Stone John H, Holbrook Janet T, Marriott Matthew A, Tibbs Andrea K, Sejismundo Lourdes P, Min Y-I, Specks Ulrich, Merkel Peter A, Spiera Robert, Davis John C, St Clair E William, McCune W Joseph, Ytterberg Steven R, Allen Nancy B, Hoffman Gary S
Johns Hopkins University, Baltimore, Maryland, USA.
Arthritis Rheum. 2006 May;54(5):1608-18. doi: 10.1002/art.21869.
Etanercept is a soluble fusion protein designed to inhibit tumor necrosis factor (TNF). During the Wegener's Granulomatosis Etanercept Trial (WGET), a placebo-controlled trial of etanercept given in addition to standard therapy for remission induction and maintenance, more solid malignancies were observed in the etanercept group than in the group treated with standard therapy alone. This study was undertaken to further explore the potential association between anti-TNF therapy and the development of malignancy in these patients.
One hundred eighty patients with active WG were enrolled and followed up for a median of 27 months. At enrollment, disease characteristics, treatment history, specific medical history items, and information about previous WG treatments and risk factors for malignancy were recorded. During the trial, the occurrence of malignancies and other adverse events was recorded prospectively.
All 6 solid malignancies observed during the WGET occurred in the etanercept group (P = 0.01 versus placebo group); based on a comparison of age- and sex-specific incidence rates, 1.92 solid malignancies would have been expected in this group. The solid malignancies included 2 cases of mucinous adenocarcinoma of the colon, 1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and 1 recurrent liposarcoma. There were no differences between the 2 treatment groups in sex distribution, disease severity, personal or family history of cancer, or tobacco and alcohol use. The etanercept group was older at baseline and less likely to be newly diagnosed with WG at the time of randomization. Patients who developed solid tumors were older than patients who did not. All etanercept-treated patients who developed solid tumors were also treated with cyclophosphamide during the trial. However, there were no differences between the groups in the amount of cyclophosphamide received during the trial or the percentage who had received cyclophosphamide before enrollment. There were also no differences in the mean duration of daily cyclophosphamide therapy or the maximum daily cyclophosphamide dosage before enrollment.
Data from the WGET, the first substantial reported experience of the combined use of etanercept and cyclophosphamide in the treatment of WG, indicate that the combination of TNF inhibition and cyclophosphamide may heighten the risk of cancer beyond that observed with cyclophosphamide alone.
依那西普是一种旨在抑制肿瘤坏死因子（TNF）的可溶性融合蛋白。在韦格纳肉芽肿依那西普试验（WGET）中，这是一项在标准治疗基础上加用依那西普进行诱导缓解和维持治疗的安慰剂对照试验，观察到依那西普组出现的实体恶性肿瘤比单纯接受标准治疗的组更多。本研究旨在进一步探讨抗TNF治疗与这些患者发生恶性肿瘤之间的潜在关联。
招募了180例活动性韦格纳肉芽肿患者，中位随访27个月。在入组时，记录疾病特征、治疗史、特定病史项目以及既往韦格纳肉芽肿治疗情况和恶性肿瘤危险因素的信息。在试验期间，前瞻性记录恶性肿瘤和其他不良事件的发生情况。
WGET期间观察到的所有6例实体恶性肿瘤均发生在依那西普组（与安慰剂组相比，P = 0.01）；根据年龄和性别特异性发病率比较，该组预计会出现1.92例实体恶性肿瘤。实体恶性肿瘤包括2例结肠黏液腺癌、1例转移性胆管癌、1例肾细胞癌、1例乳腺癌和1例复发性脂肪肉瘤。两个治疗组在性别分布、疾病严重程度、个人或家族癌症史以及吸烟和饮酒情况方面没有差异。依那西普组基线时年龄较大，随机分组时新诊断为韦格纳肉芽肿的可能性较小。发生实体肿瘤的患者比未发生实体肿瘤的患者年龄更大。所有发生实体肿瘤的接受依那西普治疗的患者在试验期间也接受了环磷酰胺治疗。然而，两组在试验期间接受环磷酰胺的量或入组前接受环磷酰胺治疗的百分比方面没有差异。入组前每日环磷酰胺治疗的平均持续时间或最大每日环磷酰胺剂量也没有差异。
WGET的数据是首次报道的依那西普和环磷酰胺联合用于治疗韦格纳肉芽肿的大量经验，表明TNF抑制与环磷酰胺联合使用可能会使癌症风险高于单独使用环磷酰胺时观察到的风险。
