# 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

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $695,222

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10372013
- **Project number:** 5R01CA238392-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Nancy Y Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $695,222
- **Award type:** 5
- **Project period:** 2020-03-03 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372013

## Citation

> US National Institutes of Health, RePORTER application 10372013, 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 (5R01CA238392-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10372013. Licensed CC0.

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