Continuous systemic 5-fluorouracil infusion in advanced colorectal cancer: results in 91 patients

Ninety-one patients with metastatic colorectal cancer were treated with continuous ambulatory 5-fluorouracil (5FU) infusion 250-300 mg/m2/day through a chronic indwelling central venous catheter. Twenty-six of the 91 patients (29%) had received previous bolus 5FU. Fifty-eight of the 91 patients (64%) had two or more sites of disease, and 74 of 91 patients (81%) had liver metastases. Results were complete remission in 5 of 91 (6%), partial remission in 25 of 91 (27%), stable disease in 33 of 91 (36%), and progressive disease in 28 of 91 (31%), for an overall response rate of 30 of 91 (33%); median duration of response was 7 months. Twenty-six of 65 previously untreated patients (40%) experienced objective response. Median survival from initiation of treatment for all patients was 11 months. Forty-one percent of patients experienced no significant toxicity and were able to continue therapy without treatment interruption. Toxicities necessitating treatment interruption included stomatitis in 35 patients (39%), hand-foot syndrome in 33 patients (36%), and diarrhea in 10 patients (11%). No significant myelosuppression or serious catheter-related complications were encountered. We conclude that continuous systemic venous infusion of 5FU produces a higher response rate than traditional bolus 5FU schedules, with apparent enhancement of survival and easily managed toxicity.     

Long-term ambulatory treatment of metastatic colorectal adenocarcinoma by continuous intravenous infusion of 5-fluorouracil

To delineate the efficacy of continuous intravenous 5-fluorouracil (5-FU) infusion therapy for advanced colorectal adenocarcinoma, a study of 36 patients with measurable metastatic disease was conducted. Patients received a daily intravenous infusion of 300 mg/m2 5-FU over a 24-h period utilizing portable infusion devices and central venous catheters. In a population characterized by substantial pretreatment exposure to radiotherapy, chemotherapy, and other indicators of poor prognosis, 13/36 (36%) patients achieved an objective response. An additional 10/36 (28%) patients manifested stable disease (no change) and experienced survival comparable to that of patients with objective response. Toxicity was minimal; patients were able to continue 5-FU infusions 95% of the total time on protocol. There were no adverse hematologic effects or catheter complications. Because previously untreated patients benefited more frequently (positive response, 50%), continuous intravenous infusion should be evaluated further as a primary modality option when 5-fluorouracil antitumor chemotherapy is contemplated.     

Low-dose trimetrexate glucuronate and protracted 5-fluorouracil infusion in previously untreated patients with advanced pancreatic cancer.

BACKGROUND: 5-Fluorouracil (5-FU)-based regimens have not been shown to prolong survival or provide clinical benefit in patients with advanced pancreatic cancer. The purpose of this study was to determine the tolerability of protracted venous infusion (PVI) of 5-FU, modulated by a low dose of the synthetic antifolate trimetrexate, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-three chemotherapy-na?ve patients were evaluated. Patients were enrolled in four consecutive cohorts in which the weekly dose of trimetrexate was escalated in 10 mg/m2 increments, from 20 to 50 mg/m2. PVI 5-FU was administered at a fixed dose of 225 mg/m2/day. Treatment was administered for 6 successive weeks, every 8 weeks. RESULTS: Twenty-two patients were assessable. The maximum tolerated dose of trimetrexate was 40 mg/m2. The most common grade 3 and 4 toxicity was diarrhea. There were no treatment-related deaths. Preliminary analysis of activity revealed a response rate of 9%, with 41% of the patients having stable disease for a median duration of 3.8 months. The median survival for the entire group was 6.9 months (range 1-29 months). A clinical benefit response was experienced by 27.2% of patients. CONCLUSIONS: Low-dose trimetrexate can be safely administered in combination with PVI 5-FU. This treatment is well tolerated and is associated with palliative activity in advanced pancreatic cancer.     

Combination chemotherapy with navelbine and continuous infusion of 5-fluorouracil in metastatic, chemotherapy refractory breast cancer

Background:The protracted continuous infusion (PCI) of5-fluorouracil (5-FU) has proven in several studies an active and welltolerated treatment for advanced, pretreated breast cancer. Navelbine has alsoactivity in this setting. Patients and methods:Heavily pretreated patients with metastaticbreast carcinoma were eligible for the study. Treatment consisted of 5-FU 250mg/m² given as a PCI by an elastomeric pump and navelbine 20mg/m² on days 1 and 8, every four weeks. Eighty-three patients(median age 54 years; range 32–82 years) entered the study. The mediannumber of metastatic tumour sites was 2, with visceral involvement in 56patients. Apart from five patients with contraindications, all patients hadbeen pretreated with anthracyclines. Thirty-one patients had received taxanesand seventy-four bolus 5-FU. Results:A median of 5 cycles (range 1–14) per patient wasadministered. The median duration of 5-FU infusion was 17 weeks (range, 4-90).In the 80 evaluable patients (3 not yet evaluable) 12 complete remissions and24 partial remissions occurred (response rate, 45%). Median durationof response was 9 months. Toxicity was mild. Median survival was 20 months. Conclusions:PCI–5-FU combined with navelbine offers areasonable chance of tumour regression with modest side effects in patientswith heavily pretreated breast cancer.     

5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer

PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425-432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47-53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter- and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m(-2)day(-1)) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to 'exposure-guided' 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand-foot syndrome was the most common dose limiting toxicity. Variability in 5FU(300)Css was considerably less than previously reported; 94 +/- 25 ng ml(-1)(CV = 27%). No relationships were demonstrated between subject mean 5FU(300)Css and PD end-points such as response, mucositis, diarrhoea and hand-foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer.     

Oxaliplatin and protracted continuous 5-fluorouracil infusion in patients with pretreated advanced colorectal carcinoma

Background:Both OHP and 5-FU are clinically active as single agents in the treatment of metastatic colorectal cancer (MCRC). Clinical and laboratory studies suggest a synergistic interaction between these agents. This phase II study was performed to evaluate the activity of a schedule including OHP and protracted 5-FU infusion in 5-FU-resistant MCRC. Patients and methods:From October 1997 to January 2000, 50 patients with measurable progressive MCRC after one or more 5-FU-based regimens were treated. OHP (2–3-hour i.v. infusion) on day 1 and 5-FU (protracted i.v. infusion using elastomeric/electronic pump through a central venous catheter) on days 1–21 were administered every 3 weeks, at the following 4 dose levels: 1) OHP 100 mg/m² + 5-FU 200 mg/m² (21 patients); 2) OHP 100 mg/m² + 5-FU 250 mg/m² (3 patients); 3) OHP 130 mg/m² + 5-FU 200 mg/m² (10 patients); 4) OHP 130 mg/m² + 5-FU 250 mg/m² (16 patients). Results:Objective responses were 1 (2%) CR; 10 (20%) PR, for a median duration of 8 months; 23 (46%) stable diseases, for a median duration of 6 months; 16 (32%) progressions. CR + PR was higher in patients who had previously received no more than one line of chemotherapy for metastatic disease as compared with patients who had received two or more lines of therapy (33% vs. 5%, P < 0.01). The median time to progression was four months (one to nine). All dose levels (313 cycles) were well tolerated with mild toxicity. Major toxicity (grade 3 WHO) included: anaemia in 1 patient (2%), nausea and vomiting in 1 patient (2%), diarrhoea in 4 patients (8%) and stomatitis in 1 patient (2%); grade 1 and 2 peripheral neuropathy were encountered, respectively, in 30 (60%) and 8 (16%) patients. The median survival was 13 months (9–17), with 32 patients still alive after a median follow-up of 8 months. Conclusions:This study suggests that 1) OHP plus protracted 5-FU infusion is an active combination in MCRC patients resistant to pre-treatment bolus 5-FU; 2) it has a good tolerability profile and 3) the optimum dose level is OHP 130 mg/m² and 5-FU 250 mg/m².     

大剂量醛氢叶酸加5-FU持续滴注联合DDP治疗晚期食管癌及生存分析

目的:评价大剂量醛氢叶酸加5氟尿嘧啶(5-FU)持续48h滴注联合顺铂(DDP)方案治晚期食管癌的客观疗效、毒副反应并进行生存分析,探索晚期食管癌较合理治疗方案及相关预后因素。方法:对入选的晚期食管癌病人采用大剂量醛氢叶酸(200mg/m2) 5FU(3.0g/m2)持续48h滴注联合顺铂方案进行治疗。结果:共48例病人入选,中位年龄52.0岁,48例均可进行疗效及毒副作用评价。完全缓解(CR)9例,部份缓解(PR)20例,稳定(NC)17例,进展(PD)2例,总有效率为60.42%。主要的毒副反应为恶心呕吐、口腔粘膜炎、骨髓抑制及脱发等,大多数为Ⅰ~Ⅱ度反应,经常规对症治疗后见好转,未见治疗相关死亡。全组48例患者中位生存期为10.00个月,95%的可信区间为7.51~12.49。晚期食管癌治疗前如KPS评分<80或已出现内脏器官转移,提示预后较差,从治疗中获益将较少。治疗前功能状态及病变或转移部位是影响预后的相关因素,两者的P值分别为0和0.048。结论:大剂量醛氢叶酸 5FU持续48h滴注联合顺铂方案治疗晚期食管癌疗效好,且毒副反应轻,可作为晚期食管癌化疗的标准一线方案。     

Arterial infusion therapy with low-dose cisplatin and continuous 5-fluorouracil for isolated hepatic recurrence of gastric carcinoma

Patients with metachronous liver metastasis after curative resection of gastric carcinoma generally have a poor prognosis, even when recurrence is confined to the liver. We report a patient in whom hepatic arterial infusion therapy with bolus low-dose cisplatin (CDDP) and continuous 5-fluorouracil (5-FU) was effective against large metastases confined to the liver. An 83-year-old man was admitted with huge liver metastases from gastric carcinoma. Intra-arterial bolus injection of low-dose CDDP (5 mg) and continuous intra-arterial infusion of 5-FU (250 mg/day for 7 days) was started. After four courses of this arterial infusion therapy, computed tomography scans revealed shrinkage of the liver metastases. He was followed-up as an outpatient and continued to receive the arterial infusion therapy once every 4 weeks. Throughout the course of the chemotherapy, a partial response of the liver metastases was maintained. The patient had an improved quality of life after starting the chemotherapy, and he survived for 16 months from the commencement of the therapy. Arterial infusion therapy with bolus low-dose CDDP and continuous 5-FU may be recommended for patients with isolated hepatic recurrence of gastric carcinoma. Received: September 6, 1999 / Accepted: January 31, 2000     

A prospective randomised trial of protracted venous infusion 5-fluorouracil with or without mitomycin C in advanced colorectal cancer

Background: To compare protracted venous infusion (PVI) 5-fluorouracil (5-FU) with and without mitomycin C (MMC) in a prospectively randomised study and analyse for tumour response, survival, toxicity and quality of life (QL).Patients and methods: Two hundred patients with advanced colorectal cancer received PVI 5-FU 300 mg/m²/day for a maximum of 24 weeks and were randomised to PVI 5-FU alone or PVI 5-FU + MMC 10 mg/m² (7 mg/m² from June 1995) 6 weekly for 4 courses.Results: Overall response was 54% (95% confidence interval [CI] 44.1%–63.9%) with PVI 5-FU + MMC compared to 38% (95% CI 28.3%–47.7%) for PVI 5-FU alone (P = 0.024). The median failure free survival was 7.9 months in PVI 5-FU plus MMC and 5.4 months with PVI 5-FU alone (P = 0.033) and at one year 31.9% for the combination compared to 17.7% for PVI 5-FU alone. Median survival was 14 months with MMC and 15 months in 5-FU alone; one-year survival 51.7% vs. 57.2%. PVI 5-FU + MMC caused more overall haematological toxicity but CTC grades 3/4 was increased only for thrombocytopaenia. Two patients treated with a cumulative dose of MMC of 40 mg/m² developed haemolytic uraemic syndrome warranting the reduction in cumulative MMC dose to 28 mg/m². The global QL scores were better for PVI 5-FU + MMC arm at 24 weeks, but the remaining QL data showed no differences.Conclusions: PVI 5-FU + MMC results in failure-free survival and response advantage, tolerable toxicity and better QL when compared to PVI 5-FU alone but no overall survival advantage. There is no irreversible toxicity with MMC at a cumulative dose of 28 mg/m².     

Five-day continuous infusion of 5-fluorouracil and pulsed folinic acid in patients with metastatic colorectal carcinoma: An effective second-line regimen

Objective: A previous phase I trial in 14 pretreated patients with progressive advanced colorectal cancer demonstrated 750 mg/m² to be the maximum tolerable dose of 5-fluorouracil (5-FU) administered as a 5-day continuous infusion modulated by short infusions of 100 mg/m² folinic acid twice daily. The dose-limiting toxicities were hand-foot syndrome and severe mucositis. A response rate of 21% and 50% stable disease could be achieved. In order to determine the effectiveness and tolerability, we initiated a multicenter phase II trial applying a 650 mg/m² recommended dose of 5-FU and 100 mg/m² folinic acid twice daily every three weeks.Patients and methods: From January 1994 to July 1996, 88 advanced and progressive colorectal cancer patients either previously treated with a bolus schedule of 5-FU and folinic acid (34 patients) or without (54 patients) previous chemotherapy were included in this trial.Results: In the group of previously treated patients, therapy led to 6% (2 of 34 patients) remissions while stable disease could be observed in 68% (23 of 34 patients) of the patients. The median survival time was 14 months. The main toxicity was mucositis grade 3 in 15% of the previously treated patients and 10% in the nonpretreated patients. In the population of nonpretreated patients, the overall response rate was 15% (eight of 54 patients) and stable disease could be induced in 67% (36 of 54 patients). The median survival time was 13.7 months.Conclusion: This regimen is an active second-line therapy in advanced colorectal cancer with minimal toxicity, thus preserving the quality of life during palliative chemotherapy. Antitumor activity in previously untreated patients does not seem superior to that obtained with weekly regimens applying 24- or 48-hour continuous infusions of 5-FU and folinic acid.     

Concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil (5-FU) and cisplatin for locally advanced resectable esophageal cancer

Background

Neoadjuvant concurrent chemoradiotherapy (CCRT) has become the standard treatment for esophageal cancer (EC) in North America. The cisplatin/5-flurouracil (5-FU) combination has been the most commonly used regimen. For the last 15 years we incorporated a daily continuous infusion of 5-FU and 2 doses of cisplatin into our neoadjuvant CCRT for potentially resectable EC.

Patients and methods

Between July 1997 and June 2012, 129 patients with locally advanced EC (T3 or N1 and higher), received neoadjuvant CCRT with cisplatin 75 mg/m² on day 1 and day 29 and continuous infusion of 5-FU (225 mg/m²/day) on the days of radiation.

Results

The median age of patients was 63 years, 85% had adenocarcinoma, 29, 74 and 26 patients had stage II, III and IVa disease respectively, 110 patients had N1 disease based on the American Joint Committee on Cancer (AJCC) 6^th edition, 118 patients experienced weight loss during treatment. All patients completed treatment. Treatment was well tolerated with 14% of patients having ≥ grade 3 toxicity and 18 patients requiring hospital admission. Sixty-four percent of patients had surgical resection following CCRT, with disease progression and patient refusal being the most common reasons for not proceeding with surgery. An R0 resection was achieved in 96% of patients. A pathological complete response (pCR) was achieved in 45% of patients. With a median follow up of 26 months (1.2-144 months), 48/129 patients recurred and 60/129 died of their disease.

Conclusions

Our study has its limitation, however, and compared to the conventional chemotherapy regimens containing the cisplatin/5-FU doublet, our treatment strategy for locally advanced EC CCRT seems to be feasible and well tolerated.     

Adjuvant radiotherapy and concomitant 5-fluorouracil by protracted venous infusion for resected pancreatic cancer

Purpose: To assess the toxicity and clinical benefit from adjuvant chemoradiotherapy consisting of protracted venous infusion 5-fluorouracil (5-FU) and concomitant radiotherapy in patients with resected pancreatic cancer.

Methods and Materials: Between 1994 and 1999, 52 patients who underwent pancreaticoduodenectomy received adjuvant chemoradiotherapy. The tumor bed and regional nodes received a dose of 45 Gy in fractions of 1.8 Gy followed by boost to the tumor bed if the surgical margins were involved (total dose, 54 Gy). The patients also received concomitant 5-FU by protracted venous infusion (200–250 mg/m²/day, 7 days/week) during the entire radiotherapy course.

Results: Fifty-two patients (30 men, 22 women) were enrolled and treated on this protocol. The median age was 63 years (range, 38–78 years), and the median Karnofsky Performance Status was 80 (range, 70–100). Thirty-five percent had involved surgical margins and 59% had involved lymph nodes. All patients completed therapy, and there were no Grade IV/V toxicities observed. With median follow-up of 24 months (range, 3–52 months) for surviving patients, the median survival is 32 months, and 2-year and 3-year survivals are 62%, and 39%, respectively.

Conclusion: Radiotherapy with concomitant 5-FU by protracted venous infusion as adjuvant treatment for resected pancreatic cancer is well tolerated. This approach allows for greater dose intensity with reduced toxicity. The median survival of this cohort of patients compares favorably with our earlier experience and other published series.     

Feasibility study of ambulatory continuous infusion of 5-fluorouracil followed by cisplatin through hepatic artery for metastatic colorectal cancer

Purpose: A great synergy has been reported in a number of preclinical studies when 5-fluorouracil (5-FU) precedes cisplatin (CDDP). The objective of this study was to determine the feasibility of ambulatory continuous infusion of 5-FU followed by CDDP through hepatic artery for metastatic colorectal cancer. Patients and methods: Seventeen patients with unresectable liver metastases, who underwent primary tumor resection, were treated with 5-FU (450 mg/m²/day) for seven consecutive days followed by CDDP (100 mg/body/week) for seven consecutive days, each administered continuously by using a balloon pump via Infuse-A-Port catheter inserted into common hepatic artery. The doses of drugs were reduced 20% in patients older than 70 years. The treatment was repeated every 4–6 weeks until disease progression. Results: Of 17 assessable patients, nine patients showed PR (53%; 95% CI, 29.3–76.7%) and eight patients had SD (47%; 95% CI, 23.3–70.7%), with disease control rate of 100%. The median overall survival was 26 months (95% CI: 17.5–41 months) and TTP 14 months (95% CI: 11–20.3 months). Two patients (11.8%), who showed progression due to collateral feeding arteries, responded to HAI again after occlusion. Grade 3 toxicity included leukopenia (12%) and anemia (24%). Grade 4 toxicity was absent. Four patients (23.5%) progressed at extrahepatic sites. Conclusions: This sequential combination of 5-FU followed by CDDP through hepatic artery is active and safe in an outpatient setting, and warrants further multi-institutional study, although prevention of micrometastasis would be mandatory to further prolong overall survival.     

Phase I study of 5-fluorouracil and leucovorin by continuous infusion chronotherapy and pelvic radiotherapy in patients with locally advanced or recurrent rectal cancer

PURPOSE: To determine the maximal tolerated dose of chronomodulated 5-fluorouracil (5-FU) and leucovorin (LV) given concurrently with radiotherapy in patients with rectal cancer. METHODS AND MATERIALS: Forty-five patients with T3, T4 or recurrent rectal cancer received concurrent radiotherapy to a minimal dose of 4500 cGy. Chemotherapy was administered by a programmable pump in chronomodulated fashion, with 62.5% of the total dose given within 7 hours around 9:30 pm. The starting doses were LV at 5 mg/m2/d and 5-FU at 150 mg/m2/d. LV was escalated in 5-mg/m2 increments to 20 mg/m2/d; 5-FU was then escalated in 25 mg/m2 increments to the maximal tolerated dose. RESULTS: Diarrhea and stomatitis were dose limiting, with Grade 3 or worse toxicity occurring in 16% and 5% of patients, respectively. Thirty-seven patients (84%) received their scheduled dose of radiotherapy (range, 4500-6000 cGy). Thirty-two patients had clinical T3 disease; all were treated with definitive surgery; 23 (71%) underwent sphincter-sparing surgery with complete resection in 28 (87%). Ten patients (31%) had no evidence of tumor in the pathologic specimen. CONCLUSION: Preoperative chemoradiotherapy in rectal cancer using chronomodulated 5-FU and LV is feasible. The recommended Phase II dose is 5-FU 200 mg/m2 and LV 20 mg/m2 daily for 5 weeks.     

Gemcitabine combined with continuous infusion 5-fluorouracil in advanced and symptomatic pancreatic cancer: a clinical benefit-oriented phase II study

Gemcitabine and 5-fluorouracil are the only two compounds with reproducible activity against advanced pancreatic cancer (APC). We have evaluated a novel combination of gemcitabine and 5-fluorouracil on the clinical benefit response (CBR) end point. Eleven consecutive patients with symptomatic APC were entered in a two-stage phase II trial. Gemcitabine was administered by intravenous (i.v.) bolus injection at the dose of 1,000 mg m(-2) on days 1, 8, 15 and 5-fluorouracil 500 mg m(-2) was given by continuous i.v. infusion on days 1-5. Treatment was repeated every 28 days. A CBR was achieved in 7/11 patients. The mean time to loss of CBR was 26.5 weeks (range 14-18, median 22). Toxicity was mild and no APC patient experienced WHO grade 3 toxicity. The gemcitabine/5-fluorouracil combination is well tolerated and produces a symptomatic relief in the majority of APC patients.     

Intermittent hepatic arterial infusion of high-dose 5FU on a weekly schedule for liver metastases from colorectal cancer

Purpose: We performed phase I and II studies to examine the usefulness of intermittent hepatic arterial infusion of high-dose 5-fluorouracid (5-FU) for patients with liver metastasis from colorectal cancer. Methods: As the phase I study, 1000, 1250 and 1500 mg/m² of 5-FU were administered over 5 h by hepatic arterial infusion on a weekly schedule to establish the recommended dose. Based on the results of the phase I study, the phase II study was performed to confirm the efficacy of the recommended dose thus obtained. Results: In the phase I study, the dose-limiting factors of this therapy were gastrointestinal and central nervous system toxicities, and the recommended dose was judged to be 1000 mg/m². In the phase II study, 1000 mg/m² of 5-FU was administered over 5 h once a week on an outpatient basis, and this therapy was repeated as long as possible. The response rate was 78% (25/32), with an overall median survival time of 25.8 months (without extrahepatic lesions 25.9 months; with extrahepatic lesions 17.3 months). Conclusions: (1) Compared with conventional continuous infusion, the advantages of this therapy were that it caused no decrease in the patient's quality of life as a result of being permanently equipped with a pump and it thus enabled more cost-effective use of the pump, (2) The phase II study on 32 patients showed that this therapy caused no serious toxicities, with a response rate of 78% and a survival time of 25.8 months, which exceeded the results with conventional continuous infusion. If the reproducibility of these results is established in further studies involving multicenter collaboration, this therapy will be able to become the standard local chemotherapy for liver metastases from colorectal cancer. (3) Important problems remaining to be solved are improvement of the technical aspects and studies of combined use with systemic chemotherapy. Furthermore, to finally determine the position of this therapy in the treatment system for liver metastasis from colorectal cancer, it is necessary to conduct comparative trials versus systemic chemotherapy, using the survival time as the end-point. Received: 13 September 1995 / Accepted: 5 March 1997     

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus ± LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m² per day and the l-LV dose being 5 mg/m² per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3–4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8–25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus ± LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin. Received: 22 September 1998 / Accepted: 5 January 1999     

A phase II study of paclitaxel combined with infusional 5-fluorouracil and low-dose leucovorin for advanced gastric cancer

Purpose The aim of this study was to investigate the efficacy and safety of the combination chemotherapy of paclitaxel, infusional 5-fluorouracil (5-FU) and leucovorin (FLT regimen) in advanced gastric cancer. The primary end point was the time to progression (TTP). Methods Patients with evaluable disease with or without measurable lesions received 175 mg/m² paclitaxel on day 1 followed by 20 mg/m² leucovorin and 24-h infusion of 5-FU 1,000 mg/m² (day 1-3) repeated every 3 weeks. Results Sixty patients were enrolled. The median TTP and overall survival duration were 13 and 60 weeks, respectively. One-year survival rate was 53.3%. Of the 50 patients with measurable lesion, the overall response rate was 31.7%. The most common grade 3–4 adverse event was neutropenia (61.7%). Conclusion The FLT regimen showed an efficacy comparable to other regimens of cisplatin or anthracycline combinations with the advantage of remarkably low non-hematological toxicity. These data about the efficacy of this regimen need confirmation in a phase III trial.     

5-Fu持续静脉注射治疗晚期胃癌近期疗效

目的　观察草酸铂加持续静脉注射 5 Fu为主联合化疗治疗晚期胃癌近期疗效。方法　选择晚期胃癌 2 1例 ,其中腺癌 15例 ,粘液腺癌 4例 ,未分化癌 2例。Karnofsky评分为 6 0分以上 ,预计生存期大于 3个月。初治 17例 ,复治 4例。采用LV/ 5 Fu2 +L OHP +E ADR ,分别行静点或静注。结果　CR2例 ,PR 7例 ,稳定 6例 ,恶化 2例。总有效率为 4 2 .9% ,无化疗相关死亡。结论　 5 Fu长时间输注可使毒性下降和药量得以增加 ,疗效提高。草酸铂有比顺铂更强的细胞毒作用和与其它化疗药的协同抗肿瘤作用 ,本组 2 1例 ,取得了CR +PR 4 2 .9% ,中位生存期 8个月的较好疗效 ,毒性发生率低且轻微。     

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer: a low cost effective regimen

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m(-2) i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m(-2) i.v. followed by 5-fluorouracil 400 mg m(-2) i.v. bolus and 600 mg m(-2) i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m(-2) i.v. bolus on day 2, every 6 weeks. Grades 3-4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1-61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials.