Dual modulation of 5-fluorouracil using leucovorin and hydroxyurea. A phase I trial.

Oral hydroxyurea (HU) was added to a regimen of 5-fluorouracil (5-FU) plus leucovorin (LCV) administered as a continuous 24-hour infusion for 14 days. A previous report of the 5-FU plus LCV infusion established optimal dosages of 200 mg/m2/d and 5 mg/m2/d, respectively, for each agent. Oral HU was added to the regimen in total dosages of 0.5 g/d, 1.0 g/d, 1.5 g/d, or 2.0 g/d. Twenty-two patients received a total of 45 courses of treatment. Stomatitis was the dose-limiting side effect; it occurred in 3 of 14 courses with HU at 0.5 g/d (21%) and 9 of 17 courses with HU at 1.0 g/d (53%). Dosage escalation to 1.5 g/d or 2.0 g/d was possible in only 3 of 22 patients (17%). The median time to stomatitis was 10 days (range, 7 to 12 days). One response was observed in this heavily pretreated population. Phase II trials of HU plus LCV dual modulation of infusional 5-FU should use initial HU dosages of 0.5 g/d for the 14-day regimen described, with dose escalation as tolerated. Variable oral absorption presumably accounts for the small group of patients who can tolerate the higher doses of HU.     

Combined 5-fluorouracil and floxuridine administered as a 14-day infusion. A phase I study

5-Fluorouracil (5-FU) and floxuridine (FUdR) were admixed in a single solution and administered via a central venous catheter on a continuous infusion schedule for 14 days. The Phase I trial design developed for admixture combinations was employed with starting doses for 5-FU at 250 mg/m2/day and for FUdR at 0.075 mg/kg/day. Twenty patients and 28 courses were studied. Dose rate limiting toxicity was pseudoregional enteritis with or without stomatitis experienced by five of ten of the courses administered at the highest dose rates of the admixture components. The simultaneous delivery of the two agents results in a modest compromise of the cumulative dose delivered for FUdR. Previous Phase I studies of single agent 5-FU and FUdR had demonstrated that the optimal dose rates for the individual agents in a 14-day continuous 24-hour infusion schedule is 350 mg/m2/d and 0.125 mg/Kg/day, respectively. The maximum dose rate of 5-FU at 350 mg/m2/day for 14 days is not restricted even with the addition of FUdR at up to 0.1 mg/kg/day. The optimal dose rates for Phase II trails should be as follows: 5-FU, 350 mg/m2/day; and FUdR, 0.1 mg/kg/day.     

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer.

BACKGROUND: Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC. PATIENTS AND METHODS: Eligible patients with ACC were randomized in double-blind fashion to receive placebo or TMTX (110 mg/m2) intravenously (i.v.) followed 24 h later by i.v. LCV 200 mg/m2, and 5-FU 500 mg/m2 plus oral LCV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumor response, quality of life (QoL) and toxicity. RESULTS: A total of 382 eligible patients were randomized. Significant toxicities were noted more frequently with TMTX/5-FU/LCV. Diarrhea was the most common grade 3 or 4 side-effect (41% and 28% on the TMTX and placebo arms, respectively). QoL scores and response rates did not differ between treatment arms. PFS was 5.3 months and 4.4 months in the TMTX and placebo arms, respectively (P = 0.77; Wilcoxon). OS was 15.8 months and 16.8 months, respectively (P = 0.73; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LCV worsened grade 3 or 4 diarrhea. The inclusion of TMTX did not yield any significant improvements in response rate, PFS or OS.     

奥沙利铂联合5-FU/CF方案治疗晚期结肠癌的临床观察

目的:评价奥沙利铂(L-OHP)联合5-FU/CF方案治疗晚期结肠癌的临床疗效和不良反应.方法:43例晚期结肠癌患者,给予L-OHP 130mg/m2静脉滴注,持续4h,d1;CF 150mg/m2静脉滴注,持续2h,d1-d5;5-FU 500mg/m2静脉滴注,持续6h,d1-d5.每3周重复1次.结果:43例患者中,完全缓解(CR) 1例,部分缓解( PR) 11例,稳定( SD) 17例,进展( PD)11例,总有效率(CR + PR)34.9%.不良反应主要是末梢神经毒性、恶心呕吐、腹泻、骨髓抑制等,均可耐受.结论:L-OHP联合5-FU/CF方案治疗晚期结肠癌疗效好,不良反应主要是末梢神经毒性和胃肠道反应.     

Evaluation of high-dose cisplatin and 5-FU infusion as initial therapy in advanced head and neck cancer

The combination of cisplatin and 5-fluorouracil (5-FU) infusion in head and neck cancer patients produces an overall response rate of 90% for advanced disease and 70% for recurrent disease. Whether or not escalating the platinum dose in combination with other agents, as has been done with refractory ovarian and testicular patients, would improve the response rates in patients with advanced head and neck cancer has not been evaluated. We undertook a study to determine the most efficacious dose of cisplatin that could be administered with 5-FU infusion in head and neck cancer patients. Eleven patients entered the study. Initial dose of cisplatin was 40 mg/m2 (in hypertonic saline) on days 1-5 plus 5-FU 1,000 mg/m2 on days 1-5 as a continuous infusion. Subsequent cisplatin doses were adjusted for the main toxicity, which was myelosuppression. The safest tolerable dose was 30 mg/m2 for 5 days. Overall response was 90% [45% complete response (CR) (5/11) plus 45% (5/11) partial response (PR)] which is comparable to that seen with cisplatin 100 mg/m2 and 5-FU in a 120-h infusion. Although patient numbers are small, there was no appreciable difference in response rate with higher dose cisplatin and there was a significant increase in serious toxicity.     

5-FU经颞浅动脉120小时持续灌注治疗高T分期鼻咽癌的Ⅰ期临床试验

目的 研究5-FU经颞浅动脉120h持续化疗高T分期鼻咽癌的最大耐受剂量(MTD).方法 对29例病理确诊为鼻咽癌的初治高T分期(T3或T4)患者采用颞浅动脉插管化疗.化疗方案:5-FU+顺铂,观察5-FU持续120h动脉灌注化疗的不良反应以及最大的耐受剂量.5-FU的剂量分别为200、300、350、400、450、500mg/m2,120h持续动脉滴注;顺铂20mg,第1～5天动脉快速滴注;21d为1疗程,共2个疗程.结果 不良反应: 29例病人均出现口腔黏膜反应,其中Ⅰ度1例为200mg/m2组;Ⅱ度12例200mg/m2组中5例,300mg/m2组5例,350mg/m2组2例;Ⅲ度11例300mg/m2组中1例,350mg/m2组3例,400mg/m2组5例,450mg/m2组2例;Ⅳ度5例450mg/m2组中3例,500mg/m2组2例;5例出现局部疼痛,对症治疗后好转.29例病人出现的骨髓抑制、消化道反应以及肝肾功能损害均在Ⅰ度和Ⅱ度.疗后原发灶CR 2例,PR 25例,SD 2例;有效率(CR+PR)为93%.颈部淋巴结CR 1例,PR 16例,SD 0例,余12例患者颈淋巴结为阴性,有效率(CR+PR)为100%.结论 5-FU经颞浅动脉持续化疗高T分期鼻咽癌,患者耐受尚可,最大耐受剂量为350mg/m2.     

Continuous 5-fluorouracil infusion and pulse methotrexate/leucovorin for colorectal adenocarcinoma. A report of excessive toxicity

Thirteen patients with metastatic colorectal adenocarcinoma underwent treatment with continuous ambulatory 5-fluorouracil (5-FU) infusion 300 mg/m2/day and intermittent bolus methotrexate (MTX) (200 mg/m2) with calcium leucovorin (LCV) 10 mg/m2 orally every 6 h X four to eight doses given 24 h after MTX. Although MTX administration was planned every 14 days, the average time between treatments exceeded 19 days (range 14-42) because of excessive toxicity. All patients experienced toxicity at some time in their treatment course, requiring interruption of 5-FU infusion in 12 of 13 patients. Significant toxicities included stomatitis (13 of 13 patients), hand-foot syndrome (8 of 13 patients), and diarrhea (3 of 13 patients). Toxicity did not appear to be minimized by attenuation of MTX and/or 5-FU dosage or by increasing the dose and/or duration of LCV. At this dosage schedule the addition of MTX/LCV to 5-FU infusion results in excessive and unacceptable toxicity and does not appear to improve treatment results.     

Treatment of liver metastases with a combination of chemotherapy and hyperfractionated external radiation therapy

Twelve patients with liver metastases from colorectal cancer were treated with 5-FUdR hepatic artery, or 5-FU i.v. infusion therapy and hyperfractionated whole liver irradiation (2,100 rad in 14 fractions, two fractions/day over a period of 9 days). All 12 patients tolerated treatments well and no unusual toxicity was noted from this therapy. Response was assessed on completion of treatment and on follow-up examinations by physical examination, repeat liver function tests (LFTS), and CT scans. Symptomatic relief was achieved in all patients. Decreased liver size and improved LFTS were noted in 10/12 (83%) of patients. CT scans showed decrease in size of metastases. Survivals ranged from 16 to 120 weeks. Infusion therapy was given either by implanted infusion pump or continuous i.v. infusion therapy, 5-FUdR 0.3 mg/kg of body weight/day or 5-FU 1,000 mg/m2/day. Hyperfractionated external radiotherapy with concomitant 5-FUdR hepatic artery of 5-FU i.v. infusion therapy for liver metastases was well-tolerated, and both subjective and objective response and quality of survival were noted. Hyperfractionated external beam irradiation with concurrent chemotherapy can be effective in palliating patients with liver metastases.     

A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers

Fifty-two patients with advanced gastrointestinal (GI) malignancies who had not received previous chemotherapy or radiation therapy were randomized to be treated either with 24-hour infusion of weekly fluorouracil (5-FU) or the same plus N-(phosphonacetyl)-L-aspartic acid (PALA). Forty-seven patients were evaluable for the assessment of toxicity and antitumor activity. PALA was administered as an intravenous (IV) bolus over 15 minutes at a fixed dose, 250 mg/m2. The latter agent was administered 24 hours before the start of 5-FU infusion. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 3,400 mg/m2. In both arms of the randomized study, the courses were repeated every week. In both arms of the study, ataxia and myelosuppression were the dose-limiting toxic effects. At 5-FU dose of 3,400 mg/m2, one patient in each arm developed grade 3 hematologic toxicity. Other reversible side effects included grade 2 skin changes, nausea, and vomiting. During the administration of 2,600 mg/m2 of 5-FU over 24 hours, the steady state plasma 5-FU concentration was approximately 20 mumol/L. The maximum tolerated dose (MTD) for 5-FU for protracted treatment is 2,600 mg/m2 in either arm of the study. Therapeutic response was predominantly seen in the combination arm: there were two patients with complete response (CR) and 11 patients with partial response (PR) of 28 patients in the study. In the 5-FU alone arm there were four PR and 19 patients in the study.     

Combination chemotherapy with nedaplatin and 5-fluorouracil for oral squamous cell carcinomas

We used a new combination chemotherapy with nedaplatin (CDGP) and 5-fluorouracil (5-FU) in eleven fresh patients with oral squamous cell carcinomas. 5-FU was administered at a dose of 1,000 mg/body by continuous infusion for 24 hours on days 1 to 5. CDGP was administered at a dose of 80 or 100 mg/m2 by drip infusion for 120 minutes on day 5. The response rates of total (1- or 2-course) and 2-course group were 54. 5% and 83.3%, respectively. Adverse drug reactions were limited to two cases of grade 3 toxicity with anorexia. The combination chemotherapy with 5-FU and CDGP in place of cisplatin and 5-FU seemed to play an important role as neo-adjuvant chemotherapy for oral squamous cell carcinomas.     

Multicenter phase II study to evaluate a 28-day regimen of oral fluorouracil plus eniluracil in the treatment of patients with previously untreated metastatic colorectal cancer.

PURPOSE: To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: In this single-arm phase II study, patients with previously untreated metastatic colorectal cancer received oral eniluracil plus 5-FU (10:1 dose ratio), at 5-FU doses of 1.00 mg/m(2) or 1.15 mg/m(2) twice daily (every 12 hours) for 28 consecutive days repeated every 5 weeks (one cycle). Treatment continued until there was documented disease progression or unacceptable toxicity. RESULTS: Thirty and 25 patients were enrolled at a starting dose of 1.00 mg/m(2) and 1.15 mg/m(2), respectively. Fourteen (25%) of 55 patients (95% confidence interval, 15% to 39%) had a partial response, and 20 patients (36%) had stable disease. The median durations of the partial responses and stable disease were 23.9 weeks (range, 12.3 to 52.1+ weeks) and 24.1 weeks (range, 17.1 to 55.6+ weeks), respectively. The median durations of progression-free and overall survival were 22.6 weeks (range, 21.0 to 29.0 weeks) and 59 weeks (range, 4 to 84+ weeks), respectively. The response rate in the 1.15 mg/m(2)-dose group was similar to the 1.00 mg/m(2)-dose group (28% v 23%, respectively). Severe (grade 3/4) nonhematologic treatment-related toxicity included diarrhea (nine patients), nausea/vomiting (one patient each), mucositis (two patients), and anorexia (one patient). Severe hematologic toxicities were rare. At the 1.15 mg/m(2)-dose level, two patients exhibited grade 3 granulocytopenia, and two patients had grade 3 anemia. CONCLUSION: The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.     

周剂量紫杉醇联合低剂量FP方案治疗晚期食管癌46例临床观察

目的　研究周剂量紫杉醇联合低剂量氟脲嘧啶持续滴注及低剂量顺铂治疗晚期食管癌的近期疗效和毒副反应。方法　晚期食管癌 46例 ,紫杉醇 60mg/(m2 ·week) ,静滴 3小时 ,连用 3周 ;5 -FU 2 0 0mg/(m2 ·d) ,持续滴注 ,连用 2 1天 ;PDD 6mg/(m2 ·d) ,静滴 2小时 ,每周 5天连用 3周 ;以上化疗方案每 4周重复。结果　总有效率 67% ,其中CR 0例 ,PR 31例 ,化疗中主要毒性反应表现为骨髓抑制、消化道反应、脱发等 ,神经毒性、过敏反应少 ,患者耐受性好。结论　紫杉醇作为一种新型抗肿瘤药 ,周剂量使用与低剂量 5-FU持续滴注及低剂量PDD联合 ,对晚期食管癌近期效果显著 ,毒性反应小 ,值得推广     

Phase I study of 5-fluorouracil administered by protracted venous infusion, leucovorin, and pelvic radiation therapy.

BACKGROUND: This study was designed to assess the toxicity of pelvic radiation therapy, 5-fluorouracil (5-FU) administered by protracted venous infusion, and leucovorin. METHODS: Pelvic radiation therapy consisted of 50.4-54 gray (Gy) administered in 28-30 fractions. Systemic treatment consisted of leucovorin (10 mg daily) administered orally and protracted venous infusion of 5-FU. The initial daily 5-FU dose was 150 mg/m(2). Dose escalations were planned in increments of 25 mg/m(2). RESULTS: Forty eligible patients were registered, of whom 37 were evaluable for chemoradiotherapy-related toxicity. Grade 3 or 4 toxicity secondary to radiation therapy, protracted venous infusion of 5-FU, and leucovorin occurred in 2 of 17 patients at a daily 5-FU dose of 150 mg/m(2), in 5 of 10 patients at a daily 5-FU dose of 175 mg/m(2), and in 5 of 10 patients at a daily 5-FU dose of 200 mg/m(2). Diarrhea was dose-limiting in 7 of 8 patients with Grade 4 toxicity. Venous thrombosis, a treatment-related complication not directly related to chemotherapy or radiation therapy, occurred in 5 of the 40 patients entered into this study. Four thromboses occurred at the site of a central catheter. No thrombotic complications occurred in the last 7 patients, who were given warfarin orally (1 mg daily) during treatment. CONCLUSIONS: Toxicity due to radiation therapy, protracted venous infusion of 5-FU, and leucovorin when 5-FU is given daily at a dose of 150 mg/m(2) is similar to that observed in current chemoradiotherapy regimens for patients with rectal carcinoma. This regimen will be considered as a possible investigational treatment arm of a future trial of adjuvant therapy for rectal carcinoma patients.     

Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer

We added high-dose oral leucovorin to the combination of cisplatin and fluorouracil (5-FU) to assess the efficacy of this regimen in the treatment of patients with head and neck cancer. Cisplatin, 100 mg/m2, was followed by a 5-FU continuous infusion at 600 mg/m2/d for five days. Leucovorin, 50 mg/m2, was administered at the start of cisplatin and every six hours throughout the duration of the 5-FU infusion. The dose of 5-FU was escalated to 800 mg/m2 and 1,000 mg/m2 according to observed toxicity. In a second phase of the study, the dose of leucovorin was escalated to 50 mg/m2 every four hours. A total of 25 patients were registered: 23 had recurrent disease after extensive prior treatment; and two had newly diagnosed metastatic disease. The maximally tolerated dose of 5-FU was 800 mg/m2/d with leucovorin administered every six hours. Toxicities at that level included mild to moderate myelosuppression and dose-limiting mucositis in the previously irradiated field. Identical toxicities were observed when administering 800 mg/m2/d of 5-FU with leucovorin every four hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who received prior cisplatin and 5-FU as induction chemotherapy); and eight patients failed to respond. The mean peak and trough plasma leucovorin concentrations were 2.61 (+/- 1.07) mumol/L and 2.46 (+/- 0.95) mumol/L with administration of the drug every six hours, and 2.75 (+/- 2.15) mumol/L and 2.52 (+/- 1.48) mumol/L with administration every four hours. We conclude that the combination of cisplatin, 5-FU, and leucovorin has activity in the treatment of recurrent head and neck cancer. The maximally tolerated dose of 5-FU in this study was 800 mg/m2/d, with mucositis in previously irradiated sites being dose-limiting. Plasma leucovorin concentrations exceeding 1 mumol/L are achieved following oral administration of this drug.     

Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: a potential role for growth factor as mucosal protectant

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxicity. This study was conducted to determine the maximum tolerated dose (MTD) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5-FU and 5-FU delivered dose intensity were higher than previously reported with 5-FU and LV administered without GM-CSF.     

A phase I, dose-finding study of irinotecan (CPT-11) short i.v. infusion combined with fixed dose of 5-fluorouracil (5-FU) protracted i.v. infusion in adult patients with advanced solid tumours

Purpose Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours. Continuous i.v. infusion (CI) of 5-FU is significantly more active and better tolerated than bolus i.v. 5-FU. This phase I pharmacokinetic and clinical study evaluated escalating CPT-11 doses administered every 3 weeks combined with a fixed dose of 5-FU CI over 14 days to find the maximum tolerated dose (MTD) of this combined chemotherapy.Patients and methods Patients with solid tumours showing failure with previous standard treatment or for whom no established curative therapy existed received CPT-11 i.v. over 90 min (six dose levels were evaluated: 150, 175, 200, 250, 300 and 350 mg/m²) plus a fixed dose of 5-FU CI 250 mg/m² per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m². In step 2, 5-FU was administered as a true protracted infusion at the recommended dose found during step 1. In step 3, the recommended dose of CPT-11 was divided and administered in a weekly schedule for 4 weeks combined with a fixed dose of 5-FU CI 250 mg/m², and then followed by 2–5 weeks rest.Results Neutropenia and diarrhoea were the main toxicities, leading to early termination of infusion in three of six patients in level 7. Therefore, CPT-11 350 mg/m² + 5-FU 250 mg/m² CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m² due to toxicity. The weekly schedule of CPT-11 75 mg/m² + 5-FU 250 mg/m² CI was feasible with only one patient experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied.Conclusion CPT-11 300 mg/m² + 5-FU 250 mg/m² protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.     

A phase I study of thiotepa administered by short-term and protracted continuous intravenous infusion

Forty-five patients received escalating dose rates of continuous infusion thio-triethylene thiophosphoramide (TEPA) for either five (26 patients) or 28 (19 patients) days. Dose rate limiting toxicity for the 5-day infusion was myelosuppression with leukocyte and platelet nadirs on days 21 and 28, respectively. The nadir was influenced by the presence and degree of liver disease. The optimal dose rate for 5-day infusion in the absence of liver disease was 12 mg/m2/d and was reduced to 8 mg/m2/d in patients with major liver disease. Dose rate limiting toxicity for the protracted 28-day infusion was leukopenia. The optimal dose rate for the 28-day infusion was 4 mg/m2/d. Pharmacologic studies included determination of plasma steady state concentrations (CSS) of thio-TEPA and TEPA. Dose rates up to 10 mg/m2/d produced thio-TEPA and TEPA CSS below the levels of detection of available analytical methodology, except in three patients infused at dose rates of 1, 2, and 4 mg/m2/d, respectively.     

Oxaliplatin with high-dose leucovorin and infusional 5-fluorouracil in irinotecan-pretreated patients with advanced colorectal cancer (ACC)

The purpose of this study was to evaluate the efficacy and tolerance of the bimonthly administration of oxaliplatin in combination with high-dose leucovorin and infusional 5-fluorouracil (5-FU) (FOLFOX2 regimen) in patients with advanced colorectal cancer (ACC) who did not respond or whose disease progressed within 3 months after front-line treatment with CPT-11-containing regimens. Forty-one patients with ACC who did not respond or whose disease progressed after front-line treatment with CPT-11 + 5-FU/leucovorin were enrolled. Oxaliplatin was administered at the dose of 100 mg/m2 on day 1 as a 2-hour infusion simultaneously but through different lines with leucovorin (500 mg/m2 on days 1 and 2); 5-FU was given at the dose of 1,750 mg/m2/d as a 22-hour continuous intravenous infusion on days 1 and 2. The regimen was repeated every 2 weeks. In an intention-to-treat analysis, complete response was achieved in one (2.4%) and partial response in six (14.6%) patients (overall response rate: 17%; 95% CI: 5.56-28.59%); stable disease and progressive disease were observed in 15 (36.6%) and in 19 (46.31%) patients, respectively. The median duration of response and the median time to tumor progression were 6 and 8.5 months, respectively. The median overall survival was 12 months and the probability for 1-year survival was 42.9%. Grade III/IV neutropenia occurred in 17 (41%) patients and febrile neutropenia developed in one of them (2%). There was no treatment-related death. Peripheral neuropathy greater than or equal to grade II occurred in 24 (58%) patients. Other toxicities were relatively mild. The bimonthly administration of oxaliplatin in combination with high-dose leucovorin and 48-hour continuous infusion of 5-FU is a relatively active and well-tolerated regimen for patients with ACC resistant or refractory to CPT-11 + 5-FU (continuous infusion)/leucovorin.     

Phase I study of 5-fluorouracil with folinic acid combined with recombinant human granulocyte-macrophage colony-stimulating factor.

A Phase I study was conducted to determine whether the addition of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to a combined 5-fluorouracil (5-FU) and folinic acid (FA) regimen would allow an escalated starting dose of 5-FU. FA (500 mg/m2) was administered as a 2-hour infusion on days 1 through 5, with 5-FU administered as a bolus injection 1 hour after the initiation of FA. Fifteen patients were enrolled in the trial; six were entered at a dose level of 375 mg/m2 of 5-FU, six at 450 mg/m2, and three at 540 mg/m2. rhGM-CSF was administered subcutaneously on days 6 through 15. A course of therapy was repeated every 28 days. Serious toxicity was observed at 450 mg/m2, with two patients developing grade 3 mucositis and one, grade 4 mucositis. Dose-limiting toxicity occurred at 540 mg/m2, at which point three patients developed grade 4 mucositis. One patient with metastatic colon cancer who received 5-FU at 540 mg/m2 achieved a partial response. Because of this persistent mucositis, the addition of rhGM-CSF used in this schedule would not allow an increased starting dose of 5-FU.     

Increased tolerability of bimonthly 12-hour timed flat infusion 5-fluorouracil/irinotecan regimen in advanced colorectal cancer: A dose-finding study

A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.