Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Lancet Gastroenterol Hepatol. 2016 Dec;1(4):283-290. doi: 10.1016/S2468-1253(16)30082-6. Epub 2016 Sep 17.
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.
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-α staining and fluorescence microscopy was done. This study is registered with the Netherlands Trial Registry, number NTR4632.
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).
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.
FP-7 Framework Programme BetaCure and SurgVision BV.
对于结直肠来源的腹膜癌，最佳的细胞减灭术联合腹腔内热灌注化疗（HIPEC）是治疗的关键。目前，外科医生依赖于视觉检查和触诊来发现肿瘤。使用分子荧光引导手术来提高肿瘤组织的检测能力，不仅有助于实现转移性病变的完全细胞减灭，还可以通过避免切除良性病变来避免过度治疗。
这是一项非随机的单中心可行性研究，纳入了计划接受细胞减灭术和 HIPEC 的结直肠腹膜转移患者。在手术前 2 天，静脉注射 4.5mg 近红外荧光示踪剂贝伐单抗-IRDye800CW。主要目的是确定使用贝伐单抗-IRDye800CW 的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，并且没有将严重不良事件归因于贝伐单抗-IRDye800CW，则认为该技术是安全的。如果贝伐单抗-IRDye800CW 能够在手术过程中检测到荧光信号，则认为该技术是可行的。次要目的是通过对新鲜手术标本进行表位成像以及对所有腹膜病变的福尔马林固定石蜡包埋（FFPE）组织进行半定量离体分析，将荧光与组织病理学相关联。此外，还进行了 VEGF-α染色和荧光显微镜检查。本研究在荷兰试验注册处注册，编号为 NTR4632。
2014 年 7 月 3 日至 2015 年 3 月 2 日期间，共有 7 名患者入组该研究。1 名患者术后 5 天发生腹部脓毒症，另 1 名患者术后 4 天因心脏停搏死亡，很可能是由于心血管血栓栓塞事件所致。然而，这两个严重的不良事件都归因于手术细胞减灭术和 HIPEC 手术。在任何患者中均未发生与贝伐单抗-IRDye800CW 相关的严重不良事件。所有患者在手术过程中均可见荧光。在 2 名患者中，分子荧光引导手术发现了最初被外科医生遗漏的额外肿瘤组织。在新鲜手术标本的表位成像中，共对 80 个区域进行了成像、标记和分析。29 个非荧光区域均被发现仅含有良性组织，而在 51 个荧光区域中的 27 个（53%）区域检测到肿瘤组织。对 79 个 FFPE 腹膜病变的离体半定量分析显示肿瘤与正常组织的比值为 6.92（标准差 2.47）。
使用近红外荧光示踪剂贝伐单抗-IRDye800CW 的分子荧光引导手术是安全可行的。该技术可能通过改善患者选择和优化细胞减灭术，为治疗结直肠腹膜转移患者提供附加价值。需要进行后续的多中心 2 期试验，以对分子荧光引导手术的诊断准确性和对临床决策的影响进行明确评估。
FP-7 框架计划 BetaCure 和 SurgVision BV。
