Background: Prior supplementation with folic acid and vitamin B12 is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen.
Methods: Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B12 by intramuscular injection and began taking 350-500 μg of oral folic acid daily. Starting 24-48 hours after the vitamin B12 injection, the patients received intravenous 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3.
Results: Thirty patients received chemotherapy starting within 48 hours of the vitamin B12 injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%.
Conclusion: The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.
摘要
背景. 培美曲塞治疗前需要补充叶酸和维生素 B12，以降低培美曲塞毒性反应；推荐的预处理时间为至少 7 天。基于既往的药代动力学和临床研究，我们假设预处理时间可缩短至 24 小时，这样能够更早开始标准化疗；因此，我们设计了本次前瞻性研究方案。
方法. 入组患者为进展期非鳞状非小细胞肺癌，且既往未接受过细胞毒性化疗。检测同型半胱氨酸浓度后，给予患者 1 000 μg 维生素 B12 肌肉注射，并开始口服叶酸 350∼500 μg 每日 1 次。维生素 B12 肌注 24∼48 小时后，给予患者静脉注射 500 mg/m2 培美曲塞和 75 mg/m2 顺铂，共 4 周期，每 3 周一次。主要终点为中性粒细胞减少≥ 3 级的患者比例。
结果. 30 例患者在维生素 B12 肌注后 48 小时内开始化疗。未发生治疗相关的死亡或 4 级毒性反应。中性粒细胞减少≥ 3 级、其他实验室毒性反应≥ 3 级以及非实验室毒性反应≥ 3 级的患者比例分别为 6.7%、13% 和 13%。毒性反应≥ 3 级的患者基线同型半胱氨酸浓度并不高于同一队列的其他患者（均值分别为 8.6 和 10.7 μmol/L）。化疗缓解率为 43%。
结论. 缩短补充维生素疗程后，患者能够耐受化疗且仍保留抗瘤活性。基线期同型半胱氨酸浓度分析证实了短程补充维生素的有效性。The Oncologist 2014;19: 1194-1199
Keywords: Chemotherapy; Homocysteine; Non-small cell lung cancer; Pemetrexed; Vitamin supplementation.
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