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阳性口咽癌(OPC)经70Gy标准剂量照射后预后良好。 然而，这些患者中有80%经历了≥2级粘膜炎，30%有永久性吞咽 功能障碍。临床数据显示，对一些HPV+OPC来说，70Gy射线可能是过度治疗。谦虚的 对HPV+OPC的非选择队列患者进行10-16Gy射线照射显示两年无进展生存 (PFS)80%，但40%的患者在1年后仍有吞咽困难。拟议的研究将采用 用于识别HPV+OPC患者可能受益于大剂量的成像(PET/MRI)生物标记物 将剂量降低到30GY，这是根据HPV+肛门癌的经验而定的剂量，目的是维持肿瘤 控制和治愈，同时大幅减少与治疗相关的毒性。19例HPV+OPC患者的初步试验 30Gy后行颈淋巴清扫术是令人鼓舞的，2年无瘤生存率为93%。重大毒性 观察到减少的情况。拟议的研究将扩大原则证明的初步调查结果。 对更大的患者队列进行研究。建议的影像指标，以选择患者进行大剂量脱毒 升级将包括基线和早期内部治疗[18F]-FMISO PET成像，这将提供 关于肿瘤缺氧的信息，这是放射抵抗的一个标志(目标1)。符合条件的患者将没有证据表明 基线影像上的缺氧或治疗过程中缺氧的缓解，这将是肿瘤的前兆 对辐射敏感。我们将通过推导定量成像来询问肿瘤微环境(目标2) 非高斯多参数扩散加权磁共振(DW-MRI)的生物标志物 体素内非相干运动(NG-IVIM)以及[18F]-FMISO)PET成像以选择合适的30GY 避免颈淋巴清扫，以进一步降低毒性为目标。内部的变化- 治疗扩散(D，替代肿瘤细胞)和峰度(K，替代组织微结构)来自 基线DW-MRI将指导哪些降级到30GY的患者可以避免颈淋巴清扫。人乳头瘤病毒是已知的 失调的DNA损伤反应(DDR)和双链断裂(DSB)修复通路 病毒复制。临床前研究表明，这种失调是HPV+对辐射敏感的原因。 OPC，尽管关于责任缺陷的确切性质有相互矛盾的数据。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修复单个HPV肿瘤中的缺陷，并表征临床对放射敏感性的影响。这个 基因组特征与肿瘤缺氧和肿瘤细胞密度的无创性成像的关系 还将探讨放射生物学敏感性的前兆。该提案的中心假设是PET/MRI 以癌症生物学的分子特征为基础的HPV+OPC分类将 产生一个强大的决策工具，对剂量降低到30GY的患者进行分层 在不影响治疗结果的情况下，临床受益并显著降低毒性。