Vokes E E, Mick R, Kies M S, Dolan M E, Malone D, Athanasiadis I, Haraf D J, Kozloff M, Weichselbaum R R, Ratain M J
Department of Medicine, University of Chicago, IL 60637-1470, USA.
J Clin Oncol. 1996 May;14(5):1663-71. doi: 10.1200/JCO.1996.14.5.1663.
To optimize the biochemical modulation of fluorouracil (5-FU), we administered the pure I-stereoisomer of leucovorin (LV) as a 132-hour continuous intravenous infusion (CIV) with cisplatin 100 mg/m2, 5-FU 640 mg/m2/d as a 120-hour CIV, and interferon alfa-2b (IFN) at 2 MU/m2/d for 6 days for three cycles (I-PFL-IFN). Pharmacologic parameters included morning (AM) and afternoon (PM) plasma concentrations of 5-FU, LV and its active metabolite 5-methyl tetrahydrofolate (MTHF), and dihydropyrimidine dehydrogenase (DPD) activity in peripheral mononuclear cells.
Eighty-nine patients were treated (86 stage IV). Neutropenia and mucositis were the most common toxicities. Sixty-six percent achieved a complete remission (CR). There was a trend for higher PM versus AM 5-FU concentrations (median, 1.64 v 1.51 mumoles/L; P = .08), but not for LV plus MTHF (P = .66). The mean +/- SD DPD activity was 0.21 +/- 0.14 nmol/min/mg and did not correlate with plasma concentrations of 5-FU or LV plus MTHF or clinical toxicities. Higher PM 5-FU concentrations correlated with worse leukopenia (P = .04) and severity of mucositis (P = .04). PM 5-FU concentration was higher in women than in men (P = .07), with no apparent difference in severity of toxicities. The maximum 5-FU concentration was higher in CR than non-CR patients (median, 2.01 v 1.54 mumoles/L; P = .02) and higher in women than men who achieved a CR (median, 2.77 v 1.91 mumoles/L; P = .03). No correlation of CR with dose-intensity was found.
L-PFL-IFN is active in stage IV head and neck cancer. 5-FU concentration is a significant predictor of toxicity. In women, optimization of response outcome requires a higher 5-FU concentration. Individualized 5-FU dosing to obtain higher 5-FU plasma concentrations may be indicated.
为优化氟尿嘧啶（5-FU）的生化调节，我们给予亚叶酸（LV）的纯I型立体异构体进行132小时持续静脉输注（CIV），同时给予顺铂100mg/m²、5-FU 640mg/m²/天进行120小时CIV，以及干扰素α-2b（IFN）2MU/m²/天，共6天，进行三个周期（I-PFL-IFN）。药理学参数包括5-FU、LV及其活性代谢物5-甲基四氢叶酸（MTHF）的上午（AM）和下午（PM）血浆浓度，以及外周血单个核细胞中的二氢嘧啶脱氢酶（DPD）活性。
89例患者接受治疗（86例为IV期）。中性粒细胞减少和粘膜炎是最常见的毒性反应。66%的患者达到完全缓解（CR）。下午的5-FU浓度有高于上午的趋势（中位数，1.64对1.51μmol/L；P = 0.08），但LV加MTHF则无此趋势（P = 0.66）。平均±标准差的DPD活性为0.21±0.14nmol/min/mg，与5-FU或LV加MTHF的血浆浓度及临床毒性均无相关性。下午较高的5-FU浓度与更严重的白细胞减少（P = 0.04）和粘膜炎严重程度（P = 0.04）相关。女性的下午5-FU浓度高于男性（P = 0.07），毒性严重程度无明显差异。CR患者的5-FU最高浓度高于未达到CR的患者（中位数，2.01对1.54μmol/L；P = 0.02），且达到CR的女性高于男性（中位数，2.77对1.91μmol/L；P = 0.03）。未发现CR与剂量强度之间的相关性。
L-PFL-IFN对IV期头颈癌有效。5-FU浓度是毒性的重要预测指标。对于女性，优化反应结果需要更高的5-FU浓度。可能需要个体化的5-FU给药以获得更高的5-FU血浆浓度。
