Department of Clinical Laboratory, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-Ku, Tokyo, 162-8655, Japan.
Department of Respiratory Medicine, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-Ku, Tokyo, 162-8655, Japan.
BMC Cancer. 2023 Aug 26;23(1):800. doi: 10.1186/s12885-023-11257-8.
Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy.
This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC.
The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3-4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3-4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2-4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A].
The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed.
This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.
培美曲塞是一种有效的多靶点叶酸拮抗剂，毒性可接受，可用于非鳞状非小细胞肺癌（非 Sq NSCLC）和恶性胸膜间皮瘤。维生素 B12 和叶酸作为预处理可以降低培美曲塞化疗严重毒性的频率。然而，在临床环境中不良反应很常见。在这项研究中，我们旨在确定与培美曲塞化疗毒性和疗效相关的临床因素和单核苷酸多态性（SNP）。
本观察性研究于 2012 年 10 月至 2019 年 12 月进行；我们使用多变量逻辑或 Cox 回归分析评估培美曲塞化疗的毒性和疗效。共有 106 名患者接受了培美曲塞化疗。对 4 名恶性胸膜间皮瘤患者和 67 名非 Sq NSCLC 患者进行了 SNP 分析。
63 名非 Sq NSCLC 患者（排除 4 名辅助治疗患者）的中位无进展生存期（PFS）和总生存期分别为 6.8 和 33.3 个月。经倾向评分调整的多变量 Cox 分析，PFS 的有利因素包括：预处理前叶酸水平≥9.3ng/mL、铂类联合治疗、贝伐珠单抗联合治疗、化疗前维生素 B12 水平<1136pg/mL、BHMT（742G> A）的 AA+AG 型和 DHFR（680C> A）的 AA+AC 型。有利的预后因素包括良好的体能状态、低吸烟指数、体重指数≥20.66kg/m2、预处理前叶酸水平≥5.55ng/mL、化疗前视黄醇结合蛋白水平较高，以及 MTRR（66A>G）的 AG 型。在分析了 71 名患者的 SNP 后，3-4 级血液学毒性和非血液学毒性的发生率分别为 38%和 36.6%。经倾向评分调整的多变量逻辑分析，3-4 级血液学毒性的危险因素包括：预处理前维生素 B12 水平<486pg/mL、化疗前白细胞计数<6120/µL、化疗前叶酸水平<15.8ng/mL、化疗剂量减少、MTHFR（677C>T）的 CT+TT 型。2-4 级非血液学毒性的危险因素包括：预处理前同型半胱氨酸水平≥11.8nmol/mL、化疗前转甲状腺素蛋白水平<21.5mg/dL、MTHFR（677C>T）的 CC+TT 型和 SLC19A1[IVS2（4935）G>T]的 AA+GG 型。
叶酸和蛋氨酸循环代谢物和 SNP 的信息将有助于预测培美曲塞的毒性和疗效。
该试验于 2012 年 11 月 20 日在大学医院医疗信息网络（UMIN000009366）进行了回顾性注册。
