Grem J L, McAtee N, Balis F, Murphy R, Venzon D, Kramer B, Goldspiel B, Begley M, Allegra C J
National Cancer Institute-Navy Medical Oncology Branch, National Naval Medical Center, Bethesda, Maryland 20889.
Cancer. 1993 Aug 1;72(3):663-8. doi: 10.1002/1097-0142(19930801)72:3<663::aid-cncr2820720307>3.0.co;2-v.
Prolonged infusional 5-fluorouracil (5-FU) and bolus 5-FU modulated by leucovorin are associated with higher response rates than bolus 5-FU alone. Cisplatin enhances 5-FU cytotoxicity in some preclinical models.
The authors tested the feasibility of combining concurrent infusional leucovorin (500 mg/m2/d) with protracted infusional 5-FU (200 mg/m2/d) and weekly bolus cisplatin (20 mg/m2) in 22 patients with metastatic colorectal cancer.
Four partial responses (PR) were noticed among 21 evaluable patients (19%). The median time to treatment failure and median survival were 6 months and 11 months, respectively. All but two patients required 5-FU dose reduction after a median of 2 weeks because of mucositis. However, severe mucositis and diarrhea occurred in only 18% and 5% of the patients, respectively. Palmar-plantar erythrodysesthesia of mild to moderate severity occurred in 55% of patients. Megaloblastic changes were evident in the peripheral blood during therapy, and may reflect prolonged DNA-directed toxicity of 5-FU. The median tolerated dose level of 5-FU was 113 mg/m2/d (range, 64-150 mg/m2/d). Mean steady-state plasma concentrations (Cpss) of 5-FU appeared to increase linearly from 0.19 microM to 0.39 microM over the dose range 64 to 200 mg/m2/d. Patients with grade 2 gastrointestinal toxicity had significantly higher 5-FU Cpss than patients with grade 0 or 1 toxicity.
The early onset of toxicity with this regimen of protracted infusional 5-FU/high-dose leucovorin and weekly cisplatin required marked attenuation of the 5-FU dose intensity, and the results were no better than that expected with infusional 5-FU alone.
与单纯推注5-氟尿嘧啶（5-FU）相比，持续输注5-FU以及用亚叶酸调节的推注5-FU具有更高的缓解率。在一些临床前模型中，顺铂可增强5-FU的细胞毒性。
作者对22例转移性结直肠癌患者进行了试验，检测了同时输注亚叶酸（500mg/m²/天）、持续输注5-FU（200mg/m²/天）和每周推注顺铂（20mg/m²）联合治疗的可行性。
21例可评估患者中有4例出现部分缓解（PR）（19%）。治疗失败的中位时间和中位生存期分别为6个月和11个月。除2例患者外，所有患者在中位2周后因黏膜炎需要降低5-FU剂量。然而，严重黏膜炎和腹泻分别仅发生在18%和5%的患者中。55%的患者出现轻度至中度的手足红斑感觉异常。治疗期间外周血中巨幼细胞改变明显，这可能反映了5-FU对DNA的长期毒性作用。5-FU的中位耐受剂量水平为113mg/m²/天（范围为64-150mg/m²/天）。在64至200mg/m²/天的剂量范围内，5-FU的平均稳态血浆浓度（Cpss）似乎从0.19微摩尔/升线性增加至0.39微摩尔/升。2级胃肠道毒性患者的5-FU Cpss显著高于0级或1级毒性患者。
这种持续输注5-FU/高剂量亚叶酸和每周顺铂方案的毒性早期出现，需要显著降低5-FU剂量强度，且结果并不优于单纯输注5-FU的预期结果。
