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

• 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
• 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

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.

HPV+口咽癌（OPC）经70戈伊标准放射治疗的预后极佳。 然而，这些患者中有80%发生≥2级粘膜炎，30%发生永久性吞咽 功能障碍临床数据表明，对于某些HPV+ OPCs，70戈伊可能是过度治疗。适度 HPV+ OPC的HPV队列减少10-16戈伊显示2年无进展生存 (PFS)80%，但40%的患者在1年时仍有吞咽困难。该研究将采用 影像学（PET/MRI）生物标志物，以识别可能从大剂量中获益的HPV+ OPC患者 减少至30戈伊，这是基于HPV+肛门癌经验的剂量，目的是维持肿瘤 控制和治愈，同时大大减少治疗相关的毒性。19例HPV+ OPC患者的初步试验 接受30戈伊治疗后行颈淋巴清扫术的患者的2年无进展生存率为93%，令人鼓舞。显著毒性 观察到减少。拟议中的研究将扩展原理证明的初步发现 对更大的患者群体进行研究。建议的成像指标，以选择患者的主要剂量去， 升级将包括基线和早期治疗期间[18 F]-FMISO PET成像， 关于肿瘤缺氧的信息，一种放射抗性的标志物（Aim 1）。符合条件的患者将没有证据表明 基线成像显示缺氧或治疗期间缺氧消退，这将预示肿瘤 辐射敏感性。我们将通过推导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）由非高斯分布组成， 体素内非相干运动（NG-IVIM）以及[18 F]-FMISO）PET成像，以选择适当的30戈伊 候选人，以避免颈淋巴结清扫术，目的是进一步降低毒性。内部的变化- 治疗扩散（D，肿瘤细胞结构的替代物）和峰度（K，组织微观结构的替代物）， 基线DW-MRI将指导哪些患者剂量降至30戈伊可以避免颈淋巴结清扫术。已知HPV DNA损伤反应（DDR）和双链断裂（DSB）修复途径失调， 病毒复制临床前研究表明，这种失调是HPV+的放射敏感性的原因。 OPC，尽管关于责任缺陷的确切性质存在相互矛盾的数据。对于目标3， 全基因组测序（WGS）和突变特征分析将用于鉴定DDR和 DSB修复个体HPV肿瘤中的缺陷并表征对放射敏感性的临床影响。的 基因组标记与肿瘤缺氧和肿瘤细胞结构的非侵入性成像之间的关系， 也将探讨放射生物学的敏感性。该提案的中心假设是， HPV+ OPC分类与癌症生物学的分子表征的基础将 产生一个强大的决策工具，对剂量递减至30戈伊的患者进行分层， 临床益处和显著降低的毒性，而不影响治疗结果。