Hypoxia Image-Guided Radiation Therapy

描述（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。尽管放疗和手术治疗取得了重大进展，但5年生存率仍未达到理想水平。为了改善治疗效果，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，并可以通过提高患者生存率和/或减少治疗相关的毒性来优化治疗策略。尽管最近对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效果方面的额外努力已经导致发现了许多有前途的表观遗传或基因组标记以及非侵入性功能成像。恶性鳞状细胞癌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，在治疗期间，HPV状态阳性且放疗前无缺氧或肿瘤缺氧快速消退（氟米唑正电子发射断层扫描或18F- FMISO PET描述）的肿瘤，低强度和低毒性方案将产生与标准70Gy方法相同的肿瘤控制（Aim 1中的强度降低或非效性方法）。为了安全地进行剂量递减，我们建议将剂量递减限制在HPV+ HNSCC的淋巴结。所有接受剂量降至淋巴结的患者也将接受颈部清扫作为其治疗的一部分。另一方面，在放疗前存在缺氧和治疗期间持续缺氧的HPV阴性肿瘤可能需要更积极的治疗（强度升级或优势方法）。在目的2中，我们将在HPV阴性队列中使用定量指标确定缺氧18F-FMISO图像结果与肿瘤治疗反应之间的关系。在Aim 3中，我们将进行影像学病理研究，详细研究18F-FMISO成像信号的演变与缺氧生物标志物表达变化之间的时空相关性。获得任何给定的缺氧生物标志物的纵向剖面将需要在放射治疗过程中反复对肿瘤进行活检，这通常不被患者所接受。因此，先验地使用无创18F-FMISO PET更具吸引力和实用性。在Aim 3中确认18f - fmiso生物标志物的相关性，将为医生提供一种非侵入性途径，以选择可能远处扩散的肿瘤，进行更强化或新的治疗。

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.