A personalized approach using hypoxia resolution to guide curative-intent radiation dose reduction to 30 Gy: A novel de-escalation paradigm for HPV-associated oropharynx cancers

使用缺氧解决方案指导治疗性辐射剂量减少至 30 Gy 的个性化方法：HPV 相关口咽癌的新型降级范例

• 批准号: 9887712
• 负责人: Nancy Y Lee
• 金额: $ 71.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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/9887712
• 关键词: Aftercare; American Joint Committee on Cancer; Beds; Biological; Cancer Biology; Cancer Patient; Cellularity; Cetuximab; Cisplatin; Clinical; Clinical Data; Conflict (Psychology); DNA; DNA Damage; Data; Defect; Deglutition; Deglutition Disorders; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Dose; Double Strand Break Repair; Ensure; Excision; Functional disorder; Gene Expression; Genes; Genomics; Goals; Human Papillomavirus; Hypoxia; Image; In complete remission; Individual; Inferior; Left; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of anus; Measures; Methods; Molecular; Monitor; Morbidity - disease rate; Motion; Mucositis; Mutation; Mutation Analysis; Nature; Neck Dissection; Nodal; Normal tissue morphology; Operative Surgical Procedures; Oxygen; PET/CT scan; Pathologic; Pathway interactions; Patients; Pilot Projects; Positron-Emission Tomography; Postoperative Period; Primary Neoplasm; Process; Progression-Free Survivals; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation therapy; Research; Resolution; Statistical Models; Survival Rate; Tissues; Toxic effect; Treatment outcome; Treatment-related toxicity; Virus Integration; Virus Replication; Work; base; biomarker discovery; cancer classification; chemoradiation; chemotherapy; cohort; disorder control; experience; fluorodeoxyglucose positron emission tomography; genome sequencing; genomic signature; imaging biomarker; magnetic resonance imaging biomarker; malignant oropharynx neoplasm; non-Gaussian model; non-invasive imaging; novel; outcome forecast; overtreatment; patient stratification; personalized approach; 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

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.

在70 Gy时用标准辐射处理的HPV+口咽癌（OPC）的预后非常好。 但是，这些患者中有80％患有≥2级粘膜炎和30％的粘膜炎已永久吞咽 功能障碍。临床数据表明，对于某些HPV+ OPC，70 GY可能过度治疗。谦虚 与HPV+ OPC未选择的队列的10-16 Gy的降低显示了2年无进展的存活率 （PFS）为80％，但有40％的患者在1年时仍很难吞咽。拟议的研究将采用 成像（PET/MRI）生物标志物可以识别可能受益于主要剂量的HPV+ OPC患者 将基于HPV+肛门癌经验的剂量还原为30 Gy，目的是保持肿瘤 控制和治愈，同时大大降低了与治疗相关的毒性。 19例HPV+ OPC患者的试验试验 在30 Gy进行治疗，然后进行颈部解剖，令人鼓舞，2年PFS为93％。显着的毒性 观察到还原。拟议的研究将扩大原则证明的初步发现 研究更大的患者队列。提出的成像指标旨在选择大剂量的患者 升级将包括基线和早期治疗[18F] -fmiso PET成像，将提供 有关肿瘤缺氧的信息，肿瘤缺氧的标志物（AIM 1）。符合条件的患者将没有证据表明 基线成像缺氧或治疗过程中缺氧分辨率，这将预示肿瘤 放射敏性。我们将通过得出定量成像来询问肿瘤微环境（AIM 2） 来自多参数扩散加权MRI（DW-MRI）的生物标志物（QIB），由非高斯人组成 Intravoxel不一致的运动（NG-IVIM）以及[18F] -FMISO）PET成像以选择适当的30 Gy 候选人避免颈部解剖，以进一步降低毒性。内部的变化 从 基线DW-MRI将指导哪些患者降级为30 Gy可以避免颈部解剖。 HPV已知 失调DNA损伤响应（DDR）和双链断裂（DSB）修复途径以促进 病毒复制。临床前工作表明，这种失调解释了HPV+的放射敏感性 OPC，尽管关于负责缺陷的确切性质存在相互矛盾的数据。对于目标3， 具有突变签名分析的全基因组测序（WGS）将用于识别DDR和 单个HPV肿瘤中的DSB修复缺陷，并表征了临床对放射敏性的影响。这 基因组特征与肿瘤缺氧和肿瘤细胞的非侵入性成像之间的关系 还将探索放射生物学敏感性。该提议的中心假设是 HPV+ OPC分类具有癌症生物学分子表征的基础 产生一个强大的决策工具，以对剂量下降至30 Gy的患者进行分层 临床益处并显着降低毒性，而不会损害治疗结果。