卡培他滨在乳腺癌治疗中的临床应用

卡培他滨是一种新型口服氟尿嘧啶类药物,目前广泛用于乳腺癌、胃肠道肿瘤及头颈部肿瘤的治疗。无论是单药还是联合用药,卡培他滨在乳腺癌的治疗中均显示了其优越性。     

卡培他滨在乳腺癌治疗中的临床应用

卡培他滨是一种新型口服氟尿嘧啶类药物,目前广泛用于乳腺癌、胃肠道肿瘤及头颈部肿瘤的治疗。无论是单药还是联合用药,卡培他滨在乳腺癌的治疗中均显示了其优越性。     

吉西他滨联合卡培他滨二线治疗晚期乳腺癌

背景与目的：含蒽环类或紫杉类药物的化疗方案是治疗晚期乳腺癌较佳的方案,但临床有20%～30%的患者疗效不佳,对这部分患者二线化疗目前无统一标准方案.本研究探讨既往接受过蒽环类和紫杉类药物治疗失败的晚期乳腺癌患者,使用吉西他滨联合卡培他滨方案治疗的疗效和毒性.方法：吉西他滨1 000 mg/m2,静脉滴注,第1、8天;卡培他滨950 mg/m2口服,每日2次,第1～14天;每3周为一周期,至少应用2疗程,评价临床疗效和毒性,并进行随访.结果：30例女性患者入本研究,疗效均可评价,CR 2例（6.7%）,PR 12例（40.0%）,SD 13例（43.3%）,PD 3例（10.0%）,总有效率（CR﹢PR）46.7%, 中位无进展生存期9个月,中位生存期12.5个月.主要毒性是骨髓抑制和手足综合征.结论：吉西他滨联合卡培他滨化疗方案二线治疗晚期乳腺癌有较好疗效,毒性可耐受.     

卡培他滨单药治疗复发性乳腺癌

目的 :研究卡培他滨单药治疗复治的晚期复发性乳腺癌的近期疗效。方法 :全组 2 1例复发的晚期乳腺癌 ,卡培他滨 2 5 0 0mg/ (m2 ·d) ,分早晚两次口服 ,连服 14天 ,2 1天为 1个周期 ,治疗至少 2个周期后评价疗效及毒性反应。结果 :2 0例可评价疗效 ,全组无CR ,PR 6例 (30 .0 % ) ,SD 8例 (40 .0 % ) ,PD 6例 (30 .0 % ) ,总有效率为 30 .0 %。主要的毒性反应为手足综合征 (6 1.1% )、恶心呕吐 (6 6 .7% )、白细胞减少 (42 .9% )及皮肤色素沉着(2 3.8% )。结论 :卡培他滨对经蒽环类、紫杉类等药物治疗后复发的晚期乳腺癌仍有较好疗效 ,且毒副反应小 ,耐受性好 ,可作为复发的晚期乳腺癌的二线治疗方案。     

吉西他滨联合卡培他滨治疗耐药性乳腺癌近期疗效观察

目的:对蒽环类和(或)紫杉类耐药性乳腺癌尚无标准解救方案.本研究探讨既往接受过蒽环类和或紫杉类药物治疗失败的晚期乳腺癌患者,使用吉西他滨联合卡培他滨方案治疗的疗效和不良反应.方法:23例患者入选,均给予吉西他滨1000mg/m2,静脉滴注,第1、8天;卡培他滨2000mg/m2,分2次口服,第1-14天;每3周为1周期,至少应用2周期,评价临床疗效和不良反应,并进行随访.结果:23例患者中完全缓解1例,部分缓解11例,总有效率52.2%.主要不良反应为骨髓毒性及手足综合症,均较轻.结论:吉西他滨联合卡培他滨方案治疗蒽环类和(或)紫杉类耐药晚期乳腺癌有较好的近期疗效,不良反应小,值得临床选择应用.     

吉西他滨联合卡培他滨治疗耐药性乳腺癌近期疗效观察

目的：对蒽环类和（或）紫杉类耐药性乳腺癌尚无标准解救方案.本研究探讨既往接受过蒽环类和或紫杉类药物治疗失败的晚期乳腺癌患者,使用吉西他滨联合卡培他滨方案治疗的疗效和不良反应.方法：23例患者入选,均给予吉西他滨1000mg/m2,静脉滴注,第1、8天;卡培他滨2000mg/m2,分2次口服,第1-14天;每3周为1周期,至少应用2周期,评价临床疗效和不良反应,并进行随访.结果：23例患者中完全缓解1例,部分缓解11例,总有效率52.2%.主要不良反应为骨髓毒性及手足综合症,均较轻.结论：吉西他滨联合卡培他滨方案治疗蒽环类和（或）紫杉类耐药晚期乳腺癌有较好的近期疗效,不良反应小,值得临床选择应用.     

吉西他滨联合卡培他滨治疗紫杉类化疗失败的晚期乳腺癌的临床观察

目的探讨吉西他滨联合卡培他滨治疗紫杉类治疗失败的晚期乳腺癌的临床疗效及不良反应。方法对2008年3月至2010年2月住院治疗的69例紫衫类及葸环类治疗失败的晚期乳腺癌患者给予吉西他滨（1000mg／m2）和卡培他滨（1500mg／m2）治疗,3周为1个疗程,至少经过2个疗程的治疗。结果完全缓解3例（4．3％）,部分缓解27例（39．1％）,稳定22例（31．9％）,进展17例（24．6％）,总有效率为43．5％,临床获益率为75．4％,中位无进展生存时间为8．2个月,中位生存时间为13．4个月。骨转移患者总有效率为100％,明显高于多发转移、肺部转移和肝脏转移等患者,差异有统计学意义（P〈0．05）。绝经前患者临床获益率明显高于绝经后患者,两组比较差异有统计学意义（P〈0．05）。不良反应以手足综合征和血小板减少为主,均为可逆性,无治疗相关死亡发生。结论吉西他滨联合卡培他滨治疗紫杉类化疗失败的晚期乳腺癌临床效果显著,对于骨转移患者和绝经前患者的治疗效果更佳。     

吉西他滨联合卡培他滨治疗难治性乳腺癌的临床观察

目的观察吉西他滨联合卡培他滨（GX方案）治疗术后复发的乳腺癌患者的疗效和不良反应。方法50例患者分别接受GX方案化疗3～6个周期,按世界卫生组织（WHO）标准评价疗效及不良反应。结果50例患者均可评价,其中完全缓解（CR）4例（8．0％）,部分缓解（PR）22例（44．0％）,稳定（SD）18例（36．0％）,进展（PD）6例（12．0％）。中位肿瘤进展时间（mTTP）为8．3个月（95％CI：6．55—10．89）,中位总生存时间（mOS）为18．0个月（95％CI：14．34～21．98）。主要不良反应为骨髓抑制和皮疹。结论GX方案治疗晚期乳腺癌安全有效,不良反应较轻,值得临床推广应用。     

吉西他滨联合卡培他滨治疗晚期三阴性乳腺癌的临床观察

目的观察吉西他滨联合卡培他滨治疗ER、PR、HER-2均阴性（三阴性）晚期转移性乳腺癌的疗效与安全性。方法 2004年7月至2009年6月共14例经免疫组化证实ER、PR、HER-2均阴性的晚期转移性乳腺癌复治患者参与研究。患者接受吉西他滨联合卡培他滨方案治疗：吉西他滨800mg/m2,静脉滴注30min,d1、d8、d15;卡培他滨2500mg/m2口服,d1～14。28d重复。结果全组14例共完成58个周期的治疗,中位数4个周期,范围2～6个周期,均可评价疗效。完全缓解0例,部分缓解4例（28.6%）,病情稳定6例（42.9%）,病情进展4例（28.6%）,客观有效率为28.6%;中位疾病进展时间（mTTP）6个月（95%CI：2～10个月）,中位生存期（OS）16个月（95%CI：6～32个月）,1年生存率为64.4%,3年生存率为14.3%。毒副反应主要为Ⅰ～Ⅲ度骨髓抑制、胃肠道反应、手足综合征、末梢神经毒性、流感样症状、轻度肝功能损伤等。结论吉西他滨联合卡培他滨治疗晚期三阴性乳腺癌患者,初步观察有一定的疗效,其毒副作用患者可以耐受。     

吉西他滨联合卡培他滨治疗复发转移乳腺癌的疗效观察

目的 探讨吉西他滨联合卡培他滨治疗复发转移乳腺癌的疗效及不良反应。方法 选取50例复发转移的乳腺癌患者,给予吉西他滨联合卡培他滨方案化疗,吉西他滨 1 000 mg/m²,静脉滴注,d1、d8;卡培他滨 1 250 mg/m²,口服,2次/d,d1~14,休息1周,21 d为1个周期。2个周期后评价疗效,每个周期评价不良反应。结果 50例患者经4个周期规范化疗后,完全缓解（CR）4例、部分缓解（PR）25例、稳定（SD）11例、进展（PD）10例,治疗有效率为58%,临床获益率为80%。主要不良反应为骨髓抑制、胃肠道反应及手足综合征。 结论 吉西他滨联合卡培他滨治疗复发转移乳腺癌的疗效肯定,不良反应可耐受。     

Use of raltitrexed as an alternative to 5-fluorouracil and capecitabine in cancer patients with cardiac history

AimFluoropyrimidines are the backbone of the majority of approved chemotherapy regimens for colorectal cancer (CRC). However, there are reports of fluoropyrimidine treatments being associated with cardiotoxicity which have led to permanent cardiovascular damage and even death. Raltitrexed is indicated for palliative treatment of advanced CRC where 5-fluorouracil (5-FU) is not tolerated or inappropriate. A systematic review was undertaken to determine the incidence of cardiotoxicity associated with 5-FU, capecitabine and raltitrexed.MethodsAn electronic search of PubMed was undertaken to identify articles relating to cardiotoxicity associated with 5-FU, capecitabine or raltitrexed, published between January 1991 and August 2011. Additionally, a retrospective review of cardiotoxicity associated with raltitrexed at our treatment centres was conducted.ResultsTwenty studies were examined. The overall incidence of cardiotoxicity associated with 5-FU/capecitabine varied between 0.55% and 19% (mean: 5.0%, median: 3.85%). No published data were identified reporting cardiotoxicity associated with raltitrexed. A retrospective review at our treatment centres revealed that the incidence was 4.5% amongst high-risk patients treated with raltitrexed (n = 111) for advanced gastrointestinal cancer with a significant cardiac history and/or previous cardiotoxicity with 5-FU or capecitabine.ConclusionThe incidence of cardiotoxicity associated with raltitrexed in patients with advanced CRC treated is favourable in a highly skewed, at-risk patient population, all of whom had documented cardiotoxicity with other fluoropyrimidines or were unable to tolerate capecitabine due to cardiac history. Raltitrexed is therefore a suitable option for patients with fluoropyrimidine-induced cardiotoxicity or significant cardiovascular risk factors.     

Severe toxicity of capecitabine following uncomplicated treatment with 5-fluorouracil/leucovorin

Colorectal carcinomas are among the most common tumor types and are generally treated with palliative chemotherapy in case of metastatic disease. Here, we describe the case of a 58 year old woman with metastatic rectal carcinoma who developed severe gastrointestinal toxicity when the thusfar well-tolerated intravenous 5-fluorouracil (5-FU)/leucovorin containing chemotherapeutic regimen was replaced by the same chemotherapeutic regimen in combination with the oral 5-FU prodrug capecitabine. This increased toxicity is probably due to the intracellular retention of polyglutamated folates induced by prior leucovorin therapy which, upon subsequent administration of capecitabine, will result in an enhanced and prolonged inhibition of the, for DNA synthesis important, enzyme thymidylate synthase, essentially creating a situation equivalent to overdosing.     

重楼复方与氟尿嘧啶对胃癌细胞的体外协同作用研究

目的:探讨重楼复方(Chong Lou Fu Fang, CLFF)与5-氟尿嘧啶(5-fluorouracil, 5-FU)对胃癌细胞有无体外协同作用及CLFF对胸苷酸合成酶(thymidylate synthase, TS)基因表达和细胞凋亡的影响.方法:MTT法检测细胞增殖能力;基于中位效应原则的联合指数法评估CLFF与5-FU对胃癌细胞系SGC-7901和BGC-823的相互作用;Annexin-Ⅴ-FITC和PI双染色法检测细胞凋亡率;荧光定量RT-PCR法测定TS和β-actin mRNA表达.结果:CLFF在两株细胞中与5-FU均产生较好的协同细胞毒性,两药合用亦以协同方式诱导肿瘤细胞凋亡;CLFF作用24 h后,SGC-7901和BGC-823细胞中TS mRNA表达水平分别为对照组的(0.30±0.03)倍和(0.46±0.03)倍,用药前后两株细胞中TS mRNA表达水平具有统计学差异.结论:CLFF与5-FU有较好的协同抗肿瘤作用,可能与二者协同诱导肿瘤细胞凋亡以及CLFF可下调胸苷酸合成酶基因表达有关.     

鼻咽癌患者5-FU血药浓度与毒性及疗效的关系

背景与目的:5-氟尿嘧啶(5-fluorouracil,5-FU)对人体的作用有几条途径,不同个体对5-FU的代谢有很大的差异,故很难预测5-FU对不同个体的治疗效果和毒副作用。本研究拟探讨5-FU的稳态血药浓度在接受相同初始剂量(按体表面积计算)的患者之间的差异,以及其与不良反应、治疗反应之间的关系。方法:在接受顺铂(cisplatin,DDP)联合5-FU连续静脉灌注治疗的20例鼻咽癌患者中,开始5-FU治疗后24h采集血样,用高效液相色谱仪(HPLC)测定5-FU的血药浓度。HPLC条件:1mmol/L磷酸盐缓冲液作为流动相,流速1.3ml/min,波长260nm,柱温25℃。结果:5-FU血药浓度在鼻咽癌患者中呈正态分布,个体间有明显差异。5-FU血药浓度低于600μg/L时,患者均没有不良反应,而高于1000μg/L时,患者均出现较严重的不良反应。不同级别不良反应及不同的治疗反应所对应的5-FU血药浓度之间存在明显的统计学差异(P<0.05)。结论:5-FU血药浓度在接受相同初始剂量(按体表面积计算)的患者之间存在明显的差异。5-FU血药浓度与其毒副作用、治疗反应有关。     

紫杉醇联合5-氟尿嘧啶、亚叶酸钙方案治疗晚期胃癌近期疗效评价

 目的 评价含紫杉醇（TAX）联合5-氟尿嘧啶（5-Fu）、亚叶酸钙（LV）组成的TF方案治疗晚期胃癌的临床疗效及安全性。方法 55例病理证实的晚期胃癌患者接受TF方案治疗，21 d为1周期，连用2 ~ 3个周期后评价疗效。结果 55例患者均可评价疗效及毒副作用，有效率为45.45 %。临床受益反应（CBR）35例可评价，疼痛缓解率为86.6 %，Karnofsky评分增加≥20分者占56.4 %。白细胞数减少发生率为56.4 %，Ⅲ度以上占10.9 %。胃肠道反应发生率为43.6 %。结论 TF方案治疗晚期胃癌疗效确切，CBR高，不良反应可以耐受，对多次使用含5-Fu及衍生物方案治疗过的患者仍有一定疗效。     

Preoperative chemoradiation in rectal cancer: Retrospective comparison between capecitabine and continuous infusion of 5-fluorouracil

BACKGROUND: We compared the efficacy and toxicity of oral capecitabine and continuous infusion of 5-fluorouracil (5-FU) in the preoperative chemoradiation treatment of patients with rectal cancer. PATIENTS AND METHODS: The files of 89 patients with rectal cancer, 43 treated preoperatively with oral capecitabine and 46 with intravenous 5-FU, were reviewed, and the outcome of the groups was compared. RESULTS: There was no statistically significant difference in the complete pathological response rate between the capecitabine and the 5-FU groups (30% vs. 17%, P = 0.15). The downstaging rate was higher in the capecitabine group (77% vs. 50%, P = 0.009). Toxicity was mild in both groups. The rate of Grade 3 gastrointestinal toxicity was similar in the two groups (diarrhea 2% vs. 4%, proctitis 5% vs. 7%), except for one patient in the 5-FU group (2%) who developed a rectovaginal fistula. In the capecitabine group, one patient (2%) had Grade 3 hand-foot syndrome, and another had an acute myocardial infarction. In the 5-FU group, two patients (4%) had Grade 3 hematological toxicity, and three (6%) had complications from Port-a-Cath insertion. CONCLUSION: Preoperative chemoradiation with oral capecitabine appears to be safe and well tolerated, and at least as good as continuous 5-FU.     

人体同时静脉滴注亚叶酸钙与5-氟尿嘧啶的耐受性试验

背景与目的：亚叶酸钙（calcium folinate,CF)作为5－氟尿嘧啶（5－fluorouracil,5-FU)的生化反应调节剂,能提高5－FU的抗肿瘤效应,已被国内外研究证实,但在用量,用法等方面还有待进一步探讨。本研究目的是探讨同时持续静脉滴注CF与5－FU,人体对5－FU的最大耐受剂量（maximum tolerated dose,MTD)及剂量限制性不良反应。方法：符合入选标准的病例,使用顺铂（cisplatin,DDP)＋CF／5－FU方案,5－FU初始剂量为500mg.(m2.d)-1,如未观察到严重不良反应,以50mg.(m2.d)^-1逐渐递增,每个剂量级3－6例,直到最大耐受剂量,CF,DDP每疗程剂量固定不变,结果：全组32例进入临床试验,共化疗64疗程,总缓解率为84．4％,5－FU最大耐受量为800mg.(m2.d)^-1,口腔粘膜炎与腹泻为剂量限制性不良反应。结论：CF与5－FU同时静脉滴注可提高5－FU给药剂量,且对晚期消化系统肿瘤及头颈部癌有较高疗效,推荐II期临床试验5－FU剂量为700mg.(m^2.d)^-1,连用5天,每3周为1个疗程。     

Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer

PURPOSE: To describe our experience with a bolus injection of 5-fluorouracil and leucovorin (FL) vs. capecitabine in terms of radiologic and pathologic findings in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. METHODS: The study enrolled 278 patients scheduled for preoperative CRT using two protocols with different chemotherapeutic regimens. Pelvic radiotherapy (50.4 Gy) was delivered concurrently with FL (n = 145) or capecitabine (n = 133). Surgery was performed 6 weeks after CRT completion. Tumor responses to CRT were measured using both radiologic and pathologic examination. Magnetic resonance volumetry was performed at the initial workup and just before surgery after completion of preoperative CRT. Post-CRT pathology tests were used to determine tumor stage and regression. RESULTS: Radiologic examination showed that tumor volume decreased by 68.2% +/- 20.5% in the FL group and 68.3% +/- 22.3% in the capecitabine group (p = 0.970). Postoperative pathologic T stage determination showed that downstaging occurred in 44.3% of FL and 49.9% of capecitabine patients (p = 0.571). The tumor regression grades after CRT were Grade 1 (minimal response) in 22.6% and 21.0%, Grade 2 (moderate response) in 53.2% and 50.0%, Grade 3 (near-complete response) in 12.9% and 12.9%, and Grade 4 (complete response) in 11.3% and 16.1% of the FL and capecitabine groups, respectively (p = 0.758). CONCLUSION: In the present study, the radiologic and pathologic findings did not reveal significant differences in short-term tumor responses between preoperative FL and capecitabine CRT for locally advanced rectal cancer. Long-term results and a prospective randomized trial are needed.     

Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine

Aim: 5-Fluorouracil (5-FU) and its prodrug capecitabine are cardiotoxic. This retrospective study aimed to identify risk factors and to give practical measures to make such chemotherapy feasible if cardiotoxicity occur. Method: Review of cardiotoxicity among 668 patients treated with 5-FU or capecitabine for gastrointestinal cancers. Results: Cardiotoxicity occurred in 29 cases (4.3%). The number of cases according to cardiotoxicity CTC grades 2–4 for patients with and without pre-existing cardiovascular disease were none, 10, and 2 cases, and 3, 14, and no cases, respectively (P=0.16). In three patients intercurrent decrease of renal clearances to <30, 48 and 71 ml min^-1 led to markedly increased cardiotoxicity. Chemotherapy dose reduction to 70 or 50%, either alone or in addition to antiangina medication prevented cardiotoxicity during subsequent chemotherapy in nine (60%) and three (20%) cases out of 15 assessable patients (P=0.001), respectively. To abolish symptoms of cardiotoxicity, sublingual nitroglycerine was efficient for 15 patients and inefficient for two (P=0.001). Conclusion: Cardiac and renal co-morbidity are risk factors for 5-FU induced cardiotoxicity. In this situation, rechallenge with modified 5-FU-based chemotherapy regimen supported by symptomatic medical treatment is feasible.     

与5-Fu相关的严重中枢神经系统毒性

目的探索5-Fu持续化疗相关中枢毒性情况及合理的防治措施.方法通过对从1999年4月～2002年11月期间在我科采用大剂量醛氢叶酸 5-Fu持续48 h滴注为主方案进行治疗的晚期癌症患者临床资料进行复习,分析5-Fu化疗与严重中枢神经毒性反应相关情况,及其采用相应的防治措施的疗效、预后,进一步总结临床经验.结果此期间共有242例患者采用大剂量醛氢叶酸 5-Fu持续48 h滴注为主方案进行治疗,总疗程数达750个,其中2例(3个疗程)出现严重的中枢毒性(浅昏迷,Ⅳ度神志改变),发生率为0.8%,未见毒性相关死亡.2例出现严重中枢毒性患者经改用不含5-Fu方案化疗,未出现类同毒性.结论 5-Fu可导致严重中枢毒性发生,但发生率不高,其中枢损害呈可逆性.5-Fu相关严重中枢毒性与用药剂量、机体差异密切相关.