诊断前使用阿司匹林对III期结直肠癌预后的影响。
The effect of prediagnostic aspirin use on the prognosis of stage III colorectal cancer.
作者信息
Kim Bun, Park Soo Jung, Hong Sung Pil, Cheon Jae Hee, Kim Won Ho, Kim Tae Il
机构信息
Department of Medicine, Graduate School, Yonsei University College of Medicine Seoul, Korea ; Center for Cancer Prevention and Detection, National Cancer Center Goyang, Korea.
Department of Internal Medicine, Division of Gastroenterology, Yonsei University College of Medicine Seoul, Korea.
出版信息
Int J Clin Exp Med. 2015 Aug 15;8(8):13435-45. eCollection 2015.
BACKGROUND
Many studies have suggested that the regular use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, has a protective effect and survival benefit on colorectal cancer (CRC). However, recent data suggest that CRCs have different responses to NSAIDs depending on the timing of NSAID initiation, duration of NSAID use, and molecular characteristics of the tumor. The aim of this study was to evaluate the effect of long-term prediagnostic aspirin use on the prognosis of stage III CRC.
METHODS
From 2007 to 2009, patients who were diagnosed with stage III CRC were recruited, and their medical records were retrospectively analyzed. Patients were divided into prediagnostic aspirin users (who used aspirin for more than three months continuously before CRC diagnosis) and non-users (who did not use of aspirin and NSAIDs). The two groups were compared in terms of recurrence, cancer-specific mortality, disease-free survival (DFS), and cancer-specific survival. In an experimental study, three CRC cell lines (Caco2, SW480, and DLD-1) were pretreated with aspirin (1 mM) for four days or 28 days to make aspirin-resistant cells, treated with 5-fluorouracil (5-FU; 2 µM), and apoptosis was measured with flow cytometry using Annexin-V and propidium iodide double staining.
RESULTS
Compared with the aspirin non-users (N=565), the prediagnostic aspirin users (N=121) were not different in terms of baseline characteristics including tumor characteristics, except for comorbidities and diabetes medication and statin use, which were higher in the prediagnostic aspirin users. Recurrence and cancer-specific mortality in stage III CRC were significantly higher in prediagnostic aspirin users than non-users (46.7% vs. 32.3%, P=0.003 and 32.2% vs. 19.8%, P=0.003, respectively). Survival analysis using Cox proportional hazards modeling demonstrated that DFS was significantly worse in prediagnostic aspirin users than non-users (HR, 1.525 (1.018-2.286); P=0.041). In cell line experiments, long-term aspirin pretreatment induced an increase in 5-FU-induced apoptosis in SW480 cells compared with control treatment without aspirin pretreatment. However, Caco2 cells showed a significant decrease of apoptosis in the same experiments and no change in DLD1 cells.
CONCLUSION
Prediagnostic long-term aspirin use in stage III CRC could be a negative prognostic factor depending on the characteristics of the CRC.
背景
许多研究表明，定期使用包括阿司匹林在内的非甾体抗炎药（NSAIDs）对结直肠癌（CRC）具有保护作用和生存益处。然而，最近的数据表明，根据NSAIDs开始使用的时间、使用持续时间以及肿瘤的分子特征，结直肠癌对NSAIDs有不同的反应。本研究的目的是评估诊断前长期使用阿司匹林对III期结直肠癌预后的影响。
方法
从2007年至2009年，招募被诊断为III期结直肠癌的患者，并对其病历进行回顾性分析。患者分为诊断前阿司匹林使用者（在结直肠癌诊断前连续使用阿司匹林超过三个月）和非使用者（未使用阿司匹林和NSAIDs）。比较两组在复发、癌症特异性死亡率、无病生存期（DFS）和癌症特异性生存期方面的情况。在一项实验研究中，将三种结直肠癌细胞系（Caco2、SW480和DLD-1）用阿司匹林（1 mM）预处理四天或28天以制备阿司匹林耐药细胞，用5-氟尿嘧啶（5-FU；2 µM）处理，并用膜联蛋白V和碘化丙啶双重染色通过流式细胞术测量细胞凋亡。
结果
与阿司匹林非使用者（N = 565）相比，诊断前阿司匹林使用者（N = 121）在包括肿瘤特征在内的基线特征方面没有差异，但合并症、糖尿病用药和他汀类药物使用情况除外，这些在诊断前阿司匹林使用者中更高。III期结直肠癌中，诊断前阿司匹林使用者的复发率和癌症特异性死亡率显著高于非使用者（分别为46.7%对32.3%，P = 0.003和32.2%对19.8%，P = 0.003）。使用Cox比例风险模型进行的生存分析表明，诊断前阿司匹林使用者的DFS显著差于非使用者（HR，1.525（1.018 - 2.286）；P = 0.041）。在细胞系实验中，与未用阿司匹林预处理的对照处理相比，长期阿司匹林预处理使SW480细胞中5-FU诱导的细胞凋亡增加。然而，在相同实验中Caco2细胞的细胞凋亡显著减少，DLD1细胞无变化。
结论
根据结直肠癌的特征，III期结直肠癌诊断前长期使用阿司匹林可能是一个不良预后因素。
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