伊立替康联合卡培他滨治疗晚期结直肠癌的临床观察

目的：观察伊立替康（CPT-11）联合卡培他滨（Capecitabine,希罗达）治疗晚期结直肠癌的疗效及毒性反应。方法：从2004年2月-2006年5月对晚期结直肠癌采用CPT-11联合卡培他滨方案化疗。入组患者均经病理组织学证实,且有可测量病灶。具体方案为：CPT-11250mg／m^2 iv,d1;希罗达1250mg／m^2 po,bid,d1-d14。21天为1个周期,化疗2个周期后评价疗效及毒性反应。结果：可评价疗效者60例,其中完全缓解（CR）4例,部分缓解（PR）22例,有效率（RR）为43．3％,稳定（SD）28例（46．7％）,进展（PD）6例（10．0％）。临床受益率为83．3％,疼痛缓解率83．3％。肿瘤中位进展时间7．2个月,中位生存期13．8个月。主要毒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联合卡培他滨方案治疗晚期结直肠癌患者有较好疗效,毒副反应可以接受。     

Phase-II study of dose attenuated schedule of irinotecan, capecitabine, and celecoxib in advanced colorectal cancer

Background The cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to chemotherapy. A Phase-II study was undertaken to determine the activity of a dose attenuated schedule of irinotecan, capecitabine, and the COX-2 inhibitor celecoxib in patients with advanced colorectal cancer. Methods The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum that was metastatic. Patients received a combination of irinotecan 70 mg/m² over 30 min I.V. on days 1 and 8, capecitabine 1,000 mg/m² twice per day orally on days 1–14, and celecoxib at a daily dose of 800 mg continuously. Cycles were repeated every 21 days. Results Fifty-one patients were enrolled (median age 58 years; M : F 31 : 20). The objective response rate was 21/51 = 41% [95% confidence intervals (CI), 0.28–0.55]. The median time to progression was 7.7 months (95% CI, 6.2–8.6 months). Median survival time and probability of survival at 1 year were 21.2 months (95% CI, 13.8–n/a), and 75% (95% CI, 0.63–0.88), respectively. The major toxicity was Grade 3 or 4 diarrhea, seen in 24 and 10% of patients, respectively. There were no treatment related deaths. Conclusions The lower dose intensity of irinotecan appeared to maintain activity and improve tolerability when combined with capecitabine. The addition of celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of this doublet based on the RECIST criteria for objective response.     

伊立替康联合卡培他滨治疗晚期结直肠癌的临床观察

目的观察伊立替康联合卡培他滨治疗晚期结直肠癌的疗效和安全性。方法回顾性分析62例复发或转移性结直肠癌患者,接受伊立替康联合卡培他滨治疗：伊立替康125mg／m^2 d1、d8、d15静脉滴注90min;卡培他滨（希罗达）2500mg/m^2,分早晚2次,第1—14天,每28天重复。治疗至少2个周期,按照WHO标准进行疗效和不良反应评价,并观察至疾病进展时间及总生存期。结果62例患者中,可评价疗效的有59例。其中一线治疗28例,RR42．8％,DCR71．4％,TTP 8．6个月,MST18．8个月;二线治疗31例,RR32．3％,DCR61．2％,TTP 7．2个月,MST13．2个月。不良反应主要为恶心与呕吐、迟发性腹泻、粒细胞减少,多为Ⅰ-Ⅱ度,且一线和二线治疗的不良反应无统计学差异。结论伊立替康联合卡培他滨治疗晚期结直肠癌疗效高,不良反应可耐受,值得扩大样本进一步观察。     

A dose finding and pharmacokinetic study of capecitabine in combination with oxaliplatin and irinotecan in metastatic colorectal cancer

Purpose  The GONO-FOLFOXIRI regimen demonstrated higher activity and efficacy than FOLFIRI in metastatic colorectal cancer patients. The aim of this study was to determine the maximum tolerated dose of capecitabine, in substitution of 5-fluorouracil, combined with oxaliplatin and irinotecan and to evaluate the pharmacokinetics of the drugs. Patients and methods  We treated 15 patients with escalating doses of capecitabine (from day 1 to 7) and fixed doses of oxaliplatin (85 mg/m²) plus irinotecan (165 mg/m²) (both administered on day 1), repeated every 2 weeks. Pharmacokinetic analysis was performed on plasma samples collected at the first cycle of treatment. Results  The maximum tolerated dose of capecitabine resulted 2,000 mg/m²/day, with diarrhea being the only dose-limiting toxicity. Large interpatient variability in the pharmacokinetic parameters of investigated drugs was observed. Results in terms of activity are promising. Conclusions  At the maximum tolerated dose of capecitabine of 2,000 mg/m²/day the combination is feasible with promising activity and deserves further investigations.     

The combination of capecitabine and irinotecan in treating 5-Fluorouracil- and Oxaliplatin-pretreated metastatic colorectal cancer

Purpose Since the combination of capecitabine and irinotecan has successfully been used as a first-line treatment in metastatic colorectal cancer (MCRC), we expected promising results when given as a second-line treatment to metastatic colorectal patients who had been pretreated with 5-Fluorouracil and Oxaliplatin. Methods Thirty-three MCRC patients participated in this study and received an oral dose of 1,000 mg/m² capecitabine twice daily on days 1–14 and a dose of 100 mg/m² irinotecan infused over 90 min on days 1 and 8, every 3 weeks. Results The overall response rate in intent-to-treat was 33.3% (95% CI, 21.5–58.3%), including one complete response (3.0%) and ten partial responses (30.3%); 12 patients (36.4%) had disease stabilization and only 9 (27.3%) progressed. The median time to progression was 6.7 months (95% CI, 4.8–8.6 months). After a median follow-up time of 12 months, nine patients (27.3%) were still alive with metastatic disease. The median response duration for all patients was 6.7 months (95% CI, 3.9–9.5 months) and the median overall survival was 13.4 months (95% CI, 11.0–15.8 months) with a 1-year survival rate of 55.4%. Myelosuppression was commonly observed; NCI-CTC (v 2.0) grade 3/4 neutropenia, however, occurred in eight (24%) patients and grade 3 anemia was seen in one patient (3%). The most common (grade 3/4) non-hematological toxicity was diarrhea (15%) and the other severe grade 3/4 toxicities included nausea/vomiting in one patient (3%), stomatitis in one patient (3%), hand-foot syndrome in one patient (3%). Conclusions The combination of capecitabine and irinotecan is an effective and well-tolerated regimen for second-line treatment of metastatic colorectal cancer. However, further phase III trials are required to clarify its use in the treatment of metastastic colorectal cancer patients who have been pretreated with 5-fluorouracil and oxaliplatin.     

羟基喜树碱联合卡培他滨治疗复发转移结直肠癌的临床观察

目的　探讨羟基喜树碱（ＨＣＰＴ）联合卡培他滨（ＣＡＰ）治疗复发转移结直肠癌的近期疗效、不良反应及预后。方法　２００７年１月至２０１０年１月收治５１例一线或二线化疗失败的复发转移结直肠癌患者,给予ＨＣＰＴ联合ＣＡＰ化疗,具体方案：ＨＣＰＴ６～８ｍｇ／ｍ^２静滴,ｄ１～ｄ５;ＣＡＰ１２５０ｍｇ／ｍ^２分２次口服,ｄ１～ｄ１４。２１天为１周期,直至疾病进展或出现不可耐受的不良反应。每周期评价不良反应,每２个周期评价客观疗效并随访生存情况。结果　全组共完成１３８个周期,其中４９例可评价客观疗效,平均化疗２.８个周期,获ＰＲ１２例,ＳＤ２２例,ＰＤ１５例,有效率为２４.５％,疾病控制率为６９.４％。５１例患者的主要不良反应为骨髓抑制、腹泻、手足综合征和疲乏,３级中性粒细胞减少和３级手足综合征各２例,其余均为１～２级,支持对症处理可以恢复。中位总生存时间为８.８个月（９５％ＣＩ：６.９～１０.７个月）,获ＰＲ或ＳＤ者均较获ＰＤ者明显延长（Ｐ＜０.０５）。结论　ＨＣＰＴ联合ＣＡＰ治疗复发转移结直肠癌的疗效较好,不良反应轻,是国人复发转移结直肠癌进展时可选择的方案之一。     

三维适形放疗联合XELOX方案治疗局部晚期和术后复发性直肠癌

目的:观察三维适形放疗加卡培他滨联合奥沙利铂化疗(XELOX方案)治疗局部晚期和术后复发性直肠癌的临床疗效及毒副反应。方法:经病理或细胞学证实的局部晚期和术后复发性直肠癌患者25例,每天口服卡培他滨2000mg/m2,d1～d14,静滴奥沙利铂130mg/m2,d1。每3周为1个治疗周期,全组共完成119周期。同步放疗为先三野同中心全盆腔放疗40Gy,后针对局部肿瘤病灶行三维适形放疗加量至60Gy。结果:25例患者中CR16%,PR64%,NC12%,PD8%,总有效率为80%,主要不良反应为消化道反应及感觉神经病变,未见大于Ⅲ级的毒性反应。结论:三维适形放疗加XELOX方案化疗治疗局部晚期和术后复发性直肠癌疗效确切,毒副反应小,是有效治疗晚期大肠癌的新方案。     

伊立替康或奥沙利铂联合卡培他滨治疗晚期胃癌的疗效比较

目的 观察并比较伊立替康(CPT-11)联合卡培他滨(CAP)与奥沙利铂(L-OHP)联合CAP治疗晚期胃癌的近期疗效和毒副反应.方法 将63例晚期胃癌患者随机分为两组,CPT-11+CAP组32例,应用CPT-11联合CAP方案治疗;L-OHP+CAP组31例,应用L-OHP联合CAP方案治疗.2个周期后评价疗效及毒副反应,有效病例4周后进行疗效确认.结果 CPT-11+CAP组PR 13例,有效率为40.6%,中位无进展生存期为6.3个月.L-OHP+CAP组PR 12例,有效率为38.7%,中位无进展生存期为6.1个月.两组有效率及中位无进展生存期比较,差异均无统计学意义(P＞0.05).两组的主要毒副反应为胃肠道反应、周围神经毒性和骨髓抑制.CPT-11+CAP组Ⅲ、Ⅳ度腹泻的发生率(28.1%)高于L-OHP+CAP组(3.2%,P=0.018),Ⅲ、Ⅳ度周围神经毒性的发生率(3.1%)低于L-OHP+CAP组(25.8%,P=0.027).两组均无化疗相关性死亡.结论 CPT-11联合CAP方案与L-OHP联合CAP方案对晚期胃癌均有较好的疗效,毒副反应均可耐受.

Abstract：

Objective To observe and compare the response rate and toxicity of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer.Methods Sixty-three patients with advanced gastric cancer were randomly divided into two groups.The CPT-11 + CAP group consisted of 32 patients who received irinotecan plus capocitabine: CPT-11 100 mg/m2 was injected in 90 minutes on d 1,8 ;capecitabine 2000 mg/m2, bid, with the first dose in the evening of day 1 and last dose the morning of day 15, repoated for every 21 days.The L-OHP + CAP group consisted of 31 patients who received oxaliplatin plus capecitabine: oxaliplatin 100 mg/m2 on day 1, capocitabine 2000 mg/m2, bid,with the first dose in the evening of day 1 and last dose the morning of day 15, repeated for every 21 days.Two or more cycle chemotherapy was completed in each group.Results In the CPT-11 + CAP group, no patient achieved complete response and 13 patients achieved partial response.The overall response rate was 40.6% (13/32), and the median progression-free survival time was 6.3 months.In the L-OHP + CAP group, no patient achieved complete response and 12 patients achieved partial response.The overall response rate was 38.7% (12./31), and the median progression-free survival time was 6.1 months.There was no significant difference between them (P ＞ 0.05 ).The most common toxicities were gastrointestinal reaction,peripheral neuropathy and myelosuppression in the two groups.Patients in CPT-11 + CAP group experienced more Ⅲ/Ⅳ diarrhea (28.1%/3.2%, P =0.018).On the contrary, the rate of Ⅲ/Ⅳ neurotoxicity in the group B was higher (25.8%/3.1%, P = 0.027).No chemotherapy-related death occurred.Conclusion The therapeutic effects of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer are good and comparable, and their toxicities are tolerable.     

Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer

Objective The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). Methods and patients Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m² bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m² twice daily. Results The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. Conclusions Capecitabine 1250 mg/m² twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients.     

Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models

Erlotinib (Tarceva, OSI-774) is a potent, orally available, small-molecule inhibitor of HER1/EGFR tyrosine-kinase activity. In this study, the antitumor activity of erlotinib was evaluated in two human colorectal tumor xenograft models (LoVo and HCT116) in athymic mice. When erlotinib was administered as monotherapy, significant tumor growth inhibition (TGI) was seen in the LoVo model at both 100 mg/kg [TGI > 100%, P < 0.001; 6/10 partial regressions (PRs)] and 25 mg/kg (TGI = 79%, P < 0.001) doses. However, the HCT116 xenograft model was not responsive to any dose of erlotinib tested. The differential response to erlotinib of these two tumor models was not a result of differences in HER1/EGFR expression levels since these were similar in both cell lines. However, it was demonstrated that resistance to erlotinib in the HCT116 model may be a result of persistent activation of ERK in these tumors. Based on the single agent activity of erlotinib in LoVo tumors, a combination study with CPT-11 (Camptosar, irinotecan) was performed. CPT-11 at the optimal dose of 60 mg/kg or a lower dose of 15 mg/kg resulted in significant TGI (TGI > 100%, P < 0.001, and TGI = 93%, P < 0.001, respectively) in LoVo-bearing mice. Combination treatment with erlotinib (25 mg/kg) and CPT-11 (15 mg/kg) produced significantly greater antitumor activity (TGI > 100%, P < 0.001; 10/10 PRs) than either agent alone (P < 0.05), with no increase in toxicity. These data indicate that erlotinib can enhance the antitumor activity of CPT-11, without enhanced toxicity, in the LoVo human colorectal tumor xenograft model.     

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。     

Modulation of irinotecan with cyclosporine: a phase II trial in advanced colorectal cancer

Introduction: Despite the extensive clinical experience with irinotecan, significant concerns remain regarding its toxicity. In a phase I trial, we modulated irinotecan pharmacokinetics by inhibiting biliary excretion of SN-38, the active metabolite of irinotecan, using cyclosporine. The modulation appeared to decrease the gastrointestinal toxicity of irinotecan and suggested that irinotecan activity might also be retained. Hence, we conducted this phase II trial in patients with colorectal cancer (CRC) to further evaluate the toxicity and activity of irinotecan modulated with cyclosporine. Patients and Methods: Sixteen patients with 5-fluorouracil refractory CRC were treated. Cyclosporine (5 mg/kg) was administered as a 6-h infusion and irinotecan (60 mg/m²/day, 90-min infusion) was started 3 h after initiation of the Cyclosporine. Both agents were given weekly for 4 weeks, every 6 weeks. Responses were assessed every 12 weeks, and toxicity was monitored weekly. Results: Sixteen patients were evaluable for toxicity and 11 for response. There was 1 partial response (6%). Five patients had SD lasting a median of 12 weeks. Grade 3/4 diarrhea was observed in only 13% of the patients. Conclusion: Pharmacokinetic modulation of irinotecan using parenteral cyclosporine appears to decrease the incidence of diarrhea in CRC patients. Given the modest activity of irinotecan monotherapy, a larger study would be required to assess if the modulation improves the toxicity without compromising this activity. The available clinical data suggest that pharmacokinetic modulation of irinotecan should be evaluated further to define its optimal clinical utility.Two of the co-authors: Edem Agamah (owns shares of Pfizer) and Mark J. Ratain [Co-inventor on several patents (pending/issued) related to the modulation or irinotecan and/or its Pharmacogenetics] would like to declare their potential conflicts of interest.     

A phase II study of irinotecan in combination with doxifluridine, an intermediate form of capecitabine, in patients with metastatic colorectal cancer

The purpose of this study was to examine the efficacy of a combination treatment of sequential irinotecan and doxifluridine, an intermediate of capecitabine, evaluated by the response rate and safety in patients with metastatic colorectal cancer. In all, 60 metastatic colorectal cancer patients with measurable disease were enrolled. The schedule of the treatment consisted of a 90 min intravenous (IV) infusion of irinotecan 150 mg/m² for on days 1 and 15, and 600–1,000 mg/body of oral doxifluridine on days 3–14 and 17–28. Cycles were repeated every 35 days. A median of three cycles of the combination therapy (range 1–14 cycles) was administered. A total of 57 patients (95%) completed at least two cycles of the therapy without any dose reductions. There was one complete response and 23 partial responses with an overall response rate of 40% [95% confidence interval (CI): 28–53%]. A total of 19 patients had stable disease, 43(72%) achieved disease control. The median time to progression was 5.9 months and the median overall survival was 20.5 months. Ten (17%) and 17 (28%) patients developed Grade 3–4 leukopenia and neutropenia, respectively. Grade 3–4 fatigue was observed in 7(12%) patients, nausea in five (8%), vomiting in four (7%), and diarrhea,in three (5%) patients. No treatment-related deaths were noted during the study. From these results, the combination of sequential irinotecan and doxifluridine is considered to be an effective, easy-to-administer regimen with acceptable tolerability.     

开普拓在晚期大肠癌治疗中的应用及研究进展

40多年来,5-氟尿嘧啶（5-Fu）一直是晚期大肠癌的主要治疗药物。经过多年的探讨,对改进5-Fu的疗效采取了一些新的治疗策略,主要有：（1）采用静脉持续输注5-Fu,与静脉推注方法如Mayo方案相比,可以明显提高有效率,减轻骨髓毒性;（2）并用醛氢叶酸（CF,亦称LV）作为生化调节,可以提高客观缓解率,且患者的存活时间延长;（3）开发了一系列5-Fu衍生物,提高治疗指数,特别是2001年经美国FDA批准用于晚期大肠癌一线治疗的卡培他滨（希罗达）。5-Fu／LV虽然对晚期大肠癌有一定疗效,但有效率仅20％左右,而且对治疗无效的患者或缓解后病变又复发进展者。亟需开发新的有效药物。现将开普拓治疗大肠癌的研究报告如下。     

A phase I study of capecitabine and a modulatory dose of irinotecan in metastatic breast cancer

Purpose There is a need for chemotherapy regimens active against anthracycline- and taxane-refractory breast cancer. Data from preclinical and pilot studies performed at Roswell Park Cancer Institute (RPCI) suggested that when irinotecan (IRN) is given with 5-fluorouracil (5-FU) efficacy is affected by the sequence of drug administration. Pretreatment with IRN 24 h before 5-FU increased the number of tumor cells in S-phase and the antitumor activity in a preclinical system. These data provided the rationale for the evaluation of IRN and capecitabine, a 5-FU prodrug, sequentially administered in patients with metastatic breast cancer. The main objective of the study was to determine the MTD and identify dose-limiting toxicities (DLTs) of capecitabine and IRN. Additionally, the degree of accumulation of cells in S-phase in tumor biopsies obtained at 24 h after the first dose of IRN was measured in consenting patients. Patients and methods Metastatic breast cancer patients who experienced disease progression after at least one (taxane or anthracycline based) chemotherapy regimen and an expected survival of at least 3 months and ECOG performance status 0–2 were eligible. Twelve patients were enrolled and treated. The starting doses were IRN 80 mg/m² given over 90 min on days 1, 8, 22, 29, and capecitabine 1,500 mg/m²/day given days 2–15 and 23–36. Evaluation for response was performed after the first cycle. Sequential tumor biopsies were performed on five patients. Results The first three patients treated exhibited modulation in cyclin A index on tumor biopsy as defined by the study, defining the modulatory dose of IRN as 80 mg/m². Overall, 4/5 biopsies showed modulation. Dose Limiting Toxicities (DLTs) were assessed during the first cycle of therapy. Two DLTs (Grade 3 nausea vomiting and dehydration; grade 3 pneumonia, hypoxia, hypotension) were seen at dose level 2 of capecitabine (2,000 mg/m²/day) and the first cohort was expanded. There were no DLTs for patients treated at DL 1. No grade 3–4 toxicities occurred at DL 1. Seven patients were evaluable for response following one cycle of treatment (partial response 1, stable disease 4, progressive disease 2) Of the five inevaluable patients, two experienced DLT, one received 50% of the planned capecitabine dose, one progressed prior to evaluation, and one withdrew consent. Conclusion IRN 80 mg/m² days 1, 8, 22, 29 in combination with capecitabine 1,500 mg/m²/day in divided dose days 2–15 and 23–36 has an acceptable toxicity profile and resulted in modulation of S-phase in 4/5 specimens examined. Further studies of the activity of this combination and modulatory effect of IRN are warranted.     

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients

Purpose: Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. Methods: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m² of capecitabine twice daily p.o. for 5–7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. Results: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P=0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P=0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. Conclusions: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5′-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues. Received: 4 June 1999 / Accepted: 28 October 1999     

雷替曲塞联合伊立替康2周方案对比FOLFIRI方案二线治疗晚期结直肠癌的疗效观察

目的 观察雷替曲塞联合伊立替康2周方案治疗转移性结直肠癌的有效性和安全性。方法 经病理组织学或细胞学确诊的50例晚期转移性结直肠癌患者分为试验组（n=25）和对照组（n=25）。试验组方案： 雷替曲塞 2.5mg／m² 静滴,d₁;伊立替康（CPT-11） 180mg／m² 静滴,d₁。对照组方案：CPT-11 180mg／m² 静滴90min,d₁;亚叶酸钙 400mg／m² 静滴,d₁;5-FU 400mg／m² 静滴,d₁;5-FU 2400mg／m² 持续静滴46～48 h,d₁、d₂。两方案均2周为1周期,每周期评价毒副反应,每3个周期评价疗效,直至疾病进展或毒性不能耐受,最多治疗12个周期。结果 试验组获CR 1例,PR 4例,SD 18例,PD 2例;对照组获PR 2例,SD 19例,PD 4例。两组有效率（RR）分别为20％和8％,疾病控制率（DCR）分别为92％和84％,差异均无统计学意义（P＞0.05）。试验组1、2级转氨酶升高的发生率为24％,高于对照组的4％（P＜0.05）;对照组1、2级中性粒细胞减少、口腔黏膜炎的发生率均高于试验组（48％ vs. 20％,32％ vs. 8％,P＜0.05）。结论 雷替曲塞联合伊立替康2周方案与FOLFIRI方案的近期疗效相当,但毒副反应更轻,可以作为转移性结直肠癌的有效姑息治疗方案。     

伊立替康联合卡培他滨二线治疗38例晚期结直肠癌的临床观察

目的：观察伊立替康联合卡培他滨二线治疗晚期结直肠癌的疗效及不良反应。方法：38例晚期结直肠癌患者予以伊立替康200mg／m^2,第1天,口服卡培他滨1000mg／m^2一日两次,联用14天,每21天重复,至少治疗2周期。结果：本组患者有效率7．9％（3／38）,疾病控制率55．3％（21／38）,其中部分缓解（PR）3例,稳定（SD）18例,进展（PD）17例。中位进展时间（TTP）及中位总生存期分别为4月和11月,临床疗效是影响TTP及OS的主要预后因素。3度以上不良反应主要为中性粒细胞减少（18．4％）及腹泻（10．5％）。结论：伊立替康联合卡培他滨二线治疗晚期结直肠癌具有良好的疗效与耐受性。     

卡培他滨联合奥沙利铂治疗晚期大肠癌的临床观察

目的观察卡培他滨联合奥沙利铂组成的XELOX方案治疗晚期大肠癌的近期疗效与安全性。方法采用XELOX方案治疗晚期大肠癌62例。卡培他滨2000mg/m^2,d1～14,分早晚口服;奥沙利铂130mg/m^2,d1,静点。每21天为1周期,至少2周期。结果近期疗效CR1例,PR26例,SD20例,PD15例,有效率43.5%。初治组有效率55.6%,显著高于复治组的26.9%（P〈0.05）。毒副反应主要为可耐受的骨髓抑制、恶心呕吐、外周神经毒性。结论XELOX方案治疗晚期大肠癌疗效较好,毒副反应轻,是晚期大肠癌,特别是初治者的有效治疗方案。     

Mitomycin-C and capecitabine as third-line chemotherapy in patients with advanced colorectal cancer: a phase II study

Purpose The aim of this study was to investigate the therapeutic value and safety of third-line treatment with mitomycin-C (MMC) and capecitabine (Xeloda) in patients with advanced colorectal cancer pretreated with combination regimens including 5-fluorouracil (5-FU), folinic acid (FA) and irinotecan (CPT-11) or 5-FU, FA and oxaliplatin (L-OHP).Patients and methods A total of 21 patients (M/F 16/5, median age 60.0 years) with advanced colorectal cancer, all of whom had developed progressive disease while receiving or within 6 months of discontinuing two sequential chemotherapy lines with 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP, were accrued to this study. At the time of their relapse or progression, cytotoxic chemotherapy, consisting of intravenous MMC 7 mg/m² on therapeutic day 1 plus oral capecitabine 1000 mg/m² twice daily on days 1–14, was initiated. After rest for 7 days, capecitabine 1000 mg/m² twice daily was administered on days 22–35 followed by 7 days rest. Treatment courses were repeated every 6 weeks unless there was evidence of progressive disease, unacceptable toxicity or patient refusal of treatment.Results All the patients were assessable for toxicity and 19 for response. The median number cycles of chemotherapy was two (range one to four). Only 1 patient (4.8%) had a partial response, 4 patients (19.0%) had stable disease, and 14 patients (66.7%) progressed. The median follow-up period was 7.3 months and median time to progression was 2.6 months. The median overall survival was 6.8 months. No toxic deaths occurred. Toxicities of third-line treatment were mild and manageable. As NCI/NIH common toxicity criteria, grade 3/4 anemia, neutropenia and thrombocytopenia occurred in two, one and one patients, respectively.Conclusion Our findings suggest that the combination of MMC and capecitabine in patients with advanced colorectal cancer pretreated with combination regimens including 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP is safe. However, this regimen had a poor response rate and no definitive contribution to increasing patients overall survival time. Further evaluation of other salvage regimens seems to be warranted.