Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m(2)/d) followed by a 5FU bolus (400 mg/m(2)/d) and 22-hour infusion (600 mg/m(2)/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P =.0003) and better response rate (50.7% v 22.3%; P =.0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P =. 12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41. 7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P =.004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.     

Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04.

PURPOSE: To compare the efficacy of leucovorin-modulated fluorouracil (FU+LV) with that of fluorouracil and levamisole (FU+LEV) or with the combination of FU+LV and levamisole (FU+LV+LEV). PATIENTS AND METHODS: Between July 1989 and December 1990, 2,151 patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the colon were entered onto National Surgical Adjuvant Breast and Bowl Project protocol C-04. Patients were randomly assigned to receive FU+LV (weekly regimen), FU + LEV, or the combination of FU+LV+LEV. The average time on study was 86 months. RESULTS: A pairwise comparison between patients treated with FU+LV or FU+LEV disclosed a prolongation in disease-free survival (DFS) in favor of the FU+LV group (65% v 60%; P =.04); there was a small prolongation in overall survival that was of borderline significance (74% v 70%; P =.07). There was no difference in the pairwise comparison between patients who received FU+LV or FU+LV+LEV for either DFS (65% v 64%; P =.67) or overall survival (74% v 73%; P =.99). There was no interaction between Dukes' stage and the effect of treatment. CONCLUSION: In patients with Dukes' B and C carcinoma of the colon, treatment with FU+LV seems to confer a small DFS advantage and a borderline prolongation in overall survival when compared with treatment with FU+LEV. The addition of LEV to FU+LV does not provide any additional benefit over and above that achieved with FU+LV. These findings support the use of adjuvant FU+LV as an acceptable therapeutic standard in patients with Dukes' B and C carcinoma of the colon.     

Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952.

PURPOSE: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. PATIENTS AND METHODS: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)-all given weekly x6 followed by a 2-week rest period. Survival was the major study end point. RESULTS: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P =.029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. CONCLUSION: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.     

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.

PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2) or dl-LV 400 mg/m(2) followed by a FU bolus 400 mg/m(2) and 46-hour infusion 2,400 to 3,000 mg/m(2) every 46 hours every 2 weeks, either with irinotecan 180 mg/m(2) or with oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULT: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P =.99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P =.64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P =.26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.     

Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: results of a phase II study.

PURPOSE: To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer. PATIENTS AND METHODS: Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m(2), oxaliplatin 130 mg/m(2) in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m(2) in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m(2), irinotecan 180 mg/m(2) in a 90-minute infusion, bolus FU 400 mg/m(2), and FU 2,400 mg/m(2) as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery). RESULTS: All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively. CONCLUSION: The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.     

Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, Fluorouracil, and leucovorin in patients with solid tumors.

PURPOSE: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. PATIENTS AND METHODS: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. RESULTS: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P =.048), but objective neurotoxicity was not seen. CONCLUSION: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.     

Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26.

PURPOSE: Paclitaxel is an active drug for the treatment of breast cancer; however, the appropriate duration of administration is unknown. We assessed and compared the response rate, event-free survival, survival, and toxicity of paclitaxel 250 mg/m(2) delivered every 3 weeks as a 3-hour or 24-hour infusion. PATIENTS AND METHODS: A total of 563 women with stage IV or IIIB breast cancer were randomized into one of two groups: 279 received 3-hour paclitaxel and 284 received 24-hour paclitaxel. Patients were stratified by age, stage of disease, and prior therapy. RESULTS: A significantly higher rate of tumor response occurred in the first four cycles of therapy in patients who received the 24-hour infusion of paclitaxel (51% v 41%, respectively; P =.025). Tumor response over all cycles was also significantly higher in the group that received 24-hour infusion (54% v 44%, respectively; P =.023). There were no significant differences in event-free survival or survival between the two arms of the study (P =.9 and.8, respectively). No treatment by stage or by age interactions were observed. During the first four cycles of therapy, at least one episode of >/= grade 3 toxicity (excluding nadir hematologic values, alopecia, and weight change) occurred in 45% of patients who received the 3-hour paclitaxel infusion and in 50% of those who received the 24-hour paclitaxel infusion. Febrile neutropenia, >/= grade 3 infection, and >/= grade 3 stomatitis were less frequent, and severe neurosensory toxicity was more frequent in those who received the 3-hour paclitaxel infusion. Ten treatment-related deaths occurred in the first four cycles. Age, stage, and prior chemotherapy did not influence the effect of treatment. CONCLUSION: When administered as a continuous 24-hour infusion, high-dose paclitaxel results in a higher tumor response rate than when administered as a 3-hour infusion but does not significantly improve event-free survival or survival. Paclitaxel as a 24-hour infusion results in increased hematologic toxicity and decreased neurosensory toxicity.     

A phase I study of a combination of allopurinol, 5-fluorouracil and leucovorin followed by hydroxyurea in patients with advanced gastrointestinal and breast cancer

Twenty patients with advanced carcinomas of the colorectum, pancreas, stomach, and breast were enrolled in a Phase I study of a sequential administration of 5-fluorouracil-leucovorin (FU-LV) combination followed by hydroxyurea (HU) with allopurinol protection (HALF regimen). As a weekly regimen for 6 weeks, followed by a rest period of 2 weeks, FU was administered intravenously (i.v.) during infusion of a 2-hour i.v. infusion of LV at a dose of 500 mg/m2. Six hours following the FU-LV combination, HU (1 gm/m2) was administered orally. Allopurinol (300 mg every 8 hours, orally) was given the day before and on the day of the administration of the FU-LV combination. The starting dose of FU was 300 mg/m2, with escalations to 900 mg/m2. Mucositis, diarrhea, and hematologic toxicities were mild and sporadic with FU doses up to 750 mg/m2 and occurred in patients who had received prior treatment with FU and/or radiotherapy. Dose-limiting neurocerebellar toxicity was observed in 2 out of 6 patients who received a FU dose of 900 mg/m2. Three additional patients experienced moderate neuromotor toxicity at this dose level. Among 17 patients evaluable for response, partial responses were seen in 3 of the 9 patients with colorectal cancer, 1 of the 3 patients each with carcinoma of breast and pancreas. Three of the 5 responses occurred in patients who had received prior treatment with FU and/or radiation therapy. An FU dose of 750 mg/m2 is recommended for a Phase II trial of the HALF regimen.     

Chemotherapy with low doses of radiation followed by definitive radiotherapy for advanced unresectable carcinoma of the head and neck

Thirty-six patients with advanced unresectable carcinoma of the head and neck were treated with a combination of three courses of chemotherapy and low doses of radiation, followed after 3 weeks by definitive irradiation. Each course was repeated every 3 weeks with the following sequence. Cisplatin (20 mg/m2) was given in a 20-minute infusion, followed by a 2-hour infusion of 5-fluorouracil (400mg/m2), on days 1,2,5, and 6. Low doses of radiation were given on days 3 and 4, followed by a 2-hour infusion of 5-fluorouracil (400 mg/m2) with a dose of 3 Gy on the target volume. For definitive irradiation, a total dose of 60 Gy was delivered in 30 fractions within 6 weeks. The complete response rate reached 30%, and the partial response rate was 30%. With a median follow-up of 11 months, median overall survival was 10 months; median survival was 21 months for patients with complete response, 9 months for patients with partial response, and 6 months for those with no response (P=.02).     

Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803.

PURPOSE: To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. PATIENTS AND METHODS: One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m(2) (2-hour infusion) followed by FU 400 mg/m(2) (bolus) and FU 600 mg/m(2) (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m(2) (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m(2) (2-hour infusion) on day 1 (arm C). RESULTS: The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. CONCLUSION: Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.     

A dose escalating study of oxaliplatin and high dose weekly leucovorin and 5-Fluorouracil in patients with advanced solid tumors

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTD) of L-OHP plus 5-FU and LV in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received escalated doses of L-OHP (starting dose 50 mg/m2) as a 2-hour IV infusion on Days 1 and 15, and LV (500 mg/m2 as a 2-hour IV infusion) followed by escalated doses of 5FU (starting dose 1,800 mg/m2) as a 22-hour continuous IV infusion on Days 1, 8, 15, 21 every 6 weeks. DLTs were evaluated in the first cycle. RESULTS: Fifty-two patients [median age: 66 years; PS (ECOG) 0-1 in 90 percent] were treated on 12 dose-levels. Five (10 percent) patients had received 2 prior chemotherapy regimens, 24 (46 percent) one, and 23 (44 percent) were chemo-na?ve. The DLT was reached at the dose of LOHP 100 mg/m2 and 5FU 2,200 mg/m2. Dose-limiting events were G3 diarrhea, G3 asthenia, G4 neutropenia, and G4 thrombocytopenia. Grade 3 diarrhea was observed in 6 (12 percent) patients and Grade 3 fatigue in 6 (12 percent). One (2 percent) patient developed Grade 4 neutropenia and another (2 percent) Grade 4 thrombocytopenia. CONCLUSION: The MTD were L-OHP 95 mg/m2 on d1 and d15 and 5FU 2,200 mg/m2/week for 4 consecutive weeks every 6 weeks.     

Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986.

PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.     

氟尿嘧啶和亚叶酸钙联合紫杉醇和奥沙利铂双周方案治疗晚期胃癌

目的：评价氟尿嘧啶和亚叶酸钙联合紫杉醇和奥沙利铂双周方案治疗晚期胃癌的有效性和安全性。方法：选择晚期胃癌患者先静脉滴注紫杉醇135mg／m^2（3h），再静脉滴注奥沙利铂85mg／m^2和亚叶酸钙400mg／m^2（2h），接着持续静脉滴注氟尿嘧啶2400mg／m^2（46h），每14d为1周期。研究的主要终点是有效率。结果：32例患者入组，总有效率是62．5％，其中4例完全缓解（CR），16例部分缓解（PR）。1年生存率为56．3％。在既往没有接受过化疗的25例患者中，有效率为68．0％。常见的Ⅲ、Ⅳ级毒副反应是中性粒细胞下降（25．0％）、疲乏（18．8％）、周围神经病变（12．5％）、口腔炎（9．4％）、恶心（6．3％）、呕吐（6．3％）。没有出现治疗相关性死亡。结论：此联合方案治疗晚期胃癌具有良好的疗效和耐受性。     

草酸铂联合氟尿嘧啶、甲酰四氢叶酸治疗晚期大肠癌临床疗效观察

目的观察应用草酸铂联合氟尿嘧啶、甲酰四氢叶酸治疗晚期大肠癌的客观疗效及不良反应。方法草酸铂联合甲酰四氢叶酸和氟尿嘧啶持续静脉滴注46小时治疗晚期大肠癌48例(L-OHP130mg/m2静注2小时,d1,CF400mg/m2静脉输注2小时,d2,再接5-FU3.0g/m2用输液泵连续静注46小时,以上治疗方案每2周重复一次,化疗第5~11天均给予升白支持),所有病人均接受3个周期以上化疗。结果PR 23例,SD 18例,PD 7例,总有效率47.9%,中位疾病无进展期6.6个月,中位生存期10.5个月,1年生存率36.8%。主要不良反应有恶心、呕吐、黏膜炎、外周神经炎等。毒性反应多为Ⅰ~Ⅱ度,病人耐受良好。结论应用草酸铂联合氟尿嘧啶、甲酰四氢叶酸治疗晚期大肠癌疗效确切,不良反应轻微,值得临床推广使用。     

Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial.

PURPOSE: In North America, no effective therapy has been available for patients with progressive metastatic colorectal cancer after front-line treatment with irinotecan, bolus fluorouracil (FU), and leucovorin (IFL). PATIENTS AND METHODS: Patients with metastatic colorectal cancer who progressed after IFL therapy were randomly assigned to bolus and infusional FU and leucovorin (LV5FU2), single-agent oxaliplatin, or the combination (FOLFOX4). This planned interim analysis evaluated objective response rate (RR), time to tumor progression (TTP), and alleviation of tumor-related symptoms (TRS) in an initial cohort of patients. RESULTS: Between November 2000 and September 2001, 463 patients from 120 sites in North America were randomly assigned to treatment. FOLFOX4 proved superior to LV5FU2 in all measures of clinical efficacy. Objective RRs determined by an independent radiology panel were 9.9% for FOLFOX4 versus 0% for LV5FU2 (Fisher's exact test, P <.0001). Median TTP was 4.6 months for FOLFOX4 versus 2.7 months for LV5FU2 (two-sided, stratified log-rank test, P <.0001). Relief of TRS occurred in 33% of patients treated with FOLFOX4 versus 12% of patients treated with LVFU2 (chi2 test, P <.001). Single-agent oxaliplatin was not superior to LV5FU2 in any measure of efficacy. Patients treated with FOLFOX4 experienced a higher incidence of clinically significant toxicities than patients treated with LV5FU2, but these toxicities were predictable and did not result in a higher rate of treatment discontinuation or 60-day mortality rate. CONCLUSION: For patients with metastatic colorectal cancer, second-line treatment with FOLFOX4 is superior to treatment with LVFU2 in terms of RR, TTP, and relief of TRS.     

Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions.

PURPOSE: The paclitaxel vehicle Cremophor EL (CrEL) profoundly influences the cellular distribution of paclitaxel in human blood in vitro by a concentration-dependent decrease of the unbound drug fraction. Because CrEL clearance increases by extending the infusion duration from 3 to 24 hours, we hypothesized that exposure to unbound paclitaxel might also be schedule-dependent. PATIENTS AND METHODS: CrEL and unbound paclitaxel pharmacokinetics were prospectively analyzed in 29 patients with advanced solid tumors treated with paclitaxel 100 mg/m(2) given as a 1-hour (n = 15) or 3-hour (n = 14) intravenous infusion. RESULTS: The systemic exposure (area under the curve [AUC]) to CrEL was significantly higher with the 1-hour as compared with the 3-hour schedule (80.2 +/- 24.2 v. 48.5 +/- 24.1 microL x h/mL; P =.002). In contrast, the AUC of unbound paclitaxel was substantially reduced after the 1-hour infusion (0.50 +/- 0.10 v. 0.62 +/- 0.12 micromol/L x h; P =.009). Similarly, clearance and volume of distribution were significantly dependent on infusion duration (P <.005). A trend was observed toward more severe hematologic toxicity with the 3-hour schedule (P =.053), consistent with increased exposure to unbound drug. CONCLUSION: Overall, these findings explain, at least in part, previous observations that short-infusion schedules of paclitaxel lack significant myelotoxicity, whereas potentially CrEL-related side effects, including peripheral neuropathy, are augmented.     

Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma.

PURPOSE: To conduct a randomized phase II trial of dose-intense gemcitabine using a standard 30-minute infusion or the fixed dose rate (FDR) infusion (10 mg/m2/min) in patients with pancreatic adenocarcinoma. PATIENTS AND METHODS: In this prospective trial, patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2 gemcitabine over 30 minutes (standard arm) or 1,500 mg/m2 gemcitabine over 150 minutes (FDR arm) on days 1, 8, and 15 of every 4-week cycle. The primary end point of this trial was time to treatment failure. Secondary end points included time to progression, median survival, safety, and pharmacokinetic studies of gemcitabine. RESULTS: Ninety-two patients were enrolled onto this study; 91% of the patients had metastatic disease. Time to treatment failure was comparable in both treatment groups; however, the median survival for all patients was 5.0 months in the standard arm and 8.0 months in the FDR arm (P =.013). For patients with metastases, the median survival was 4.9 months in the standard arm and 7.3 months in FDR arm (P =.094). The 1- and 2-year survival rates for all patients were 9% (standard arm) versus 28.8% (FDR; P =.014) and 2.2% (standard arm) versus 18.3% (FDR; P =.007), respectively. Patients in the FDR infusion arm experienced consistently more hematologic toxicity. Pharmacokinetic analyses demonstrated a two-fold increase in intracellular gemcitabine triphosphate concentration in the FDR arm (P =.046). CONCLUSION: Pharmacokinetic and clinical data in this trial supports the continued evaluation of the FDR infusion strategy with gemcitabine.     

Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer.

PURPOSE: To evaluate the toxicity and activity of infusional fluorouracil (FU), folinic acid (FA), and oxaliplatin, administered every 2 weeks in patients with metastatic gastric cancer. PATIENTS AND METHODS: Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed. RESULTS: All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths. CONCLUSION: Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.     

A phase I and pharmacokinetic study of docetaxel administered in combination with continuous intravenous infusion of 5-fluorouracil in patients with advanced solid tumors.

Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5FU), we conducted a Phase I study of docetaxel in combination with continuous i.v. infusion of 5FU in patients with advanced solid tumors to determine the maximum tolerated dose, the recommended dose for Phase II studies, and the safety and pharmacokinetic profiles of this combination. Forty-two patients with advanced solid tumors, most of whom had been previously treated, received docetaxel on day 1 as a 1-h i.v. infusion, immediately followed by a 5-day continuous i.v. infusion of 5FU, every 3 weeks without hematopoietic growth factor support. All patients were premedicated with methylprednisolone. Dose levels of docetaxel/SFU studied were (daily dose, in mg/m2) 60/300, 75/300, 75/500, 75/750, 85/750, 85/1000, and 75/1000. Forty-one patients were assessable for toxicity. The maximum tolerated dose determined during the first cycle was 1000 mg/m2/day for 5 days of 5FU with either 75 or 85 mg/m2 docetaxel. Dose-limiting toxicities at these dose levels were reversible secretory diarrhea (4 of 12 evaluable patients), stomatitis (2 patients), and febrile neutropenia (2 patients). Overall, grade 3/4 neutropenia and febrile neutropenia were seen in 63.4% and 9.8% of the patients, respectively. Four patients experienced grade 3/4 infection, which led to toxic death in one of them. There were five early deaths: (a) one was clearly treatment related; (b) two others were possibly treatment related or remotely treatment related; and (c) two deaths were not related to the study drugs. Partial responses were documented in 5 of 39 evaluable patients. Pharmacokinetic results of both drugs were consistent with those from single-agent studies. The recommended dose of this combination, which showed acceptable toxicity and antitumoral activity at various dose levels, is 85 mg/m2 docetaxel given as a 1-h i.v. infusion on day 1 immediately followed by a 5-day continuous i.v. infusion of 5FU (750 mg/m2/day). This study has been extended by adding cisplatin on day 1 of the combination of docetaxel and 5FU.     

Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group.

PURPOSE: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. PATIENTS AND METHODS: Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status < or = 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. RESULT: Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P =.017), median time to progression (TTP; 9.4 v 6.1 months; P =.003) and median survival (14.2 v 9.3 months; P =.026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P =.005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P =.089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P =.006), thrombocytopenia (5.7% v 0.9%; P =.046), and neutropenic sepsis (11.6% v 3.8%; P =.001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. CONCLUSION: MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma.