Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial
Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial
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DOI：
10.1002/cncr.32950
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发表时间：
2020-06-13
期刊：
影响因子：
6.2
通讯作者：
Ben-Eliyahu, Shamgar
中科院分区：
文献类型：
--
作者：
Haider, Rita;Ricon-Becker, Itay;Ben-Eliyahu, Shamgar
背景临床前研究表明，在癌症的外科治疗过程中，儿茶酚胺和三尖杉酯碱的过量释放介导了促转移过程。在这项研究中，我们测试了结直肠癌（CRC）患者围手术期联合阻断这些途径。方法在一项涉及34例患者的随机、双盲、安慰剂对照生物标志物试验中，从术前5天开始，在围手术期给予β受体阻滞剂普萘洛尔和COX 2抑制剂依托度酸20天。对切除的肿瘤进行全基因组信使RNA谱分析和转录控制途径分析。结果治疗组和安慰剂组患者对药物耐受性良好，并发症轻微。治疗导致恶性和转移潜能的肿瘤分子标志物的显著改善（P <0.05），包括1）减少上皮-间质转化，2）减少肿瘤浸润性CD 14（+）单核细胞和CD 19（+）B细胞，和3）增加肿瘤浸润性CD 56（+）自然杀伤细胞。转录活性分析表明，药物对19种先验假设的CRC相关转录因子中的12种有有利的影响，包括加塔、STAT和EGR家族以及介导β-肾上腺素能和肾上腺素信号传导的基因调控影响的CREB家族。在这些转录活性中观察到的改变先前与改善的长期临床结果相关。评估3年复发率以进行长期安全性分析。意向治疗分析显示，治疗组复发率为12.5%（2/16），安慰剂组为33.3%（6/18）（P = 0.239），在方案依从性患者中，治疗组复发率为0%（0/11），安慰剂组为29.4%（5/17）（P = 0.054）。结论有利的生物标志物的影响和临床结果提供了一个合理的未来随机安慰剂对照试验在更大的样本，以评估围手术期普萘洛尔/依托度酸治疗对肿瘤临床结果的影响。
Background Preclinical studies have implicated excess release of catecholamines and prostaglandins in the mediation of prometastatic processes during surgical treatment of cancer. In this study, we tested the combined perioperative blockade of these pathways in patients with colorectal cancer (CRC). Methods In a randomized, double-blind, placebo-controlled biomarker trial involving 34 patients, the beta-blocker propranolol and the COX2-inhibitor etodolac were administered for 20 perioperative days, starting 5 days before surgery. Excised tumors were subjected to whole genome messenger RNA profiling and transcriptional control pathway analyses. Results Drugs were well-tolerated, with minor complications in both the treatment group and the placebo group. Treatment resulted in a significant improvement (P < .05) of tumor molecular markers of malignant and metastatic potential, including 1) reduced epithelial-to-mesenchymal transition, 2) reduced tumor infiltrating CD14(+)monocytes and CD19(+)B cells, and 3) increased tumor infiltrating CD56(+)natural killer cells. Transcriptional activity analyses indicated a favorable drug impact on 12 of 19 a priori hypothesized CRC-related transcription factors, including the GATA, STAT, and EGR families as well as the CREB family that mediates the gene regulatory impact of beta-adrenergic- and prostaglandin-signaling. Alterations observed in these transcriptional activities were previously associated with improved long-term clinical outcomes. Three-year recurrence rates were assessed for long-term safety analyses. An intent-to-treat analysis revealed that recurrence rates were 12.5% (2/16) in the treatment group and 33.3% (6/18) in the placebo group (P = .239), and in protocol-compliant patients, recurrence rates were 0% (0/11) in the treatment group and 29.4% (5/17) in the placebo group (P = .054). Conclusions The favorable biomarker impacts and clinical outcomes provide a rationale for future randomized placebo-controlled trials in larger samples to assess the effects of perioperative propranolol/etodolac treatment on oncological clinical outcomes.