Schupper Alexander J, Baron Rebecca B, Cheung William, Rodriguez Jessica, Kalkanis Steven N, Chohan Muhammad O, Andersen Bruce J, Chamoun Roukoz, Nahed Brian V, Zacharia Brad E, Kennedy Jerone, Moulding Hugh D, Zucker Lloyd, Chicoine Michael R, Olson Jeffrey J, Jensen Randy L, Sherman Jonathan H, Zhang Xiangnan, Price Gabrielle, Fowkes Mary, Germano Isabelle M, Carter Bob S, Hadjipanayis Constantinos G, Yong Raymund L
1Department of Neurological Surgery, Mount Sinai Health System, New York, New York.
2Department of Neurological Surgery, Henry Ford Medical Center, Detroit, Michigan.
J Neurosurg. 2021 Oct 8;136(6):1525-1534. doi: 10.3171/2021.5.JNS21310. Print 2022 Jun 1.
Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors' knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA-induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity.
This single-arm, multicenter, prospective study included adults aged 18-80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3-5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables.
Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume.
PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.
在高级别胶质瘤（HGG）患者中，更大范围的切除（EOR）与更长的总生存期相关。5-氨基乙酰丙酸（5-ALA）可通过在荧光引导手术（FGS）期间改善术中对增强肿瘤的可视化来提高EOR。口服给药时，5-ALA被胶质瘤细胞转化为原卟啉IX（PPIX），其在400nm蓝光下发出荧光。自2010年以来，5-ALA已在欧洲可供使用，但直到最近才获得美国食品药品监督管理局（FDA）批准作为HGG组织的术中成像剂。据作者所知，这是在美国进行的首个多中心5-ALA FGS研究，其主要目标如下：1）评估5-ALA诱导的PPIX荧光对不同中心和外科医生的HGG组织病理学的诊断准确性；2）评估5-ALA FGS的安全性，特别关注神经功能障碍。
这项单臂、多中心、前瞻性研究纳入了年龄在18 - 80岁、卡氏功能状态（KPS）评分>60且MRI诊断为疑似新发病例或复发性可切除HGG的成年人。术中，每个肿瘤取3 - 5个样本，外科医生记录其荧光状态。样本提交进行组织病理学分析。术后对患者随访6周，观察不良事件、神经学检查变化和KPS评分。对KPS下降、EOR和残余增强肿瘤体积的结果进行多变量分析，以确定预测患者和术中变量。
69例患者接受了5-ALA FGS，提供了275个肿瘤样本用于分析。PPIX荧光对HGG组织病理学的敏感性为96.5%，特异性为29.4%，阳性预测值（PPV）为95.4%，诊断准确性为92.4%。药物相关不良事件发生率为22%。因术中神经损伤导致的严重不良事件（可能由FGS引起）发生率为4.3%。有2例死亡与FGS无关。与术前KPS评分相比，术后48小时和2周时KPS评分显著降低，但术后6周时无差异。51.9%的患者实现了增强肿瘤的完全切除。术前肿瘤体积较小和术中使用MRI预测残余肿瘤体积较低。
外科医生判断，PPIX荧光对HGG具有高敏感性和PPV。就药物相关不良事件而言，5-ALA耐受性良好，并且训练有素的外科医生在HGG的FGS中应用5-ALA与任何额外的神经功能障碍无关。
