Gemcitabine increases systemic 5-fluorouracil exposure in advanced cancer patients

A number of recent clinical trials testing the combination of 5-fluorouracil (5-FU) and gemcitabine in patients with advanced pancreatic adenocarcinoma have shown a significant clinical response rate, but also significant toxicity. As the two antimetabolites may interact at several biochemical levels along their pathways of activation, we investigated whether gemcitabine (GEM) affects 5-FU pharmacokinetics in cancer patients. Thus, we compared 5-FU pharmacokinetics in two groups of patients with various cancers who received the same schedule of 5-FU and folinic acid (FUFA), with or without GEM. There was a significant increase in systemic (5-FU) exposure and toxicity in the FUFA plus GEM group. Our finding may be useful in designing future studies of the combination in order to reduce the occurrence of side-effects and to maximise the antitumour activity.     

Weekly gemcitabine and 24-hour infusional 5-fluorouracil in advanced pancreatic cancer: a phase I-II study

OBJECTIVE: In this phase I-II study we explored the potential of the combination of weekly gemcitabine (GEM) and 24-hour continuous infusion of 5-fluorouracil (5-FU) in order to determine the toxicity profile in pancreatic cancer. The efficacy of this drug combination was studied as a secondary endpoint. METHODS: Twenty-one patients with histologically or cytologically proven unresectable or metastatic previously untreated pancreatic adenocarcinoma were included in this study. Two dose levels of GEM and two dose levels of 5-FU were evaluated in three cohorts of patients who received GEM 1,000 mg/m(2) and 5-FU 2,000 mg/m(2), GEM 1,200 mg/m(2) and 5-FU 2,000 mg/m(2), or GEM 1,200 mg/m(2) and 5-FU 2,250 mg/m(2), on days 1, 8, and 15, every 4 weeks, respectively. RESULTS: Grade 3-4 neutropenia was observed in 10% of the cycles. Non-myelosuppressive toxicities included fatigue (22%), grade 1-2 diarrhea (12%) and grade 1 liver toxicity. There was no limiting toxicity and the maximum tolerated dose has not been reached. Two patients experienced a partial response (9.5 +/- 12.6%) and 12 patients had stable disease (57.1 +/- 21.2%). Seven of the 14 symptomatic patients improved their disease-related symptoms and 4 of the 8 patients evaluable for clinical benefit had a clinically beneficial response (50 +/- 34.6%). The median progression-free survival was 6 months (range 2-28), median survival was 11 months (range 3-32+), and the actuarial 1-year survival rate 33%. CONCLUSION: The weekly administration of GEM combined with 24-hour continuous infusion of 5-FU shows a good safety profile at the dose levels evaluated. Some partial responses had also been achieved, disregarding the dose level of the two drugs. Survival confirms the activity of this drug combination.     

Phase II study of gemcitabine, UFT and leucovorin in patients with advanced pancreatic cancer

The combination of gemcitabine with protracted 5-fluorouracil (5-FU) in the treatment of metastatic pancreatic cancer has shown activity with tolerable toxicity. The administration of UFT may simulate the effects of a protracted infusion of 5-FU. Patients with previously untreated metastatic or unresectable measurable pancreatic adenocarcinoma received gemcitabine (800 mg/m2 i.v., administered as an 80-min infusion on days 1, 8 and 15), UFT (200 mg/m2/day, on days 1 to 21), and oral leucovorin (90 mg/day, on days 1 to 21). Thirty patients were enrolled in this study. Five patients had partial responses, with an overall response rate of 17% (5/30), using the intent-to-treat principle (95% confidence interval (CI), 3-30%). Nine out of 25 (36%) patients experienced clinical benefit responses (95% CI; 17-55%). The median time to progression was 3.0 months, and the median overall survival was 7.2 months. The principal adverse event was neutropenia. The combination of gemcitabine, UFT, plus oral leucovorin shows significant antitumor activity and a beneficial clinical effect with an acceptable level of toxicity.     

Phase II Study of Gemcitabine, UFT and Leucovorin in Patients with Advanced Pancreatic Cancer

The combination of gemcitabine with protracted 5-fluorouracil(5-FU) in the treatment of metastatic pancreatic cancer has shown activity with tolerable toxicity. The administration of UFT may simulate the effects of a protracted infusion of 5-FU. Patients with previously untreated metastatic or unresectable measurable pancreatic adenocarcinoma received gemcitabine (800 mg/m2 i.v., administered as an 80-min infusion on days 1, 8 and 15), UFT (200 mg/m2/day, on days 1 to 21), and oral leucovorin (90 mg/day, on days 1 to 21). Thirty patients were enrolled in this study. Five patients had partial responses, with an overall response rate of 17% (5/30), using the intent-to-treat principle (95% confidence interval (CI), 3-30%). Nine out of 25 (36%) patients experienced clinical benefit responses (95% CI; 17-55%). The median time to progression was 3.0 months, and the median overall survival was 7.2 months. The principal adverse event was neutropenia. The combination of gemcitabine, UFT, plus oral leucovorin shows significant antitumor activity and a beneficial clinical effect with an acceptable level of toxicity.     

Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer

We conducted a phase II trial of gemcitabine with S-1, oral fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate, to evaluate the activity and toxicity of such a combination in metastatic pancreatic cancer (MPC) patients. Patients who had pathologically proven pancreatic cancer with metastatic lesions were eligible candidates for entry into the study. S-1 was given orally (30 mg m(-2)) b.i.d. for 14 consecutive days and gemcitabine (1000 mg m(-2)) was given on days 8 and 15. The cycle was repeated every 21 days. We enrolled 33 MPC patients. The median number of cycles was eight (range 1-20). Grade 3-4 toxicities were leucopenia (33%), neutropenia (55%), anaemia (9%), thrombocytopenia (15%), anorexia (6%), fever (9%), and interstitial pneumonia (6%). Objective responses were obtained in 16 patients (one complete response and 15 partial responses; response rate, 48%; 95% confidence interval (CI), 33-65). Median survival and 1-year survival rate were 12.5 months (95% CI, 5.9-19.1) and 54% (95% CI, 36-72), respectively. Combination chemotherapy with GEM and S-1 was well tolerated and yielded a significantly high response rate.     

Gemcitabine (GEM), 5-fluorouracil (5-FU) and folinic acid (FA) in patients with different gastroenteric malignancies

This phase II clinical trial was performed in order to evaluate the pharmacokinetics, toxicity and anti-tumor activity of a novel combination of gemcitabine (GEM), 5-fluorouracil (5-FU) and folinic acid (FA) designed on a specific translational basis. Every 4 weeks, 44 patients with various gastroenteric malignancies, 29 of whom had pancreas carcinoma, received a short intravenous (i.v.) infusion of FA (100 mg/m2) and 5-FU (400 mg/m2) on days 1-5, and GEM 1000 mg/m2 on days 1, 8 and 16. Our results suggest that, although this treatment leads to hematological and gastroenteric toxicity, it is very active in patients with pancreatic carcinoma. We therefore believe that an improved version would merit further investigation in larger scale trials.     

Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas

Adenocarcinomas of the pancreas and biliary tract are highly malignant neoplasms, which are found in the advanced stage. Chemotherapy commonly plays a palliative role in the treatment of pancreatic and biliary tract cancers. 5-Fluorouracil (5-FU) is the most widely studied single agent; the response rate of 5-FU is only 20%. Recently, some reports presented interesting results, in which 5-FU, modulated with levofolinic acid (leucovorin), was active in patients with colorectal cancer. In relation, we performed a phase II study of 5-FU, modulated with leucovorin, in patients affected by advanced pancreatic or biliary tract cancer. Fifty-one patients with nonresectable carcinomas of the pancreas or biliary tract admitted to Korea University Hospital between May 1995 and December 1998 were included in this study. Chemotherapy consisted of leucovorin 25 mg/m2/day by 2-hour intravenous infusion, followed by 5-FU 375 mg/m2/day by bolus intravenous infusion, from day I to day 5. The treatment was repeated every 3 to 4 weeks. A total of 51 eligible patients with advanced adenocarcinoma of the pancreas or biliary tract were enrolled. Of 23 enrolled patients with pancreatic adenocarcinoma, one patient showed complete remission with a survival duration of 13 months (response duration was 9 months). Three patients had partial responses (PRs) with survival times of 6, 12, and 15 months, respectively. The overall response rate was 17.4% (95% confidence interval [CI], 7.2%-36.2%). The median time of overall survival was 6 months (range: 1-15 months). Of 28 enrolled patients with biliary tract cancer, complete responses were observed in 2 patients (7.1%) with survival time of 14 and 16 months, respectively. Seven patients had PRs with a median survival of 8 months. The overall response rate was 32.1% (95% CI, 20.3%-57.5%). The median time of overall survival was 6 months (range: 1-16 months). The most prominent toxicity was mucositis. Hematologic toxicity was less severe. 5-Fluorouracil in modulation with intravenous leucovorin is well tolerated by patients with stage IV pancreatic adenocarcinoma or biliary tract cancer. Although the response rate for patients with pancreatic adenocarcinoma is not better than that achieved using 5-FU monochemotherapy, the 32.1% overall response rate achieved in patients with biliary tract cancer suggests that 5-FU modulation with leucovorin is active in biliary tract cancer.     

A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.     

Irinotecan combined with bolus 5-fluorouracil and folinic acid Nordic schedule as first-line therapy in advanced colorectal cancer.

BACKGROUND: This multicentre phase II study evaluated the efficacy and safety of irinotecan combined with the Nordic schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line therapy in patients with advanced colorectal cancer. PATIENTS AND METHODS: Seventy-four patients with measurable disease and a WHO performance status of 2 or less were treated with irinotecan 210 mg/m(2) as a 30-90 min intravenous infusion on day 1, followed by 5-FU 500 mg/m(2) and FA 60 mg/m(2) bolus on days 1 and 2, every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was the objective response rate. RESULTS: Twenty-nine out of 68 evaluable patients achieved a complete (n = 7) or partial (n = 22) response, leading to an overall response rate of 43% [95% confidence interval (CI) 31% to 55%]. The median duration of response was 10 months. The estimated median time to progression and survival were 6.4 months (95% CI 5.4-9.0) and 15.6 months (95% CI 13.3-19.0), respectively, in the intention-to-treat population. A total of 860 cycles were administered to 74 patients. Neutropenia was the main adverse event with grade 3-4 toxicity in 66% of patients and 17.5% of cycles. Grade 3-4 non-haematological toxicities were infrequent and included diarrhoea in 16% of patients and 2% of cycles and nausea/vomiting in 10% of patients and 1% of cycles. CONCLUSIONS: Irinotecan combined with the bolus Nordic schedule of 5-FU/FA is active in advanced colorectal cancer with an easily managed safety profile which ensures good schedule compliance. The low incidence of grade 3-4 non-haematological toxicity justifies the further evaluation of this combination in the context of randomised clinical trials.     

吉西他滨为基础的化疗方案治疗进展期胰腺癌的临床研究

背景与目的:进展期胰腺癌预后差.吉西他滨可以改善胰腺癌患者的生存质量,但吉西他滨联合方案疗效是否优于单药,还存在争议,国内更缺乏相关的临床研究.本研究目的是比较吉西他滨为基础的联合化疗方案与吉西他滨单药治疗进展期胰腺癌的疗效.方法:回顾性分析2000～2005年收治的40例经临床或病理确诊的进展期胰腺癌临床资料,其中吉西他滨单药组15例,吉西他滨剂量为1 000 mg/m2,每周1次,连用7周,休息2周,之后每周1次,连用3周,4周重复;吉西他滨联合治疗组25例,联合化疗方案包括吉西他滨1 000 mg/m2,每周1次,连用2周,分别联合:(1)氟尿嘧啶425～600 mg/m2,静脉滴注或持续静脉泵入,d1-5,3周重复;(2)顺铂60～75 mg/m2,分第1、2天,3周重复;(3)奥沙利铂85～130 mg/m2,d1,3周重复;(4)卡培他滨l000 mg/m2,2次/天,d1-14,3周重复.采用Kaplan-Meier生存曲线分析患者的生存期,并比较两组间的临床受益反应、中位疾病进展时间、中位生存时间和不良反应.结果:吉西他滨联合组与单药组患者的临床受益反应均得到改善(56.0% vs.46.7%),但疾病控制率、中位生存时间、临床受益反应在两组之间差异无统计学意义(P＞0.05),不良反应的发生率也相似(P＞0.05).对Ⅲ～Ⅳ期患者进行分层分析,发现吉西他滨联合组疾病控制率高于单药组(75.0% vs.45.5%),但无统计学意义(P=0.13).结论:吉西他滨联合方案与单药治疗进展期胰腺癌相比,疗效、临床受益反应、中位生存时间两组相似.     

Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases

The main objectives of this study were to assess the use of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FA) as neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases and to determine the response rate and proportion of patients that could be down-staged to resectable tumors. Forty patients were treated with irinotecan (180 mg/m2 over 30 min) on d 1, FA (200 mg/m2 over 30 min) followed by 5-FU (400 mg/m2 bolus and continuous infusion of 600 mg/m2 over 22 h) on d 1 and 2 every 2 wk. The overall response rate was 55% (95% CI: 39.5-70.4%). The progression-free survival was 12.1 mo (95% CI: 11.4-14.8 mo). The median overall survival was 20 mo (95% CI: 17.7-26.6 mo). Four patients (10%) have undergone liver resection after a median of eight cycles. Those patients remained alive with a median follow up period of 33 mo. The principal grade 3-4 toxicity was neutropenia in 20 patients (50%). We conclude that the regimen of irinotecan/5-FU/FA was highly active in patients with colorectal cancer and liver metastases with limited toxicity. In a subgroup of patients with initial inoperable liver metastases, this regimen was able to down-stage the disease to an operable stage.     

A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

In a randomized clinical trial, gemcitabine (GEM) was more effective than 5-fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have different mechanisms of action and their combination, from a theoretical point of view, could result in a higher activity. To test activity and feasibility of such a combination, a multi-institutional phase II study was initiated in November 1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD). Primary objectives of this study were to determine the activity in terms of response rate and clinical benefit, while the secondary objective was toxicity. According to the optimal two-stage phase II design, 54 patients were enrolled. Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients (51%) (95% confidence interval (CI) 38-64%). Two patients achieved a partial response and 34 a stable disease. Median survival for all the patients was 7 months. Side-effects were mild: no gastrointestinal or haematological grade 3-4 toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO) leukopenia and seven episodes of thrombocytopenia. Although the non-randomized design of this study suggests caution in the interpretation of these data, in consideration of the low incidence of toxicity and the favourable results obtained in terms of clinical benefit, it may be worthwhile to test more active schedules of 5-FU (continuous infusion) in combination with gemcitabine.     

Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience.

BACKGROUND: Unresectable biliary tract cancer has a very poor prognosis. A combination of weekly gemcitabine plus continuous infusional 5-fluorouracil (5-FU) (GEM/CVI 5-FU) was evaluated as therapy for this cancer. PATIENTS AND METHODS: The charts of 27 patients with advanced biliary tract adenocarcinoma treated with GEM/CVI 5-FU at the Princess Margaret Hospital were evaluated for response, survival and toxicity. The treatment consisted of a 30-min infusion of gemcitabine at 900 mg/m(2) on days 1, 8 and 15 of a 28-day cycle plus 5-FU given via a peripherally inserted central line at 200 mg/m(2)/day continuously for 21 days, every 28 days. RESULTS: Objective responses were observed in nine patients (33%; 95% confidence interval 17% to 54%). An additional eight patients (30%) achieved stable disease for a median of 4 months (range 2.3-11). Median time to progression and overall survival were 3.7 and 5.3 months, respectively. Direct chemotherapy-related toxicity was mild, with only 11% grade > or =3 myelosuppression. Central venous catheter complications were common (26%). There were no treatment-related deaths. CONCLUSIONS: This study shows that GEM/CVI 5-FU is active and well tolerated in advanced and metastatic biliary tract cancers.     

Phase II study of gemcitabine combined with uracil-tegafur in metastatic pancreatic cancer

OBJECTIVE: The single agent gemcitabine is the standard first-line treatment for advanced pancreatic cancer. Recent studies of a combination of gemcitabine and 5-fluorouracil (5-FU) revealed that survival data were superior to those with gemcitabine or 5-FU alone. The administration of oral uracil-tegafur (UFT) is more convenient and simulates the effect of a continuous or protracted infusion of 5-FU. Therefore, we conducted a phase II study of gemcitabine combined with UFT in metastatic pancreatic cancer patients and assessed the efficacy and the toxicity of the regimen. METHODS: Twenty-two pancreatic adenocarcinoma patients (18 males, 4 females) were enrolled from December 2000 to September 2002. The regimen consisted of gemcitabine 1,000 mg/m(2) once weekly for 3 consecutive weeks, and oral UFT 390 mg/m(2)/day (in 3 divided doses) on days 1-14. The cycle was repeated every 28 days. The objective tumor response was evaluated after 2 courses of chemotherapy. RESULTS: 82 cycles were administered in total, with a median of 3 cycles per patient (range 1-6 cycles). The median age was 52 years (range 28-69 years). Response to treatment could be assessed in all patients. The objective response rate was 22.7% (95% CI, 7.8-45.4) with no complete response and 5 partial responses. Four patients (18.2%) had stable disease and 13 patients (59.1%) had a progression. The median time to progression was 4.2 months (range 0.9-13.6). The median overall survival was 5.8 months (range 0.5-13.6). Of 10 patients eligible for the assessment of clinical benefit response, 4 (40%, 95% CI 12.2-73.8) showed clinical benefit. Among 21 patients with baseline CA 19-9 levels, CA 19-9 was reduced by 50% or more in 12 patients (57.1%). The chemotherapy was generally well tolerated and the most common grade 3-4 toxic side effects were neutropenia (18.2%), anemia (4.5%), and diarrhea (4.5%). CONCLUSIONS: The combination chemotherapy with gemcitabine and UFT in metastatic pancreatic cancer was tolerable for most patients but showed modest response rates and clinical benefit. However, a randomized phase III study should be conducted in order to further test the efficacy of the regimen.     

Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil,a randomized controlled study

PURPOSE: To determine the efficacy and tolerability of gemcitabine (GEM)-concurrent chemoradiotherapy (CCRT) vs. 5-fluorouracil (5-FU) CCRT for locally advanced pancreatic cancer. METHODS AND MATERIALS: Thirty-four patients with locally advanced pancreatic cancer were studied. Eighteen patients were randomized to receive GEM CCRT (600 mg/m(2)/wk for 6 weeks) and 16 patients to receive bolus 5-FU CCRT (500 mg/m(2)/d for 3 days repeated every 2 weeks for 6 weeks). All patients were to receive 3D-CRT 50.4-61.2 Gy at 1.8-Gy/d fractions and GEM (1000 mg/m(2) weekly for 3 weeks repeated every 4 weeks) after RT. RESULTS: The median survival and median time to progression were 14.5 months and 7.1 months for the GEM CCRT group and 6.7 months and 2.7 months for the 5-FU CCRT group (p = 0.027 and p = 0.019, respectively). The quality-adjusted life month survival time was 11.2 +/- 0.5 months for GEM CCRT and 6.0 +/- 0.3 months for 5-FU CCRT patients (p <0.001). The response rate was 50% (four complete responses and five partial responses) for GEM CCRT and 13% (two partial responses) for 5-FU CCRT (p = 0.005). Pain control was 39% for GEM CCRT and 6% for 5-FU CCRT (p = 0.043). Grade 3-4 neutropenia (34% vs. 19%), thrombocytopenia (0% vs. 7%), nausea (33% vs. 31%), vomiting (17% vs. 19%), hospitalization days per month of survival (7.4 +/- 1.7 days vs. 8.0 +/- 1.3 days), and full dose of RT received (78% vs. 75%) were not significantly different between the GEM CCRT and 5-FU CCRT patients. CONCLUSION: GEM CCRT appears more effective than 5-FU CCRT for locally advanced pancreatic cancer and has comparable tolerability.     

Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study

The aim of this study was to define the maximum tolerated dose (MTD) of bolus mitomycin C (MMC) in combination with 24 h-continuous infusion of 5-flourouracil (FU) plus folinic acid, and to assess the toxicity and activity in patients with previously treated colorectal and gastric cancer. Escalating doses of MMC starting from 6 mg m(-2) in 2 mg m(-2)-steps to a maximum of 10 mg m(-2) were applied on days 1 and 22, given to fixed doses of 5-FU (2.600 mg m(-2)) as 24 h infusion and folinic acid 500 mg m(-2) prior to 5-FU weekly for 6 weeks. At least three patients were treated at each dose level. A total of 16 patients have been included in the phase I study. At the highest dose level (MMC 10 mg m(-2)), grade III thrombocytopenia, dyspnoea, mucositis and diarrhoea were observed in one patient each (17 %). In the phase II study 45 patients, 33 with colorectal cancer and 12 with gastric cancer, 23 patients after failure of first- and 22 patients after at least second-line or subsequent chemotherapy have been treated. Seven partial responses (PR) were registered (16%), one (3%; CI(95%), 0-16) in colorectal and six (50%; CI(95%), 21-79%) in gastric cancer patients. In all, 17 (38%) achieved disease stabilisation, 15 colorectal (45%, CI(95%), 28-64%) and two gastric cancer patients (17%; CI(95%), 2-48%). The median progression-free survival was 3.1 months (range, 0.9-9.1) in colorectal and 4.6 months (range, 0.7-12.4) in gastric cancer. The median overall survival time was 6.6 months (range, 1.9-15.6) in colorectal and 7.1 months (range, 1.7-20.8) in patients with gastric cancer. This regimen was considered to be safe and well tolerated for pretreated patients with gastrointestinal adenocarcinoma. In gastric cancer,MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen with promising antitumour activity.     

Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer

Oxaliplatin plus fluorouracil/folinic acid (5-FU/FA) every 2 weeks has shown promising activity in advanced gastric cancer. This study assessed the efficacy and safety of weekly oxaliplatin plus 5-FU/FA (FUFOX regimen) in the metastatic setting. Patients with previously untreated metastatic gastric cancer received oxaliplatin (50 mg m(-2)) plus FA (500 mg m(-2), 2-h infusion) followed by 5-FU (2000 mg m(-2), 24-h infusion) given on days 1, 8, 15 and 22 of a 5-week cycle. The primary end point of this multicentre phase II study was the response rate according to RECIST criteria. A total of 48 patients were enrolled. Median age was 62 years and all patients had metastatic disease, with a median number of three involved organs. The most common treatment-related grade 3/4 adverse events were diarrhoea (17%), deep vein thrombosis (15%), neutropenia (8%), nausea (6%), febrile neutropenia (4%), fatigue (4%), anaemia (4%), tumour bleeding (4%), emesis (2%), cardiac ischaemia (2%) and pneumonia (2%). Grade 1/2 sensory neuropathy occurred in 67% of patients but there were no episodes of grade 3 neuropathy. Intent-to-treat analysis showed a response rate of 54% (95% CI, 39-69%), including two complete responses. At a median follow-up of 18.1 months (range 11.2-26.2 months), median survival is 11.4 months (95% CI, 8.0-14.9 months) and the median time to progression is 6.5 months (95% CI, 3.9-9.2 months). The weekly FUFOX regimen is well tolerated and shows notable activity as first-line treatment in metastatic gastric cancer.     

Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and efficacy of gemcitabine combined with fluorouracil (5-FU) in patients with pancreatic cancer. PATIENTS AND METHODS: Patients with measurable, locally advanced, nonresectable or metastatic pancreatic cancer were candidates for the study. 5-FU was given via protracted venous infusion (PVI) at a fixed dosage of 200 mg/m2/d, and gemcitabine was administered weekly for 3 consecutive weeks every 4 weeks. The initial dose of gemcitabine was 700 mg/m2 and was escalated in increments of 100 mg/m2/wk until the appearance of severe toxicity. Measurements of efficacy included the following: response rate; clinical benefit response, which is a composite measurement of pain, performance status, and weight loss; time to disease progression; and survival. RESULTS: Twenty-six patients received a total of 109 courses. Dose-limiting toxicity, which consisted of grade 4 neutropenia with fever (one patient) and grade 4 thrombocytopenia (one patient), was observed in two of three patients treated with 1,100 mg/m2/wk of gemcitabine. On the basis of these results, the MTD of gemcitabine with 5-FU via PVI on this schedule was 1,000 mg/m2. Sixteen patients developed grade 3-4 neutropenia, and three patients developed grade 3-4 thrombocytopenia. Grade 3-4 nonhematologic toxicity consisted of diarrhea (two patients) and cutaneous toxicity, asthenia, edema, mucositis, and nausea and vomiting (one patient each). The delivered dose-intensity of gemcitabine was similar at the 1,000 mg/m2 dose level (599 mg/m2/wk) as at the 900 mg/m2 (601 mg/m2/wk) dose level. For this reason, the recommended dose of gemcitabine for phase II evaluation on this schedule was 900 mg/m2. Five patients had objective responses (one complete response and four partial responses; response rate, 19.2%; 95% confidence interval [CI], 6.5 to 39.3), and 10 patients had improvement of disease-related symptoms (45%; 95% CI, 24 to 67). After a median follow-up of 17.7 months (range, 7.8 to 24.8 months), the median progression-free survival and overall survival times were 7.4 months (95% CI, 3.3 to 11.4) and 10.3 months (95% CI, 8.1 to 12.5), respectively. CONCLUSION: The MTD of gemcitabine when combined with 5-FU via PVI on this schedule was 1,000 mg/m2/ wk; however, on the basis of administered dose-intensity, the recommended dose for additional investigation is 900 mg/m2. This combination chemotherapy regimen was well tolerated and showed promising antitumor activity in the treatment of pancreatic cancer.     

Bolus/infusional 5-fluorouracil and folinic acid for metastatic colorectal carcinoma: are suboptimal dosages being used in the UK?

Bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA) is reported to be highly active [partial response (PR) = 54%, median survival 18 months] in patients with metastatic colorectal carcinoma (MCCa). To confirm this level of activity, we conducted a retrospective analysis of 95 previously untreated patients with MCCa treated with FA by 2 h i.v. infusion (200 mg m-2) followed by 5-FU bolus/22 h i.v. infusion (300-500 mg m-2) on days 1 and 2 every 2 weeks. Thirty patients also received N-(phosphonacetyl)-L-aspartate (PALA), 250 mg m-2, 24 h prior to 5-FU/FA. In 81 evaluable patients, the response rate was low: PR = 11%, stable disease (SD) = 36% and median survival = 8 months. There was an improvement in survival with increased 5-FU dosage (500 mg m-2) [relative hazard (RH) = 0.38, 95% CI 0.21-0.70], controlled for age, primary site, PALA, liver function and performance status. Good performance status (PS 0 or 1) was also associated with improved survival (RH = 0.21, 95% CI 0.10-0.46). Response, survival and toxicity were not altered by the co-administration of PALA. Bolus/infusional 5-FU (500 mg m-2) and FA was well tolerated. WHO toxicities (grade 3) were: mucositis, 2%; diarrhoea, 14%; nausea and vomiting, 5%. In light of the apparent dose effect, poor response and low toxicity, we recommend that regimes incorporating higher 5-FU dosages are explored and prospectively validated before bolus/infusional 5-FU becomes accepted standard practice.     

High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study

BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur.