Importance Quantifying Head and Neck Lymphedema and Fibrosis (HN-LEF) is crucial in the investigation and management of this highly prevalent treatment sequelae in head and neck cancer (HNC). The HN-LEF grading system classifies physically palpable soft-tissue injury categorically. Imaging biomarkers from MRI may serve to complement or validate physical HN-LEF grading when assessing the effectiveness of therapeutic interventions or toxicity profiles of patients.

Objective To explore the relationship between 1) physical HN-LEF classification in submental and oral regions of interest (ROI) and the MRI T1- and T2-weighted signal intensity (SI) in close proximity regions, and 2) a novel HN-LEF score and MRI T1 and T2 structural volumes.

Design Post hoc analysis of pilot single arm MANTLE trial (NCT03612531).

Setting Single institution, NCI-designated comprehensive cancer center.

Participants A total of 16 individuals (mean [SD] age, 68.28 [7.0] years; 3[19%] female) enrolled in the MANTLE trial underwent MRI. All participants were disease-free at least two years post radiotherapy with grade ≥2 fibrosis (in any cervical ROI) and grade ≥2 dysphagia (per DIGEST). Over a 12-week period, participants engaged in manual therapy sessions accompanied by concurrent standardized multiparametric, serial MRI examinations and palpation-based HN-LEF evaluations at 3 time points: baseline, post-manual therapy, and post-washout.

Exposures The independent variable HN-LEF included its categorical classification (No-LEF, A-B = edema, C= edema + fibrosis, D=fibrosis) and a novel metric (10-point scale) derived from the HN-LEF categories (considering both type and severity classification).

Main Outcomes and Measures The T1- and T2-weighted MRI SI was examined by Kruskal-Wallis tests in relation to HN-LEF categories and the novel HN-LEF score. We hypothesized higher T2 SI in edema states, higher T1 SI in fibrotic states, and decreasing structural volume as HN-LEF score increased.

Results We identified differences in mean ranks among HN-LEF categories in relation to the MRI SI (A-B and C are higher than D and No-LEF for T2 SI, and A-B is the highest for T1). Furthermore, six pairs of FOM volumes on MRI demonstrated a strong negative correlation (p<0.05) with the HN-LEF score at adjacent palpable sites: digastric vs. submental left (ρ = -0.421; 95% CI, -0.65∼ -0.10, T1), mylohyoid vs. submental left (ρ = -0.36; 95% CI, -0. 62∼ 0.03, T1), digastric vs. submental left (ρ = --0.45; 95% CI, -0. 72∼ -0.06, T2), genioglossus vs. Intraoral left (ρ = -0.47; 95% CI, -0. 74∼ -0.07, T2), mylohyoid vs. Intraoral left (ρ = -0.48; 95% CI, -0. 75∼ -0.09, T2), tongue base vs. Intraoral left (r = -0.42; 95% CI, -0. 71∼ -0.01, T2).

Conclusions and Relevance This exploratory analysis provides hypothesis generating data supporting further study of MRI SI as an imaging biomarker of edematous soft tissue states after RT in HNC, but does not support the hypothesized T2 SI relationship with fibrotic tissue states. The inverse correlation between the novel HN-LEF scores and structural volumes points to the potential validity of this novel metric assuming structural volume diminishes as patients move from edema to fibrotic states. This study highlights the potential for enhancing the LEF quantification using imaging metrics, which might further aid in the early detection and precise measurement of lymphedema and fibrosis severity in post-radiation HNC patients.

The individual collaborators/authors declare the following competing interests: National Institutes of Health (grants, travel, honoraria); Padagis (honoraria); NPi (honoraria); Castle Biosciences (consulting); Galera Therapeutics (consulting, grants); EMD Serono (advisory board, in-kind support, consulting, grants); UpToDate Inc (royalties); Cardinal Health (grants, consulting); Guy's and St Thomas' NHS Foundation Trust (grants); King's College London (grants); Canadian Institutes of Health Research (grants); Canadian Foundation for Innovation (grants);Cancer Research Society (grants); Merck (advisory service, consulting, honoraria, travel, grants); Pfizer (stock, consulting, honoraria). Moderna (stock); Healthcare Services Group (stock); Dr. Reddy's Laboratories (stock); CVS Health (stock). Organon (stock); Myomo (stock); Rewalk Robotics (stock); Elekta AB (grants, in-kind support, honoraria, travel); Philips Medical System (honoraria, travel); Varian/Siemens Healthineers (honoraria, travel). Kallsio, Inc. (royalties, licenses);Nanobiotix (consulting); LEO SAB (consulting, stock options);Shanghai JoAnn Medical Company(consulting); Yingming (consulting); Sanofi-Regeneron (honoraria); Merck Sharp & Dohme (honoraria); Glaxo Smith Kline (honoraria); Merus (honoraria); Sun Pharma (honoraria); Angelini (honoraria, consulting); MeiraGtx (grants);PCCA (grants); Mureva (grants); K pharmaceuticals (honoraria, consulting); Lipella Pharmaceuticals (honoraria, consulting); Amgen (honoraria, consulting); Bristol Myers Squibb (grants); Debiopharm (grants);ACI Clinical (consulting);Genentech (consulting); Astellas (consulting); Immunitas (consulting, stock);SIRPant (consulting); LEK (consulting); Burns and White (expert testimony); Doximity (stock).

Drs. Hutcheson and Fuller received direct project support from the National Cancer Insititute (NCI) Clinical and Translational Exploratory/Developmental Studies Program (R21CA226200). Drs. Naser and Fuller receive related funds from NIH/NIDCR R03 grant (R03DE033550). Dr. Fuller receives related grant support from the NIH/NCI Cancer Center Support Grant (CCSG) Image-Guided Biologically-Informed Therapy (IDBT) Program (P30CA016672) as well as additional unrelated salary/effort support from NIH institutes. Drs. Fuller & Hutcheson receive philanthropic grant and infrastructure support from MD Anderson Cancer Center via the Charles and Daneen Stiefel Center for Head and Neck Cancer Oropharyngeal Cancer Research Program. Drs. Lai and Fuller and the Program in Image-guided Cancer Therapy. Kareem A. Wahid was supported by an Image Guided Cancer Therapy (IGCT) T32 Training Program Fellowship from T32CA261856. Dr. Moreno was supported directly or in part by funding/resources from the National Institutes of Health (NIH) National Institute for Dental and Craniofacial Research (K01DE030524, R21DE031082); NIH National Cancer Institute (K12CA088084); the University of Texas MD Anderson Cancer Center Charles and Daneen Stiefel Center for Head and Neck Cancer Oropharyngeal Cancer Research Program.

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IRB of The University of Texas M.D. Anderson Cancer Center gave ethical approval for this work

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Data availability statement: In accordance with the Final NIH Policy for Data Management and Sharing, NOT-OD-21-013, anonymized tabular analytic and NIFTI data that support the findings of this study are openly available in an NIH-supported generalist scientific data repository (figshare) no later than the time of an associated peer-reviewed publication; while public data is embargoed pending peer review, the data is available upon request pre-peer-review through email to the corresponding author.