NIR Imaging of Sentinel Nodes in Lung Cancer: Finding Micrometastases

描述（由申请人提供）：肺癌是美国癌症死亡的主要原因，每年造成超过160，000人死亡。手术切除后生存的最佳预测因素是区域淋巴结转移的存在或不存在。然而，即使是淋巴结疾病阴性（N0）的早期患者，也显示出40%的总复发率。回顾性分析表明，相当数量的早期肺癌患者在组织学检查时具有“隐匿性”转移，如乳腺癌和黑色素瘤中的前哨淋巴结（SLN），这些患者表现出较差的生存率和复发风险增加。肺癌前哨淋巴结的识别和切除将允许必要的组织学检查，以检测微转移疾病，并允许微转移疾病与肺癌复发风险的准确相关性。不幸的是，由于技术上的困难，以前的SLN定位技术在肺癌中受到严重限制，使得SLN定位基本上无法用于肺癌患者。因此，尚不清楚SLN分析是否可以改善临床结局。我们开发了一种光学成像平台，该平台利用不可见的近红外（NIR）荧光灯结合彩色视频，为外科医生提供实时术中图像引导，从而允许进行准确的SLN标测和切除。在大型动物中进行的广泛优化和成功的临床前确认导致需要进行临床可行性研究，特别是关于器械和造影剂组合的安全性和有效性。IRB已批准使用FDA批准的NIR荧光团吲哚菁绿色（ICG）进行临床试验，我们描述了一项系统计划，以评估该器械和荧光团在人肺癌手术期间的安全性和有效性。本研究的总体目标是在早期肺癌手术切除期间通过图像引导最大限度地检测肿瘤特异性SLN，未来的目标是改善目前方法每年遗漏的估计15，000例转移性淋巴结疾病的早期肺癌患者的结局。具体目标I的重点是在SLN定位过程中优化ICG注射技术、荧光团浓度和激发光通量率。具体目标2将确定近红外荧光成像是否可以改善识别和分析SLN超过目前的淋巴结切除术。特定目标3将确定NIR图像引导的SLN切除是否增强转移性疾病的检测，以及微转移性疾病的存在是否是疾病复发的预测因子。这些特定目标的完成将导致新型光学成像技术从临床前应用转化为临床应用，将确保未来利用近红外荧光在肺癌中进行的临床研究能够使用优化的成像参数安全进行，并开始评估早期肺癌患者SLN分析的治疗益处。 对新型近红外（NIR）引导在术中进行早期肺癌前哨淋巴结（SLN）清扫的可行性、安全性和有效性的临床评价有可能改变手术可切除肺癌患者的当前护理标准。近红外荧光成像代表了肺癌患者SLN识别的一个重大进展，并有望大大提高目前在美国估计每年有15，000名潜在可治愈肺癌患者的局部淋巴结中遗漏的隐匿性转移性疾病的检测。鉴于先前未检测到的微转移性疾病导致生存率显著降低和复发率增加近3倍，准确和安全地识别可能从辅助治疗中获益的早期肺癌患者亚组，在与肺癌的持续斗争中至关重要。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States, accounting for over 160,000 deaths each year. The best predictor of survival following surgical resection is the presence or absence of metastatic disease in regional lymph nodes. However, even early stage patients believed to be negative for nodal disease (N0), exhibit a 40% overall recurrence rate. Retrospective analysis has demonstrated that a significant number of early stage lung cancer patients harbor "occult" metastases when histologically scrutinized as is done for sentinel lymph nodes (SLNs) in breast cancer and melanoma, and these patients demonstrate poorer survival and an increased risk of recurrence. The identification and excision of SLNs for lung cancer would permit the histologic scrutiny necessary to detect micrometastatic disease and allow accurate correlation of micrometastatic disease with the risk of lung cancer recurrence. Unfortunately, previous SLN mapping techniques have been severely limited in lung cancer due to formidable technical difficulties, making SLN mapping essentially unavailable for patients with lung cancer. As such, it remains unknown if SLN analysis can improve clinical outcomes. We have developed an optical imaging platform that utilizes invisible near-infrared (NIR) fluorescent light combined with color video, to provide the surgeon with real-time, intraoperative image guidance that permits accurate SLN mapping and resection to be performed. Extensive optimization and successful pre-clinical validation in large animals has lead to the need for clinical feasibility studies, especially with regard to safety and efficacy of the device and contrast agent combination. IRB approval has been obtained to conduct a clinical trial with the FDA- approved NIR fluorophore indocyanine green (ICG) and we describe a systematic plan to assess safety and efficacy of the device and fluorophore during human lung cancer surgery. The overall goal of this study is to maximize the detection of tumor-specific SLN via image-guidance during operative resection of early lung cancer, with the future goal of improving outcomes for the estimated 15,000 early lung cancer patients with metastatic nodal disease missed each year by current methods. Specific Aim I is focused on optimizing ICG injection technique, fluorophore concentration and excitation light fluence rate during SLN mapping. Specific Aim 2 will determine whether NIR fluorescence imaging can improve identification and analysis of SLN over current lymphadenectomy. Specific Aim 3 will determine if NIR image-guided SLN excision enhances detection of metastatic disease and whether the presence of micrometastatic disease is a predictor of disease recurrence. Completion of these specific aims will result in translation of a novel optical imaging technology from pre-clinical to clinical use, will ensure that future clinical studies utilizing NIR fluorescence in lung cancer are conducted safely using optimized imaging parameters, and begin to assess the therapeutic benefit of SLN analysis in patients with early stage lung cancer. The clinical evaluation of the feasibility, safety and efficacy of novel near-infrared (NIR) guidance for sentinel lymph node (SLN) dissection for early lung cancer in an intraoperative setting has the potential to change the current standard-of-care for patients with surgically resectable lung cancer. NIR fluorescent imaging represents a significant advance in SLN identification for lung cancer patients and promises to substantially improve the detection of the occult metastatic disease currently missed in local lymph nodes of an estimated 15,000 patients with potentially curable lung cancer each year in the US. Given that previously undetected micrometastatic disease results in a significant decrease in survival and a nearly 3 fold increase in recurrence, accurate and safe identification of a subset of early lung cancer patients that could potentially benefit from adjuvant therapy, is of vital importance in the ongoing battle against lung cancer.