Hypoxia Image-Guided Radiation Therapy

缺氧影像引导放射治疗

• 批准号: 8236498
• 负责人: Nancy Y Lee
• 金额: $ 43.75万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236498
• 关键词: Acute; Adverse effects; Applications Grants; Biological Markers; Biological Markers; Biopsy; Biopsy Specimen; Clinical; Core Biopsy; Data; Development; Disease; Distant; Distant Metastasis; Dose; Early treatment; Epigenetic Process; Evolution; Failure; Functional Imaging; Genomics; Goals; Grant; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; High Dose Chemotherapy; Human Papillomavirus; Hypoxia; Image; Imagery; Individual; Intensity-Modulated Radiotherapy; Knowledge; Lead; Link; Low Dose Radiation; Malignant Neoplasms; Methods; Metric; Misonidazole; Neck; Neck Dissection; Nodal; Outcome; Outpatients; Pathologic; Patients; Phenotype; Physicians; Population; Positron-Emission Tomography; Primary Neoplasm; Probability; Prognostic Marker; Protein-Lysine 6-Oxidase; Radiation; Radiation therapy; Recording of previous events; Regimen; Reporting; Resolution; Sampling Errors; Signal Transduction; Site; Spatial Distribution; Staging; Staining method; Stains; Stratification; Surgical Management; Survival Rate; Systemic Therapy; Techniques; Testing; Therapeutic; Time; Toxic effect; Treatment Failure; Treatment outcome; Tumor Markers; Validation; aggressive therapy; base; chemotherapy; cohort; combat; experience; human study; improved; molecular marker; novel; outcome forecast; prognostic; response; therapeutic target; treatment response; tumor; uptake

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. PUBLIC HEALTH RELEVANCE: Patients with head and neck cancer receiving chemotherapy and high dose radiation therapy have experienced excellent local cure of their cancer. However, the treatment- related side effects are significant. In this grant, we propose to use image-guidance (PET scan) to select out the patients who can undergo a lower dose of radiation with chemotherapy, with the goal of decreasing side effects while maintaining tumor cure. We will also use PET scan to help determine which patients may have spread of the disease despite obtaining local cure of their cancer.

描述（由申请人提供）：头颈鳞状细胞癌（HNSCC）是一种使人衰弱且致命的疾病。尽管放射治疗和手术治疗取得了显着进步，但 5 年生存率仍然不理想。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。新型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/或减少治疗相关毒性来优化治疗策略。尽管最近对 HNSCC 生物标志物的关注重点是人乳头状瘤病毒 (HPV) 状态，但在提高个体化治疗功效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志物以及非侵入性功能成像。 HNSCC 放疗后局部区域失败或远处转移的已知原因之一是肿瘤缺氧。我们建议，对于HPV状态呈阳性且放射治疗前无缺氧或治疗期间肿瘤缺氧快速解决（通过氟米索硝唑正电子发射断层扫描或18F-FMISO PET描述）的肿瘤，较低强度和较低毒性的治疗方案将产生与标准70Gy方法相同的肿瘤控制（目标1中的强度降低或非劣效方法）。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。所有这些接受淋巴结剂量递减的患者也将接受颈清扫术作为治疗的一部分。另一方面，在放疗前存在缺氧以及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。获得任何给定缺氧生物标志物的纵向分布将需要在放射治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，先验地使用无创18F-FMISO PET更具吸引力和实用性。目标 3 中 18F-FMISO-生物标志物相关性的确认将为医生提供一种无创途径，以选择可能远处扩散的肿瘤以进行更强化或新颖的治疗。 公众健康相关性：接受化疗和高剂量放射治疗的头颈癌患者的癌症得到了良好的局部治愈。然而，与治疗相关的副作用是显着的。在这笔资助中，我们建议使用图像引导（PET 扫描）来选择可以接受较低剂量化疗的患者，目的是在维持肿瘤治愈的同时减少副作用。我们还将使用 PET 扫描来帮助确定哪些患者尽管获得了局部癌症治愈，但仍可能出现疾病扩散。