
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.20.24312311
preprint
1
Article
Mandibular dose-volume predicts time-to-osteoradionecrosis in an actuarial normal-tissue complication probability (NTCP) model: External validation of right-censored clinico-dosimetric and competing risk application across international multi-institutional observational cohorts and online graphical user interface clinical support tool assessment
MD Anderson Head and Neck Symptom Working Group
Humbert-Vidan Laia http://orcid.org/0000-0002-8005-6770

Kamel Serageldin http://orcid.org/0000-0002-0046-4337

Wentzel Andrew http://orcid.org/0000-0002-2003-2750

Kaffey Zaphanlene http://orcid.org/0009-0008-7999-5245

Abdelaal Moamen http://orcid.org/0000-0003-4476-2122

Spier Kyle B. http://orcid.org/0009-0004-9931-3644

West Natalie A. http://orcid.org/0009-0007-0211-8845

Marai G. Elisabeta http://orcid.org/0000-0002-7212-9669

Canahuate Guadalupe http://orcid.org/0000-0001-5873-5454

Zhang Xinhua http://orcid.org/0000-0002-4084-6022

Chen Melissa M. http://orcid.org/0000-0002-3274-2653

Wahid Kareem A. http://orcid.org/0000-0002-0503-0175

Rigert Jillian http://orcid.org/0000-0001-5419-980X

Hosseinian Seyedmohammadhossein http://orcid.org/0000-0001-7016-5925

Schaefer Andrew J. http://orcid.org/0000-0002-0379-741X

Brock Kristy K. http://orcid.org/0000-0001-9364-5040

Chambers Mark http://orcid.org/0000-0001-8901-6583

Otun Adegbenga O. http://orcid.org/0000-0001-7599-1628

Aponte-Wesson Ruth http://orcid.org/0000-0003-0233-9035

Patel Vinod http://orcid.org/0000-0002-3709-5619

Hope Andrew http://orcid.org/0000-0001-6793-2863

Phan Jack http://orcid.org/0000-0001-5977-6004

Garden Adam S. http://orcid.org/0000-0001-7926-2641

Frank Steven J. http://orcid.org/0000-0001-6517-7884

Morrison William H http://orcid.org/0000-0002-9546-0805

Spiotto Michael T http://orcid.org/0000-0003-4484-462X

Rosenthal David http://orcid.org/0000-0003-2728-7745

Lee Anna http://orcid.org/0000-0002-9114-1815

He Renjie http://orcid.org/0000-0001-9166-6286

Naser Mohamed A. http://orcid.org/0000-0003-1020-4966

Watson Erin http://orcid.org/0000-0002-2096-7732

Hutcheson Katherine A. http://orcid.org/0000-0003-3710-5706

Mohamed Abdallah S. R. http://orcid.org/0000-0003-2064-7613

Sandulache Vlad C. http://orcid.org/0000-0002-9205-385X

van Dijk Lisanne V. http://orcid.org/0000-0002-9515-5616

Moreno Amy C. http://orcid.org/0000-0001-6762-6807

Guerrero Urbano Teresa http://orcid.org/0000-0003-3090-541X

Lai Stephen Y. http://orcid.org/0000-0001-8301-7286

Fuller Clifton D. http://orcid.org/0000-0002-5264-3994

20 8 2024
2024.08.20.24312311https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://medrxiv.org/lookup/doi/10.1101/2024.08.20.24312311
nihpp-2024.08.20.24312311.pdf
Abstract

Background

Existing studies on osteoradionecrosis of the jaw (ORNJ) have primarily used cross-sectional data, assessing risk factors at a single time point. Determining the time-to-event profile of ORNJ has important implications to monitor oral health in head and neck cancer (HNC) long-term survivors.

Methods

Demographic, clinical and dosimetric data were retrospectively obtained for a clinical observational cohort of 1129 patients with HNC treated with radiotherapy (RT) at The University of Texas MD Anderson Cancer Center. ORNJ was diagnosed in 198 patients (18%). A multivariable logistic regression analysis with forward stepwise variable selection identified significant predictors for ORNJ. These predictors were then used to train a Weibull Accelerated Failure Time (AFT) model, which was externally validated using an independent cohort of 265 patients (92 ORNJ cases and 173 controls) treated at Guy’s and St. Thomas’ Hospitals.

Findings

Our model identified that each unit increase in D25% is significantly associated with a 12% shorter time to ORNJ (Adjusted Time Ratio [ATR] 0·88, p<0·005); pre-RT dental extractions was associated to a 27% faster (ATR 0·73, p=0·13) onset of ORNJ; male patients experienced a 38% shorter time to ORNJ (ATR 0·62, p = 0·11). The model demonstrated strong internal calibration (integrated Brier score of 0·133, D-calibration p-value 0.998) and optimal discrimination at 72 months (Harrell’s C-index of 0·72). The model also showed good generalization to the independent cohort, despite a slight drop in performance.

Interpretation

This study is the first to demonstrate a direct relationship between radiation dose and the time to ORNJ onset, providing a novel characterization of the impact of delivered dose not only on the probability of a late effect (ORNJ), but the conditional risk during survivorship.

Funding

This work was supported by various funding sources including NIH, NIDCR, NCI, NAPT, NASA, BCM, Affirmed Pharma, CRUK, KWF Dutch Cancer Society, NWO ZonMw, and the Apache Corporation.
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pmc
