羟基喜树碱联合用药治疗进展期结直肠癌的临床研究

目的：比较羟基喜树碱联合草酸铂（OH方案）和羟基喜树碱联合亚叶酸钙、氟尿嘧啶（HLF方案）治疗进展期结直肠癌的临床疗效和安全性。方法：经病理证实的进展期结直肠癌病例59例,37例采用OH方案化疗,22例采用HLF方案化疗,观察化疗毒副反应,2周期后评价疗效,随访观察无疾病进展生存期、总生存期,统计1年生存率。结果：OH和HLF方案化疗完全缓解率均为0,部分缓解率分别为32.4%（12/37）和22.7%（5/22）,两组差异无统计学意义（P〉0.05）;中位无进展生存期（mPFS）分别为5.7个月和7.3个月,两组差异无统计学意义（P〉0.05）;中位总生存期（mOS）分别为11.1个月和10.1个月,两组差异无统计学意义（P〉0.05）;1年生存率分别为30.98%和15.02%,两组差异无统计学意义（P〉0.05）。两组Ⅲ、Ⅳ度毒副反应均以骨髓抑制和消化道反应为主,其中粒细胞减少、恶心和呕吐、腹泻、外周神经毒性的发生率方面,OH组均高于HLF组（P〈0.05）。结论：OH和HLF方案治疗进展期结直肠癌疗效相似,前者粒细胞减少、胃肠道反应和外周神经毒性较常见,而贫血和血小板减少两者相似。     

Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer

Purpose

To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC).

Patients and methods

A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m², 5-fluorouracil 2000 mg/m², folinic acid 500 mg/m² weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m² applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS).

Results

A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio = 1.14; 95% confidence interval (CI) 0.94-1.37; P = 0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio = 1.08, P = 0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P = 0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P = 0.006)

Conclusion

mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.     

奥沙利铂联合5-氟尿嘧啶和醛氢叶酸钙时辰治疗晚期胃癌的初步临床研究

目的观察奥沙利铂(L-OHP)联合5-氟尿嘧啶(5-Fu)、醛氢叶酸钙(FA)方案(FFL方案)时辰输注法治疗晚期胃癌的疗效和不良反应。方法FFL方案时辰输注法治疗26例晚期胃癌患者,L-OHP 25 mg.m-2.d-1,5-Fu 600 mg.m-2.d-1,FA 300 mg.m-2.d-1,多通道程控时辰输液泵连续给药4 d,每14 d为1个周期,至少用2个周期。结果26例晚期胃癌患者中,完全缓解(CR)2例(7.7%),部分缓解(PR)13例(50.0%),稳定(SD)6例(23.1%),进展(PD)5例(19.2%),总有效率为57.7%。在共80个周期的化疗中,最常见的不良反应为血液学毒性、胃肠道毒性、外周神经毒性,但均以Ⅰ度为主,Ⅲ度中性粒细胞减少发生2例次,血小板减少、呕吐和口腔黏膜炎分别发生1例次,未出现Ⅳ度不良反应。中位缓解时间为3.5个月,中位肿瘤进展时间为4.5个月,全组患者中位生存期为8个月。结论FFL方案时辰输注法是治疗晚期胃癌安全有效的化疗方案。     

多西紫杉醇联合奥沙利铂和5-氟尿嘧啶双周方案治疗晚期胃癌的初步研究

目的 探讨多西紫杉醇(DOC)联合奥沙利铂(L-OHP)和5-氟尿嘧啶(5-Fu)的DOF双周方案对晚期胃癌的临床疗效和毒副反应.方法 37例晚期胃癌患者均行锁骨下深静脉穿刺或外周肘正中静脉穿刺,置入单腔输液导管,经电脑输液泵控制5-Fu的输液速度.DOC 35 mg/m2, 静脉滴注1 h,第1天;L-OHP 85 mg/m2,静脉滴注2 h,第1天;甲酰四氢叶酸(LV) 200 mg/m2,静脉滴注2 h,第1天;5-Fu 1500 mg/m2,持续静脉滴注48 h,第1～2天.14 d为1个周期,至少应用3个周期进行疗效评估.结果 全组37例均可评价疗效,总有效率为67.6%,其中完全缓解率为27.0%,部分缓解率为40.5%.至肿瘤进展时间为9.2个月,中位生存期为13.7个月.在初次化疗的11例患者中,有效率为81.8%;在既往接受过化疗的26例患者中,有效率为61.5%.主要剂量限制性毒性反应为骨髓功能抑制,其中Ⅲ～Ⅳ度白细胞下降率为29.7%,无治疗相关性死亡. 结论 DOF双周方案是晚期胃癌的有效化疗方案,其毒副反应轻微,患者易于耐受,值得进一步研究.     

替吉奥与5-氟尿嘧啶联合奥沙利铂治疗晚期胃癌的临床疗效及安全性分析

目的分析替吉奥与5-氟尿嘧啶联合奥沙利铂治疗晚期胃癌的临床疗效及安全性。方法选取2011年1月至2014年7月间收治的90例晚期胃癌患者,采取随机数字表法分为对照组和试验组,每组45例。对照组给予5-氟尿嘧啶、奥沙利铂及亚叶酸钙治疗,试验组给予替吉奥联合奥沙利铂治疗,比较两组患者的临床疗效及不良反应。结果试验组患者的有效率和临床获益率分别为44.4%和91.1%,对照组分别为31.1%和75.6%,差异均有统计学意义(均P<0.05)。试验组与对照组在血细胞减少、血小板减少、恶心呕吐、贫血、外周神经毒性、腹泻及口腔黏膜炎方面差异均有统计学意义(均P<0.05)。结论采用替吉奥联合奥沙利铂治疗晚期胃癌的临床疗效较为确切,不良反应较少,安全性较高,值得推广。     

Clinical study of combining chemotherapy of oxaliplatin or 5-fluorouracil/leucovorin with hydroxycamptothecine for advanced colorectal cancer

OBJECTIVE To estimate effects, survival rate after the short-time efficacy, side the treatment of combining chemotherapy of oxaliplatin or 5-fluorouracil/leucovorin with hydroxycamptothecine （HCPT） for the patients with advanced colorectal cancer.
METHODS From January 2002 to November 2005, 59 patients with advanced colorectal cancer confirmed by pathology were enrolled into this study in the department of medical oncology, in the Sixth People＇s Hospital of Shanghai Jiaotong University, Shanghai. Patients＇ characteristics in two groups were similarly confirmed by statistic. All 37 patients in OH group received oxalip21atin （130 mg/m^2 d1） plus hydroxycamptothecine （6 mg/m d1-4）, and all 22 patients in the HLF group received hydroxycamptothecine （6 mg/m^2 d1-4） plus leucovorin （300 mg d1-5） and 5-fluorouracil （0.375 g/m^2 d1-5）. The regimens in both groups were 21-day cycle that was repeated three weeks. The side effects were evaluated. The efficacy was estimated after two cycles of chemotherapy for each patient.
RESULTS The efficacy of the treatment in the OH group with 37 patients and in the HLF group with 22 patients was estimated. The overall response rate （CR ＋ PR） was 32.4% in the OH group and 22.7% in the HLF group. There was no complete response （CR） and there was no statistical significantly difference （%2= 0.876, P = 0.704） in two groups. The 1-year survival rate was 30.98% in the OH group and 15.02% in the HLF group, and it had no significant difference between the two groups. The median PSF and OS were 5.83 months and 11.17 months in the OH group vs. 7.40 months and 10.48 months in the HLF group, and it had no significant differences between the two groups （P 〉 0.05）. The major side effects of grade III and IV in the two groups were myelosuppression and gastrointestinal reactions. The statistically significant difference in side effects appeared in leukopenia （χ^2= 17.173, P = 0.001）, nausea/vomiting （χ^2= 6.426, P = 0.039）, diarrhea （χ^2= 16.245, P = 0.000） and peripheral neuropathy. CONCLUSION The efficacy was almost equal between the OH and the HLF groups, and the two regimens can be used as the second-line treatments for the patients with colorectal cancer. Leucopenia, nausea, diarrhea and peripheral neuropathy appeared more in OH group, and anemia and thrombocytopenia were almost equal between the OH and the HLF groups.     

Dose-finding study of weekly 24-h continuous infusion of 5-fluorouracil associated with alternating oxaliplatin or irinotecan in advanced colorectal cancer patients.

PURPOSE: To determine maximum tolerated dose, safety and efficacy of weekly 24 h infusional 5-fluorouracil (5-FU) combined alternately with oxaliplatin and irinotecan. PATIENTS AND METHODS: Advanced colorectal carcinoma patients in first- or second-line chemotherapy received increasing doses of 5-FU (weekly 24 h continuous intravenous infusion without leucovorin) on days 1, 8, 15 and 22, irinotecan days 1 and 15; and oxaliplatin days 8 and 22, every 35 days. RESULTS: Thirty-four patients received 175 cycles. The median age was 64 years (range 47-78). Eighteen per cent of patients had the primary tumor in the rectum, with a median of one disease site (range one to three), and liver involvement in 88% and lung in 38%. Six (18%) patients had chemotherapy for prior advanced disease. The most frequent grade 3-4 toxicity was neutropenia (41% of patients), but the regimen was well tolerated clinically, with febrile neutropenia in two patients and grade 4 neutropenia lasting >7 days in one; grade 3-4 diarrhea, nausea and vomiting in 6% of patients; grade 3-4 peripheral neuropathy in 9% of patients. Seventeen patients had a partial response (50%; 95% confidence interval 33%-67%), 13 had stable disease and one had progressive disease. Five patients underwent metastatic surgical resection after tumor shrinkage. Median response duration was 14 months (range 4.7-29.2+) and median time to progression was 11.3 months (range 1.1+-30.7+). CONCLUSIONS: This combination three-drug regimen is feasible and well tolerated without toxicity overlap. Preliminary antitumor activity compares well with standard double combinations, with an unusually long median time to progression. The recommended dose is 5-FU 3000 mg/m(2), weekly for 4 weeks, irinotecan 100 mg/m(2) days 1 and 15, oxaliplatin 80 mg/m(2) days 8 and 22. Further assessment of antitumor activity and safety is warranted.     

伊立替康或奥沙利铂联合卡培他滨治疗晚期胃癌的疗效比较

目的 观察并比较伊立替康(CPT-11)联合卡培他滨(CAP)与奥沙利铂(L-OHP)联合CAP治疗晚期胃癌的近期疗效和毒副反应.方法 将63例晚期胃癌患者随机分为两组,CPT-11+CAP组32例,应用CPT-11联合CAP方案治疗;L-OHP+CAP组31例,应用L-OHP联合CAP方案治疗.2个周期后评价疗效及毒副反应,有效病例4周后进行疗效确认.结果 CPT-11+CAP组PR 13例,有效率为40.6%,中位无进展生存期为6.3个月.L-OHP+CAP组PR 12例,有效率为38.7%,中位无进展生存期为6.1个月.两组有效率及中位无进展生存期比较,差异均无统计学意义(P＞0.05).两组的主要毒副反应为胃肠道反应、周围神经毒性和骨髓抑制.CPT-11+CAP组Ⅲ、Ⅳ度腹泻的发生率(28.1%)高于L-OHP+CAP组(3.2%,P=0.018),Ⅲ、Ⅳ度周围神经毒性的发生率(3.1%)低于L-OHP+CAP组(25.8%,P=0.027).两组均无化疗相关性死亡.结论 CPT-11联合CAP方案与L-OHP联合CAP方案对晚期胃癌均有较好的疗效,毒副反应均可耐受.

Abstract：

Objective To observe and compare the response rate and toxicity of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer.Methods Sixty-three patients with advanced gastric cancer were randomly divided into two groups.The CPT-11 + CAP group consisted of 32 patients who received irinotecan plus capocitabine: CPT-11 100 mg/m2 was injected in 90 minutes on d 1,8 ;capecitabine 2000 mg/m2, bid, with the first dose in the evening of day 1 and last dose the morning of day 15, repoated for every 21 days.The L-OHP + CAP group consisted of 31 patients who received oxaliplatin plus capecitabine: oxaliplatin 100 mg/m2 on day 1, capocitabine 2000 mg/m2, bid,with the first dose in the evening of day 1 and last dose the morning of day 15, repeated for every 21 days.Two or more cycle chemotherapy was completed in each group.Results In the CPT-11 + CAP group, no patient achieved complete response and 13 patients achieved partial response.The overall response rate was 40.6% (13/32), and the median progression-free survival time was 6.3 months.In the L-OHP + CAP group, no patient achieved complete response and 12 patients achieved partial response.The overall response rate was 38.7% (12./31), and the median progression-free survival time was 6.1 months.There was no significant difference between them (P ＞ 0.05 ).The most common toxicities were gastrointestinal reaction,peripheral neuropathy and myelosuppression in the two groups.Patients in CPT-11 + CAP group experienced more Ⅲ/Ⅳ diarrhea (28.1%/3.2%, P =0.018).On the contrary, the rate of Ⅲ/Ⅳ neurotoxicity in the group B was higher (25.8%/3.1%, P = 0.027).No chemotherapy-related death occurred.Conclusion The therapeutic effects of irinotecan or oxaliplatin combined with capecitabine in the treatment of advanced gastric cancer are good and comparable, and their toxicities are tolerable.     

国产奥沙利铂联合亚叶酸钙和5-氟脲嘧啶治疗晚期结直肠癌的临床观察

目的：评价奥沙利铂联合亚叶酸钙、5—氟脲嘧啶(OXA—CF—5—Fu)方案治疗晚期结直肠癌的疗效与安全性。方法：奥沙利铂(OXA)130mg／m^2，静脉滴注4h，d1；亚叶酸钙(CF)200mg静脉滴注2小时，5—氟脲嘧啶(5—Fu)0．25g于CF滴完后静脉推注，5-Fu0．5g持续静脉滴注6-8小时，d1-5，每3周重复。结果：全组26例患者，有效率(CR PR)为42．31％，不良反应为恶心、呕吐和骨髓抑制，但多为Ⅰ～Ⅱ度，一过性感觉异常。结论：奥沙利铂联合亚叶酸钙和5—氟脲嘧啶治疗晚期结直肠癌疗效较高，不良反应轻而且安全。     

奥沙利铂联合表柔吡星和5-Fu治疗晚期胃癌疗效和安全性研究

目的REAL2研究中使用奥沙利铂的EOF方案由于较好的疗效和安全性获得了广泛关注,但中国胃癌患者对REAL2研究中的三药联合EOF方案耐受性较差,本研究使用了改良的EOF方案,将氟尿嘧啶（5-Fu）由原来的静脉输注21天改为5天,观察奥沙利铂联合5-Fu／LV、表柔吡星治疗晚期胃癌的疗效及不良反应。方法30例晚期胃癌患者,初治19例,复治11例。表柔吡星50mg／m^2静脉注射d1,奥沙利铂130mg／m^2静脉滴注2小时d1,5-Fu375～425mg／（m^2·d）d1～5静脉持续输注120小时,每3周重复,每化疗2个疗程评价1次疗效。结果30例患者中,总缓解率43．33％,完全缓解1例,部分缓解12例。初治病例缓解率52．63％（10／19）,略高于REAL2研究中标准EOF方案的42．4％缓解率,复治病例缓解率27．33％（3／11）。KPS评分提高10分以上者10例（33．33％）。在治疗中,主要的Ⅲ～Ⅳ度不良反应为：中性粒细胞减少33．3％（10／30）,血小板减少10％（3／30）,贫血13．33％（4／30）,恶心呕吐23．33％（7／30）．RE．A12研究中标准EOF方案的Ⅲ～Ⅳ度中性粒细胞减少29．9％,与本研究类似,标准EOF方案中的Ⅲ～Ⅳ度血小板减少4．3％,贫血6．5％,恶心呕吐13．8％,略低于本研究,但在本研究中没有观察到Ⅲ～Ⅳ度发热性中性粒细胞减少及血栓栓塞等严重不良反应,而REAL2研究中,发热性中性粒细胞减少和血栓栓塞均为8．5％。结论奥沙利铂联合5-Fu及表柔吡星的改良EOF方案治疗晚期胃癌疗效较好,毒副作用可以很好耐受,值得临床进一步应用。     

Feasibility of carbon ion radiotherapy for locally advanced sinonasal adenocarcinoma

Background and purposeTo evaluate the safety and efficacy of carbon ion radiotherapy (CIRT) for locally advanced sinonasal adenocarcinoma.Material and methodsTwenty-two patients with sinonasal adenocarcinoma were treated with CIRT. CIRT was the primary treatment for 16 patients. Four patients received CIRT for local recurrence after surgery and two for residual tumour after surgery or chemotherapy. At the start of CIRT, 1 patient had T-classification (T) 2 disease, 2 had T3 disease, 5 had T4a disease, and 14 had T4b disease. Fourteen patients were treated with 57.6 Gy equivalent (GyE)/16 fractions, and 8, with 64.0 GyE/16 fractions.ResultsThe median follow-up period was 43 months for all patients. The 3-year local control and loco-regional control rates for all patients were 76.9% (95% confidence interval [CI] = 56.7–97.1%) and 61.3% (95% CI = 38.5–84.1%), respectively. The 3-year overall survival and disease-specific survival rates were 59.1% (95% CI = 38.6–79.6%) and 65.6% (95% CI = 44.9–86.3%), respectively. Acute reactions of grade 3 of the skin and mucosa were observed in 2 and 4 patients, respectively. Late reactions included lateral visual loss (5 patients), mucosal ulceration (1 patient), and brain necrosis with clinical symptoms (1 patient). In the 5 patients who developed visual loss, the optic nerve was close to the tumour.ConclusionsCIRT was effective and generally safe for locally advanced sinonasal adenocarcinoma.     

A Phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer

PURPOSE: The aim of this study was to evaluate the efficacy and tolerance of preoperative chemoradiotherapy (CRT) with irinotecan (CPT-11) and 5-fluorouracil (5-FU) in patients with resectable rectal cancer. METHODS AND MATERIALS: Patients with resectable T3-T4 rectal cancer and Eastern Cooperative Oncology Group performance status <2 were included. CPT-11 (50 mg/m(2) weekly) and 5-FU (225 mg/m(2)/day continuous infusion, 5 days/week) were concurrently administered with radiation therapy (RT) (45 Gy, 1.8 Gy/day, 5 days/week), during 5 weeks. RESULTS: A total of 74 patients were enrolled: mean age, 59 years (20-74 years; SD, 11.7). Planned treatment was delivered to most patients (median relative dose intensity for both drugs was 100%). Grade 3/4 lymphocytopenia occurred in 35 patients (47%), neutropenia in 5 (7%), and anemia in 2 (3%). Main Grade 3 nonhematologic toxicities were diarrhea (14%), asthenia (9%), rectal mucositis (8%), and abdominal pain (8%). Of the 73 resected specimens, 13.7% (95% confidence interval [CI], 6.8-23.7) had a pathologic complete response and 49.3% (95% CI, 37.4-61.3) were downstaged. Additionally, 66.7% (95% CI, 51.1-80.0) of patients with ultrasound staged N1/N2 disease had no pathologic evidence of nodal involvement after CRT. CONCLUSIONS: This preoperative CRT schedule has been shown to be effective and feasible in a large population of patients with resectable rectal cancer.     

奥沙利铂联合5-FU和吡柔比星治疗晚期胃癌临床疗效分析

目的:观察奥沙利铂联合5-FU和吡柔比星治疗晚期胃癌的疗效及不良反应.方法:36例晚期胃癌患者,初治20例,复治16例.吡柔比星40mg/m2静脉注射d1,奥沙利铂130mg/m2静脉滴注2小时d1,5-FU 375mg/m2·d1-5静脉滴注,每3周重复,每化疗2个周期评价1次疗效. 结果: 36例患者中,总缓解率 44.37%,完全缓解1例,部分缓解41.6%(15例).初治病例缓解率45%(9/20),复治病例缓解率31.25%(5/16).KPS评分提高10分以上者15例(15/36).主要的Ⅲ-Ⅳ度不良反应为:中性粒细胞减少27.7%(10/36),血小板减少13.8%(5/36),贫血16.6%(6/36),恶心呕吐22.2%(8/36).结论:奥沙利铂联合5-FU及吡柔比星治疗晚期胃癌疗效较好,不良反应可以耐受,值得临床进一步应用.     

奥沙利铂联合吡柔比星和氟尿嘧啶治疗晚期肝癌的临床疗效分析

目的：探讨联合化疗方案治疗晚期原发性肝癌患者的有效性与安全性。方法：31例晚期原发性肝癌患者,采用奥沙利铂（L-OHP）、吡柔比星（THP）、氟尿嘧啶（5-FU）组成的联合方案进行化疗,观察和评价其疗效及毒副反应。结果：31例患者中,获得CR 0例,PR 9例,SD 14例,PD 8例,疾病控制率（DCR）74.2%;中位肿瘤进展时间（TTP）4.2月;中位生存期（OS）为10.2月;临床受益反应（CBR）率达77.4%;化疗后的血清AFP值较前明显下降。主要的毒副反应为骨髓抑制、消化道反应和感觉神经毒性。结论：奥沙利铂、吡柔比星、氟尿嘧啶组成的联合方案治疗晚期原发性肝癌的疗效安全可靠,不良反应可以接受。     

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study

Background:

Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer.

Methods:

Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m⁻² plus irinotecan 250 mg m⁻² (Day 1)) or 3-weekly DF (docetaxel 85 mg m⁻² (Day 1) followed by 5-fluorouracil 750 mg m⁻² per day as a continuous infusion (Days 1–5)).

Results:

A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively).

Conclusion:

Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.     

Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM)

Background:Gemcitabine alone or 5-fluorouracil (5-FU) according to several schedules are used for palliation of metastatic and locally advanced (LA) pancreatic adenocarcinoma. This study was designed to test the efficacy of the leucovorin–5-FU and gemcitabine combination. Patients and methods:This phase II trial combined a simplified bimonthly LV5FU2 with gemcitabine: leucovorin 400 mg/m² in a two-hour infusion, followed by 5-fluorouracil 400 mg/m² bolus and 2 or 3 g/m² continuous infusion over 46 hours; gemcitabine 1 g/m² was infused over 30 min on day 3 after 5-FU. Treatment was repeated every two weeks. Gemcitabine dose could be increased (250 mg/m² every two cycles up to 1500 mg/m²) in the absence of NCI-CTC toxicity >2. Results:Among the 62 patients included in this study, 22 had LA and 40 had metastatic disease. Objective response rate for the 54 patients with measurable disease was 25.9% (95% confidence interval (CI): 14%–37.8%) and 22.6% (95% CI: 12%–33.2%) in the intent-to-treat population; the clinical benefit rate for the 59 assessable patients was 49.2%. Median progression-free survival and median overall survival were 4.8 and 9 months, respectively, with 32.3% of patients alive at 1 year. The most frequent toxicity (grade 3–4) was neutropenia (56.5%) usually asymptomatic (1.1% febrile neutropenia), but requiring decreases of 5-FU and gemcitabine doses. Unexpected complete alopecia occurred in 97% of patients. Conclusions:Palliative effects, response rate and survival observed in this multicenter study seem to be superior to those obtained with gemcitabine or 5-FU alone, despite a limiting hematological toxicity.     

Gemcitabine (GEM) plus oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX-4) in patients with advanced gastric cancer

Background and aims: oxaliplatin in combination with folinic acid (FA) and infusional 5-fluorouracil (5-FU) has shown significant anti-tumor activity in gastric cancer patients (FOLFOX). Previous studies have shown that gemcitabine (GEM), a new fluorinated anti-metabolite, enhances the individual anti-tumor activity of either 5-FU or oxaliplatin. We have therefore designed a multi-center phase II trial in order to test a novel GEM + FOLFOX-4 regimen in patients with metastatic gastric cancer. Methods: we enrolled 36 patients, 28 males and 8 females, with an average age of 64.4 years (range 37–78), who received bi-weekly treatment with GEM (1,000 mg/m² on day 1), levo-FA (100 mg/m² on days 1 and 2), a 5-FU (400 mg/m²) bolus injection followed by 22-h continuous infusion (800 mg/m²) on days 1 and 2, and oxaliplatin 85 mg/m² in a 4–6 h intravenous (i.v.) infusion before the second FUFA administration on day 2. Results: the most frequent side effect was grade 1–2 hematological toxicity and late sensorial neurotoxicity. Two patients developed hypersensitivity to oxaliplatin while another developed an aseptic eosinophilic pneumonitis. Two patients refused to continue the treatment after two cycles of chemotherapy and were lost at the follow-up. Among the remaining 34 patients four achieved a complete response, 15 a partial response, 12 had a stable disease and three progressed. Conclusions: these results may grant the rationale to evaluate this multi-drug combination in randomized phase III trials in advanced gastric cancer.     

伊立替康（艾力）联合氟尿嘧啶与四氢叶酸钙治疗晚期耐药胃癌的临床探讨

目的观察伊立替康（irinotecan,CPT-11）联合氟尿嘧啶（5-fluorouracil,5-Fu）与四氢叶酸钙（Leucovorin,CF）组成IFL方案治疗晚期耐药胃癌的近期疗效及其安全性。方法回顾性分析我科2003年3月至2009年3月收治的33例具有完整临床资料的晚期耐药胃癌患者接受伊立替康（艾力）联合5-氟尿嘧啶与四氢叶酸钙治疗的情况,艾力100 mg/m2,静滴,第1天;四氢叶酸钙100mg/m2,静滴,第1~5天;氟尿嘧啶300 mg/m2,静滴,第1~5天,21 d为1周期,至少2个周期后按照WHO标准评估疗效及不良反应。结果完全缓解（CR）0例,部分缓解（PR）8例,稳定（SD）12例,进展（PD）13例,客观有效率（ORR）为24.2%（8/33）,临床肿瘤控制率（tumor control rate,TCR）为60.6%（20/33）。主要不良反应是恶心、呕吐、腹泻及骨髓抑制等,而肝功能异常、口腔黏膜炎、发热等较轻,无明显肾毒性和心脏毒性,未发生因化疗产生严重不良反应而终止治疗者,无化疗相关性死亡病例。结论伊立替康（艾力）联合氟尿嘧啶与四氢叶酸钙治疗晚期耐药胃癌安全有效,且适合我国社会与经济情况。     

FOLFOX4方案治疗晚期胃癌的临床观察

目的:观察FOLFOX4方案治疗国人晚期胃癌的近期疗效和毒副反应。方法:28例晚期胃癌患者,先给予FOLFOX4方案,即:奥沙利铂(L-OHP)85mg/m2静脉点滴2h,d1;亚叶酸钙(CF)200mg/m2静脉点滴,2h,d1、d2;随后氟尿嘧啶(5-FU)400mg/m2静脉推注,d1、d2,5-FU600mg/m2微泵持续静脉滴注22h,d1、d2。2周重复。4个周期后以WHO评价标准评价疗效和毒性。结果:全组28例均可评价,其中完全缓解(CR)2例,部分缓解(PR)14例,稳定(SD)7例,进展(PD)5例,总有效率(CR PR)57.1%。中位肿瘤进展时间(TTP)5.5个月,中位生存时间(MST)为9个月。毒副反应主要是骨髓抑制,白细胞降低发生率达82.1%,其次为胃肠道反应,恶心呕吐发生率78.6%,口腔粘膜炎为21.4%,腹泻35.7%,无Ⅲ/Ⅳ度胃肠道反应;周围神经毒性发生率为46.4%。结论:FOLFOX4方案治疗国人晚期胃癌的近期疗效较好,毒副反应可以耐受,值得进一步研究应用。     

First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule.

BACKGROUND: In a previous phase I-II study we demonstrated that the FOLFOXIRI regimen [irinotecan 125-175 mg/m2 day 1, oxaliplatin 100 mg/m2 day 1, l-leucovorin (l-LV) 200 mg/m2 day 1, 5-fluorouracil (5-FU) 3800 mg/m2 as a 48-h chronomodulated continuous infusion starting on day 1, repeated every 2 weeks] has promising activity and efficacy in metastatic colorectal cancer. However, this regimen required a chronomodulated infusion of 5-FU, and because neutropenia occurred in 32% of cycles, granulocyte colony-stimulating factor (G-CSF) was used and the delivered dose intensity was only approximately 78% of planned. Therefore, we conducted the present phase II study in order to develop a simplified FOLFOXIRI regimen that could be more easily administered in clinical practice as well as in multicenter settings. PATIENTS AND METHODS: A total of 32 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, l-LV 200 mg/m2 day 1 and 5-FU 3200 mg/m2 as a 48-h continuous (not chronomodulated) infusion starting on day 1, repeated every 2 weeks. RESULTS: All 32 patients were evaluated for safety and the incidence of grade 3-4 toxic effects, and the use of G-CSF seemed to be lower than with the previous FOLFOXIRI regimen: grade 4 neutropenia (34%), grade 3 diarrhea (16%), grade 3 stomatitis (6%) and grade 2-3 peripheral neurotoxicity (37%) were reported, and G-CSF was used in 23% of cycles. Delivered dose intensity was 88% of that planned, and no toxic deaths occurred. The intention-to-treat analysis for activity showed four complete responses, 19 partial responses, seven stable disease and two progressive disease, for an overall response rate of 72% (95% confidence interval 53% to 86%). Eight (25%) patients with residual liver or lung metastases were radically resected after chemotherapy. After a median follow-up of 18.1 months, the median progression-free survival is 10.8 months and median survival is 28.4 months. CONCLUSIONS: This simplified FOLFOXIRI combination can be delivered easily in outpatient settings, with manageable toxic effects, and has very promising antitumor activity. While the safety profile seems to be improved in comparison with our previous FOLFOXIRI regimen, antitumor activity and efficacy appear to be maintained.