Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study
Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study
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DOI：
10.1016/s2468-1253(16)30082-6
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发表时间：
2016-12-01
影响因子：
35.7
通讯作者：
van Dam, Gooitzen M.
中科院分区：
文献类型：
--
作者：
Harlaar, Niels J.;Koller, Marjory;van Dam, Gooitzen M.
研究背景：优化的肿瘤细胞减灭术联合腹腔温热化疗（HIPEC）是根治性治疗结直肠癌腹膜转移的关键。目前，外科医生依靠目视检查和触诊来检测肿瘤。使用分子荧光引导手术的肿瘤组织的改进检测，不仅可以帮助实现一个完整的cytoreduction转移性病变，但也可能防止过度治疗，避免切除良性lesions.Methods为这个非随机，单中心的可行性研究，我们招募患者结直肠腹膜转移预定cytoreduction手术和HIPEC。手术前2天，静脉内给予4.5 mg近红外荧光示踪剂贝伐珠单抗-IRDye 800 CW。主要目的是确定使用贝伐珠单抗-IRDye 800 CW进行分子荧光引导手术的安全性和可行性。如果没有记录到过敏或过敏反应，并且没有严重不良事件归因于贝伐珠单抗-IRDye 800 CW，则分子荧光引导的手术被认为是安全的。如果贝伐珠单抗-IRDye 800 CW能够在术中检测到荧光信号，则该技术被认为是可行的。次要目的是通过新鲜手术标本的后台成像和所有腹膜病变上福尔马林固定石蜡包埋（FFPE）组织的半定量离体分析，将荧光与组织病理学进行相关性。另外，进行VEGF-a染色和荧光显微镜检查。该研究在荷兰试验注册处注册，编号NTR 4632。结果在2014年7月3日至2015年3月2日期间，7名患者入组本研究。1例患者术后5天发生腹部败血症，另1例患者术后4天死于心搏停止，最可能是由于心血管血栓栓塞事件。然而，两起严重不良事件均归因于外科细胞减灭术和HIPEC手术。所有患者均未发生与贝伐珠单抗-IRDye 800 CW相关的严重不良事件。术中，所有患者均可见荧光。在两名患者中，通过分子荧光引导手术检测到了额外的肿瘤组织，这最初被外科医生错过了。在新鲜手术标本的后台成像期间，对总共80个区域进行了成像、标记和分析。发现所有29个非荧光区域仅包含良性组织，而在51个荧光区域中的27个（53%）中检测到肿瘤组织。79个FFPE腹膜病变的离体半定量显示肿瘤与正常的比率为6.92（SD 2.47）。解释使用近红外荧光示踪剂贝伐珠单抗-IRDye 800 CW的分子荧光引导手术是安全可行的。通过改善患者选择和优化细胞减灭术，该技术可能对治疗结直肠腹膜转移患者具有附加价值。需要随后的多中心2期试验来明确评估分子荧光引导手术的诊断准确性和对临床决策的影响。
Background Optimum cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is essential for the curative treatment of peritoneal carcinomatosis of colorectal origin. At present, surgeons depend on visual inspection and palpation for tumour detection. Improved detection of tumour tissue using molecular fluorescence-guided surgery could not only help attain a complete cytoreduction of metastatic lesions, but might also prevent overtreatment by avoiding resection of benign lesions.Methods For this non-randomised, single-centre feasibility study, we enrolled patients with colorectal peritoneal metastases scheduled for cytoreductive surgery and HIPEC. 2 days before surgery, 4.5 mg of the near-infrared fluorescent tracer bevacizumab-IRDye800CW was administered intravenously. The primary objectives were to determine the safety and feasibility of molecular fluorescence-guided surgery using bevacizumab-IRDye800CW. Molecular fluorescence-guided surgery was deemed safe if no allergic or anaphylactic reactions were recorded and no serious adverse events were attributed to bevacizumab-IRDye800CW. The technique was deemed feasible if bevacizumab-IRDye800CW enabled detection of fluorescence signals intraoperatively. Secondary objectives were correlation of fluorescence with histopathology by back-table imaging of the fresh surgical specimen and semi-quantitative ex-vivo analyses of formalin-fixed paraffin embedded (FFPE) tissue on all peritoneal lesions. Additionally, VEGF-a staining and fluorescence microscopy was done. This study is registered with the Netherlands Trial Registry, number NTR4632.Findings Between July 3, 2014, and March 2, 2015, seven patients were enrolled in the study. One patient developed an abdominal sepsis 5 days postoperatively and another died from an asystole 4 days postoperatively, most probably due to a cardiovascular thromboembolic event. However, both serious adverse events were attributed to the surgical cytoreductive surgery and HIPEC procedure. No serious adverse events related to bevacizumab-IRDye800CW occurred in any of the patients. Intraoperatively, fluorescence was seen in all patients. In two patients, additional tumour tissue was detected by molecular fluorescence-guided surgery that was initially missed by the surgeons. During back-table imaging of fresh surgical specimens, a total of 80 areas were imaged, marked, and analysed. All of the 29 non-fluorescent areas were found to contain only benign tissue, whereas tumour tissue was detected in 27 of 51 fluorescent areas (53%). Ex-vivo semi-quantification of 79 FFPE peritoneal lesions showed a tumour-to-normal ratio of 6.92 (SD 2.47).Interpretation Molecular fluorescence-guided surgery using the near-infrared fluorescent tracer bevacizumab-IRDye800CW is safe and feasible. This technique might be of added value for the treatment of patients with colorectal peritoneal metastases through improved patient selection and optimisation of cytoreductive surgery. A subsequent multicentre phase 2 trial is needed to make a definitive assessment of the diagnostic accuracy and the effect on clinical decision making of molecular fluorescence-guided surgery.