Hypoxia Image-Guided Radiation Therapy

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是一种使人衰弱和致命的疾病。尽管放射治疗和手术治疗取得了重大进展，但5年生存率仍不理想。为了改善治疗结果，需要更好的生物标志物和靶向治疗方法。新的生物标志物可以为患者分层提供指导，并可以通过改善患者生存和/或降低治疗相关毒性来优化治疗策略。虽然最近对HNSCC生物标志物的关注一直集中在人乳头瘤病毒（HPV）状态上，但在提高个体化治疗疗效方面的额外努力已经导致发现了许多有前途的基于表观遗传或基因组的标志物以及非侵入性功能成像。HNSCC放疗后局部失败或远处转移的一个已知原因是肿瘤缺氧。我们提出，在具有阳性HPV状态且在放疗前无缺氧或在治疗期间肿瘤缺氧快速消退（通过氟咪唑正电子发射断层扫描或18F-FMISO PET描绘）的肿瘤中，强度较低且毒性较低的方案将产生与标准70 Gy方法相同的肿瘤控制（目标1中的强度降低或非劣效性方法）。为了以安全的方式进行剂量递减，我们建议将剂量递减限制在HPV+ HNSCC的淋巴结。所有接受剂量递减至淋巴结的患者也将接受颈清扫术作为其治疗的一部分。另一方面，HPV阴性肿瘤在放疗前存在缺氧和治疗期间持续缺氧可能需要更积极的治疗（强度递增或优效性方法）。在目标2中，我们将使用定量指标确定HPV阴性队列中缺氧18F-FMISO图像结果与肿瘤治疗反应之间的关系。在目标3中，我们将进行成像-病理学研究，以详细说明18F-FMISO成像信号的演变与缺氧生物标志物表达变化之间的空间和时间相关性。获得任何给定的缺氧生物标志物的纵向分布将需要在放疗过程中对肿瘤进行重复活检，这通常没有被患者很好地接受。因此，先验使用无创18F-FMISO PET更有吸引力和实用性。目的3中18F-FMISO-生物标志物相关性的确认将为医生提供一种选择可能远距离扩散的肿瘤进行更密集或新治疗的非侵入性途径。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is a debilitating and lethal disease. Despite significant advances in radiotherapy and surgical management, the 5-year survival rates have remained suboptimal. To improve therapeutic outcomes, better biomarkers and targeted therapeutic approaches are needed. Novel biomarkers can provide guidance for patient stratification and can optimize therapeutic strategy by improving patient survival and/or decreasing treatment-related toxicities. Although the recent focus on biomarkers for HNSCC has been on the human papilloma virus (HPV) status, additional efforts in improving the efficacy of individualized therapy have lead to the discovery of a number of promising epigenetic or genomic based markers as well as non-invasive functional imaging. One known cause of locoregional failure or distant metastasis after radiotherapy for HNSCC is tumor hypoxia. We propose that in tumors with positive HPV status and no hypoxia before radiotherapy or rapid resolution of tumor hypoxia (depicted by fluoromisonidazole positron emission tomography or 18F- FMISO PET) during treatment, a less intensive and less toxic regimen will yield the same tumor control as the standard 70Gy approach (intensity reduction or non- inferiority approach in Aim 1). To perform dose de-escalation in a safe manner, we propose to limit de-escalation to the node(s) of HPV+ HNSCC. All of these patients who underwent dose de-escalation to the node(s) will also undergo neck dissection as part of their treatment. On the other hand, HPV negative tumors with the presence of hypoxia before radiotherapy and with persistent hypoxia during treatment may require more aggressive therapy (intensity escalation or superiority approach). In Aim 2, we will determine using quantitative metrics between hypoxia 18F-FMISO image findings versus tumor treatment response in a HPV negative cohort. In Aim 3, we will conduct an imaging-pathological study to detail the spatial and temporal correlation between the evolution of 18F-FMISO imaging signal and change in hypoxia biomarker expression. Obtaining longitudinal profile of any given hypoxia biomarker will require repeated biopsies of tumors during a course of radiotherapy which in general has not been received well by the patient. Therefore, a priori using noninvasive 18F-FMISO PET is more appealing and practical. Confirmation of 18F-FMISO-biomarker correlation in Aim 3 will provide physicians a noninvasive avenue in selecting tumors likely to spread distantly for more intensive or novel therapy.