Yoneda Ken Y, Shelton David K, Beckett Laurel A, Gandara David R
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, UC Davis School of Medicine, Sacramento, California 95817, USA.
J Thorac Oncol. 2007 Jun;2(6):537-43. doi: 10.1097/JTO.0b013e318060d329.
A rare but serious complication of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is a lung injury syndrome commonly referred to as a drug-induced interstitial lung disease (ILD). It has a typical clinical presentation of rapidly progressive acute or subacute dyspnea and a histopathology of diffuse alveolar damage (DAD). The incidence, severity, and risk factors for EGFR TKI-induced ILD remain poorly understood. Whether concurrent chemotherapy increases its risk is also unclear. The primary focus of this blinded review was to determine the incidence of ILD leading to death in 1059 TRIBUTE patients randomized to chemotherapy plus erlotinib or placebo.
All fatal serious adverse events (SAEs) were reviewed by an independent three-person panel composed of a medical oncologist, radiologist, and pulmonologist not associated with the study and without knowledge of treatment assignment. Fatal respiratory SAEs were identified and assigned to one of four potential attributions: progressive cancer, concurrent illness, drug-induced ILD, or other toxicities not related to ILD. Each panel member first made an independent assignation; then each case was discussed jointly. If needed, consensus was reached by vote.
Fatal SAEs were reported in 80 of 1059 patients (7.6%): 53 of 526 patients on erlotinib (10.1%) and 27 of 533 on placebo (5.1%) (p < 0.05). Consensus assignation for 41 fatal respiratory SAEs was as follows: cancer, 18 (44%); concurrent illness, 15 (37%); other toxicities not related to ILD, five (12%); ILD, three (7%). All three ILD cases occurred in the erlotinib arm (3/526; 0.6%). The one biopsy-confirmed case of ILD revealed bronchiolitis obliterans organizing pneumonia, a histopathologic finding that has not previously been reported. All three cases of fatal ILD had a typical clinical presentation of acute or subacute onset of dyspnea with rapid progression to respiratory failure.
This independent blinded analysis of the TRIBUTE study identified fatal ILD in 0.6% of cases treated with the combination of erlotinib plus chemotherapy, possibly higher than previous reports of EGFR TKIs alone in the non-Japanese population. Fatal ILD alone does not fully account for the imbalance in fatal SAEs observed in TRIBUTE. EGFR TKI-induced fatal ILD typically presents with acute or subacute dyspnea with rapid progression and a typical histopathology of diffuse alveolar damage both consistent with the acute respiratory distress syndrome, but can also be associated with a histopathology of bronchiolitis obliterans organizing pneumonia. Further studies designed to better understand the underlying pathophysiology and risk factors for ILD are needed.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗中一种罕见但严重的并发症是肺部损伤综合征，通常称为药物性间质性肺疾病（ILD）。其典型临床表现为迅速进展的急性或亚急性呼吸困难，组织病理学表现为弥漫性肺泡损伤（DAD）。EGFR TKI 诱导的 ILD 的发病率、严重程度和危险因素仍知之甚少。同时进行化疗是否会增加其风险也不清楚。这项盲法评估的主要重点是确定 1059 例随机接受化疗加厄洛替尼或安慰剂治疗的TRIBUTE 患者中导致死亡的 ILD 的发生率。
所有致命严重不良事件（SAE）均由一个独立的三人小组进行评估，该小组由一名医学肿瘤学家、一名放射科医生和一名肺科医生组成，他们与该研究无关且不知道治疗分配情况。确定致命的呼吸道 SAE 并将其归为以下四种潜在原因之一：进行性癌症、并发疾病、药物性 ILD 或与 ILD 无关的其他毒性。每位小组成员首先进行独立分类；然后对每个病例进行共同讨论。如有必要，通过投票达成共识。
1059 例患者中有 80 例报告了致命 SAE（7.6%）：厄洛替尼治疗的 526 例患者中有 53 例（10.1%），安慰剂治疗的 533 例患者中有 27 例（5.1%）（p < 0.05）。对 41 例致命呼吸道 SAE 的共识分类如下：癌症，18 例（44%）；并发疾病，15 例（37%）；与 ILD 无关的其他毒性，5 例（12%）；ILD，3 例（7%）。所有 3 例 ILD 病例均发生在厄洛替尼组（3/526；0.6%）。1 例经活检证实的 ILD 病例显示为闭塞性细支气管炎伴机化性肺炎，这是一种以前未报告过的组织病理学发现。所有 3 例致命 ILD 病例均具有急性或亚急性呼吸困难起病、迅速进展至呼吸衰竭的典型临床表现。
对TRIBUTE 研究的这项独立盲法分析发现，在接受厄洛替尼加化疗联合治疗的病例中，致命 ILD 的发生率为 0.6%，这可能高于之前非日本人群中单独使用 EGFR TKIs 的报告。仅致命 ILD 并不能完全解释TRIBUTE 研究中观察到的致命 SAE 的不平衡。EGFR TKI 诱导的致命 ILD 通常表现为急性或亚急性呼吸困难且迅速进展，具有与急性呼吸窘迫综合征一致的典型弥漫性肺泡损伤组织病理学表现，但也可能与闭塞性细支气管炎伴机化性肺炎的组织病理学有关。需要进一步开展研究以更好地了解 ILD 的潜在病理生理学和危险因素。
