Leucovorin, 5-fluorouracil,and gemcitabine: A phase I study

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU).The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0–2, and signed informed consent.Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m², 5FU 255 mg/m² and gemcitabine 600 mg/m². 5FU and gemcitabine were escalated in tandem to 340 mg/m² and 800 mg/m² and thereafter to 425 mg/m² and 1000 mg/m², respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1–32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses.The maximum tolerated dose is leucovorin 20 mg/m², 5FU 340 mg/m², and gemcitabine 800 mg/m². The impact of drug sequence remains undetermined.     

氟尿苷在大鼠子宫组织内的分布及药动学研究

 目的研究氟尿苷(FUDR)在大鼠血清及子宫组织内的分布、代谢特征并进一步探讨FUDR与氟尿嘧啶(5FU)转化关系。方法建立了大鼠血清和子宫组织中FUDR及5FU的HPLC测定方法。130只雌性Wistar大鼠随机分组，尾静脉恒速输注FUDR或5FU，并按照设计的时间点断头放血，采集血及子宫组织标本，测定各标本中的FUDR及5FU浓度。考察FUDR在大鼠体内的动力学特征及其与5FU的转化关系，以及FUDR与5FU在大鼠子宫组织的分布特征。结果在本实验的剂量下，FUDR在大鼠体内呈现线性代谢特征，而其代谢物5FU则符合非线性特征。静脉输注时，5FU具有较强的血液/子宫组织穿透能力，其子宫组织5FU浓度(2.19～5.87) μg·g^-1与血液浓度(4.52～5.41) mg·L^-1相当。而输注FUDR时，子宫组织内的FUDR浓度很低，代谢物5FU的浓度(2.53～5.11)μg·g^-1却与输注5FU时的相当，而此时血清5FU浓度(0.47～0.83) mg·L^-1却远低于输注5FU时的血清浓度。结论FUDR具有更强的子宫组织亲和力，静脉输注FUDR后子宫组织内其代谢物5FU的浓度较高。     

气固顶空色谱法测定植入用缓释氟尿嘧啶中环己烷

目的:测定植入用缓释氟尿嘧啶中环已烧残留量。方法:研碎供试品,置针管中于60℃保温作气固顶空平衡,顶空气以气相色谱法测定,氢焰检测器,SE-30固定相,柱温80℃。结果:方法的精密度RSD为2.8％,回收率为101.4％,10～110ng·mL~(-1)范围内线性良好,检出限为3.4ng·mL~(-1)。结论:为类似难溶性固体药物的有机溶剂残留量检测提供了可靠的方法。     

FOLFOX方案治疗30例晚期胃癌疗效观察

目的：观察每二周高剂量亚叶酸钙（CF）／氟脲嘧啶（5－FU）与草酸铂（L－OHP）方案（FOLFOX方案）治疗晚期胃癌的临床疗效和毒副反应。方法：采用高剂量CF／5－FU／L－OHP深静脉输注方案（CF200mg.m^2-1.d^-1，静滴2小时，第1、2天；5-FU400mg.m^2-1.d^-1,静推，第1天，5－FU1600mg.m^2-1.d^-1，静滴22小时，第1、2天；L－OHP130mg.m^2-1.d^-1，静脉输注4小时，第1天），化疗方案以14天为1周期，重复4周期后间隔1个月评定疗效。结果：全组30例，总有效率为53．3％，18例初治组的有效率为61．11％，其中CR1例。12例复治组的有效率为41．7％，初治组中位缓解期为5个月。复治组的中位缓解期为3个月。Ⅱ、Ⅲ度口腔炎发生率为26．7％，7例出现手足综合征，血液学毒性轻微。结论：每二周高剂量CF／5－FU／L－OHP方案是治疗晚期胃癌有效安全的化疗方案。     

5-FU超声雾化吸入联合放化疗治疗非小细胞肺癌的临床研究

探讨 5 FU超声雾化吸入联合放疗及全身化疗治疗非小细胞肺癌 (NSCLC)的疗效 ,探讨一种新的非手术综合治疗方案。60例非小细胞肺癌患者随机分为两个组。研究组采用 5 FU超声雾化吸入联合常规放疗及以顺铂为主的全身化疗 2个周期 ,对照组采用常规放疗及全身化疗。结果示研究组和对照组的总有效率分别为 86 67%(2 6/3 0 )和 63 3 3 % (19/3 0 ) ,χ2 =4 3 5 6,P <0 0 5。 1、2、3年生存率研究组为 79 89%、5 6 2 6%和 3 0 3 9% ;对照组分别为 5 1 5 7%、3 4 81%和 11 60 % ,χ2 =4 42 1,P <0 0 5。两组的毒副反应差别无统计学意义 ,P >0 0 5。 5 FU超声雾化吸入联合放疗和以顺铂为主的全身化疗提高了NSCLC的 1、2、3年生存率 ,毒副反应可耐受 ,是一种有效的非手术综合治疗方案。     

Comparative Study of Gemcitabine Plus Cisplatin and Gemcitabine Plus Fluorouracil in the Treatment of Advanced Pancreatic Cancer

Objective To compare the efficacy and toxicity of gemcitabine plus cisplatin and gemcitabine plus fluorouracil in the treatment of advanced pancreatic cancer. Methods Sixty patients with advanced pancreatic cancer were randomly divided into a GP group (gemcitabine + cisplatin, 30 cases) and a GF group (gemcitabine + fluorouracil, 30 cases). All patients were treated with gemcitabine at a dose of 1,000mg/m² (diluted in 100ml saline solution over 30 min) once a week for 3 consecutive weeks. The GP Group was followed by 40mg cisplatin via intravenous drip on days 15,16,17. Group GF was followed by 500mg/m²5-Fu (diluted in 5% glucose-saline (GS) 500ml, intravenously, over 6 hr) every day for five subsequent days. Results In the GP group, eight cases (32.0%) were PR and MR, the median survival time was 8.7 months, the Clinical Beneficial Rate (CBR) was 57.7%, and the CA19-9 decreased by over 50% in 13 cases (48.1%). In the GF group, 11 cases (45.8%) were PR and MR, the survival time was 10.1 months, the CBR was 82.1%, and CA19-9 decreased by over 50% in 15 cases(53.6%). There was a significant difference in the CBR between the two groups (P<0.05). The main toxicities in both groups were leucopenia and thrombocytopenia with no significant difference. Conclusions The treatment given to either the GP or GF group is a feasible and well-tolerated chemotherapy regimen for treating advanced pancreatic cancer with improved therapeutic efficacy and few side effects. The median survival period is long and the CBR is high, especially with the GF regimen.     

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study

Purpose: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer.Patients and methods: A total of 306 patients were randomized to receive either 5-FU 425 mg/m² given by bolus injection on days 1–5 plus intravenous (i.v.) LV 20 mg/m² every four to five weeks or 5-FU 3.5 g/m²/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms.Results: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3–4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm.Conclusions: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3–4 toxicity.     

庚铂治疗晚期胃癌Ⅱ期临床研究

目的评价庚铂（cis-malonato platinum,Hetaplatin）单药和联合治疗晚期胃癌的安全性和有效性.方法多中心、开放式、前瞻性随机对照Ⅱ期临床研究;单药组：庚铂360 mg/m^2,第1天;庚铂联合氟尿嘧啶和亚叶酸钙（5-FU/CF）试验组：庚铂用法同单药组,5-FU 375 mg/m^2静脉输注,第1～5天,CF 200 mg/m^2静脉输注,第1～5天;顺铂（DDP）联合5-FU/CF对照组：DDP 25 mg/m^2稀释于生理盐水500 ml,第1～3天,5-FU/CF用法同庚铂联合试验组.以上三个方案每3周重复一次,为一疗程.采用WHO实体瘤近期疗效标准评价,于第2个疗程后第三周进行疗效评价：采用加拿大国家癌症研究所CTG补充常用毒性标准评价安全性.结果 200例可评价疗效的患者中,庚铂单药组总有效率（CR＋PR）14.9%;庚铂联合试验组总有效率为22.8%;顺铂联合对照组总有效率为22.0%;两联合组疗效之间差异无显著性.在庚铂单药治疗组,血液学毒性轻微,非血液学毒性包括较严重的恶心、呕吐和食欲下降;庚铂联合试验组与DDP联合对照组相比,前者血液学不良反应低,而非血液学不良反应略高,但差异均无显著性.结论治疗晚期胃癌庚铂单药安全有效;庚铂加5-FU/CF联合治疗疗效与DDP加5-FU/CF相当;药物不良反应相似.     

奥沙利铂联合方案治疗晚期胃癌的临床疗效

目的　研究奥沙利铂(L OHP)与氟尿嘧啶(5 FU)、亚叶酸钙(CF)联合化疗方案治疗晚期胃癌的近期疗效及不良反应。方法　2 0 0 2年6月至2 0 0 4年6月2 4例晚期胃癌患者入组本次临床试验。入组病例接受L OHP联合5 FU及CF治疗方案:d1,L OPH 130mg·m-2 ,ivgtt;d1～5 ,CF 2 0 0mg·m-2 ,ivgtt;d1～5 ,5 FU 5 0 0mg·m-2 ,ivgtt×6h ,2 1d为一个周期,至少完成3周期。分别观察其近期疗效及不良反应。结果　近期疗效判定参照WHO实体瘤疗效评价标准;不良反应按实体瘤(1981年)NCI分级标准。全组2 4例患者总有效率(CR +PR)为5 0 % (12 / 2 4 ) ;主要不良反应为轻度骨髓抑制、消化道反应及外周神经毒性。结论　L OHP联合化疗方案治疗晚期胃癌疗效确切,不良反应能耐受     

氟尿嘧啶和卡铂周围静脉给药与舌动脉灌注栓塞后药代动力学实验研究

目的研究对比经数字减影血管造影术(DSA)舌动脉介入灌注与经周围静脉给药两种途径抗癌药物在血和组织中浓度的不同变化。方法选4只杂种健康犬,分为两组,一组先静脉给予氟尿嘧啶(Fu)和卡铂(CBP)各75 mg,于给药后10 min、20 min、30 min、1 h、2 h、3 h、5 h、3 d、5 d、8 d静脉取血,于给药后10 min、20 min3、0 min3、d、5 d8、d行舌及颊组织活检,应用高效液相色谱法(HPLC)测定血、组织中药物浓度;3周后行DSA超选择性舌动脉介入灌注抗癌药物栓塞,同上检测血、组织中药物浓度。另一组先行动脉给药,再行静脉给药,余同前组。结果DSA超选择性舌动脉介入灌注抗癌药物栓塞后,血药浓度的衰减比静脉给药变慢,而舌组织中药物浓度显著增加,给药后10、203、0 min舌组织中Fu浓度是静脉用药组的25、20、4倍,颊组织中药物浓度是静脉用药组的25、44、25倍,差异有显著性(F=4.81~52.02,t=2.82~9.75,P<0.01、0.05)。结论术前DSA动脉介入灌注抗癌药物栓塞,能减缓血药浓度的衰减,增加组织中药物浓度。