Grem J L, Quinn M, Ismail A S, Takimoto C H, Lush R, Liewehr D J, Steinberg S M, Balis F M, Chen A P, Monahan B P, Harold N, Corse W, Pang J, Murphy R F, Allegra C J, Hamilton J M
National Cancer Institute-Medicine Branch, National Naval Medical Center, Bethesda, MD 20889, USA.
Cancer Chemother Pharmacol. 2001;47(2):117-25. doi: 10.1007/s002800000189.
Clinical toxicity associated with 5-fluorouracil (5-FU) is related to the area under the plasma concentration-time curve (AUC). Recently, short-term infusions of 5-FU given over 30 or 60 min have been substituted for conventional "bolus" 5-FU given over 3-5 min in randomized clinical trials, but there are only limited pharmacokinetic data for these altered infusion durations. We therefore wished to determine the pharmacokinetics and toxicity associated with 5-FU given as a 1-h intravenous (i.v.) infusion.
A group of 22 adults with advanced gastrointestinal tract cancers and no prior systemic chemotherapy for advanced disease received interferon alpha-2a (5 MU/m2 s.c., days 1-7), leucovorin (500 mg/m2 i.v. over 30 min, days 2-6) and 5-FU (370 mg/m2 i.v. over 1 h, days 2-6). The doses of 5-FU and interferon-alpha were adjusted according to individual tolerance. The pharmacokinetics and clinical toxicity were retrospectively compared with patients receiving the same regimen under the same treatment guidelines except that 5-FU was given over 5 min.
The regimen was well tolerated, and 41% of the patients tolerated 5-FU dose escalations to 425-560 mg/m2 per day. Grade 3 or worse diarrhea and fatigue ultimately occurred in 14% of the patients each. Granulocytopenia, mucositis, and diarrhea appeared to be appreciably milder in the present trial compared with our prior phase II experience in colorectal cancer. The peak 5-FU plasma levels and AUC with 370 mg/m2 5-FU given over 1 h were 7.3-fold and 2.4-fold lower than previously measured in 31 patients who received 5-FU over 5 min.
Increasing the length of 5-FU infusion to 1 h seemed to substantially reduce the clinical toxicity with this modulated 5-FU regimen, likely due to markedly lower peak 5-FU plasma levels and AUC. Changes in the duration of a short infusion of 5-FU clearly affects the clinical toxicity, but raises the concern of a potentially adverse impact on its antitumor activity. These results suggest the importance of including precise guidelines concerning the time over which 5-FU is given in clinical trials. Having a specified duration of 5-FU infusion is also important if 5-FU dose escalation is considered.
与5-氟尿嘧啶（5-FU）相关的临床毒性与血浆浓度-时间曲线下面积（AUC）有关。最近，在随机临床试验中，30或60分钟的5-FU短期输注已取代了传统的3-5分钟“推注”5-FU，但关于这些改变的输注持续时间的药代动力学数据有限。因此，我们希望确定5-FU静脉输注1小时的药代动力学和毒性。
一组22名患有晚期胃肠道癌且未接受过晚期疾病全身化疗的成年人接受了α-2a干扰素（5 MU/m²皮下注射，第1-7天）、亚叶酸钙（500 mg/m²静脉输注30分钟，第2-6天）和5-FU（370 mg/m²静脉输注1小时，第2-6天）。5-FU和α-干扰素的剂量根据个体耐受性进行调整。将药代动力学和临床毒性与在相同治疗指南下接受相同方案但5-FU输注5分钟的患者进行回顾性比较。
该方案耐受性良好，41%的患者耐受5-FU剂量增加至每天425-560 mg/m²。最终分别有14%的患者出现3级或更严重的腹泻和疲劳。与我们之前在结直肠癌的II期试验经验相比，本试验中的粒细胞减少、粘膜炎和腹泻明显较轻。5-FU剂量为370 mg/m²时，静脉输注1小时的5-FU血浆峰值水平和AUC分别比之前31名接受5-FU输注5分钟的患者低7.3倍和2.4倍。
将5-FU输注时间延长至1小时似乎可显著降低这种5-FU调整方案的临床毒性，这可能是由于5-FU血浆峰值水平和AUC明显降低所致。5-FU短时间输注持续时间的改变明显影响临床毒性，但引发了对其抗肿瘤活性潜在不利影响的担忧。这些结果表明在临床试验中纳入关于5-FU给药时间的精确指南很重要。如果考虑5-FU剂量增加，规定5-FU输注持续时间也很重要。
