Kim Sun Young, Lee Ji Sung, Kang Junho, Morita Satoshi, Park Young Suk, Sakamoto Junichi, Muro Kei, Xu Rui-Hua, Kim Tae Won
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Oncologist. 2021 Jun;26(6):e954-e962. doi: 10.1002/onco.13735. Epub 2021 Mar 23.
Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer.
Out of the per-protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined after adjusting for stratification factors.
Of the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression-free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment-by-PPI-use interaction was significant for overall survival and progression-free survival.
The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression-free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs.
This study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug-drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer.
有研究表明，质子泵抑制剂（PPI）与卡培他滨联合使用与胃肠道癌症预后不良有关。我们利用AXEPT试验的数据集分析了PPI使用对卡培他滨和氟尿嘧啶的不同影响，AXEPT试验是一项III期随机试验，证明了改良的XELIRI方案（mXELIRI：卡培他滨加伊立替康）在转移性结直肠癌患者中，无论是否联合贝伐单抗，均不劣于FOLFIRI方案（亚叶酸、氟尿嘧啶和伊立替康）。
在符合方案集（n = 620）中，纳入有合并用药信息的患者（n = 482）进行这项事后分析。PPI使用定义为在研究期间20%或更长时间内同时使用卡培他滨和任何PPI。在调整分层因素后，检验治疗与PPI使用之间的相互作用。
482例患者中，49例（10.1%）使用了PPI。在使用PPI的患者中，mXELIRI组的总生存期与FOLFIRI组相比往往较差。相比之下，在未使用PPI的患者中，mXELIRI组的总生存期显著优于FOLFIRI组。同样，在使用PPI的患者中观察到mXELIRI组的无进展生存期比FOLFIRI组差的趋势，但在未使用PPI的患者中未观察到。治疗与PPI使用之间的相互作用在总生存期和无进展生存期方面具有显著性。
PPI使用与氟嘧啶类型在总生存期和无进展生存期方面存在显著相互作用，这表明对于使用PPI的转移性结直肠癌患者，氟尿嘧啶可能是比卡培他滨更有利的选择。
本研究显示质子泵抑制剂（PPI）的使用与氟嘧啶类型之间存在显著相互作用。这种相互作用主要源于PPI对氟尿嘧啶组生存结局的积极影响，而非PPI对卡培他滨组的负面影响
