Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Internal Medicine, Amstelland Hospital, Amstelveen, The Netherlands.
Cancer Chemother Pharmacol. 2018 Jul;82(1):39-48. doi: 10.1007/s00280-018-3588-6. Epub 2018 Apr 25.
Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC).
Patients with AEGC were randomized to gemcitabine 1250 mg/m (i.v. days 1, 8) and cisplatin 80 mg/m (i.v. day 1) q 3 weeks with or without folic acid (450 µg/day p.o.) and vitamin B12 (1000 µg i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro.
Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 ± 1.6 (mean ± standard error of mean, SEM) µM; vs. 12.5 ± 4.0 µM; p < 0.001]. There was no significant difference in the C of gemcitabine and cisplatin in the two treatment groups.
Folic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC.
临床前研究和先前的临床观察表明，由于叶酸和维生素 B12 的补充，顺铂的毒性降低，并提示其疗效增强。在这项随机的 2 期临床试验中，我们评估了在晚期胃食管腺癌（AEGC）患者中，在一线姑息性顺铂和吉西他滨治疗中添加叶酸和维生素 B12 的效果。
AEGC 患者被随机分为吉西他滨 1250mg/m2（静脉注射，第 1、8 天）和顺铂 80mg/m2（静脉注射，第 1 天），每 3 周 1 次，同时给予叶酸（450μg/天，口服）和维生素 B12（1000μg，肌肉注射，每 9 周 1 次）或不给予。主要终点是缓解率（RR）。次要终点包括总生存期（OS）、无进展生存期（TTP）、毒性和探索性生物标志物分析。在体外高叶酸条件下培养的腺癌细胞系中，测定顺铂敏感性和细胞内铂水平。
在高叶酸培养基中培养的腺癌细胞对顺铂更敏感，这与细胞内铂水平的增加有关。在 2004 年 10 月至 2013 年 9 月进行的随机 2 期临床试验中，对 82 名随机患者中的 78 名开始治疗，每组 39 名。补充组的 RR 相似，分别为 42.1%和 32.4%；补充组和未补充组的中位 OS 和 TTP 分别为 10.0 个月和 5.9 个月；补充组和未补充组的中位 OS 和 TTP 分别为 7.7 个月和 5.4 个月（OS，p=0.9；TTP，p=0.9）。补充组的血浆同型半胱氨酸水平较低[n=20，6.9±1.6（均值±标准误差，SEM）µM；vs. 12.5±4.0µM；p<0.001]。两组中吉西他滨和顺铂的 C 无显著差异。
叶酸和维生素 B12 的补充并不能提高 AEGC 患者顺铂和吉西他滨的 RR、PFS 或 OS。
