Hypoxia Image-Guided Radiation Therapy

描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是一种衰弱和致命的疾病。尽管放射治疗和外科治疗取得了显著进展，但5年存活率仍未达到最佳水平。为了改善治疗结果，需要更好的生物标志物和有针对性的治疗方法。新的生物标志物可以为患者分层提供指导，并可以通过提高患者存活率和/或减少治疗相关毒性来优化治疗策略。尽管最近对HNSCC生物标志物的关注集中在人类乳头瘤病毒(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一些有前途的表观遗传学或基因组标记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。我们建议，在HPV阳性且在放疗前没有缺氧或治疗期间肿瘤缺氧迅速消失(通过氟异硝唑正电子发射断层扫描或18F-FMISO PET描绘)的肿瘤中，较低强度和较低毒性的方案将产生与标准70GY方案相同的肿瘤控制效果(目标1中的强度降低或非劣质方案)。为了以安全的方式进行剂量降级，我们建议将降级限制在HPV+HNSCC的结节(S)。所有这些接受了淋巴结剂量降级的患者(S)也将接受颈淋巴清扫术作为治疗的一部分。另一方面，HPV阴性肿瘤放疗前存在低氧，治疗期间持续低氧，可能需要更积极的治疗(强度递增或优势方法)。在目标2中，我们将使用定量指标来确定HPV阴性队列中乏氧18F-FMISO影像表现与肿瘤治疗反应之间的关系。在目标3中，我们将进行影像病理学研究，以详细说明18F-FMISO影像信号的演变与缺氧生物标记物表达变化之间的空间和时间相关性。要获得任何特定缺氧生物标志物的纵向轮廓，需要在放射治疗过程中反复进行肿瘤活组织检查，这通常并没有被患者很好地接受。因此，先验使用无创的18F-FMISO PET更具吸引力和实用性。AIM 3中18F-FMISO-生物标记物相关性的确认将为医生提供一种非侵入性途径，以选择可能远距离扩散的肿瘤进行更密集或新的治疗。

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.