Phase I-II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancer

BACKGROUND: Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer. METHODS: Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m2), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m2) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL24 regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m2 in the phase I study, and fixed MTD for subsequent enrolled patients. RESULTS: Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m2, with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m2 per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. CONCLUSIONS: The GemFL24 regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs.     

Randomized trial comparing weekly bolus 5-fluorouracil plus leucovorin versus monthly 5-day 5-fluorouracil plus leucovorin in metastatic colorectal cancer

BACKGROUND/AIMS: The purpose of this study was to compare the efficacy and toxicity profiles of weekly intravenous (i.v.) bolus injection of 5-fluorouracil plus low-dose leucovorin with the Mayo Clinics' monthly 5-day schedule of 5-fluorouracil and leucovorin in the treatment of metastatic colorectal cancer. METHODOLOGY: A total of 96 patients with previously untreated metastatic colorectal cancer were randomized to receive either a weekly i.v. bolus injection of 5-fluorouracil 400 mg/m2 plus leucovorin 20 mg/m2 (weekly arm), or i.v. bolus injection of 5-fluorouracil 425 mg/m2 plus leucovorin 20 mg/m2 for 5 consecutive days every 4 or 5 weeks (monthly arm). Therapy was continued until disease progression or unacceptable toxicity appeared. In the presence of disease progression, the study regimen was stopped and second-line treatment was instituted after the patient was discontinued from this study. RESULTS: There was no significant difference of response rates between both regimens. The response rate were 14.3% in the weekly arm (2 CR and 5 PR, 95% CI: 2.6-25.2%) and 10.6% in the monthly arm (1 CR and 4 PR; 95% CI: 6.5-32.3%), respectively (P = 0.8957). The survival times were also similar between the two (P = 0.4207, log-rank test). The median survival were 15.8 months in the monthly arm and 18.4 months in the weekly arm. Hematologic toxicity was minimal in both arms. However, the monthly arm produced a higher toxicity in severe (grade 3-4) diarrhea (14.9% vs. 2%; P = 0.029) and stomatitis (8.5% vs. 0; P = 0.054). CONCLUSIONS: Weekly bolus injection of 5-fluorouracil and low-dose leucovorin achieved a similar response rate and survival as compared with the Mayo Clinics' monthly 5-day schedule, but severe toxicity was less commonly seen using the weekly regimen. As current chemotherapeutic treatment for metastatic colorectal cancer is largely palliative rather than curative, the weekly bolus regimen may be a more favorable approach in managing metastatic colorectal cancer.     

Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer

Background. Advanced pancreatic cancer has limited treatment options. 5-fluorouracil (5-FU) is frequently used in the treatment of pancreatic cancer. Preclinical studies suggest synergism between trimetrexate (TMTX), 5-FU, and leucovorin (NFL). Aim. We conducted a phase II trial to evaluate the activity and safety of NFL in pancreatic cancer. Method. Eligible patients (n=21) with untreated advanced pancreatic cancer were treated with 110 mg/m² intravenous (IV) THTX on day 1 and 200 mg/m² IV leucovorin prior to 500 mg/m² IV 5-FU on day 2. Oral leucovorin (15 mg every 6 h for seven doses) started intravenous 24 h later. Results. Treatment was administered for 6 wk followed by a 2-wk rest period. Response was evaluated every 8 wk. All patients were evaluable for response and toxicity. Most patients (80%) had distant metastases. Forty-five cycles of chemotherapy were administered. The most common serious toxicities were Grade 3 diarrhea (23.8%) and nausea and vomiting (14.2%). The response rate was 4.1% (95% CI, 0–23%), median survival was 6.8 mo, and 1-yr survival was 19%. Conclusion. Treatment with NFL is well-tolerated in patients with advanced pancreatic cancer. The median survival and 1-yr survival in these patients with poor prognosis compares favorably with other treatment options.     

Phase II trial of 5-fluorouracil,high-dose leucovorin calcium,and dipyridamole in advanced prostate cancer

Summary To examine the effect of altering intracellular folate pools on the efficacy of 5-fluorouracil (FUra) in the treatment of advanced prostate cancer, we performed a phase II trial of FUra (300–370 mg m^–2 day^–1×5 as an i.v. bolus) combined with high-dose folinic acid (500 mg m^–2 day^–1×5.5 days by continuous i.v. infusion) and dipyridamole (75 mg p.o. every 6h×5.5 days) administered on a 28-day schedule in patients with stage D₂ disease. A group of 13 patients have been treated. The median age was 68 years (range 48–78 years); the performance status ranged from 50% to 90%. Among 12 evaluable patients, there were no objective responders; the median time to progression was 1.9 months. Median survival after entry on this trial was 8.6 months. Treatment with FUra, high-dose folinic acid and dipyridamole was well tolerated. Only one episode each of grade 3 leukopenia, granulocytopenia, and thrombocytopenia was observed. These results suggest that, despite previous trials demonstrating activity for FUra in stage D₂ prostate cancer, this disease may be relatively resistant to fluoropyrimidines and, thus, less amenable to biochemical modulation with high-dose folinic acid and dipyridamole.This study was supported, in part, by NCI Cancer Center support grant CA 33572     

Pilot trial of prolonged continuous-infusion 5-fluorouracil and weekly cisplatin in advanced colorectal cancer

Thirty-five patients with previously untreated, advanced, measurable metastatic colorectal carcinoma were treated with a 12-week course of continuous 5-fluorouracil (5-FU) and weekly cisplatin. Twenty of 32 evaluable patients responded (five complete and 15 partial responses), for an overall response rate of 63% (90% confidence limits, 43%-75%). Toxicity was generally mild and reversible and included mucositis (40%), painful erythema of the palmar and plantar skin (30%), diarrhea (21%), nausea and vomiting (15%), and leukopenia (6%). One patient died of sepsis secondary to mucositis and myelosuppression. This program is a well-tolerated outpatient regimen for metastatic colorectal carcinoma. The response rate is higher than expected for 5-FU and cisplatin and suggests clinical therapeutic synergism at this dose rate and schedule.     

A combination immunochemotherapy of 5-fluorouracil, cisplatin, leucovorin, and OK-432 for advanced and recurrent gastric carcinoma

BACKGROUND/AIMS: Based on theories of biochemical modulation and immunotherapy, a novel regimen consisting of 5-fluorouracil, cisplatin, leucovorin, and OK-432 (FLPO therapy) was devised for the treatment of patients with advanced and recurrent gastric carcinoma. METHODOLOGY: The 14-day combination therapy consisted of continuous infusion of 5-fluorouracil (250 mg/m2/day), a bolus injection of 10 mg cisplatin and 30 mg leucovorin every other day, and a subcutaneous injection or per oral administration of OK-432 (3KE or 5KE) every other day. Thirty patients completed 59 courses of treatment consisting of 2 weeks of therapy followed by at least 2 weeks rest. RESULTS: The overall response rate was 40%, with 1 complete response and 11 partial responses observed. All twelve patients responded after 1 course of treatment. The response rate differed depending upon tumor location, 22.2% at the primary site, 60.0% in the lymph nodes, 45.5% with peritoneal dissemination, 44.4% with liver metastases, 50.0% in the lung, and 100.0% with skin metastases. The most frequently observed toxicity was stomatitis (53.3%). The overall incidence of toxicities of grade 3 or greater was 6.6%, including diarrhea (3.3%) and stomatitis (3.3%). One patient required treatment interruption because of the grade 3 toxicity of diarrhea. The median survival time was 198 days overall, 242 days for responders and 125 days for non-responders. CONCLUSIONS: FLPO therapy seemed to be an effective regimen for the treatment of advanced and recurrent gastric carcinoma.     

Phase II study of leucovorin, 5-fluorouracil and gemcitabine for locally advanced and metastatic pancreatic cancer (FOLFUGEM 2)

AIM: FOLFUGEM 1 (leucovorin 400 mg/m2 combined with 5-flurorouracil (FU) bolus 400 mg/m2 then 5-FU 2-3 g/m2/46 hours and gemcitabine 1000 mg/m2 in 30 min) in patients with locally-advanced and metastatic pancreatic adenocarcinoma appeared to be toxic (neutropenia and alopecia). The aims of this phase II multicentric study were to evaluate the response rate, clinical benefit and tolerance of a new scheme of combined leucovorin, 5-FU and gemcitabine (FOLFUGEM 2). PATIENTS AND METHODS: FOLFUGEM 2 associated leucovorin 400 mg/m2 in 2 hours followed by 5-FU 1000 mg/m2 in 22 hours, then gemcitabine 800 mg/m2 (10 mg/m2/min) with cycles every 14 days. Gemcitabine dose could be increased (1000 then 1250 mg/m2) when NCI/CTC toxicity was < or = grade 2. RESULTS: Fifty-eight patients were included (locally-advanced tumor: N = 13 and metastatic: N = 45). Among the 39 patients with measurable disease, 11 had partial response (28.2%, 95% confidence interval: 14-42%) and 11 had stable disease (28.2%). On an intent-to-treat analysis, the objective response rate was 19% (95% confidence interval: 9-29%). Clinical benefit rate was 46%. Median progression-free survival and median overall survival were 3.1 and 7.2 months, respectively. There were 13% grade 3-4 neutropenia and 36% complete alopecia. CONCLUSION: FOLFUGEM 2 schema has an antitumoral effect in advanced pancreatic cancer and has an acceptable toxicity which appears to be less than that of FOLFUGEM 1.     

A phase II study of combination chemotherapy with gemcitabine, 5-fluorouracil, and cisplatin for advanced pancreatic cancer]

BACKGROUND/AIMS: Gemcitabine has been the standard regimen for advanced pancreatic cancer, but the effect on the response rate and survival is still disappointing, leading to many trials of combination chemotherapy. 5-FU and cisplatin were combined with gemcitabine in this trial, as they are synergistic with gemcitabine and each other as well. This study was aimed to assess the effectiveness and safety of combination chemotherapy with gemcitabine, 5-FU, and cisplatin for advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were entered into this study. Gemcitabine at a dose of 800 mg/m2 on day 1 and 8, 5-FU 1,000 mg/m2/day from day 1 to 3 for 72 hours, and cisplatin 60 mg/m2 on day 2, 24 hours after the start of gemcitabine were administered every 3 weeks. RESULTS: From December 2001 to January 2004, twenty patients were enrolled in this study. Among 17 of these patients assessable, 3 patients had a partial remission with the response rate of 23.6% (95% confidence interval, 6.2-41.0%). The median time to disease progression was 230 days and median duration of survival was 322 days. Among total of 91 cycles, leukopenia, neutropenia, and thrombocytopenia of grade 3 or 4 occurred in 12 cycles (13.2%), 12 cycles (13.2%), and 23 cycles (24.4%), respectively. Grade 3 or 4 mucositis developed at 2 cycles (2.2%), and nausea and vomiting were encountered in 3 cycles (3.3%). CONCLUSIONS: Combination chemotherapy with gemcitabine, 5-FU, and cisplatin for advanced pancreatic cancer is active and well-tolerated, warranting a phase III study.     

Double modulation of 5-fluorouracil by leucovorin and low-dose methotrexate in advanced colorectal cancer

A phase II study was carried out to evaluate the efficacy and toxicity of a double biochemical modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and leucovorin (LV) in patients with advanced unresectable colorectal cancer. Forty-two patients with measurable metastases of colorectal cancer were treated with 5-FU in daily doses of 600 mg/m2 given in a 6-hour intravenous (i.v.) infusion on days 1-5, LV 50 mg/m2 i.v. on days 2,3 and 5, and MTX 40 mg/m2 i.v. on days 1 and 4, every 4 weeks. Twenty-eight patients had a single metastatic site, eleven double, whereas three had more than two metastatic sites. Objective response (one complete response) was observed in 12 of 40 patients (30%) (95% confidence interval 16-48), stable disease in 19 patients (47%) and progression in 9 patients (23%). Overall median survival was 12 months. Median time to progression was 6 months. Treatment was generally well tolerated. The most frequent adverse reactions were stomatitis (38%), nausea and vomiting (35%), diarrhea (31%), leukopenia (18%), and plantar-palmar erythroderma (15%). The combination of 5-FU, LV and MTX seems to be an active regimen in advanced colorectal cancer.     

奥沙利铂、顺铂联合5-FU/LV治疗晚期胃癌的系统评价

目的:收集中英文相关随机对照试验的研究结果进行Meta分析,对奥沙利铂联合5-FU/LV(FOLFOX)方案的疗效进行评价.方法:采用Cochrane系统评价方法.检索Cochrane Library、PubMed、EMBase、中国生物医学文献数据库(CBM)、中文期刊全文数据库,中文科技期刊全文数据库(CSJD)等数据库,并辅以手工检索和其他检索.结果:共8个随机对照试验662例患者纳入研究,其中1个随机对照研究来自美国,另7个均来自中国:且8篇RCT存在偏倚的可能性均为中等程度.FOLFOX与顺铂联合5-FU/LV(PLF)方案治疗胃癌在1年生存率方面差异无统计学意义,但在总的生存率方面有显著差异.其OR值和95%CI分别为1.37(0.93,2.01)、1.93(1.41,2.66).3/4级的不良反应中白细胞减少和恶心呕吐等治疗组轻于对照组;在外周神经毒性反应方面,治疗组重于对照组,差异有统计学意义;而血小板减少方面差异无统计学意义.其OR值和95%CI分别为0.48(0.28,0.83)、0.26(0.16,0.42)、7.38(2.16,25.23)及1.20(0.44,3.30).结论:FOLFOX方案总有效率优于PLF方案,但是1年生存率并不优于对照组.白细胞减少和恶心呕吐治疗组轻于对照组,外周神经毒性重于对照组.     

5-fluorouracil continuous infusion combined with cisplatin for advanced pancreatic cancer: a Japanese Cooperative Study

BACKGROUND/AIMS: The prognosis of patients with advanced pancreatic cancer is extremely poor. To improve their prognosis, providing effective chemotherapy is necessary. The aim of this study was to evaluate the anti-tumor activity and toxicity of combined chemotherapy (FP therapy) using 5-fluorouracil and cisplatin in Japanese chemo-naive patients with advanced pancreatic cancer. METHODOLOGY: Thirty-seven previously untreated patients with histologically proven pancreatic adenocarcinoma were treated with FP therapy. 5-fluorouracil was administered at 500 mg/m2/day by continuous intravenous infusion for 5 days and cisplatin was administered at 80 mg/m2 intravenously on the 1st day. Therapy was repeated every 4 weeks until there was evidence of disease progression or unacceptable toxicity. RESULTS: Three patients achieved partial responses, whereas none exhibited a complete response. The overall response rate was 8% (95% confidence interval, 2-22%) and the response durations were 6, 9 and 12 months, respectively. The median survival time of patients was 5 months. Toxicities were generally mild and acceptable, although nausea/vomiting was the most commonly observed toxicity. CONCLUSIONS: FP therapy on this schedule had limited anti-tumor activity for pancreatic cancer, indicating that, practically, it should not be performed in Japanese patients with advanced pancreatic cancer.     

A combination chemotherapy of 5-fluorouracil and cisplatin against advanced gastric cancer

BACKGROUND/AIMS: This study was designed to clarify the effects of treatment and toxicity between 5-fluorouracil (5-FU) plus bolus infusion of Cisplatin (CDDP) and 5-FU plus continuous infusion of low-dose CDDP in advanced gastric cancer. METHODOLOGY: Seventy-three patients with advanced gastric cancer were enrolled in this study to compare the antitumor effect and toxicity between the bolus infusion of CDDP and the continuous infusion of low-dose CDDP in combination with the continuous infusion of 5-FU. Sixty-five eligible patients were divided into two groups: group A: curative resection cases; and, group B: non-curative, recurrent or inoperable cases. Patients were classified into two arms in each group. One arm of treatment regimen is 5-FU and bolus infusion of CDDP (A-1, B-1) and the other arm is 5-FU and continuous infusion of low-dose CDDP (A-2, B-2). RESULTS: Response rates were 9.1% and 38.5% in arm B-1 and arm B-2, respectively, although the difference between the two was not at a significant level. Frequently observed toxicities during the treatment were gastrointestinal symptoms such as nausea, vomiting, and anorexia. The incidence of side effects in arm A-2 and arm B-2 was almost the same as that in arm A-1 and arm B-1. CONCLUSIONS: These results revealed that there was no advantage of low-dose continuous infusion of CDDP with 5-FU in terms of response rate and clinical toxicity in our present study.     

Neoadjuvant chemotherapy of irinotecan, 5-fluorouracil and leucovorin in patients with advanced rectal cancer. Report of two cases

We report on two patients with T3N1 rectal cancer treated with a combination of irinotecan, 5-fluorouracil and leucovorin as neoadjuvant chemotherapy. On days 1, 8 and 15 of this 4-week cycle, leucovorin (250 mg/m2) was administered in a 2-hour intravenous infusion, followed by 5-fluorouracil (500 mg/m2) in a 10-min intravenous bolus, and then irinotecan (80 mg/m2) in a 90-min intravenous infusion. During the chemotherapy, no grade 3-4 toxicities were observed. Two weeks after the completion of 2 cycles of this regimen, both patients underwent surgery without postoperative complications. The responses were one pathological and one macroscopic complete response. Both patients with T3 tumors were down-staged to pT0 and pT2, respectively. As for the N stage, both patients were down-staged to pN0. The combination of irinotecan/5-fluorouracil/leucovorin appears to be feasible and effective, and to have a potential as an optimal neoadjuvant therapy in patients with advanced rectal cancer.     

Phase II trial of 5-fluorouracil, adriamycin, and mitomycin C in advanced colorectal cancer.

Thirty-five patients with advanced measurable colorectal cancer were treated with a combination of 5-fluorouracil (5-FU), adriamycin, and mitomycin C (FAM). Objective regression of tumor was observed in six patients (17%); seven patients (20%) demonstrated stabilization of disease. The FAM regimen was generally well tolerated with toxic effects limited to bone marrow depression and mild-to-moderate nausea and vomiting. FAM combination chemotherapy did not significantly improve survival in responding patients, nor was it more effective than 5-FU alone in achieving objective regression of disease.     

Combination chemotherapy comprising 5-fluorouracil,leucovorin, etoposide,and cis-diamminedichloroplatinum for the treatment of advanced gastric cancer

PURPOSE: The FLEP regimen (5-FU, LV, ETP, and CDDP) has been recommended as a combination chemotherapy to control advanced and recurrent gastric cancer. We performed a phase II study of this regimen in 49 patients with advanced gastric cancer. METHODS: The treatment regimen consisted of: 5-FU at 370 mg/m(2) (days 1-5, i.v. 24 h); LV at a dose of 30 mg (days 1-5, i.v. bolus); and ETP and CDDP each at 70 mg/m(2) (days 7 and 21, i.a. 2 h), which was repeated every five weeks. RESULTS: The overall response rate was 40.8% (20/49 patients) and the median survival time was 12.6 months (range 1.1-41.8). The adverse events were Grade 3/4 leukocytopenia (16.3%), Grade 3/4 thrombocytopenia (8.2%), Grade 3 nausea and/or vomiting (4.1%), and Grade 3 stomatitis (2.0%). CONCLUSIONS: Based on the encouraging response rate and prognosis, we recommend applying the FLEP regimen to patients with primary advanced gastric cancer.     

Sequential high-dose methotrexate, 5-fluorouracil,and doxorubicin for treatment of advanced pancreatic cancer

Summary A phase II trial of sequential high-dose methotrexate, 1500 mg/m², and 5-fluorouracil, 1500 mg/m² intravenously on day 1, plus doxorubicin, 30 mg/m² i. v. on day 14, has been undertaken in patients with locally advanced or metastatic adenocarcinoma of the pancreas. Of 25 evaluable patients there were 1 complete response and 3 partial responses for an overall response rate of 16% (95% confidence interval 5%–36%). The median survival of all patients was 6.7 months (range 1–17 months). There was one treatment-related death due to pancytopenia and sepsis. In all other patients therapy was generally well-tolerated. We conclude that this combination protocol has only modest activity in the treatment of advanced pancreatic cancer.