MR-predictive-assay in pre-operative lung cancer therapy: response/resectability

描述(申请人提供)：肺癌的手术可切除性仍然是影响存活率的关键因素，但大约50%的患者由于纵隔疾病而出现不能切除的III期疾病。通过5周的术前新辅助化疗/放疗(PNT)来减少纵隔疾病，67-85%的III期肺癌有资格接受手术切除，报告称5年生存率提高了33%。手术切除的决定取决于纵隔病变对PNT反应良好的CT证据。然而，在符合手术切除条件的患者中，有10%-20%的患者后来发现术中无法切除，结果是灾难性的。能否识别出那些CT判断为PNT反应良好但手术切除失败的患者，对治疗策略和结果具有深远的影响。 这项基于影像的结果研究是为了验证这样一种假设，即治疗过程中肿瘤的血流状态(由动态对比增强(DCE)MR反映)会影响接受PNT治疗的III期肺癌的可切除性。这项转化研究应用了一种新的方法来监测PNT的体内反应，方法是：(1)直接评估在治疗过程中对肿瘤的化疗或氧气(缺氧)输送的效率，这两个因素分别对化疗或放射治疗的有效性产生至关重要的影响；(2)间接评估肿瘤缩小率，以反映肿瘤对正在进行的治疗的反应。 具体目标1：开发、改进和测试用于评估PNT对肺癌疗效的MR成像方案和分析方法。具体目标2：在临床人群中应用序贯MR研究和影像分析，结合CT、手术和病理结果评估PNT的反应。具体目标3：确定MR预测分析的附加预测价值和最佳时机。 完成后，PNT治疗的III期肺癌基于MR的早期预测分析将在临床环境中与有限的患者一起开发、测试和改进，并将根据CT、手术和病理结果对MR参数的附加预测价值进行初步评估。我们将进一步辨别PNT的有利和不利应答者之间的差异，并通过以下方法改进基于成像的预测算法：(1)多光谱逐像素分析和聚类分析，通过表征异质肿块中可能代表导致治疗失败的低灌注区的低DCE象素；以及(2)多时相成像分析(序贯磁共振研究)，通过确定最佳反应评估时间来进行。项目描述 通过这项研究，即使肺癌存活率有轻微(例如10%)的改善，也可能导致美国每年挽救或延长数千人的生命，我们相信，考虑到肺癌的高发病率和死亡率，这项拟议的研究的总体影响可能是巨大的。

DESCRIPTION (provided by applicant): Surgical resectability of lung cancer remains a critical factor influencing survival, but approximately 50% of patients present with unresectable stage III disease due to mediastinal disease. With 5 weeks of preoperative neoadjuvant chemo/radiotherapy (PNT) to reduce the mediastinal disease, 67- 85% of Stage III lung cancers become eligible for surgical resection with reported 33% improvement in 5-year survival. The decision for surgical resection depends upon CT evidence of mediastinal disease responding favorably to PNT. However, 10-20% of the patients becoming eligible for surgical resection are later found unresectable intraoperatively with devastating outcome. The ability to identify those patients who may show excellent PNT response as judged by CT but fail in surgical resection can have profound impact to the treatment strategy and outcome. This imaging-based outcome research is to test the hypothesis that tumor perfusion status during treatment, reflected by the dynamic contrast enhanced (DCE) MR, influences the resectability of stage III lung cancer treated with PNT. This translational research applies a novel approach to in vivo monitoring of PNT response by assessing (1) directly the efficiency in delivery of chemotherapy or oxygen (hypoxia) to the tumor during treatment that critically influence the effectiveness of chemo- or radiation therapy respectively, and (2), indirectly the tumor shrinkage rate that reflects the response of the tumor to the ongoing treatment. Specific Aim 1: To develop, refine, and test MR imaging protocol and analysis methodologies for assessing response of PNT in lung cancer. Specific Aim 2: To apply sequential MR studies and imaging analysis in a clinical population during the course of PNT and assess PNT response with CT, surgical and pathological findings. Specific Aim 3: To determine the added predictive value and best timing of the MR predictive assay. On completion, a MR based early predictive assay for stage III lung cancer treated with PNT will be developed, tested and refined with limited patients in a clinical setting, and the preliminary assessment of the added predictive value of MR parameters will be made by the CT, surgical and pathological findings. We will further discern the differences between favorable and unfavorable responders to PNT and refine the imaging-based predictive algorithm with (1) multi-spectral pixel-by-pixel analysis and cluster analysis by characterizing those low-DCE pixels within a heterogeneous tumor mass which likely represent poorly-perfused tumor regions contributing to treatment failure; and with (2) multi-temporal imaging analysis (sequential MR studies) by identifying the best timing for response assessment.Project Narrative Even a modest (e.g., 10%) improvement in lung cancer survival rates through this study may result in thousands of lives saved or prolonged every year in the U.S and we believe even with marginal improvement, the overall impact of this proposed study can be enormous considering the high incidence and mortality of lung cancer.