Mackean M J, Cassidy J, Jodrell D I, Paul J, Reed N S, Canney P A, Yosef H, Habeshaw T, Robertson A G, McInnes A, Twelves C J
CRC Department of Medical Oncology, Beatson Oncology Centre, Glasgow, UK.
Br J Cancer. 1998 May;77(9):1480-6. doi: 10.1038/bjc.1998.243.
We have used a relatively new trial methodology, the group sequential design, to prospectively evaluate two dose levels of bolus/infusional 5-fluorouracil (5-FU) and folinic acid in 192 consecutive-patients with advanced colorectal carcinoma. On day 1, all patients received 200 mg m(-2) of folinic acid infusion over 2 h. Cohort A (n = 102 patients) received 500 mg m(-2) 5-FU by i.v. 15-min infusion followed by an infusion of 500 mg m(-2) 5-FU over 22 h. Treatment was repeated on day 2 and further cycles given 2-weekly. After sequential analysis excluded a response rate of over 40%, cohort B (n = 90 patients) received an increased dose of 600 mg m(-2) 5-FU bolus and infusion. Patients had received no prior 5-FU therapy and the two cohorts had similar demographic features. In 179 evaluable patients, the overall response rate was 18% (95% CI 12-24%) with CR of 6% and PR of 12%, with no difference between the two cohorts. Overall median survival was 34 weeks (95% CI 30-39) with no significant difference between cohorts (median survival 32 and 37 weeks in cohort A and B respectively; P = 0.27). On multivariate analysis, poor performance status, elevated initial WBC and alkaline phosphatase and low serum albumin were associated with reduced survival (P < 0.05), and initial raised WBC showed an association with reduced likelihood of response (P = 0.002). Overall toxicity was low with CTC grade 3 mucositis, diarrhoea, nausea or vomiting in < or = 6% of patients and no treatment-related deaths. Significant (grade 3 or above) leucopenia was more common in cohort B than in cohort A (9% and 1% respectively); there were more dose reductions, and the median administered dose intensity was lower in cohort B than in cohort A (89% and 97% respectively; P = 0.006). In this group of relatively unselected patients, we have confirmed a relatively low objective response rate and median survival of 7.8 months with this regimen. There was no significant difference in outcome between the two dose levels but the higher dose of 5-FU was associated with more dose reductions and greater toxicity.
我们采用了一种相对较新的试验方法——成组序贯设计，对192例连续性晚期结直肠癌患者前瞻性评估大剂量冲击/输注用5-氟尿嘧啶（5-FU）和亚叶酸钙的两个剂量水平。第1天，所有患者接受200mg/m²亚叶酸钙静脉输注2小时。A组（n = 102例患者）接受500mg/m² 5-FU静脉注射15分钟，随后22小时输注500mg/m² 5-FU。第2天重复治疗，此后每2周进行进一步周期治疗。序贯分析排除缓解率超过40%后，B组（n = 90例患者）接受增加剂量至600mg/m²的5-FU冲击和输注。患者此前未接受过5-FU治疗，两组的人口统计学特征相似。179例可评估患者中，总缓解率为18%（95%CI 12-24%），完全缓解率为6%，部分缓解率为12%，两组之间无差异。总中位生存期为34周（95%CI 30-39），两组之间无显著差异（A组和B组中位生存期分别为32周和37周；P = 0.27）。多因素分析显示，体能状态差、初始白细胞计数、碱性磷酸酶升高及血清白蛋白降低与生存期缩短相关（P < 0.05），初始白细胞计数升高与缓解可能性降低相关（P = 0.002）。总体毒性较低，≤6%的患者出现CTC 3级黏膜炎、腹泻、恶心或呕吐，无治疗相关死亡。显著（3级及以上）白细胞减少在B组比A组更常见（分别为9%和1%）；B组剂量减少更多，B组的中位给药剂量强度低于A组（分别为89%和97%；P = 0.006）。在这组相对未经筛选的患者中，我们证实该方案的客观缓解率相对较低，中位生存期为7.8个月。两个剂量水平的结果无显著差异，但5-FU较高剂量与更多剂量减少和更大毒性相关。
