A phase II study of sequential methotrexate and fluorouracil in advanced colorectal cancer

Summary Twenty-nine patients with advanced colorectal cancer were treated with methotrexate (MTX) 200 mg/m² followed 1 h later by fluorouracil (FU) (1000 mg/m²) and 24 h later by oral leucovorin 20 mg every 6 h for six doses. The cycle was repeated every 2 weeks. Among the 25 evaluable patients there were 2 complete responses (confirmed by liver scan) and 5 partial responses. Although hematological toxicity was mild, there were four episodes of nonfatal sepsis. The majority of patients developed an erythematous scaly rash on the palms and soles plus eye irritation after six courses of chemotherapy. In addition, the sequential MTX-FU had to be discontinued in 6 of the 7 responders because of (a) severe chills, (b) severe hyperpigmentation, or (c) neurologic complications (ataxic gait or disorientation).These results indicate that this sequential MTX-FU has modest activity in colorectal cancer but is associated with moderately severe toxicity. Only randomized trials of FU alone versus sequential MTX-FU can determine whether sequential MTX-FU has a therapeutic advantage over FU alone in the treatment of advanced colorectal cancer.     

伊立替康与氟尿嘧啶/亚叶酸钙方案治疗转移性结直肠癌的临床观察

为了评价和观察伊立替康(CPT-11)联合氟尿嘧啶(5-FU)与亚叶酸钙(LV)双周方案(FOLFIRI)治疗转移性结直肠癌的临床疗效和不良反应,对56例转移性结直肠癌患者采用FOLFIRI双周方案治疗,剂量为CPT-11180 mg/m2,静脉滴入90 min,d1,LV 200 mg/m2,静脉滴入,d1,d2,5-FU 400 mg/m2,静脉推注,d1,d2,5-FU600 mg/m2,持续静脉滴入22 h,d1,d2,14 d为1个周期.54例可评价疗效,CR 1例,PR 17例,SD 23例,PD 13例,有效率33.3%.不良反应主要为延迟性腹泻、中性粒细胞减少及胆碱能综合征.初步研究结果提示,FOLFIRI双周方案治疗转移性结直肠癌疗效肯定,安全性好,不良反应可耐受,值得临床推广应用.     

High-dose leucovorin, fluorouracil and oral dipyridamole in the treatment of advanced colorectal cancer

Fifty-five patients with advanced colorectal cancer were treated with the combination of leucovorin (LV), fluorouracil (FU) and dipyridamole (DP). Two (4%) patients achieved a clinical complete remission, 4 (7%) a partial remission, 24 (44%) had stable disease while 25 (45%) patients progressed during the chemotherapy period. Median survival was 47 weeks and median time to progression 19.5 weeks. Major toxicities included diarrhea (66%), leukopenia (45%), anemia (50%) and nausea/vomiting (44%). In conclusion, the addition of oral DP does not appear to improve the efficacy of the standard LV/FU regimen in patients with advanced colorectal cancer.     

口服氟尿嘧啶类制剂治疗进展期结直肠癌的现状与进展

氟尿嘧啶类化疗药物在结直肠癌治疗中占有非常重要的地位,口服氟尿嘧啶类制剂包括优福啶、脱氧氟尿苷、卡培他滨、替吉奥等,与传统氟尿嘧啶（5-FU）相比具有高效、低毒、应用方便等优点,其临床应用也越来越广泛。本文回顾分析了5 FU的作用机制以及口服氟尿嘧啶类制剂的研发情况,并就口服氟尿嘧啶类制剂治疗进展期结直肠癌的现状与进展作一综述。     

氟尿嘧啶缓释剂术中局部植入治疗32例进展期大肠癌

Objective: The aim of our study was to probe into the effect of fluorouracil controlled release formulation in the local implant treatment of patients with advanced colorectal cancer. Methods: Sixty-four cases of patients advanced colorectal cancer from August 2004 to February 2008 were selected for radical surgery, including 32 cases injected with intraoperative fluorouracil controlled release formulation in local implantation for 600 mg (the treatment group). Patients in another 32 cases received abdomina...     

The influence of isorel on the advanced colorectal cancer

There is still no therapy method in the colorectal cancers that is good enough for such a complex disease. Combined surgery, chemotherapy, and radiotherapy improved survival, but the side effects and the poor performance status of the patients seriously affect the use of these methods. We used a therapeutical approach of surgery and chemotherapy combined with biotherapy by Viscum album extract Isorel, aiming to improve the patients' resistance to the disease and to render the treatment's side effects more tolerable. Isorel is aqueous extract well known for its anticancer effects obtained by various in vitro and in vivo experimental models and which was validated by an in vitro bioassay on murine melanoma B16F10 and human cervical carcinoma HeLa cells. Isorel strongly reduced human colon cancer HT 29 cell line growth in vitro in the MTT bioassay. Hence, it was further used in a prospective, randomized, and controlled study which compared the postoperative results for patients with colorectal cancer stages Dukes C (40 patients) and D (24 patients) who, beside surgery, received either only chemotherapy (5-FU), 6 cycles (either the Mayo or the De Gramont protocol) or chemotherapy combined with Isorel biotherapy. These 64 patients were randomly allocated into three groups "only chemotherapy" for 21 cases, chemo + biotherapy for 29 cases and 14 patients underwent only surgery as the control group. We noted no toxic deaths due to either chemo or biotherapy. The patients operated on and treated with chemo and biotherapy had median survival significantly better and a cumulative proportion survival (Kaplan-Maier) superior to those of the patients receiving only postoperative chemotherapy. Thus, colorectal cancer patients seem to benefit in terms of survival from combined postoperative chemotherapy and Isorel biotherapy, either adjuvant or palliative.     

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     

OLF与LFP方案治疗晚期大肠癌的临床对比观察

目的：研究奥沙利铂与氟尿嘧啶、亚叶酸钙联合运用，治疗晚期大肠癌的疗效和毒副反应。方法：治疗组（A=35例）采用奥沙利铂100rag／m2静滴2小时，第1天；亚叶酸钙200rag／m2；静滴2小时，第1—5天；氟尿嘧啶300mg／m2静滴24小时，第1—5天（于亚叶酸钙静滴完后用）。对照组（B=33例）采用顺铂20mg／m2静滴，第1—5天；亚叶酸钙200mg／m2静滴2小时，第1—5天；氟尿嘧啶500mg／m2静滴24小时，第1—5天；21天或28天为1周期。结果：总有效率A组为45．7％，B组为33．3％，两组1，3年无进展生存率分别为71．4％和48．5％，51．4％和27．3％；均有显著性差异（P〈0．05）；毒副反应以骨髓抑制、恶心呕吐、感觉性神经毒性为主，多为Ⅰ-Ⅱ度。结论：奥沙利铂与氟尿嘧啶、亚叶酸钙联合运用治疗晚期大肠癌疗效肯定，毒副反应轻病人能耐受。     

奥沙利铂与氟尿嘧啶、亚叶酸钙联合治疗晚期大肠癌

目的：研究奥沙利铂与氟尿嘧啶、亚叶酸钙联合应用治疗晚期大肠癌的疗效和毒副反应。方法：采用奥沙利铂130mg/m^2，静滴2小时，第1天；亚叶酸钙200mg/m^2，静滴2小时，第1－5天；氟尿嘧啶300mg/m^2(≤500mg/d)，静滴4小时，第1－5天（亚叶酸钙滴完后用）；21或28天为1周期。结果：总有效率为29．7％，毒副反应以骨髓抑制、感染性神经毒性为主，白细胞减少45．9％，Ⅲ级和Ⅳ级为8．1％，感觉性神经毒性81．1％，Ⅲ级和Ⅳ级为5．4％。结论：奥沙利铂与氟尿嘧啶、亚叶酸钙联合应用晚期大肠癌疗效肯定，毒副反应能耐受。     

国产奥沙利铂联合氟尿嘧啶和亚叶酸钙治疗晚期结直肠癌的临床观察

目的评价奥沙利铂(L-OHP)联合氟尿嘧啶(5-Fu)、亚叶酸钙(CF)方案治疗晚期结直肠癌的疗效与毒副反应.方法奥沙利铂130 mg/m2,静滴4 h,第1天;亚叶酸钙200 mg静脉滴注2 h,5-Fu 300 mg/m2,持续静滴6～8 h,第1～5天(亚叶酸钙滴完后用);21 d为1周期,行2周期治疗后评价疗效.结果全组完全缓解(CR)1例,部分缓解(PR)12例,总有效率(CR PR)为43.3%.毒性反应以骨髓抑制、感觉性神经毒性为主,多为Ⅰ～Ⅱ度,其中白细胞减少发生率为46.7%,感觉性神经毒性发生率为77.7%,无化疗相关死亡.结论奥沙利铂联合氟尿嘧啶、亚叶酸钙治疗晚期结直肠癌疗效肯定,毒副反应能耐受.     

氟尿嘧啶为主方案持续和间断输注治疗晚期结直肠癌

目的比较氟尿嘧啶(5-FU)持续静脉输注120小时和每天静脉输注2小时,连续5天的两种给药方法治疗晚期结直肠癌的近期疗效和不良反应.方法17例晚期结直肠癌患者接受5-FU 2.5g+5%葡萄糖注射液100 ml置入Baxter公司生产的049002便携式泵持续输注120小时(A组);16例晚期结直肠癌患者接受5-FU 500mg+5%葡萄糖注射液500 ml每天输注2小时,连续5天(B组).33例均联合亚叶酸钙(CF)200 mg+5%葡萄糖注射液100 ml输注1小时,连续5天;羟基喜树碱(HCPT)10 mg+5%葡萄糖注射液250ml输注2小时,连续6天.每3～4周为1疗程,连续2疗程后进行疗效评价.结果A组17例中 CR 1例,PR 8例,RR 52.94%,B组 16例中CR 0例,PR 3例,RR 18.75%.两组疗效χ2检验有差异(P<0.05).不良反应主要有白细胞下降、口腔溃疡、呕吐和腹泻,经Wiloxon秩和检验,两组结果差异无显著性 (P值>0.05).结论5-FU持续静脉输注120小时方法治疗晚期结直肠癌的近期疗效优于间断静脉输注方法,而且毒性可以耐受,尤其适宜老年患者.     

Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m(2)/d) followed by a 5FU bolus (400 mg/m(2)/d) and 22-hour infusion (600 mg/m(2)/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P =.0003) and better response rate (50.7% v 22.3%; P =.0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P =. 12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41. 7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P =.004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.     

Effect of a 3-hour interval between methotrexate and 5-fluorouracil in the treatment of metastatic colorectal cancer

OBJECTIVE: This phase II study was designed to evaluate the efficacy and toxicity of 3-h interval sequential methotrexate (MTX) and 5-fluorouracil (5-FU) with leucovorin (LV) rescue in the treatment of patients with metastatic colorectal cancer. METHODS: Forty-two patients with histologically confirmed metastatic colorectal cancer and at least one two-dimensionally measurable lesion, aged 30-74 years old, with performance status < or =2 and no or one prior chemotherapy were selected. Patients received sequential MTX 100 mg/m2 by bolus injection and 5-FU 600 mg/m2 at 3 h followed by LV rescue initiated after 24 h (15 mg per body every 6 h for six doses). The treatment was repeated every week or every 2 weeks until disease progression. All patients were treated as out-patients unless complications arose. RESULTS: All 42 patients entered in this study were assessable both for response and toxicity. Fifteen patients achieved objective responses (one complete and 14 partial), for an overall response rate of 36% (95% CI: 11-51%). Response rates in pretreated patients and patients with naive chemotherapy were 27 and 42%, respectively. Sixteen patients had stable disease and 11 progressed with therapy. The median survival for all patients was 378 days. The hematological toxicity was mild with no grade 3/4 leukopenia. The major non-hematological toxicity was diarrhea (one grade 4, four grade 3). CONCLUSIONS: This 3-h interval sequential MTX and 5-FU with LV rescue is an active regimen in patients with metastatic colorectal cancer. The treatment showed mild toxicity and was administered on an out-patient basis. The present findings suggest that this regimen warrants further investigation in patients with metastatic colorectal cancer.     

伊立替康联合氟尿嘧啶时辰化疗在晚期结直肠癌中的应用

目的　探讨伊立替康联合氟尿嘧啶时辰化疗治疗晚期结直肠癌的疗效和毒副反应。方法　分析我院自２００７年６月至２００８年１２月应用伊立替康联合氟尿嘧啶时辰化疗方案治疗的３２例晚期结直肠癌患者的疗效和毒副反应,并与我院同时期应用ＦＯＬＦＩＲＩ方案化疗的３１例晚期结直肠癌患者进行比较。结果　时辰化疗方案和ＦＯＬＦＩＲＩ方案的总有效率（ＲＲ）、疾病控制率（ＤＣＲ）分别为２１.９％、６５.６％和２５.８％、５８.１％。时辰化疗方案的中位疾病进展时间（ｍＴＴＰ）为６.４个月,中位总生存时间（ｍＯＳ）为９.０个月;ＦＯＬＦＩＲＩ方案的ｍＴＴＰ为５.０个月,ｍＯＳ为７.９个月,两组比较差异均无统计学意义（Ｐ＞０.０５）。两方案常见的毒副反应为恶心呕吐、中性粒细胞减少和腹泻,但多以１～２级为主;３～４级毒副反应在时辰化疗方案中的发生率低于ＦＯＬＦＩＲＩ方案。结论　伊立替康联合氟尿嘧啶时辰化疗方案具有疗效高、毒副作用低等优点,可作为晚期结直肠癌的推荐化疗方案之一。     

艾力联合5-Fu及CF治疗晚期大肠癌的临床研究

目的观察艾力(CPT-11)及5-氟脲嘧啶(5-Fu)治疗晚期大肠癌近期疗效及不良反应。方法艾力120mg/m2,静滴,第1天;CF 100mg天/,静滴,第1至5天;5-Fu 500mg/m2,静滴,第1至5天;3周为1周期,2个周期后评估疗效及毒性反应。结果24例患者可评估者22例,其中CR 1例,PR 7例,SD 8例,PD6例,有效率36.4%。主要不良反应为恶心、呕吐、迟发性腹泻和骨髓抑制等。结论艾力 5-Fu/CF治疗晚期大肠癌有较好的疗效,且毒副反应可以耐受。     

多西紫杉醇联合氟尿嘧啶和奥沙利铂治疗晚期胃癌的临床观察

目的:观察多西紫杉醇(TAT)联合氟尿嘧啶(5-FU)及奥沙利铂(OXA)组成TFO方案治疗国人晚期胃癌的临床疗效及毒副反应。方法:50例晚期胃癌患者随机分为研究组及对照组。研究组25例给予TFO方案,对照组25例给予5-FU联合顺铂(PDD)组成的PF方案。每28天为1周期,至少2个周期后评价疗效。结果:全组可评价病例50例,疗效按RE-CIST标准评定,以CR PR合计为有效,研究组中CR2例,PR11例,有效率52.0%;对照组中CR1例,PR3例,有效率16.0%,两组间疗效差异有显著性(P<0.05)。TFO方案主要毒副反应为Ⅰ～Ⅱ度为主的白细胞减少、脱发和胃肠道反应。结论:TFO方案治疗晚期胃癌疗效肯定,特别对初治者,毒副反应较轻,但有部分患者出现不同程度骨髓抑制,需集落刺激因子支持治疗。     

Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients.

PURPOSE: To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD). PATIENTS AND METHODS: Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle. RESULTS: Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU. CONCLUSION: The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.     

多西他赛联合顺铂、氟尿嘧啶治疗进展期胃癌近期疗效观察

目的 观察多西他赛联合顺铂、氟尿嘧啶方案治疗晚期胃癌的近期疗效和毒副反应.方法 对31例进展期胃癌患者采用多西他赛75／m2 d1静滴1小时,用药前均予预处理;顺铂20 mg／m2静滴d1～d5,氟尿嘧啶750 mg／m2持续静滴120小时,每4周重复,至少治疗2周期,按WHO标准进行评价.结果 31例均可评价疗效,其中完全缓解2例,部分缓解14例,总有效率为51.6％;剂量限制性毒性主要表现为骨髓抑制.结论 多西他赛联合顺铂、氟尿嘧啶方案治疗进展期胃癌患者疗效确切,毒副反应可以耐受.