A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas
A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas
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DOI：
10.3171/2015.5.jns1577
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发表时间：
2016-05-01
影响因子：
4.1
通讯作者：
Berger, Mitchel S.
中科院分区：
文献类型：
--
作者：
Lau, Darryl;Hervey-Jumper, Shawn L.;Berger, Mitchel S.
目的有证据表明5-氨基乙酰丙酸（ALA）有助于高级别胶质瘤患者更大程度的切除，并提高6个月无进展生存率。但是仍然缺乏研究来检查ALA荧光的强度是否与肿瘤细胞结构相关。因此，第二阶段的临床试验进行检查ALA荧光强度与肿瘤cellularity.METHODS程度的相关性的单中心，前瞻性，单臂，开放标签的第二阶段临床试验ALA荧光引导切除高级别胶质瘤（III级和IV级）举行了43个月的时间（2010年8月至2014年2月）。ALA以20 mg/kg体重的剂量给药。从切除腔收集术中活检。由外科医生根据ALA荧光强度，并由神经病理学家独立根据肿瘤细胞构成，对活检进行4分制（0至3）分级。主要研究结果是ALA荧光强度与肿瘤细胞结构的相关性。关注的次要结局是ALA不良事件。敏感性，特异性，阳性预测值（PPV），阴性预测值（NPVs），和斯皮尔曼相关系数进行了计算。平均年龄为53.3岁，59.5%为男性。大多数活检是胶质母细胞瘤（GBM）（79.7%）。略多于一半（52.5%）的肿瘤复发。ALA强度3与97.4%（PPV）的肿瘤存在相关。然而，ALA荧光的缺失（强度0）与肿瘤的缺失仅在37.7%（NPV）的时间相关。对于所有肿瘤类型，GBM、III级胶质瘤和复发性肿瘤，ALA强度3与细胞性3级强相关;斯皮尔曼相关系数（r）分别为0.65、0.66、0.65和0.62。ALA强度3与细胞结构3级相关的特异性和PPV范围分别为95%-100%和86%-100%。在无肿瘤的活检（细胞性0级）中，35.4%仍显示ALA荧光。在这些活检中，90.9%含有异常脑组织，其特征在于反应性星形胶质细胞，分散的非典型细胞或炎症，8.1%具有正常脑。在非荧光（ALA强度0）活检中，62.3%有肿瘤细胞存在。ALA相关并发症的发生率为3.4%。结论：ALA荧光强度（熔岩样橙子）作为预测肿瘤存在的PPV值较高。然而，利用不存在荧光作为没有肿瘤的指标的NPV是差的。对于大多数荧光区域，ALA强度是肿瘤细胞性程度的强预测因子，但对于较低ALA强度，其预测作用较小。即使在没有肿瘤细胞的情况下，反应性变化也可能导致ALA荧光。
OBJECTIVE There is evidence that 5-aminolevulinic acid (ALA) facilitates greater extent of resection and improves 6-month progression-free survival in patients with high-grade gliomas. But there remains a paucity of studies that have examined whether the intensity of ALA fluorescence correlates with tumor cellularity. Therefore, a Phase II clinical trial was undertaken to examine the correlation of intensity of ALA fluorescence with the degree of tumor cellularity.METHODS A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated.RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients (r) were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating with cellularity Grade 3 ranged from 95% to 100% and 86% to 100%, respectively. In biopsies without tumor (cellularity Grade 0), 35.4% still demonstrated ALA fluorescence. Of those biopsies, 90.9% contained abnormal brain tissue, characterized by reactive astrocytes, scattered atypical cells, or inflammation, and 8.1% had normal brain. In nonfluorescent (ALA intensity 0) biopsies, 62.3% had tumor cells present. The ALA-associated complication rate among the study cohort was 3.4%.CONCLUSIONS The PPV of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the NPV of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence.