Rini Brian I, Weinberg Vivian, Dunlap Sarah, Elchinoff Alexandra, Yu Nancy, Bok Robert, Simko Jeffery, Small Eric J
Department of Hematology and Oncology, Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio 44195, USA.
Cancer. 2006 Feb 1;106(3):566-75. doi: 10.1002/cncr.21661.
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 (IFNalpha) and celecoxib, an oral COX-2 inhibitor, were given to metastatic RCC patients in a Phase II trial.
Patients with untreated, metastatic RCC received IFNalpha 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.
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.
The addition of celecoxib to IFNalpha 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 IFNalpha. Further investigation of this combination in 3+ COX-2-overexpressing RCC tumors is warranted.
环氧合酶-2（COX-2）通过多种机制在癌症发展中起主要作用。COX-2在大多数肾细胞癌（RCC）肿瘤中表达，并与分期、分级和微血管密度相关。基于潜在的相加或协同抗肿瘤作用，在一项II期试验中，将干扰素-α（IFNα）和口服COX-2抑制剂塞来昔布给予转移性RCC患者。
未经治疗的转移性RCC患者每天接受300万单位（MU）的IFNα，连续口服（p.o.）塞来昔布400 mg，每日两次，直至疾病进展或出现不可接受的毒性。预处理时，对石蜡包埋的RCC肿瘤样本进行COX-2表达的免疫组织化学染色，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，以确定预测或预后潜力。
25例接受治疗的患者中有3例部分缓解（客观缓解率为12%；95%置信区间[CI]，3%-31%）。整个队列观察到的疾病进展中位时间（TTP）为三个月。观察到最大COX-2染色与临床反应之间存在显著关联：所有出现客观反应的患者均表现为COX-2肿瘤免疫染色3+（趋势检验：P=0.03）。治疗耐受性良好，无心脏或其他明显毒性。
在IFNα中添加塞来昔布并未提高该未选择队列的客观缓解率或TTP。最大COX-2肿瘤免疫染色可能识别出更有可能通过COX-2抑制联合IFNα获得临床益处的RCC患者。有必要对这种联合治疗在COX-2过表达3+的RCC肿瘤中进行进一步研究。
