Maximal COX-2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma
Maximal COX-2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma
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DOI：
10.1002/cncr.21661
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发表时间：
2006-02-01
期刊：
影响因子：
6.2
通讯作者：
Small, EJ
中科院分区：
文献类型：
--
作者：
Rini, BI;Weinberg, V;Small, EJ
背景资料。环氧合酶-2(COX-2)通过多种机制在肿瘤的发生发展中发挥重要作用。COX-2在大多数肾细胞癌(RCC)肿瘤中表达，并与分期、分级和微血管密度有关。根据潜在的相加或协同抗肿瘤作用，在11期试验中，转移性肾癌患者服用干扰素-α(干扰素-α)和口服COX-2抑制剂塞来昔布。方法：未经治疗的转移性肾癌患者每天接受IFNA 300万单位(MU)，塞来昔布400 mg(P.O.)每天连续两次，直至病情恶化或出现不可接受的毒性。治疗前采用免疫组织化学方法检测肾细胞癌石蜡包埋标本中COX-2的表达，并检测血浆碱性成纤维细胞生长因子(BFGF)和血管内皮生长因子(VEGF)水平以判断预后。结果：25例患者中有3个部分反应(客观有效率为12%，95%可信区间为3-31%)。观察到整个队列的中位疾病进展时间(TTP)为3.3个月。COX-2最大染色与临床疗效显著相关：所有经历客观反应的患者均有3+COX-2肿瘤免疫染色(趋势检验：P=0.03)。治疗耐受性良好，没有心脏或其他明显的毒性。结论：在干扰素α中加入塞来昔布并没有增加这个未选择的队列的客观应答率或TTP。最大的COX-2肿瘤免疫染色可以确定肾细胞癌患者更有可能通过联合应用COX-2抑制和干扰素α而获得临床益处。在3+COX-2过表达的肾癌中，这种联合作用的进一步研究是有必要的。
BACKGROUND. Cyclooxygenase-2 (COX-2) plays a major role in the development of cancer through numerous mechanisms. COX-2 is expressed in the majority of renal cell carcinoma (RCC) tumors and correlates with stage, grade, and microvessel density. Based on potential additive or synergistic antitumor effects, interferon-alpha (IFN alpha) and celecoxib, an oral COX-2 inhibitor, were given to metastatic RCC patients in a Phase 11 trial.METHODS. Patients with untreated, metastatic RCC received IFNa 3 million units (MU) daily and celecoxib 400 mg orally (p.o.) twice daily continuously until disease progression or unacceptable toxicity. Pretreatment, paraffin-embedded RCC tumor samples were immunohistochemically stained for COX-2 expression and plasma basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels were assayed to determine predictive or prognostic potential.RESULTS. There were three partial responses among 25 patients treated (objective response rate, 12%; 95% confidence interval [CI], 3-31%). The observed median time to disease progression (TTP) for the entire cohort was 3.3 months. A significant association between maximal COX-2 staining and clinical response was observed: all patients who experienced an objective response demonstrated 3+ COX-2 tumor immunostaining (trend test: P = 0.03). Therapy was well tolerated without cardiac or other notable toxicity.CONCLUSIONS. The addition of celecoxib to IFN alpha did not increase the objective response rate or TTP of this unselected cohort. Maximal COX-2 tumor immunostaining may identify RCC patents more likely to achieve clinical benefit with COX-2 inhibition in combination with IFN alpha. Further investigation of this combination in 3+ COX-2-overexpressing RCC tumors is warranted.