxicity (11 patients: 32.4%; 14 infusions: 3.3%), and delayed diarrhea (10 patients: 29.4%; 16 infusions: 3.8%) as the main grade 3/4 non-hematological toxicity. In conclusion, weekly CPT-11 at 100 mg/m² for four consecutive weeks followed by a 2-wk rest period showed antitumor efficacy and may be safely administered to heavily pretreated patients with advanced colorectal cancer and a poor performance status. Weekly CPT-11 monotherapy may be considered as a therapeutic option for this population of patients.     

CPT-11联合草酸铂、5-FU方案二线治疗晚期卵巢癌的临床研究

目的:观察CPT-11联合草酸铂、5-FU作为二线治疗晚期卵巢癌的近期疗效及不良反应。方法:25例晚期卵巢癌一线治疗失败后,行二线化疗。具体方案为草酸铂85mg/m2,iv gtt,d1,8,15;5-FU 600mg/m2,iv gtt d1-5;CPT-11 60mg/m2,iv gtt,d2,9,16。28d为1周期,2个周期后评估疗效及不良反应。结果:可评价疗效25例,其中CR 7例,PR 5例,SD 6例,PD 7例,临床获益率72%。主要不良反应为恶心、呕吐、迟发性腹泻、肝脏损害、神经毒性和骨髓抑制等。结论:CPT-11联合草酸铂、5-FU方案二线治疗晚期卵巢癌有较好的疗效,且不良反应可以耐受。     

Chemotherapy with Irinotecan (CPT-11), a Topoisomerase-I Inhibitor, for Refractory and Relapsed Non-Hodgkin's Lymphoma

Irinotecan hydrochloride (CPT-11), a DNA topoisomerase-I inhibitor, is now widely used in the treatment of various solid tumors, including colorectal, gastric, breast, lung, and ovarian cancer. Despite the good response shown in the late phase-II study, CPT-11 was not often employed in the treatment of malignant lymphoma, mainly because of severe leukopenia and diarrhea caused by the recommended schedule: 40 mg/m² of CPT-11 on days 1 to 3, 8 to 10, 15 to 17, then discontinued for at least 2 weeks. In clinical use, administration of CPT-11 had to be ceased on days 15 to 17 in almost all cases, and on days 8 to 10 in a considerable number of patients. Subsequently, a lower dose schedule (less than 40 mg/m²) was developed. Our phase II trial employing a reduced dose of CPT-11 on days 1 and 2, plus ADM on day 3 with 3-week interval in patients with refractory and relapsed NHL showed a fairly good response of relapsed B-cell lymphoma and a substantial response of T-cell lymphoma with acceptable toxicity. The combination of a topoisomerase-I inhibitor (CPT-11) and a topoisomerase-II inhibitor is an interesting concept for the treatment of NHL. Another phase II trial in combination with CPT-11 and other anti-cancer drugs, particularly cisplatin or topoisomerase-II inhibitors, is warranted. A superior salvage chemotherapy regimen could be found in the future by investigating combinations of low-dose CPT-11 and cisplatin or topoisomerase-II inhibitors.     

A Phase I Study of Irinotecan,Capecitabine (Xeloda), and Oxaliplatin in Patients With Advanced Colorectal Cancer

Background

The objective of the present phase I study was to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of irinotecan, capecitabine, and oxaliplatin given in combination (IXO regimen) to patients with previously untreated, unresectable advanced or metastatic colorectal cancer (CRC).

伊利替康联合顺铂二线治疗晚期胃癌

目的观察伊利替康（CPT-11）联合顺铂（DDP）二线治疗晚期胃癌的疗效和不良反应。方法28例经组织学及影像学证实的晚期胃癌患者,二线按CPT-11/DDP方案化疗。具体：CPT-11 70 mg/m2 d1,8 1h静脉输注;DDP70 mg/m2 d1 2 h静脉输注,3 周为1周期。每化疗2周期后按RECIST标准评价疗效,每1周期后根据CTCAE3.0进行不良反应分级。所有患者随访30月,结果采用Kaplan-Meier进行生存分析。结果28例患者均可评价疗效,完全缓解（CR）1例(3.6%), 部分缓解（PR）11例(39.3%),疾病稳定（SD）6例(21.4%), 疾病进展（PD）10例(35.7%),有效率（CR+PR）42.9% 。中位至疾病进展时间（TTP）5月（95%［CI］,3.0～24月）,中位总生存时间（OS）8月（95%［CI］,5.0～30.0月）。3～4级血液学毒性：白细胞减少、血小板减少及贫血分别为35.7%、 25%及14.3%。3~4级非血液学毒性发生率最高的是消化道反应：恶心呕吐发生率为35.7%;腹泻发生率为17.8%。本研究中无治疗相关性死亡。结论伊利替康联合顺铂二线治疗晚期胃癌疗效显著,耐受性好。     

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.     

Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study

Purpose To evaluate the efficacy and safety of irinotecan as second-line treatment in patients with advanced colorectal cancer (ACC) failing or relapsing after 5-fluorouracil (5-FU) plus leucovorin (LV) standard chemotherapy.Patients and methods Irinotecan was randomly administered in two different schedules (once every 3 weeks, and every 10 days) in patients failing prior 5-FU plus LV. Patients were randomized to two treatment groups: group A received irinotecan 350 mg/m² every 21 days and group B received irinotecan 175 mg/m² days 1 and 10 every 21 days.Results Group A comprised 60 patients: 34 male/26 female, median age 64 years (range 48–70 years), and median Karnofsky performance status (PS) 90. Their metastatic sites included liver (n=47), lymph nodes (n=27), lung (n=14), abdomen (n=14), pelvis (n=8), "other" (n=2), and local recurrence (n=12). Group B comprised 60 patients: 36 male/24 female, median age 62 years (46–70 years), and median PS 90. Their metastatic sites included liver (n=49), lymph nodes (n=29), lung (n=17), abdomen (n=16), pelvis (n=11), "other" (n=2), and local recurrence (n=13). Group A showed the following responses: complete response (CR) 2, partial response (PR) 12, stable disease (SD) 21, progressive disease (PD) 26, overall response rate (ORR) 23%, tumor growth control 58%. Group B showed the following responses: CR 1, PR 14, SD 22, PD 23; ORR 25%; tumor growth control 62%. Toxicities included acute cholinergic syndrome (group A 53%, group B 19%; P<0.0001), late-onset diarrhea grade 1/2 (group A 21%, group B 46%) and grade 3/4 (group A 41%, group B 66%; P<0.0001), nausea and vomiting grade 1/2 (group A 34%, group B 59%) and grade 3/4 (group A 30%, group B 12%; P<0.0001), neutropenia grade 3/4 (group A 27%, group B 28%; P<0.03), with febrile neutropenia seen in only four patients in group A, anemia grade more than 2 (group A 28%, group B 12%; P<0.05), asthenia grade more than 3 (group A 24%, group B 18%; P<0.001), and alopecia grade more than 3 (group A 40%, group B 34%; P<0.2).Conclusions The present study indicates that, in patients with ACC who have relapsed after 5-FU plus LV, the administration of irinotecan fractionated into two doses every 21 days yields a similar efficacy to, but a much lower incidence of toxicity than, the same total dose of irinotecan administered once every 21 days.     

Pharmacological Correlation between Total Drug Concentration and Lactones of CPT-11 and SN-38 in Patients Treated with CPT-11

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m² of CPT-11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin-containing syringes. Analysis by high-performance liquid chromatography showed that the ratio of CPT-11 lactone to total CPT-11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN-38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT-11 or SN-38 to total drug concentration at each sampling point were less than 12%. The area under the concentration-time curve (AUC) of total CPT-11 and that of total SN-38 were significantly correlated with the AUCs of the lactone CPT-11 and those of lactone SN-38, respectively. We conclude that, for practical purposes, monitoring of total CPT-11 and SN-38 has essentially the same clinical significance as monitoring of lactone CPT-11 and SN-38.     

Phase I/II study of CPT-11 plus UFT in patients with advanced/recurrent colorectal cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG): Protocol 0102

OBJECTIVE: The primary objective of this study was to explore the efficacy and safety of combined chemotherapy with CPT-11 and UFT in patients with advanced/metastatic colorectal cancer. METHODS: Twenty-two patients with metastatic colorectal cancer were enrolled in the phase I trial and 35 patients (including eight patients treated at level 4 during phase I) were evaluated in the phase II trial. Treatment consisted of two 35-day cycles of combination chemotherapy with CPT-11 and UFT. During phase I, CPT-11 was administered on days 1 and 15 as an intravenous infusion over 90 min at four different dose levels, starting from a dose of 80 mg/m2 (level 1). During phase II, the dose of CPT-11 was fixed at 150 mg/m2 based on the results of the phase I study. UFT was administered orally at a fixed dose of 300 mg/m2 on days 1-28, followed by a 1-week drug holiday, during each course (35 days). RESULTS: The maximum tolerated dose (MTD) of CPT-11 was determined to be 150 mg/m2 during the phase I trial. The major toxicities detected during phase II in 35 patients receiving CPT-11 at this recommended dose were grade 3/4 neutropenia in nine patients (25.7%) and grade 3/4 anorexia in six patients (11.4%). No severe adverse events occurred. The overall response rate and the median overall survival time was 22.9% (8/35) and 23.9 months for all patients, respectively. For pre-treated patients they were 26.3% (5/19) and 25.1 months, respectively. CONCLUSION: This combination of CPT-11 and UFT is considered to be both feasible and relatively safe. The response rate of the patients receiving CPT-11 at a dose of 150 mg/m2 was comparable to that reported previously for 5-FU-based regimens coupled with CPT-11, and this regimen can probably be beneficial for patients with pre-treated advanced colorectal cancer on an outpatient basis.