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. 2024 Dec 16;30(24):5620-5629.
doi: 10.1158/1078-0432.CCR-24-1170.

Oxygen-Enhanced MRI Detects Incidence, Onset, and Heterogeneity of Radiation-Induced Hypoxia Modification in HPV-Associated Oropharyngeal Cancer

Michael J Dubec  1   2 , James Price  3 , Michael Berks  1 , John Gaffney  3 , Ross A Little  1 , Nuria Porta  4 , Nivetha Sridharan  4 , Anubhav Datta  1   5 , Damien J McHugh  1   2 , Christina J Hague  3 , Susan Cheung  1 , Prakash Manoharan  5 , Marcel van Herk  1 , Ananya Choudhury  1   3 , Julian C Matthews  6 , Geoff J M Parker  7   8 , David L Buckley  2   9 , Kevin J Harrington  10 , Andrew McPartlin  3   11 , James P B O'Connor  1   5   10
Affiliations

Oxygen-Enhanced MRI Detects Incidence, Onset, and Heterogeneity of Radiation-Induced Hypoxia Modification in HPV-Associated Oropharyngeal Cancer

Michael J Dubec et al. Clin Cancer Res. .

Abstract

Purpose: Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in human papillomavirus-associated oropharyngeal head and neck squamous cell cancer.

Experimental design: A total of 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy and then at weeks 2 and 4 (W2 and W4) into therapy. Two pretreatment scans assessed biomarker within-subject coefficient of variation and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modeling. Responding lesions were identified by comparing HVMRI change with RC limits of agreement.

Results: Oxygen-enhanced MRI identified hypoxia in all lesions. The HVMRI within-subject coefficient of variation was 24.6%, and RC limits of agreement were -45.7% to 84.1%. A cohort median pretreatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both P < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients.

Conclusions: Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in human papillomavirus-associated oropharyngeal carcinoma. See related commentary by Mason, p. 5503.

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Conflict of interest statement

M.J. Dubec reports grants from Medical Research Council and Cancer Research UK during the conduct of the study. A. Choudhury reports grants from UK Research Innovation and Cancer Research UK during the conduct of the study as well as grants from Prostate Cancer UK, The Urology Foundation, Action Bladder Cancer, and Elekta AB and personal fees from BMJ, Merck, AstraZeneca, and Bayer outside the submitted work. J.C. Matthews reports grants from UK Medical Research Council during the conduct of the study. G.J.M. Parker reports personal fees and other support from Bioxydyn Limited, other support from Quantitative Imaging Limited and Queen Square Analytics Limited, and grants from GSK outside the submitted work. A. McPartlin reports personal fees from Philips Healthcare outside the submitted work. J.P.B. O’Connor reports grants from Cancer Research UK during the conduct of the study. No conflicts of interest were disclosed by the other authors.

Figures

Figure 1.
Figure 1.
Treatment-induced changes in OE-MRI–derived biomarkers. A, Example hypoxia maps for a large metastatic lymph node (patient 7) obtained at two BL timepoints (BL0 and BL1) and W2 and W4 of radiation treatment. Corresponding ΔR1 maps are provided in Supplementary Fig. S7A–S7C. B, Bar charts plot the relative sizes of HVMRI along with NVMRI and nonperfused volume for this patient. Note: The combination of HVMRI, NVMRI, and nonperfused volume equate to the WTV. C, Patient cohort assessment of treatment effects illustrated as plots of standard error of the mean (SEM) for (top left to bottom right) HVMRI, NVMRI, nonperfused volume, WTV, HFMRI, and ΔR1.
Figure 2.
Figure 2.
HVMRI changes at W2. A, Waterfall plot showing the percentage change in HVMRI from BL to W2 in all lesions, categorized as primary tumors or nodal metastases. B, Analysis of the 17 lesions imaged at both W2 and W4 compares the reduction from BL at W2 (light blue) and W4 (dark blue). Dashed lines are the asymmetrical RC LOA for HVMRI (i.e., −45.7% and +84.1%).
Figure 3.
Figure 3.
Waterfall plots showing change in HVMRI, NVMRI, and WTV at W2. Four patterns seen were (A) lesions with significant hypoxia modification and reduction in WTV. Diamonds indicate tumors in which the hypoxic fraction remained unchanged; B, tumors with significant hypoxia modification that did not have change in WTV; (C) tumors that did not have significant individual changes in hypoxia, but significant reduction in WTV was driven by reduction in NVMRI; (D) tumors with no reduction in HVMRI, NVMRI, or WTV.
See this image and copyright information in PMC

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