Dose de-escalation of HPV-associated oropharynx cancers: Exploration of HPV mediated radiation sensitivity

HPV 相关口咽癌的剂量递减：HPV 介导的辐射敏感性的探索

基本信息

批准号：
10747663
负责人：
Nancy Y Lee
金额：
$ 24.32万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-03 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747663
关键词：
Aftercare American Joint Committee on Cancer Beds Biological Biological Markers Cancer Biology Cancer Patient Cellularity Cetuximab Cisplatin Clinical Clinical Data DNA DNA Damage Data Defect Deglutition Deglutition Disorders Diffusion Diffusion Magnetic Resonance Imaging Disease Dose Double Strand Break Repair Eligibility Determination Ensure Excision Functional disorder Gene Expression Gene Expression Profiling Genes Genomics Goals HPV oropharyngeal cancer Human Papillomavirus Hypoxia Image In complete remission Individual Inferior Left Lesion Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of anus Measures Mediating Methods Molecular Monitor Morbidity - disease rate Motion Mucositis Mutation Nature Neck Dissection Nodal Normal tissue morphology Operative Surgical Procedures Oxygen PET/CT scan Pathologic Pathway interactions Patient Selection Patients Pilot Projects Positron-Emission Tomography Postoperative Period Primary Neoplasm Process Prognosis Progression-Free Survivals Radiation Radiation Dose Unit Radiation Tolerance Radiation therapy Research Resolution Statistical Models Structure Survival Rate Tissues Toxic effect Treatment outcome Treatment-related toxicity Virus Integration Virus Replication Work biomarker discovery cancer classification candidate identification chemoradiation chemotherapy cohort disorder control experience fluorodeoxyglucose positron emission tomography genome sequencing genomic signature imaging biomarker non-invasive imaging novel overtreatment patient stratification pilot trial pre-clinical primary endpoint quantitative imaging radiation resistance randomized trial response side effect tool treatment response tumor tumor hypoxia tumor microenvironment whole genome

项目摘要

The prognosis of HPV+ oropharyngeal cancer (OPC) treated with standard radiation at 70 Gy is excellent. However, 80% of these patients experience grade ≥2 mucositis and 30% have permanent swallowing dysfunction. Clinical data suggest that 70 Gy may be overtreatment for some HPV+ OPCs. A modest reduction of 10-16 Gy for an unselected cohort with HPV+ OPC showed a 2-year progression-free survival (PFS) of 80%, but 40% of patients still had difficulty swallowing at 1 year. The proposed research will employ imaging (PET/MRI) biomarkers to identify patients with HPV+ OPC who may benefit from a major dose reduction to 30 Gy, a dose based on experience in HPV+ anal cancer, with the goal of maintaining tumor control and cure while substantially reducing treatment-related toxicity. A pilot trial of 19 HPV+ OPC patients treated at 30 Gy followed by neck dissection was encouraging, with a 2-year PFS of 93%. Significant toxicity reduction was observed. The proposed research will expand on the initial findings of the proof- of-principle study to a larger cohort of patients. The proposed imaging metrics to select patients for major dose de- escalation will include baseline and early intra-treatment [18F]-FMISO PET imaging, which will provide information on tumor hypoxia, a marker of radioresistance (Aim 1). Eligible patients will have no evidence of hypoxia on baseline imaging or have resolution of hypoxia during treatment, which will portend tumor radiosensitivity. We will interrogate the tumor microenvironment (Aim 2) by deriving quantitative imaging biomarkers (QIBs) from multi-parametric diffusion-weighted MRI (DW-MRI) consisting of non-Gaussian intravoxel incoherent motion (NG-IVIM) as well as [18F]-FMISO) PET imaging to select appropriate 30 Gy candidates to avoid neck dissection, with the goal of further toxicity reduction. The change in intra- treatment diffusion (D, surrogate of tumor cellularity) and kurtosis (K, surrogate of tissue microstructure) from baseline DW-MRI will guide which patients de-escalated to 30 Gy can avoid neck dissection. HPV is known to dysregulate the DNA damage response (DDR) and double-strand break (DSB) repair pathways to facilitate viral replication. Preclinical work suggests that this dysregulation accounts for the radiosensitivity of HPV+ OPC, although there are conflicting data regarding the precise nature of the responsible defect. For Aim 3, whole-genome sequencing (WGS) with mutational signature analyses will be used to identify DDR and DSB repair defects in individual HPV tumors and characterize the clinical influence on radiosensitivity. The relationship between genomic signatures and non-invasive imaging of tumor hypoxia and tumor cellularity that portend radiobiological sensitivity also will be explored. The proposal's central hypothesis is that PET/MRI of HPV+ OPC classification with the underpinnings of a molecular characterization of the cancer biology will yield a robust decision tool to stratify patients for whom dose de-escalation to 30 Gy will provide a clinical benefit and significantly reduced toxicity, without compromising treatment outcome.

使用 70 Gy 标准放射治疗的 HPV+ 口咽癌 (OPC) 的预后非常好。然而，这些患者中 80% 经历≥2 级粘膜炎，30% 患有永久性吞咽临床数据表明，70 Gy 对于某些 HPV+ OPC 可能是过度治疗。对于未选择的 HPV+ OPC 队列，减少 10-16 Gy 显示出 2 年无进展生存期 (PFS) 为 80%，但 40% 的患者在 1 岁时仍有吞咽困难。拟议的研究将采用这种方法。成像 (PET/MRI) 生物标记物可识别可能受益于大剂量的 HPV+ OPC 患者减少至 30 Gy，该剂量基于 HPV+ 肛门癌的经验，目的是维持肿瘤控制和治愈，同时大幅降低治疗相关毒性对 19 名 HPV+ OPC 患者进行的试点试验。 30 Gy 的显着毒性以及随后的颈清扫术令人鼓舞，2 年 PFS 为 93%。拟议的研究将扩展原理验证的初步发现。研究对更大的患者群体进行的研究，以选择患者进行主要剂量调整。升级将包括基线和早期治疗中 [18F]-FMISO PET 成像，这将提供有关肿瘤缺氧的信息，这是放射抗性的标志（目标 1）。基线成像缺氧或治疗期间缺氧得到缓解，这将预示着肿瘤我们将通过定量成像来探究肿瘤微环境（目标 2）。来自多参数扩散加权 MRI (DW-MRI) 的生物标志物 (QIB)，由非高斯组成体素内不相干运动 (NG-IVIM) 以及 [18F]-FMISO) PET 成像以选择适当的 30 Gy 候选人避免颈清扫术，以进一步减少体内毒性的变化。治疗扩散（D，肿瘤细胞结构的替代）和峰度（K，组织微观结构的替代）基线 DW-MRI 将指导哪些患者降级至 30 Gy 可以避免已知的 HPV 颈清扫术。失调 DNA 损伤反应 (DDR) 和双链断裂 (DSB) 修复途径，以促进病毒复制表明，这种失调是 HPV+ 放射敏感性的原因。 OPC，尽管对于目标 3 的缺陷的确切性质存在相互矛盾的数据，带有突变特征分析的全基因组测序 (WGS) 将用于识别 DDR 和 DSB 修复个体 HPV 肿瘤的缺陷并表征其对放射敏感性的临床影响。基因组特征与肿瘤缺氧和肿瘤细胞结构的非侵入性成像之间的关系该提案的中心假设是 PET/MRI 也将探讨预示的放射生物学敏感性。以癌症生物学分子特征为基础的 HPV+ OPC 分类将产生一个强大的决策工具来对患者进行分层，剂量降级至 30 Gy 将提供临床获益并显着降低毒性，而不影响治疗结果。