Multicenter phase II trial evaluating a three-weekly schedule of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer.

BACKGROUND: Irinotecan (CPT-11) and raltitrexed are active against advanced colorectal cancer (ACC), act through different mechanisms, and have only partially overlapping toxicity profiles. Phase I studies have shown that single-agent full doses of both drugs can be safely combined. The aim of this multicenter study was to assess the efficacy and toxicity of the combination in patients with 5-fluorouracil (5-FU)-refractory ACC. PATIENTS AND METHODS: Between October 1999 and December 2000, 52 patients (31 males, 21 females) with a median age of 62 years (range 39-75) were included and received CPT-11 (350 mg/m(2) as a 60-min infusion) plus raltitrexed (3 mg/m(2) as a 15-min infusion, 1 h after CPT-11), with courses repeated every 21 days. Objective response was assessed after every three courses, and treatment maintained until tumor progression or unacceptable toxicity. RESULTS: A total of 313 cycles were administered, with a median of six cycles per patient (range 1-14). Seven patients (13.5%) achieved a partial response and one a complete response (1.9%), for an overall intention-to-treat response rate of 15.4% (95% confidence interval 6.1% to 27.2%). The incidence of grade 3/4 toxicity was 23.1% for diarrhea, 21.2% for asthenia, 17.3% for neutropenia, 13.4% for emesis and 7.7% for infection. There were no treatment-related deaths. With a median follow-up of 20 months, median survival was 11.9 months and median time to progression was 4.6 months. CONCLUSIONS: CPT-11 plus raltitrexed is active in patients with 5-FU-refractory ACC, at the expense of moderate toxicity.     

贝伐珠单抗联合伊立替康与雷替曲塞治疗氟尿嘧啶耐药晚期结直肠癌的疗效和安全性

目的 观察贝伐珠单抗联合伊立替康与雷替曲塞方案在氟尿嘧啶类药物耐药后的晚期结直肠癌患者中的疗效及安全性。方法 收集中国医科大学附属第一医院2014—2019年收治的氟尿嘧啶类耐药的60例晚期结直肠癌患者,对照组30例,应用伊立替康联合雷替曲塞方案（IR）;实验组30例,应用IR联合贝伐珠单抗方案。分析比较两组患者的客观有效率（ORR）、疾病控制率（DCR）、无进展生存时间（PFS）及不良反应发生情况。结果 实验组和对照组ORR分别为6.67%和3.33%,DCR分别为66.67%和53.33%,两组ORR和DCR比较差异无统计学意义。实验组和对照组中位PFS分别为6.0个月和3.1个月,差异有统计学意义（P=0.020 4）。两组不良反应以Ⅰ/Ⅱ级多见,Ⅲ/Ⅳ级不良反应发生率低,实验组蛋白尿的发生率高于对照组,差异有统计学意义（P=0.001）。其余如出血、转氨酶升高、恶心、呕吐、腹泻、发热、皮疹、高血压等不良反应发生率均为实验组高于对照组,但差异无统计学意义。结论 贝伐珠单抗联合伊立替康与雷替曲塞方案可提高既往氟尿嘧啶类治疗耐药后的晚期结直肠癌患者的疗效,无进展生存期增加,不良反应可耐受,值得进一步研究。     

雷替曲塞对人胃癌细胞MGC-803裸鼠移植瘤的抑制作用

 目的 通过研究雷替曲塞抑制裸鼠MGC-803胃癌移植瘤的生长,初步探讨其相关作用机制。方法 建立人胃癌裸鼠皮下移植瘤模型,把24只裸鼠随机分为3 组,每组8只。对照组(生理盐水),低剂量组(雷替曲塞5 mg/kg),高剂量组(雷替曲塞12 mg/kg)。每周经腹腔注射给药2次,持续2周。详细记录裸鼠精神状态、体重以及肿瘤生长情况,免疫组化法检测裸鼠肿瘤组织Ki67及PCNA蛋白表达,并通过Western blottting法检测裸鼠肿瘤组织Caspase-3及Bax蛋白表达。结果 治疗期间雷替曲塞低剂量组和高剂量组裸鼠体重均低于对照组,低剂量组、高剂量组的抑瘤率分别为27.54%、44.20%,差异有统计学意义(P<0.05);免疫组化法显示低剂量组、高剂量组Ki67阳性细胞率分别为58.95%、42.16%,PCNA阳性细胞率分别为51.36%、37.27%,均明显低于对照组(P<0.05);Western blotting法表明低剂量组、高剂量组Caspase-3和Bax蛋白表达均明显高于对照组(P<0.05)。结论 雷替曲塞可抑制人胃癌裸鼠移植瘤的生长增殖,其机制可能与提高Caspase-3和Bax蛋白表达、从而促进细胞凋亡有关。     

培美曲塞与雷替曲塞联合顺铂治疗恶性胸膜间皮瘤的疗效与安全性

目的：探讨培美曲塞联合顺铂与雷替曲塞联合顺铂治疗恶性胸膜间皮瘤的疗效和安全性。方法回顾性分析64例恶性胸膜间皮瘤患者的临床资料,采用培美曲塞联合顺铂化疗的纳入PP组（32例）,采用雷替曲塞联合顺铂方案的为RP 组（32例）,比较两组不同化疗方案的疗效及不良反应。结果两组患者客观有效率、疾病控制率比较,差异均无统计学意义（χ2分别=2.35、3.76,P均＞0.05）。PP组患者中位总生存期为11.62个月,中位无疾病进展生存期为5.61个月;RP组患者中位总生存期为11.33个月,中位无疾病进展生存期为4.93个月,两组患者在中位总生存期、中位无疾病进展生存期之间的差异均无统计学意义（t分别=1.06、2.08,P均＞0.05）。两组患者不良反应均以骨髓抑制和胃肠道反应为主,两组之间不良反应比较,差异无统计学意义（χ2=2.82,P＞0.05）。结论培美曲塞或雷替曲塞联合顺铂用于MPM的临床疗效相当,对于经济条件较差的MPM患者来说,选用雷替曲塞联合顺铂治疗也可以作为MPM的一线方案。     

伊立替康联合雷替曲塞3周方案二线治疗晚期结直肠癌的疗效观察

目的:观察伊立替康联合雷替曲塞二线治疗晚期结直肠癌的疗效及安全性.方法 :对22例一线治疗失败的晚期结直肠癌病人予以二线治疗:伊立替康180 mg/m2,静脉滴注1 h,第1天;雷替曲塞3 mg/m2,静脉滴注15 min,第2天;21 d为1个周期.每2个周期评价疗效,并分析其安全性.结果 :22例病人均可评价近期疗效,其中完全缓解1例,部分缓解4例,疾病稳定11例,疾病进展6例,客观有效率为22.7%,疾病控制率为72.7%,病人的中位肿瘤进展时间为5.0个月,中位总生存时间11.8个月.严重不良反应为中性粒细胞减少和腹泻,发生率分别为13.6%和4.5%.结论 :伊立替康联合雷替曲塞在晚期结直肠癌的二线化疗中,有效率较高,不良反应能够耐受,值得在临床上推广.     

抗癌药雷替曲塞的合成

目的研究抗癌药雷替曲塞的合成。方法以2-噻吩甲醛为起始原料,经硝化、氧化、酯化、还原、氨基保护、N-甲基化、水解、缩合、脱保护、N-烷基化、水解11步反应合成雷替曲塞。结果与结论总收率为12.9%,其结构经核磁共振氢谱、质谱确证。     

Raltitrexed treatment promotes systemic inflammatory reaction in patients with colorectal carcinoma

We studied longitudinally inflammatory reactions and serum C-reactive protein (S-CRP) levels in 52 colorectal cancer patients treated with a median of six 3-weekly cycles of raltitrexed 1.5-3.0 mg m(-2) combined with oral carmofur (1-hexylcarbomoyl-5-fluorouracil) 300-400 mg m(-2) on cycle days 2-14. Thirty-nine (75%) of these patients had fever on days 2 to 9 after receiving raltitrexed, 49 (94%) had fatigue Gr. > or = 1, and 49 (94%) elevated S-CRP without a documented infection. The systemic inflammatory composite score (consists of body temperature, fatigue, S-CRP, interleukin-6 (S-IL-6), S-IL-8, and tumour necrosis factor-alpha (S-TNF alpha) levels) was calculated in a cross-sectional one-cycle study involving 60 colorectal cancer patients treated with single-agent raltitrexed, raltitrexed and carmofur, or 5-fluorouracil-based chemotherapy (n=20 in each group). The median S-CRP, S-IL-6, and S-TNF alpha levels were higher 7 days after giving raltitrexed (57 vs 23 mg l(-1), 64 vs 10 ng l(-1), and 11 vs 10 ng l(-1), respectively) or raltitrexed+carmofur (142 vs 10 mg l(-1), 64 vs 10 ng l(-1), and 16 vs 9 ng l(-1), respectively) than at baseline (P<0.01 for each comparison), but not when 5-fluorouracil-based regimens were administered. These findings suggest that colorectal cancer patients treated with raltitrexed may develop drug-related systemic inflammation, which may be difficult to discriminate from infection.     

Multicenter non-randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non-pretreated metastatic colorectal cancer patients.

BACKGROUND: This multicenter, phase II, open-label study evaluated the antitumor efficacy and safety of oxaliplatin and raltitrexed (Tomudex) in non-pretreated advanced colorectal cancer patients. PATIENTS AND METHODS: Seventy-one patients received oxaliplatin 130 mg/m(2) and raltitrexed 3 mg/m(2) intravenously on an outpatient basis every 3 weeks. All patients had histologically proven metastatic colorectal adenocarcinoma, performance status raltitrexed, respectively. The most common grade 3-4 toxicities (National Cancer Institute Common Toxicity Criteria) among treated patients were as follows: neutropenia (21 patients, 30%), asthenia (eight, 11%), diarrhea (12, 17%), liver function test abnormalities (24, 34%), nausea (nine, 13%) and vomiting (nine, 13%). Two treatment-related deaths occurred (hematotoxicity in one patient and gastrointestinal toxicity in the other) and two further deaths were possibly related to treatment (hepatic dysfunction in one patient and neuropathy in the other). Thirty-seven objective responses (one complete) were obtained [objective response rate 54%; 95% confidence interval (CI) 42% to 65%] in eligible patients. The median response duration was 8.5 months (95% CI 6.7-12.2 months), while median progression-free and overall survival among eligible patients were 6.2 (95% CI 5.1-6.9 months) and 14.6 months (95% CI 11.0-18.9 months), respectively. CONCLUSIONS: The present study confirms the feasibility of the raltitrexed plus oxaliplatin combination and its activity in non-pretreated advanced colorectal cancer patients.     

Open label, multi-centre phase II study of raltitrexed (`Tomudex') in patients with inoperable squamous-cell carcinoma of head and neck

Background:Raltitrexed (`Tomudex') is a folate based inhibitorof thymidylate synthase which has been registered in Europe and Australia forthe treatment of advanced colorectal cancer. In a European phase I trial ofraltitrexed anti-tumour activity was seen in two patients with head and neckcancer, prompting the current study. Patients and methods:From November 1996 to December 1998, 24patients with metastatic or recurrent squamous-cell carcinoma of the head andneck from 7 Australian centres received raltitrexed, 3 mg/m² givenintravenously over 15 minutes every 3 weeks, for a maximum of 6 cycles.Patients were required to be chemotherapy naïve and have measurabledisease, age >18 years, WHO performance status initially 2, nosignificant intercurrent illness or organ dysfunction and a life expectancy>12 weeks. Results:Twenty-two men and two women, median age 65 years, medianperformance status 1 were enrolled. Fifteen patients (63%) had receivedboth prior surgery and radiotherapy. In 15 patients (63%) there wasrecurrent locoregional disease only. Twelve patients (50%) received onecycle of treatment with only four patients (17%) receiving four or morecycles of treatment. No patient achieved a complete or partial response,although 5 patients experienced stable disease which lasted a median of 188days (range 61–436). The median survival for the whole group was 101days (range 20–436). Raltitrexed was generally well tolerated withminimal anti-proliferative toxicity. Conclusions:Single-agent raltitrexed does not demonstratesignificant anti-tumour response rates in patients with predominantly locallyrecurrent head and neck cancer.     

Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma

There is no established second-line treatment for advanced pancreatic cancer after gemcitabine failure. In view of the urgent need for such therapy, and since preclinical and phase I clinical data suggest an encouraging, potentially synergistic activity between raltitrexed and irinotecan, the present randomised phase II study was initiated. A total of 38 patients with metastatic pancreatic adenocarcinoma, who progressed while receiving or within 6 months after discontinuation of palliative first-line chemotherapy with gemcitabine, were enrolled in this study. They were randomised to 3-weekly courses of raltitrexed 3 mg x m(-2) on day 1 (arm A) or irinotecan 200 mg x m(-2) on day 1 plus raltitrexed 3 mg x m(-2) on day 2 (arm B). The primary study end point was objective response, secondary end points included progression-free survival (PFS) and overall survival (OS), as well as clinical benefit response in symptomatic patients (n=28). In the combination arm, the IRC-confirmed objective response rate was 16% (three out of 19 patients had a partial remission; 95% CI, 3-40%), which was clearly superior to that in the comparator/control arm with raltitrexed alone, in which no response was obtained. Therefore, the trial was already stopped at the first stage of accrual. Also, the secondary study end points, median PFS (2.5 vs 4.0 months), OS (4.3 vs 6.5 months), and clinical benefit response (8 vs 29%) were superior in the combination arm. The objective and subjective benefits of raltitrexed+irinotecan were not negated by severe, clinically relevant treatment-related toxicities: gastrointestinal symptoms (42 vs 68%), partial alopecia (0 vs 42%), and cholinergic syndrome (0 vs 21%) were more commonly noted in arm B; however, grade 3 adverse events occurred in only three patients in both treatment groups. Our data indicate that combined raltitrexed+irinotecan seems to be an effective salvage regimen in patients with gemcitabine-pretreated pancreatic cancer. The superior response activity, PFS and OS (when compared to raltitrexed), as well as its tolerability and ease of administration suggest that future trials with this combination are warranted.