Minimal Toxicity to Myeloid Progenitor Cells of Weekly24‐Hr Infusion of High‐Dose 5‐Fluorouracil: Direct Evidence from Colony Forming Unit‐Granulocyte andMonocyte (CFU‐GM) Clonogenic Assay

Although very high doses of 5‐fluorouracil was used in the weekly 24‐h infusion, high‐dose 5‐fluorouracil (2600 mg/m²/week) and leucovorin (500 mg/m²/week) protocol, myelosuppression was surprisingly low. The current study was conducted to investigate the possible mechanism underlying the low myelosuppression. To mimic the clinical situation, peripheral blood progenitor cells collected from 12 patients were used for colony forming unit‐granulocyte and monocyte clonogenic assay; and 2 representative modes of 5‐fluorouracil exposure (30 min. versus 24 hr) were examined for cytotoxic effects on human myeloid progenitor cells. Previous pharmacokinetic studies have estimated the concentrations of 5‐fluorouracil in the bone marrow to be 200–400 μM and 1–2 μM for the 30 min. infusion (600–900 mg/m²) and the 24 hr‐infusion (1000–2000 mg/m²) regimens, respectively. The results of our colony‐forming unit‐granulocyte and monocyte clonogenic assay showed that 24‐hr exposure to 5‐fluorouracil (2 μM) and 30 min. exposure to 5‐fluorouracil (100 μM) resulted in 27.2% and 78.2% inhibition of the colony formation, respectively. Our data provided direct evidence which may explain why myelotoxicity is significantly less in weekly 24 hr infusion of fluorouracil than in the conventional bolus regimens.     

吉西他滨联合5-FU与奈达铂方案时辰化疗晚期食管癌临床观察

目的探讨吉西他滨（GEM）联合5-氟尿嘧啶（5-Fu）与奈达铂（NDP）时辰化疗晚期食管癌的近期疗效及不良反应。方法 GEM2000 mg/m2分d1、8静脉点滴,5-Fu 2500 mg/m2分d1～5（15：00-18：00）微量泵静脉输注,奈达铂75 mg/m2分d1-3静脉点滴,于5-Fu前2 h应用亚叶酸钙200 mg/d,21 d为1个周期,2个周期后评价疗效。结果治疗周期中位值为4.5个周期,CR2例,PR14例,SD5例,PD5例,总有效率（CR＋PR）为61.5%（16/26）。主要不良反应是骨髓抑制和胃肠道反应。无Ⅳ度骨髓抑制,口腔炎、肝肾毒性等均较轻。结论吉西他滨（GEM）联合5-氟尿嘧啶（5-Fu）与奈达铂（NDP）时辰化疗晚期食管癌疗效确切,安全性好。     

Phase II study of weekly paclitaxel plus 24-h continuous infusion 5-fluorouracil,folinic acid and 3-weekly cisplatin for the treatment of patients with advanced gastric cancer

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22-72) were consecutively enrolled at three centers. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2-h infusion. Paclitaxel 80 mg/m2 was administered as a 1-h infusion weekly and cisplatin 50 mg/m2 as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1-5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29-68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1-23) and 11 months (range 1-23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0-5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2 given every 3 weeks, the protocol with weekly application of paclitaxel 80 mg/m2 shows a reduced incidence of hematologic toxicity, particularly leukopenia. Other organ toxicities apart from a slightly higher incidence of peripheral neuropathy were comparable between the two treatment protocols. Efficacy with a response rate of 50% was well preserved by this weekly regimen.     

Phase I trial of gemcitabine (Gemzar), 24 h infusion 5-fluorouracil and folinic acid in patients with inoperable pancreatic cancer

Gemcitabine (Gemzar) has a significant impact upon survival and quality of life for patients with pancreatic cancer, compared with 5-fluorouracil (5-FU). This phase I study was initiated to define the recommended dose of 5-FU delivered as a 24 h infusion in combination with gemcitabine (1000 mg/m2) and folinic acid (200 mg/m2) in patients with inoperable pancreatic cancer, treated on an outpatient basis. Drugs were administered weekly for 4 weeks out of 6 weeks. Sixteen chemonaive patients (median age 59 years, range 51-66) were enrolled, 15 had stage IV and one stage III disease. The median Karnofsky performance score (KPS) was 70 (range 60-80). Six patients received 5-FU 750 mg/m2, eight received 5-FU 1000 mg/m2 and two received 5-FU 1250 mg/m2. The maximum tolerated dose of 5-FU was 1000 mg/m2. Hepatotoxicity was dose limiting. One patient who received 5-FU 1250 mg/m2 died as a result of hepatorenal failure. There was one partial response, nine patients had stable disease for more than 3 months and 13 patients had improved KPS. The median time to progressive disease was 31 weeks (range 5-50 weeks). A phase 11 trial is underway to further assess the activity of this combination at the recommended dose of 750 mg/m2 5-FU.     

Exposure of Tg.AC transgenic mice to benzene suppresses hematopoietic progenitor cells and alters gene expression in critical signaling pathways

The effects of acute benzene (BZ) exposure on hematopoietic progenitor cells (HPCs) derived from bone marrow cells were studied using homozygous male v-Ha-ras Tg.AC mice at 8-10 weeks of age. The mice were given 0.02% BZ in their drinking water for 28 days with the dose rate estimated to be 34 mg benzene/kg BW/day. Analysis of cultured HPCs indicated that BZ suppressed the proliferation of the multilineage colony forming unit-granulocyte, erythrocyte, macrophage, megakaryocyte (CFU-GEMM); colony forming unit-granulocyte, macrophage (CFU-GM); and blast forming unit erythrocyte/colony forming unit erythrocyte (BFUE/CFUE). A gene expression profile was generated using nylon arrays spotted with 23 cDNAs involved in selected signal pathways involved in cell distress, inflammation, DNA damage, cell cycle arrest, and apoptosis. Of the 23 marker genes, 6 (bax, c-fos, E124, hsf1, ikBa, and p57) were significantly (Mann-Whitney U tests, P < 0.05) overexpressed in BZ-exposed mice. Two genes (c-myc and IL-2) approached significance (at P = 0.053). The pattern of gene expression was consistent with BZ toxicity and the suppression of HPCs.     

Weekly high-dose 5-fluorouracil as 24-h infusion and folinic acid (AIO) plus irinotecan as second- and third-line treatment in patients with colorectal cancer pre-treated with AIO plus oxaliplatin

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.     

Mitomycin C with weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract and periampullar carcinomas

We have reported a 33% partial response rate with acceptable toxicity using weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in patients with far advanced biliary tract cancers (BTC). In this study, we added mitomycin (MMC) to 5-FU and LV in an attempt to improve the response rate and survival. From July 1997 to September 1999, 25 chemotherapy-naive patients with pathology-proven far advanced BTC and periampullar cancers were enrolled. The regimen consisted of MMC 10 mg/m(2) every 8 weeks combined with 5-FU 2600 mg/m(2) and LV 150 mg at a schedule of 24-h infusion weekly for 6 weeks followed by a 2 week break. There were 10 males and 15 females with a median age of 57 years (range 40-76). The sites of primary tumor were 15 intrahepatic cholangiocarcinomas (CC), one perihilar CCs, three distal BTC, three gallbladder cancers (GB) and three periampullar cancers. A total of 148 sessions of chemotherapy were given with a mean of 8 (range 2-18). Nineteen patients were evaluable for response. The response rate was: 26% (five of 19) partial response, 42% (eight of 19) stable disease and 32% (six of 19) progressive disease. All of the patients were evaluable for toxicity. Toxicities more than grade III-IV were thrombocytopenia 16% (four of 25), leukopenia 12% (three of 25) and vomiting 4% (one of 25). There were four treatment-related deaths. The median time to disease progression was 3 months. The median survival was 6 months. A combination of MMC with weekly high-dose 5-FU and LV in patients with BTC did not improve the response rate, but produced more toxicity than weekly high-dose 5-FU and LV alone.     

Population pharmacokinetics/toxicodynamics (PK/TD) relationship of SAM486A in phase I studies in patients with advanced cancers

SAM486A (previously termed CGP 48664), a potent inhibitor of S-adenosylmethionine decarboxylase, is under clinical development for the treatment of advanced refractory malignancies. Hematological toxicity manifested by dose-dependent neutropenia has been observed in phase I studies. Population methods were used to investigate pharmacokinetics (PK) as a prognostic factor for safety end point (hematological toxicity) in patients with advanced cancers. SAM486A plasma concentrations and neutrophil counts were collected from three ascending-dose tolerability and PK studies (study 1: single 5-day continuous intravenous (IV) infusion with doses ranging from 24-700 mg/m2/cycle; study 2: 10-minute to 3-hour IV infusion once weekly with doses ranging from 16-325 mg/m2/week; study 3: 1-hour IV infusion once daily for 5 days with doses ranging from 3.6-202.8 mg/m2/day). The PK of SAM486A were best estimated by a population linear three-compartment model with NONMEM (version 5) using data from 9 patients in studies 1 through 3. The population pharmacokinetic parameters (SD) were CL = 6.2 (0.4) l/h/m2, Q2 = 15.4 (1.5) l/h/m2, Q3 = 33.6 (5.3) l/h/m2, V1 = 9.5 (1.6) l/m2, V2 = 672 (52) l/m2, and V3 = 39.9 (8.3) l/m2, and the corresponding intersubject variability was 45.4%, 74.0%, 85.3%, 80.1%, 37.0%, and 103%, respectively, where CL is total body clearance, Q2 and Q3 are intercompartmental clearances, and V1, V2, and V3 are the volumes of distribution in central and peripheral compartments, respectively. The intrasubject variability was 24.0%. The cumulative AUC before the onset of neutrophil nadir count (AUC) and the duration of exposure over threshold SAM486A concentrations in the range of 0.05 to 0.1 microM based on Bayesian PK parameter estimates significantly correlated with absolute neutrophil count nadir (< 5 x 10(9)/l). AUC showed the best correlation (R2 = 0.72) with absolute neutrophil count nadir by an inhibitory sigmoid Emax model and also correlated with percent decrease in neutrophil count from baseline to nadir by a simple Emax model (R2 = 0.53). Logistic regression analysis indicated that AUC and the duration of exposure over 0.05 to 0.1 microM, but not Cmax, were strong predictors of grade 4 neutropenia (< 0.5 x 10(9)/l). Drug exposure parameters such as AUC derived from population analysis may be used clinically as a useful predictor of drug-induced neutropenia.     

Adding weekly irinotecan to high-dose 5-fluorouracil and folinic acid (HD-5-FU/FA) after failure for first-line HD-5-FU/FA in advanced colorectal cancer--a phase II study

Irinotecan (CPT-11) has been shown to prolong survival and improve quality of life in comparison to best supportive care in colorectal cancer patients with pretreatment of bolus 5-fluorouracil (5-FU). After first-line 24-h high-dose (HD) 5-FU/folinic acid (FA) an objective response rate of 11% with 3-weekly CPT-11 350 mg/m was reported. In the present study we investigated weekly CPT-11 in combination with 24-h HD-5-FU/FA as second-line treatment after prior exposure to 24-h HD-5-FU. Synergy between 5-FU and CPT-11 is the rationale to combine both substances for second-line therapy in order to overcome resistance to 5-FU. Thirty-five patients were recruited in a single institution to receive 6 x weekly CPT-11 80 mg/m(2), FA 200 mg/m(2) and 24-h HD-5-FU 2000 mg/m(2). Treatment was repeated on day 57. Patient characteristics: M/F=20/15, median WHO performance status 1, range (0-2). Thirty-four patients were evaluable for response: partial response 17% and no change 40%. Median time to progression and overall survival were 3.3 and 8.4 months, respectively. All patients were evaluable for toxicity analysis (National Cancer Institute Common Toxicity Criteria grade 3): leukocytopenia 3%, diarrhea 12% and vomiting/nausea 6%. Of the assigned doses, a median 100% of 5-FU and 92% of CPT-11 were administered during the first cycle of chemotherapy. We conclude that weekly CPT-11 and HD-5-FU/FA is an active and safe combination chemotherapy resulting in response rates in the upper range of other CPT-11-based second-line regimen. The toxicity profile in our series compared to 3-weekly CPT-11 seems favorable.     

艾素联合奥沙利铂、氟尿嘧啶治疗进展期胃癌的疗效分析

目的观察多西他赛注射液（艾素）联合奥沙利铂、氟尿嘧啶治疗进展期胃癌的疗效及不良反应。方法 30例进展期胃癌患者采用艾素75mg/m^2静脉滴注第1,8天,奥沙利铂130mg/m^2,第1天静脉滴注;氟尿嘧啶500mg/m^2,第2～6天静脉滴注;21d为1周期,每2周期评价疗效。结果 30例患者中完全缓解0例,部分缓解17例（56.7%）,稳定7例（23.3%）,病情进展6例（20%）,总有效率为56.7%,临床受益率为80%。不良反应主要为骨髓抑制、脱发、消化道反应和神经毒性。结论艾素联合奥沙利铂、氟尿嘧啶治疗进展期胃癌患者疗效较高,耐受性较好。     

大剂量醛氢叶酸加氟尿嘧啶持续滴注联合顺铂治疗晚期食管癌临床研究

目的 观察大剂量醛氢叶酸(Leucovorin,LV)加氟尿嘧啶(5-Fluorouracil,5-Fu)持续48 h滴注联合顺铂(Cisplantin,DDP)治疗晚期食管癌与传统DF方案疗效及其不良反应的差别.方法 病理确诊的食管癌60例,随机分成治疗组30例,采用DDP 25 mg/m2静脉滴注30 min,第1～3天;LV 200 mg/m2静脉滴注2h,5-Fu 0.5静脉注射10 min,然后5-Fu 2.5/m2,用输液泵连续输注48 h,每21天重复,2个周期以上评定疗效.对照组30例,采用DDP 25mg/m2静脉滴注30 min,第1～3天;LV 60 mg/m2静脉滴注2h,第1～5天,5-Fu 500 mg/m2静脉滴注8h,每21天重复,2个周期以上评定疗效.结果 近期疗效,治疗组,完全缓解(CR)1例,部分缓解(PR)15例,稳定(SD)9例,进展(PD)5例,总有效率CR+ PR53.3％(16/30).对照组,PR 11例,SD 11例,PD 8例,无PR病例,总有效率36.7％(11/30).恶心、呕吐、口腔粘膜炎、骨髓抑制、腹泻及脱发为主要不良反应.两组均能耐受,未发生Ⅳ度毒性,骨髓抑制对照组比治疗组明显.结论 大剂量LV+ 5-Fu 48 h滴注联合铂治疗晚期食管癌近期疗效较传统DF方案好,不良反应较小,值得进一步扩大研究.     

Weekly 24-h infusion of high-dose 5-flurouracil and leucovorin in patients with advanced gastric cancer.

The effect of biochemical modulation of weekly high-dose 5-fluorouracil (5-FU) 24 h infusion by leucovorin (LV) in the treatment of 39 consecutive patients with advanced gastric cancer without prior chemotherapy from October 1996 to August 1997 was examined. There were 21 male and 18 female patients with a median age of 56 years. The regimen consisted of 5-FU 2600 mg/m2 and LV 150 mg administered by 24 h infusion weekly for 6 weeks followed by a 2 week break. The treatment was repeated every 8 weeks until disease progression, patient refusal or unacceptable toxicity. Placement of a central vascular device and a portable external infusion pump was required in all patients and was used for outpatient treatment. The response to treatment was evaluated every 8 weeks. A total of 395 chemotherapy treatments were given with a mean of 10 (2-24). This response rate was: 33% (12 of 36) partial response (PR) rate, 33% (12 of 36) stable disease (SD) and 33% (12 of 36) progressive disease (PD). In general, the toxicity was mild but two toxic deaths occurred, one due to neutropenic sepsis and the other due to hyperammonemia. The median time to progression was 4 months. The overall median survival was 7 months. The survivals of the PR, SD and PD were 12, 8 and 5 months, respectively. This regimen showed a modest activity against gastric cancer with acceptable toxicity. Weekly 24 h infusion of high-dose 5-FU with LV in an outpatient setting for patients with gastric cancer is feasible and deserves further study as a basis for combination therapy.     

Phase II study of epirubicin plus oxaliplatin and infusional 5-fluorouracil as first-line combination therapy in patients with metastatic or advanced gastric cancer

The purpose of this study was to evaluate the efficacy and safety of an epirubicin, oxaliplatin and infusional 5-fluorouracil combination in patients with advanced gastric cancer. Patients with previously untreated advanced measurable gastric cancer received epirubicin (50 mg/m2, day 1), oxaliplatin (130 mg/m2 2-h infusion, day 1) and 5-fluorouracil (750 mg/m2, 24-h infusion, day 1-3) every 3 weeks. The primary endpoint of this phase II study was the response rate according to Response Evaluation Criteria in Solid Tumors. Out of 48 patients, 46 were evaluable for efficacy and 48 for toxicity. A median of five cycles (range 1-6) was administered. The overall best response rate was 47.8% (95% confidence interval 33-63%) including 2.2% complete responses and 45.6% partial responses. The median time for progression and median overall survival was 5 (95% confidence interval 4.1-5.9) and 11 months (95% confidence interval 8.1-13.9), respectively. Grade 3/4 neutropenia and leukocytopenia were observed in 25 and 12.5% of patients, respectively. Grade 3/4 nonhematological toxicities included nausea (6.3%), vomiting (14.6%), neurological toxicity (10.4%) and mucositis (2.1%). The epirubicin, oxaliplatin and infusional 5-fluorouracil regimen was effective and well tolerated as a front-line chemotherapy for patients with metastatic or advanced gastric cancer, and should be evaluated further.     

改良FOLFOX方案治疗晚期大肠癌24例临床观察

目的观察改良的FOLFOX方案治疗晚期大肠癌的临床疗效和毒副反应。方法对24例晚期大肠癌患者,用奥沙利铂(L-OHP)85 mg/m2静脉滴注3 h,亚叶酸钙(CF)400 mg静脉滴注2 h,5-氟尿嘧啶(5-Fu)500 mg在CF滴完后静冲,其后再予5-Fu 2800 mg/m2深静脉连续滴注48 h,每2周重复给药,治疗4周期后评价疗效。结果 24例中,CR 1例,PR 8例,SD 11例,PD 4例,总有效率(CR+PR)为37.5%。主要毒副作用是外周神经毒性、恶心呕吐、骨髓抑制。结论改良FOLFOX方案治疗晚期大肠癌疗效确切,毒副反应可耐受,值得推广使用。     

Multifractionated paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin in patients with metastatic or recurrent esophageal squamous cell carcinoma

This study assessed the clinical activity and safety of twice-weekly paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin (TP-HDFL) in patients with recurrent or metastatic esophageal squamous cell carcinoma. The regimen, composed of paclitaxel 35 mg/m 1-h intravenous infusion on days 1, 4, 8 and 11; cisplatin 20 mg/m 2-h intravenous infusion on days 2, 5, 9 and 12; and 5-flourouracil 2000 mg/m and leucovorin 300 mg/m 24-h intravenous infusion on days 5 and 12; repeated every 21 days. Forty-one patients (median age 51), 15 with de-novo metastatic disease and 26 with recurrent disease, were enrolled. Grades 3-4 neutropenia, leukopenia and diarrhea occurred in 37.8, 29.4 and 14.2% of cycles, respectively. One patient died of invasive fungal infection. Three complete responses, 13 partial response and 13 stable diseases were observed. The intent-to-treat response rate was 39.0% (95% confidence interval: 24-54). The median progression-free and overall survival were 6.3 and 8.9 months (range 1-50+), respectively. Twice-weekly TP-HDFL has the activity and toxicity profile similar to the previously reported same three-drug combination for advanced esophageal cancer.     

多西紫杉醇联合奥沙利铂治疗进展期胃癌87例临床分析

目的评估多西紫杉醇联合奥沙利铂治疗进展期胃癌的效果和安全性。方法130例进展期胃癌患者随机分为实验组87例,对照组43例,实验组给予多西紫杉醇50mg／m^2静脉滴注,第1—3天;奥沙利铂65mg／m^2静脉滴注,第1天;氟脲嘧啶（5-Fu）500mg／m^2静脉滴注,第1～5天;亚叶酸钙（CF）300mg,第1～5天,在5-Fu之前2h静脉滴注。对照组用奥沙利铂130mg／m^2静脉滴注,第1天;5-Fu与CF的给药方法同实验组。3周为1个周期,治疗2个周期后评价疗效。结果实验组近期疗效、组织学变化、影像学变化等与对照组比较,差异均有统计学意义（均P〈0．05）。两组在白细胞减少、血小板减少、消化道反应、肝肾功能损害等不良反应方面比较,差异无统计学意义（均P〉0．05）。结论多西紫杉醇联合奥沙利铂化疗方案治疗进展期胃癌安全、有效。     

A phase II study of an oxaliplatin/vinorelbine/5-fluorouracil combination in patients with anthracycline-pretreated and taxane-pretreated metastatic breast cancer

The aim of this phase II study was to evaluate safety and efficacy of an oxaliplatin/vinorelbine/5-fluorouracil (FON) combination in anthracycline and taxane-pretreated metastatic breast cancer patients. The following treatment was given: on day 1 of a 21-day cycle, oxaliplatin 130 mg/m (2-h intravenous infusion); on days 1 and 5, vinorelbine [dose level (DL) 1: 17.5 mg/m; DL2: 22 mg/m]; on days 1-5, continuous infusion 5-fluorouracil (DL1: 600 mg/m/day; DL2: 750 mg/m/day). Forty-seven patients were treated (DL1: 43; DL2: 4). Median age was 54 years; 68% had liver metastases, 53% were taxane refractory/resistant and 38% were anthracycline refractory/resistant. Patients received a median of six treatment cycles. Of 46 eligible patients, 16 had partial response; the overall response rate was 34.8% (95% confidence interval 21.3-50.3%), 11 had stable disease lasting more than 4 months. Median follow-up was 13.0 months, median time to progression 5.7 months and estimated overall survival 18.8 months. DL2 was too toxic with three patients having grade 3-4 toxicity, including one death. At DL1, 26 patients (60%) experienced grade 3-4 neutropenia (six febrile neutropenia) and eight had grade 3 oxaliplatin-specific peripheral neuropathy after a median of 646.4 mg/m oxaliplatin (range 124-1619 mg/m). Oxaliplatin (130 mg/m, day 1)/vinorelbine (17.5 mg/m, days 1,5)/5-fluorouracil (600 mg/m/day, days 1-5) demonstrate encouraging activity and a manageable safety profile in anthracycline- and taxane-pretreated metastatic breast cancer patients.     

Therapy of patients with metastatic breast cancer with 5-fluorouracil, leucovorin and carboplatin.

Thirty-four women with metastatic breast cancer were treated at the National Cancer Institute of the National Institutes of Health, with a regimen of leucovorin (L), 500 mg/m2 i.v. over 30 min, followed in 1 h by 5-fluorouracil (5-FU), 375 mg/m2 i.v. bolus on days 1-5, and carboplatin (CBDCA), 50-100 mg/m2 i.v. bolus on days 2-4, every 28 days. All patients had received previous combination chemotherapy with at least one regimen (29 patients with 5-FU-containing regimens). CBDCA, 100 mg/m2 on days 2-4, resulted in grade 4 neutropenia in 10 out of 11 patients associated with sepsis in all 10 patients. CBDCA, 75 mg/m2 (seven patients) and 50 mg/m2 (15 patients), resulted in grade 4 neutropenia in six and eight patients, and neutropenic sepsis in five and two cases, respectively. Grade 4 thrombocytopenia occurred in 10, five and two patients receiving 100, 75 and 50 mg/m2 of CBDCA, respectively. Other toxicities included grade 3/4 mucositis in 18 patients and grade 3/4 diarrhea in 10 patients. Twenty nine patients were evaluable for response, with one pathologic complete response (3%), two partial responses (6%), 18 stable disease (53%) and eight (24%) progressive disease. Sites of response included bone, viscera and soft tissue. The median time from entry on study to progression, for responders, was 15 months. When platinum-DNA adduct formation in peripheral white blood cells was analyzed in 27 patients at 24 h after drug administration, a significant correlation between adduct level and CBDCA cumulative dose was found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of adenosine A(3) receptor agonist on bone marrow granulocytic system in 5-fluorouracil-treated mice

The purpose of the experiments reported was to investigate effects of N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), a selective adenosine A(3) receptor agonist, on the granulocytic system in femoral marrow of mice depleted by the cytotoxic drug 5-fluorouracil. In the phase of the highest cell depletion IB-MECA was injected i.p. at single doses of 200 nmol/kg given either once or twice daily in 2- and 4-day regimens starting on day 1 after 5-fluorouracil administration; the effects were evaluated on days 3 and 5, respectively. The general effect of IB-MECA in all these experiments was an enhancement of the counts of morphologically recognizable proliferative granulocytic cells, interpreted as evidence of the differentiation of committed progenitor cells. A more expressive effect was observed after IB-MECA injected twice daily. It was found that the induction of the strong differentiation pressures by IB-MECA given twice daily shortly after 5-fluorouracil treatment can be counterproductive due to the preponderance of differentiaton processes over the proliferation control. In additional experiments, it has been shown that the use of the 2-day administration of IB-MECA given twice daily in the recovery phase, i.e., on days 5 and 6 after 5-fluorouracil administration, does not induce stimulatory effects. Thus, the dosing and timing of IB-MECA treatment determines its effectivity in stimulating granulopoiesis under conditions of myelosuppression.     

Pooled efficacy analysis from a phase I-II study of biweekly irinotecan in combination with gemcitabine, 5-fluorouracil, leucovorin and cisplatin in patients with metastatic pancreatic cancer

Development of treatments to improve the outcomes achieved with single-agent gemcitabine therapy for metastatic pancreatic cancer remains a research priority. G-FLIP (gemcitabine, 5-fluorouracil, leucovorin and cisplatin) is a four-drug regimen designed to maximize sequence-dependent synergy, while attempting to minimize toxicity among the four drugs. The dose-limiting toxicities and maximum tolerated dose of irinotecan as part of the G-FLIP regimen have been published. For phase II testing, G-FLIP consisted of sequential gemcitabine 500 mg/m2 at a fixed rate of 10 mg/m2/min, irinotecan 120 mg/m2, bolus 5-fluorouracil 400 mg/m2 and leucovorin 300 mg, followed by a 24-h 5-fluorouracil infusion of 1500 mg/m2 on day 1 and cisplatin 35 mg/m2 on day 2. Cycles were repeated every 14 days. Thirty-three patients with metastatic pancreatic cancer (22 men and 11 women) were treated and 31 were evaluable. Median patient age was 63 years (range 44-78 years) and median Karnofsky performance status score was 70-80. Estimated median time to disease progression was 171 days (6.1 months) and Kaplan-Meir-estimated median overall survival was 229 days (8.1 months). Twelve- and 18-month survivals were 33 and 21%, respectively. As per Response Evaluation Criteria in Solid Tumors criteria, 13 patients had stable disease, seven (22%) attained a partial response, and 10 (32%) had disease progression. One patient attained a complete response and two were not evaluable (one withdrew consent and one died suddenly, each after cycle 1). Treatment generally was well tolerated. Grade 3-4 toxicities/patient were thrombocytopenia (3.1%), leukopenia (15%), neutropenia (21%), neutropenic fever (3%), fatigue (18%) and thrombosis (12.5%). Common grade 1-2 toxicities per patient included nausea/vomiting (69%), diarrhea (45%), constipation (21%) and fatigue (39%). In conclusion, G-FLIP is a feasible outpatient regimen with acceptable toxicity for metastatic pancreatic cancer patients. Disease control rate (stable disease rate plus partial or complete responses) and 1-year survival outcomes are encouraging.