Abstract：
OBJECTIVE: Only one phase III prospective randomized study, published in 2006, has assessed the performance of 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery (FGS) for glioblastoma resection. The aim of the RESECT study was to compare the onco-functional results associated with 5-ALA fluorescence and with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care.
METHODS: This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3-5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis.
RESULTS: Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94-8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%-79.6%] and 68.4% [95% CI 55.7%-78.1%]; p = 0.39) and 24-month OS (30.1% [95% CI 18.9%-42.0%] and 37.7% [95% CI 25.8%-49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36-0.86], p = 0.008) and OS (hazard ratio 0.65 [95% CI 0.42-1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€-3794.11€).
CONCLUSIONS: The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.
METHODS: This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3-5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis.
RESULTS: Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94-8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%-79.6%] and 68.4% [95% CI 55.7%-78.1%]; p = 0.39) and 24-month OS (30.1% [95% CI 18.9%-42.0%] and 37.7% [95% CI 25.8%-49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36-0.86], p = 0.008) and OS (hazard ratio 0.65 [95% CI 0.42-1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€-3794.11€).
CONCLUSIONS: The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.
摘要：
目的：只有一项III期前瞻性随机研究，发表于2006年，评估了5-氨基乙酰丙酸（5-ALA）荧光引导手术（FGS）切除胶质母细胞瘤的性能。RESECT研究的目的是比较根据当前护理标准治疗的胶质母细胞瘤患者与5-ALA荧光和白光常规显微手术相关的肿瘤功能结果。
方法：这是一项III期前瞻性随机单盲研究，涉及21个法国神经外科中心，比较5-ALAFGS与白光常规显微手术治疗的胶质母细胞瘤患者，根据当前的护理标准，包括神经导航使用和术后放化疗。按机构分层，以1：1的比例进行随机化。在切口前3-5小时口服施用5-ALA(20mg/kg)或安慰剂(抗坏血酸)。主要终点是由独立委员会盲目评估的总切除率（GTR）。未确诊胶质母细胞瘤病理诊断或术后MRI研究不可用的患者被排除在符合方案分析之外。
结果：在2013年3月至2016年8月之间，共有171名患者被分配到5-ALA荧光组（n=88）或安慰剂组（n=83）。由于不符合WHO4级神经胶质瘤的组织学标准，因此排除了24例。5-ALA荧光组(53/67,79.1%)的GTR比例显著高于安慰剂组(33/69,47.8%;p=0.0002)。调整后的年龄，术前Karnofsky表现量表评分,和肿瘤的位置，GTR仍与5-ALA荧光相关(OR4.13[95%CI1.94-8.79])。术后7天平均Karnofsky性能量表评分（49/71≥80％，69.0％[5-ALA组]；50/71，70.4％[安慰剂组]，p=0.86）和术后3个月神经系统状况恶化的患者比例（9/68，13.2％[5-ALA组]；9/70，12.9％[安慰剂组]，p=0.95）组间相似。与5-ALA摄入相关的不良事件很少见，包括4/87（4.6％）患者的光敏化和1/87（1.1％）患者的肝细胞溶解。6个月PFS（70.2%[95%CI57.7%-79.6%]和68.4%[95%CI55.7%-78.1%]；p=0.39）和24个月OS（30.1%[95%CI18.9%-42.0%]和37.7%[95%CI25.8%-49.5%]；p=0.89）无显著差异。在多变量分析中，GTR是PFS的独立预测因子(风险比0.56[95%CI0.36-0.86]，p=0.008)和OS(危险比0.65[95%CI0.42-1.01]，p=0.05)。使用5-ALAFGS会产生2732.36欧元（95％CI1658.40欧元-3794.11欧元）的显着额外成本。
结论：作者发现5-ALAFGS易于使用，成本效益高,和最耗时的技术，可以安全地优化患有胶质母细胞瘤的患者的切除范围。
方法：这是一项III期前瞻性随机单盲研究，涉及21个法国神经外科中心，比较5-ALAFGS与白光常规显微手术治疗的胶质母细胞瘤患者，根据当前的护理标准，包括神经导航使用和术后放化疗。按机构分层，以1：1的比例进行随机化。在切口前3-5小时口服施用5-ALA(20mg/kg)或安慰剂(抗坏血酸)。主要终点是由独立委员会盲目评估的总切除率（GTR）。未确诊胶质母细胞瘤病理诊断或术后MRI研究不可用的患者被排除在符合方案分析之外。
结果：在2013年3月至2016年8月之间，共有171名患者被分配到5-ALA荧光组（n=88）或安慰剂组（n=83）。由于不符合WHO4级神经胶质瘤的组织学标准，因此排除了24例。5-ALA荧光组(53/67,79.1%)的GTR比例显著高于安慰剂组(33/69,47.8%;p=0.0002)。调整后的年龄，术前Karnofsky表现量表评分,和肿瘤的位置，GTR仍与5-ALA荧光相关(OR4.13[95%CI1.94-8.79])。术后7天平均Karnofsky性能量表评分（49/71≥80％，69.0％[5-ALA组]；50/71，70.4％[安慰剂组]，p=0.86）和术后3个月神经系统状况恶化的患者比例（9/68，13.2％[5-ALA组]；9/70，12.9％[安慰剂组]，p=0.95）组间相似。与5-ALA摄入相关的不良事件很少见，包括4/87（4.6％）患者的光敏化和1/87（1.1％）患者的肝细胞溶解。6个月PFS（70.2%[95%CI57.7%-79.6%]和68.4%[95%CI55.7%-78.1%]；p=0.39）和24个月OS（30.1%[95%CI18.9%-42.0%]和37.7%[95%CI25.8%-49.5%]；p=0.89）无显著差异。在多变量分析中，GTR是PFS的独立预测因子(风险比0.56[95%CI0.36-0.86]，p=0.008)和OS(危险比0.65[95%CI0.42-1.01]，p=0.05)。使用5-ALAFGS会产生2732.36欧元（95％CI1658.40欧元-3794.11欧元）的显着额外成本。
结论：作者发现5-ALAFGS易于使用，成本效益高,和最耗时的技术，可以安全地优化患有胶质母细胞瘤的患者的切除范围。
