消癌平治疗小鼠恶性腹水的实验研究

目的:观察消癌平注射液治疗小鼠肝癌H22细胞腹水瘤效果,并初步探讨其作用机制。方法:建立小鼠H22腹水瘤模型,随机区组分为生理盐水组和消癌平组,每组小鼠各20只。建模后48 h开始给药,消癌平组连续腹腔给药(0.2 mL/d)6 d,生理盐水组给予同体积生理盐水。末次给药24 h后处死各组小鼠半数。计算各组小鼠平均腹水量,腹水抑制率、腹水中瘤细胞数、肿瘤细胞生存率;并检测腹水肿瘤细胞凋亡、细胞周期及Bcl-2蛋白表达。剩余小鼠继续观察一般状态及生存期。结果:和生理盐水组相比,消癌平组小鼠精神好、动作灵敏、反应快;消癌平组平均腹水体积(7.5±1.3)mL低于生理盐水组平均腹水体积(10.3±1.7)mL,P<0.05;消癌平组腹水中肿瘤细胞数(2.0±1.1)×107明显低于生理盐水组腹水中肿瘤细胞数(6.6±2.8)×107,P<0.01;消癌平组腹水肿瘤细胞生存率(34%)明显低于生理盐水组肿瘤细胞生存率(58%),P<0.001;消癌平组小鼠生存期(16.0±1.5)d高于生理盐水组小鼠生存期(14.2±1.1)d,P<0.05。消癌平组小鼠腹水H22细胞凋亡增加,P<0.05;H22细胞G2/M期百分...     

不同剂量氟尿嘧啶缓释植入剂腹腔给药治疗Ｈ２２小鼠腹水瘤疗效的实验研究

目的　探讨不同剂量氟尿嘧啶缓释植入剂（中人氟安）治疗小鼠恶性腹腔积液的有效性和安全性。方法　采用肝癌Ｈ２２细胞株建立小鼠腹水瘤模型,６８只成模小鼠随机分为４组,即赋型剂对照组、中人氟安低剂量组（２ｍｇ／只）、中剂量组（４ｍｇ／只）和高剂量组（６ｍｇ／只）。观察小鼠的一般状态、体重变化和生存期,计算腹水体积并计数腹水内肿瘤细胞,流式细胞仪检测腹水肿瘤细胞凋亡及细胞周期。结果　与对照组相比,中人氟安三个剂量组小鼠的一般状态良好,体重增长缓慢,全身症状出现较晚,中位生存期均有延长（１６、２０、２０天ｖｓ．１３天,Ｐ＜０.０１）,但中、高剂量组间生存期差异无统计学意义（Ｐ＞０.０５）。实验第１３天,中人氟安低、中、高３个剂量组的腹水体积（ｍｌ）分别为９.２±０.９、５.６±１.０和５.９±１.１,每毫升中的肿瘤细胞数分别为（１０.１１±１.３１）×１０^８、（７.２５±１.００）×１０^８ 和（７.４７±１.１１）×１０^８,均少于对照组的（１３.３±１.５）ｍｌ和（１４.７３±１.２５）×１０^８（Ｐ均＜０.０１）;腹水肿瘤细胞的凋亡率分别为（１４.８±１.４）％、（２３.９±２.６）％和（２１.５±３.１）％,Ｓ期比例分别为（３１.２３±３.２６）％、（５０.１７±４.６０）％和（４７.０８±４.１１）％,均高于对照组的（７.６±１.９）％ 和（２０.５７±４.０８）％ （Ｐ均＜０.０１）,其中中、高剂量组与低剂量组的差异具有统计学意义（Ｐ＜０.０５）,而中、高剂量组差异无统计学意义（Ｐ＞０.０５）。结论　中人氟安对于实验小鼠Ｈ２２腹水瘤的形成具有良好的控制作用,可以延长腹水瘤小鼠的生存期,且安全性好,以中剂量组的效果最佳。因此,提示在临床上对于恶性腹腔积液和腹膜转移的患者,可以应用中人氟安进行局部治疗,但需选择合适的剂量。     

刺参酸性黏多糖对5-FU治疗小鼠肝癌的减毒增效作用

目的探讨刺参酸性黏多糖(stichopus japonicus acid mucopolysaccharide,SJAMP)联合5-FU对肝癌小鼠肿瘤生长及免疫功能的影响,了解其对化疗药的减毒增效作用。方法将60只小鼠随机分为正常对照组(生理盐水)、空白对照组(生理盐水)、5-FU组〔5-FU 20 mg/(kg·d)〕、SJAMP组〔SLAMP 25 mg/(kg·d)〕、SJAMP+低5-FU组〔SLAMP 25 mg/(kg·d)和5-FU 10 mg/(kg·d)〕和SJAMP+高5-FU组〔SLAMP 25 mg/(kg·d)和5-FU20mg/(kg·d)〕。除正常对照组外其他各组均于右腋皮下接种H22(Hepatocarcinoma22)细胞。接种后第2天开始给药,连续给药12d后处死小鼠,计算抑瘤率、胸腺指数和脾脏指数,ELISA检测血清TNF-α和IL-2含量,中性红法检测腹腔巨嗜细胞吞噬功能,CCK-8法测定脾脏淋巴细胞增殖能力,MTT法测NK细胞杀伤功能,流式细胞术检测小鼠外周血T细胞亚群。结果各干预组小鼠肿瘤生长明显受到抑制,SJAMP+高5-FU组抑瘤率(62.73%)高于5-FU组(55.53%),P=1.000。SJAMP组和SJAMP+低5-FU组小鼠脾脏指数显著高于其他组,P值均<0.05。SJAMP组和SJAMP+低5-FU组小鼠胸腺指数分别为(2.19±1.18)和(2.13±1.00)mg/g,高于5-FU组的(1.14±0.53)mg/g,P值分别为0.026和0.048;也高于SJAMP+高5-FU组的(1.07±0.49)mg/g,P值分别为0.011和0.020。各药物干预组TNF-α较空白对照组均降低,P值均<0.001。和空白对照组(33.27±6.13)相比,5-FU组(23.52±3.31)血清IL-2水平明显降低,P<0.001;SJAMP组(39.56±2.39)血清IL-2水平显著提高,P=0.001。与5-FU组相比,SJAMP组和联合用药组IL-2明显提高,P值均<0.001。SJAMP组和SJAMP+低5-FU组腹腔巨嗜细胞吞噬中性红能力显著高于正常对照组、空白对照组、5-FU组和SJAMP+高5-FU组,P值均<0.001;SJAMP+高5-FU组与5-FU组相比明显提高,P=0.012。SJAMP组和SJAMP+低5-FU组脾脏淋巴细胞增殖能力显著高于正常对照组(P值均<0.001)、空白对照组(P值均<0.001)、5-FU组(P值均<0.001)和SJAMP+高5-FU组(P值分别为0.005和0.011);SJAMP+高5-FU组与5-FU组相比明显提高,P=0.005。SJAMP组和SJAMP+低5-FU组NK细胞杀伤能力高于5-FU组,P值分别为0.002和0.030。空白对照组和5-FU组CD3+CD4+与CD3+CD8+细胞比值低于正常对照组(P值均<0.001)、SJAMP组(P值分别为0.001和<0.001)和SJAMP+低5-FU组(P值分别为0.003和0.024),SJAMP+高5-FU组高于5-FU组(P=0.329)。结论 SJAMP能够增强5-FU对肿瘤的抑制作用,减少5-FU对小鼠免疫功能的损伤。     

重组人血管内皮抑素间插联合顺铂对H22小鼠腹水瘤抑制作用的研究

目的 观察重组人血管内皮抑制素（恩度）间插联合顺铂腹腔内注射治疗小鼠腹水瘤的疗效和安全性。方法 采用肝细胞癌H22腹水瘤细胞株建立小鼠腹水瘤模型。120只造模后的ICR小鼠随机分为4组：对照组（生理盐水d1～d10）、恩度组（恩度8mg／kg,d1～d5,d7～d10,生理盐水d6）、顺铂组（顺铂004mg／kg,d6,生理盐水d1～d5,d7～d10）及恩度联合顺铂组（恩度8mg／kg,d1～d5,d7～d10;顺铂0.04mg／kg,d6）,每组30只,每只小鼠腹腔注射的药物体积均为0.2ml。记录各组小鼠腹水体积、腹水中肿瘤细胞、红细胞计数以及生存期;观察各组荷瘤小鼠腹膜和腹腔脏器种植转移情况;检测各组小鼠的腹膜渗透性、血常规和肝肾功能;流式细胞仪检测各组小鼠腹腔积液中肿瘤细胞凋亡情况。结果 与对照组相比,恩度组和顺铂组和恩度联合顺铂组均能减少荷瘤小鼠腹腔积液的体积、肿瘤细胞数和红细胞数,延长荷瘤小鼠的生存时间。在上述指标中,恩度联合顺铂组与恩度组和顺铂组比较,差异有统计学意义（P＜0.05）。恩度联合顺铂组小鼠腹腔积液中肿瘤细胞的凋亡率显著高于恩度组和对照组（P＜0.05）,但与顺铂组比较差异无统计学意义（P＞0.05）;恩度联合顺铂组小鼠的腹膜渗透性明显低于顺铂组和对照组（P＜0.05）,但恩度联合顺铂组与恩度组比较差异无统计学意义（P＞0.05）。恩度联合顺铂组小鼠的体重增加及腹腔种植转移均少于其他3组。各组小鼠均未出现血常规和肝肾功能明显异常。结论 恩度间插联合顺铂腹腔内应用治疗小鼠H22腹水瘤疗效显著,安全性好。     

重组人血管内皮抑制素联合顺铂对小鼠腹水瘤抑制作用及其机制探讨

目的研究重组人血管内皮抑制素(恩度)联合顺铂治疗小鼠S180腹水瘤的有效性和安全性,并探索其相关作用机制。方法应用小鼠S180细胞株建立腹水瘤动物模型。120只造模后的ICR小鼠随机分为对照组(0.9%NaCl,d1~d10)、恩度组(恩度8mg/kg,d1~d5,d7~d10;0.9%NaCl,d6)、顺铂组(顺铂0.04 mg/kg,d6;0.9%NaCl d1~d5,d7~d10)和恩度联合顺铂组(恩度8mg/kg,d1~d5,d7~d10;顺铂0.04mg/kg,d6)。记录各组小鼠体质量、腹水体积、腹水中肿瘤细胞、红细胞数以及生存期;检测各组小鼠的腹膜渗透性和肝肾功能;流式细胞仪检测腹水肿瘤细胞的凋亡率;ELISA方法检测腹水中血管内皮生长因子(vascular endothelial growth factor,VEGF)和基质金属蛋白酶2(matrix metalloproteinases 2,MMP-2)的表达。结果恩度联合顺铂组小鼠的腹水体积为(2.1±1.0)mL,肿瘤细胞数为(10.6±2.5)×107 mL-1,红细胞数为(12.0±3.1)×107 mL-1,上述各指标均低于对照组、恩度组和顺铂组。联合组的中位存活期为24.1d,明显长于对照组(12.7d)、恩度组(16.8d)和顺铂组(18.9d)。顺铂组小鼠腹水中肿瘤细胞的凋亡率为(68.9±5.4)%,明显高于对照组(12.4±2.3)%和恩度组(11.0±3.8)%。恩度组小鼠的腹膜渗透性为(2.03±0.05)ng/mL,VEGF浓度为(23.7±3.0)ng/mL,MMP-2为(10.3±1.1)ng/mL,显著低于对照组和顺铂组。各组小鼠的肝肾功能未发现明显异常。结论恩度联合顺铂治疗S180腹水瘤疗效显著,安全性好;其机制可能与恩度下调VEGF和MMP-2的表达及顺铂促进肿瘤细胞的凋亡有关。     

症痛散的抗癌作用及与抗肿瘤药合用的协同作用实验研究

目的：探讨症痛散的体内抗肿瘤活性及其与抗癌药的协同作用效果。方法：用小鼠腹水型H22、EAC模型，观察药物对小鼠腹水生成量的影响；用小鼠实体瘤U14模型，观察药物对小鼠瘤块生长的影响；同时观察症痛散与5-氟脲嘧啶(5-FU)、环磷酰胺(CTX)联合应用对抗肿瘤活性的协同作用。结果：症痛散对腹水瘤有显著抑制腹水的生成，对实体瘤亦有显著抑制瘤块生长。症痛散与5-FU(每天25mg／kg，ig)合用能显著提高5-Fu对腹水瘤小鼠腹水生成的抑制作用。与轻度抑瘤作用的CTX(每天25mg，kg，ig)合用，对实体瘤抑瘤活性高于单独给药组。结论：症痛散具有抗肿瘤作用并能增强5-FU、CTX的抗肿瘤活性，且毒性无明显增强。     

平调饮抗肿瘤作用的实验研究

背景与目的:建立H22肝癌腹水瘤荷瘤小鼠模型,通过给予模型鼠平调饮灌胃评价其抗肿瘤作用.材料与方法:用H22腹水肝癌株种植于小鼠右腋皮下,致移植性肿瘤,建立H22肝癌腹水瘤荷瘤小鼠模型.将模型鼠分成阴性对照组,平调饮组,平调饮+5-Fu组和5-Fu组,共4组,各组模型鼠分别灌胃生理盐水、平调饮、平调饮+5-Fu和5-Fu,连续灌胃10 d后,观察瘤体大小、胸腺指数、脾脏指数、抑瘤率、生命延长率和VEGF在肿瘤及肿瘤周围组织中的表达.结果:平调饮组肿瘤平均瘤体、VEGF值减小,胸腺指数、脾脏指数、抑瘤率(48.6%)及生命延长率(168.3%)增高.结论:平调饮可提高胸腺指数,降低5-Fu对免疫功能的毒性作用,显著延长荷瘤小鼠的生存期.平调饮可能通过促进肿瘤细胞分化成熟,抑制肿瘤细胞增殖,降低肿瘤组织和肿瘤周围组织中VEGF表达,而对H22腹水型小鼠肿瘤的发展起抑制作用.     

重组人血管内皮抑制素对肝癌H22腹水瘤小鼠腹水的抑制作用

目的探讨血管内皮抑制素腹腔内给药对H22小鼠腹水瘤生长及腹水的抑制作用。方法取110只昆明小鼠腹腔内接种H22细胞（2x106细胞／只）,建立小鼠腹水瘤模型,接种后随机分为5组：模型对照组（0．9％NS）;低剂量血管内皮抑制素组（4mg／kg）;中剂量血管内皮抑制素组（8mg／kg）;高剂量血管内皮抑制素组（12mg／kg）;阳性对照组（顺铂0．6mg／kg）。接种24h后连续10d给予各药物腹腔内注射,停药24h后处死各组小鼠,测量腹水量并取腹水行相关检测;解剖小鼠,观察腹腔脏器及肺脏的转移情况;通过Evan蓝的吸光度值反映小鼠的腹膜渗透性;观察各组小鼠的生存时间。结果与模型对照组相比,中、高剂量血管内皮抑制素组可显著抑制荷H22腹水瘤小鼠腹水的生成,并减少腹腔内及肺脏转移,延长生存时间。结论血管内皮抑制素腹腔内用药治疗荷H22腹水瘤小鼠腹水具有显著的抑制作用。     

TNP-470对小鼠肝癌H22腹水瘤的治疗研究

 目的 探讨TNP-470治疗小鼠肝癌H22腹水瘤的疗效及机制。方法 体外采用细胞增生法和迁移法探讨TNF-470的治疗机制；体内建立H22腹水瘤小鼠模型评价TNP-470的疗效。结果TNP-470对瘤细胞H22的增生、血管内皮细胞HMEC的增生和迁移都有抑制作用；能明显提高小鼠生活质量、降低腹水的产生和瘤细胞的存活率及小鼠失明率，延长生存期。结论 TNP-470对荷H22腹水瘤小鼠有明显疗效。     

新城疫病毒7793株对结肠癌小鼠肝转移的抑制效果及其可能的机制

目的：以脾脏保留法建立结肠癌小鼠肝转移模型,评价新城疫病毒（Newcastle disease virus,NDV）7793株对小鼠结肠癌肝转移的抑制效果,并初步探讨NDV抑瘤的免疫激活机制。方法：经脾注入1×107/ml小鼠结肠癌细胞CT26的单细胞悬液0.1 ml,建立结肠癌CT26小鼠肝脏转移瘤模型;建模小鼠随机分3组（每组20只）: PBS阴性对照组、NDV7793给药组和5-FU给药组,于建模当天起连续5 d经腹腔分别注射PBS(0.1 ml/d)、NDV7793(512 HU/kg)和5-FU(20 mg/kg)。观察各组小鼠的生存状态,分析肝脏成瘤情况,计算抑瘤率和胸腺指数。ELISA法检测模型小鼠肝脏的IFN-γ水平。结果：成功构建小鼠结肠癌肝转移模型。NDV7793给药组小鼠未观察到明显的不良反应,生活状态好于PBS组和5-FU组。NDV7793组和5-FU组小鼠的肝转移瘤数量较PBS组均显著减少\[ (20.40±5.20) 、(205.50±19.21) vs (265.30±35.73)个,均 P <0.01\],NDV7793组的抑瘤率明显高于5-FU组（75.4% vs 48.0%, P <0.05）,NDV7793组小鼠的肝脏癌灶范围小,癌细胞以坏死或凋亡为主。NDV7793组和5-FU组小鼠的中位生存期明显长于PBS阴性对照组（30、22 vs 17 d, P <0.01）。NDV7793组小鼠肝脏IFN-γ的表达和胸腺指数均显著高于5-FU组和PBS组（均 P <0.05）。结论：NDV7793株对结肠癌小鼠的肝转移具有较强的抑制效果,并可能通过上调肝脏的IFN-γ以及提升胸腺指数来抑制结肠癌的肝转移。     

Leucovorin and fluorouracil vs levamisole and fluorouracil as adjuvant chemotherapy in rectal cancer

The aim of this study was to evaluate the effectiveness of 6-month therapy with leucovorin (LV) + 5-fluorouracil (5-FU) vs 12 months of therapy with levamisole (LVZ) + 5-FU, as adjuvant chemotherapy in patients with completely resected Dukes' stage B2 or C rectal cancer. One hundred and fifty patients with surgically resected rectal carcinoma, were enrolled in the present study; Dukes' stage B2 (n=70) or C (n=80), were randomly assigned to chemotherapy with 5-FU + LV x 6 months or 5-FU + LVZ x 12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant CT consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v., on days 1-5 every 4 weeks for 6 cycles or 5-FU 450 mg/m(2) i.v. every week plus LVZ 50 mg t.i.d x 3 days for 1 year. All patients received radiotherapy with a three-field technique to a total dose of 45 Gy, over 5 weeks. After a median follow-up of 7.4 years there were no significant differences between the two treatment groups with respect to the recurrence rates (P=0.821). Moreover, there was no difference in disease-free survival for patients stage Dukes' B2 (log-rank p=0.73); median for LV group 90 (8-131) months, and for LVZ group 86.5 (3-129) months. No difference was noted in disease-free survival for patients stage Dukes' C (log-rank p=0.73); median for LV group 60 (17-128) months, and for LVZ group 64 (2-123) months. There was no difference in overall survival for patients stage Dukes' B2 (log-rank p=0.75); median for LV group 90 (22-131) months, and for LVZ group 86 (10-129) months. For stage Dukes' C (log-rank p=0.73); median for LV group 67 (17-128) months, and for LVZ group 64 (5-123) months. Toxicities were as follows in the 5-FU + LVZ vs 5-FU + LV group; myelosuppression (leucopenia grade 3, 12% vs 4%, p<0.04), diarrhea (grade 0, 60% vs 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients vs 2, p<0.03), were more frequent in LVZ group. None of the patients stopped chemotherapy because of the toxicity, and there were no toxicity-related deaths. In conclusion, adjuvant chemotherapy in RC with LV + 5-FU for 6 months is equally effective and less toxic than LVZ + 5-FU for 12 months.     

Biochemical modulation of fluorouracil: comparison of methotrexate,folinic acid,and fluorouracil versus folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial

 Recent advances in biochemical pharmacology have revealed the basis for the biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in enhanced cell kill in vitro and in vivo. In addition, administration of FA prior to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary complex of thymidine synthase. In the present randomized study, two groups of patients with advanced colorectal cancer were treated as follows: 43 patients (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA + MTX. The dosage was as follows: group A received FA i. v. at 300 mg/m² per day, prior to i. v. 5-FU at 500 mg/m² per day on days 1 – 4; group B was given MTX i. v. at 130 mg/m² per day on day 0, followed 24 h later by FA at 15 mg q6h × 6, and 5-FU + FA was started on day 1 and given at the same doses and schedule described for group A. Objective responses were achieved by 8/43 pts in group A (1 complete response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15 partial responses), all occurring in the liver. There was no significant difference in the median time to progression (group A 6.1 months, group B 6.8 months) or the median survival (group A 9.2 months, group B 10.3 months). Toxicity was significantly greater in group B [grade 2 – 3 mucositis 20% versus only 2% in group A (P <0.0001); grade 3 diarrhea in group B 15% versus 3% in group A (P <0.001)]. According to our results, double biological modulation of 5-FU with MTX + FA led to an enhanced response rate with increased toxicity as compared with the 5-FU + FA regimen given at less than its maximally tolerated dose. Received: 8 May 1995 / Accepted: 25 January 1996     

Allopurinol modulation of fluorouracil toxicity

Summary Considerable interest has developed in the modulation of fluorouracil activity by nucleosides. The toxicity of fluorouracil in mice is known to be reduced by concurrent administration of allopurinol, presumably because biochemical pathways activating fluorouracil in normal tissues are blocked.We have given allopurinol (300 mg t.d.s. PO) concurrently with continuous infusions of fluorouracil (2.0–2.25 g/m²/day x 5) to 34 patients with colorectal cancer and 11 patients with various adenocarcinomas. There were 41 patients assessable for toxicity. Stomatitis was the predominant dose-limiting toxicity (22% grade 1, 19% grade 2, and 27% grade 3 toxicity). Neutropenia (<1,000/l) occurred in 17% patients. Among 26 colorectal cancer patients assessable for response there was a 15.4% response rate.We conclude that allopurinol modulates fluorouracil toxicity in man, allowing a two-fold increase in dose. However, at least in colorectal cancer no greater frequency of tumour response is seen than with lower doses of fluorouracil given by standard schedules of administration without allopurinol.     

Cost effectiveness of chemoradiotherapy with cisplatin/fluorouracil and nedaplatin/fluorouracil for patients with esophageal cancer

OBJECTIVE: To assess the cost-effectiveness of chemoradiotherapy (CRT) regimens for patients with esophageal cancer, we compared two regimens consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP) or 5-FU and nedaplatin (CDGP) with radiotherapy. METHODS: Medical records of 108 patients with esophageal cancer who received CRT of 5-FU+CDDP (CDDP group) or 5-FU+CDGP (CDGP group) were analyzed. In both groups, most of the patients were men with a pathological diagnosis of squamous cell carcinoma. A Markov model was used to show the clinical courses of esophageal cancer after the CRT therapy. An outcome used for economic evaluation was life year gained (LYG). We calculated the cost per-effectiveness ratio (CER) and incremental cost effectiveness ratio (ICER). Clinical effectiveness and costs in this model were investigated retrospectively, and the costs were estimated from the perspective of the medical institution. Sensitivity analysis was used to check the robustness of this model. RESULTS: In CDDP and CDGP group, LYG was 18.23 and 16.31 years and CER was 270,373 and 406,264 yen/LYG, respectively. As a result, ICER was .883,999 yen/LYG. The sensitivity analysis showed that this model was definitely robust. CONCLUSION: Our results suggested that CDDP could prolong LYG with less cost than CDGP and that CRT of 5-FU and CDDP was markedly cost effective treatment.     

Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy.

PURPOSE: Chemoradiotherapy, the combination of external radiation therapy and concurrent chemotherapy, has been the basis for the oncologic management of many patients since its development in the 1960s. Fluorouracil (FU) chemoradiotherapy has demonstrated success in several organ sites with multiple dosing schedules that now guide the selection of oral analogs of FU to provide new chemoradiotherapy options. METHODS: This article reviews the metabolism and pharmacology of FU and the advantages of administration of FU by continuous infusion or bolus. The potential role and impact of the oral fluorouracil prodrugs UFT, S-1, BOF-A2, and capecitabine as replacements for intravenous administration are discussed. The results of recent chemoradiotherapy studies with FU from 2000 to 2003 are summarized in rectal, head and neck, esophageal, gastric, pancreatic, biliary, anal, and cervical cancers. RESULTS: Chemoradiotherapy with FU has the potential to widen the therapeutic window by minimizing normal tissue toxicity while maintaining effective tumor toxicity. Overall, FU chemoradiotherapy maximizes local control and, for some tumor sites (such as head and neck, pancreatic, biliary, cervical, esophageal, and gastric cancers), improves survival rates. Moreover, FU chemoradiotherapy results in improved organ preservation with excellent functional outcome in several anatomic sites including head and neck cancer, anal, and rectal cancer, with improved sphincter preservation. CONCLUSION: FU chemoradiotherapy continues to play an important role in the management of many cancer sites. During the last four decades, optimal dosing schedules have produced a therapeutic gain. The introduction of oral prodrug analogs will likely further improve the results of FU therapy in several organ systems, such as the rectum, head and neck, and esophagus.     

Cost-effectiveness projections of oxaliplatin and infusional fluorouracil versus irinotecan and bolus fluorouracil in first-line therapy for metastatic colorectal carcinoma

BACKGROUND: The results of a randomized comparison study (N9741) showed that oxaliplatin and infusional fluorouracil (FU) (FOLFOX) was superior to the previous standard of care in the United States, irinotecan and bolus FU (IFL), as first-line therapy for patients with metastatic colon carcinoma. The trade-offs between costs and survival for these two regimens have not been explored. METHODS: A post-hoc, incremental cost-effectiveness (ICE) projection using simulated cohorts of patients starting FOLFOX or IFL was tracked for major clinical events, toxicities, and survival. Recurrence and survival risks were based on clinical trial data. Resource use was projected using observed dose intensity, duration of therapy, delays in therapy, and toxicities Grade > 2 in N9741. The frequency, costs, and consequences of second-line therapy were examined. The time frame was 5 years, and the perspective was that of Medicare as a third-party payer. RESULTS: Initial treatment with FOLFOX versus IFL had an average incremental cost of dollars 29,523, a survival benefit of 4.4 months, and an ICE of dollars 80,410 per life year (LY), dollars 111,890 per quality-adjusted LY, and dollars 89,080 per progression-free year. By using the 95% confidence interval for the time to progression observed in N9741, the ICE associated with FOLFOX ranged from dollars 121,220 to dollars 59,250 per LY. In the clinical trial, dose delays and skipped doses were frequent. If progression-free patients were treated without delay for the first year or lifetime, then the ICE for FOLFOX increased to dollars 117,910 and dollars 222,200 per LY, respectively. The ICE increased to dollars 84,780 per LY when the model incorporated a revised IFL schedule with lower early toxicity and similar rates of treatment with second-line regimens. CONCLUSIONS: FOLFOX provided substantial benefits that incurred substantial additional costs. The ICE for FOLFOX fell into the upper range of commonly accepted oncology interventions in the context of the United States healthcare system.     

Oral fluorouracil therapy of hepatoma.

Oral fluorouracil was administered weekly to 12 consecutive patients with unresectable hepatoma. Six patients showed an objective response with a significant increase in survival duration compared to nonresponders and to untreated patients. The clinical features of these cases are discussed, along with details of therapy, and possible reasons for the encouraging results noted with this treatment regimen.     

Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer

One hundred twenty-two chemotherapy-naive patients with histologically confirmed colorectal adenocarcinoma were entered into a randomized trial comparing infusional fluorouracil (FU) versus cisplatin (CDDP) and FU. In both groups, patients received continuous infusion FU 1,000 mg/m2/d for 5 consecutive days every 4 weeks. Patients randomized to CDDP/FU also received CDDP 20 mg/m2 intravenous (IV) bolus on days 1 to 5 of each cycle. Patients were comparable in terms of age, performance status, baseline laboratory values, dominant sites of measurable disease, and percent of liver involvement. The partial response rate was significantly greater in patients who received CDDP/FU versus FU alone (25% v 3%, P = .001). Patients who received CDDP/FU experienced significantly greater toxicity compared with FU alone: grades 3 and 4 hematologic toxicity occurred in 22% and 0% of patients, respectively (P = .0001); grades 2 to 4 nausea and vomiting occurred in 80% and 15% of patients, respectively (P = .0001). There were no significant differences in either the duration of response (median, 6 and 4.7 months for CDDP/FU and FU groups, respectively) or survival (median 10, and 12 months, respectively). Compared with infusional FU alone, CDDP/FU provided a significantly greater partial response rate with increased toxicity, but it did not improve overall survival in patients with advanced colorectal carcinoma. Therefore, the use of CDDP/FU as routine therapy for the treatment of colorectal carcinoma cannot be recommended.