Temporal Characterization of Longitudinal Sequelae Including Acute Pain, Physiologic Status, and Toxicity Kinetics in Head and Neck Cancer Patients Receiving Radiotherapy: A Prospective Electronic Health Record Embedded Registry Study

Background Pain is a common, debilitating symptom experienced by patients with oral cavity and oropharyngeal cancer (OC/OPC) treated with radiotherapy (RT). Managing acute pain (AP) over 6 - 7 weeks of RT remains a significant challenge, warranting further investigation. Using a modern prospective registry, the objective of this study was to characterize longitudinal AP profiles and temporal changes in vital signs (VS), radiation toxicities, and analgesic prescribing patterns during RT. Methods A total of 351 patients with OC (n=120) and OPC (n=228) treated with curative RT from 2013-2021 were included. Baseline cohort characteristics, weekly patient-reported pain descriptors, physician-graded toxicities (CTCAE v5), and analgesic orders during RT were extracted. Temporal changes in AP scores and VS were analyzed using linear mixed effect models. AP trajectories were reduced to single metric area under the curve calculations (AUC pain ). Correlations were assessed using Spearman correlation coefficients. Results Median age was 60 years, and 70% and 42% received chemotherapy and surgery, respectively. A significant increase in pain, mucositis, dermatitis, and overall treatment toxicity severity were observed by the end of RT. AUC pain was significantly different based on gender, primary tumor site, surgery, drug use history and pre-RT pain. There was a temporal mean weight loss of 7.1% bodyweight (95%CI, 10-8.2; P <0.001), a mean arterial pressure (MAP) decline of 6.8 mmHg (95%CI, −8.8 to −4.7; P <0.001), and increased pulse rate of 11 beats/min (95%CI, 7.6-13.8; P <0.001). AP and pulse rate were positively associated over time ( P<0 . 001 ) while weight and MAP were negatively associated over time ( P <0.001). A temporal increase in analgesics use, mainly opioids, was detected. Conclusion This study characterizes longitudinal treatment-related toxicity kinetics using a prospective OC/OPC registry and demonstrates an ongoing need for optimized, timely pain control. Pain AUC metrics preserve temporal information and may be useful for developing algorithmic pain prediction and management models. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Principal Investigator, 8 months, Pain-directed Pragmatic Automation of Informatics-based Novel Frameworks for Reducing Radiotherapy-associated Effects (PAINFREE), 5K12CA088084, Paul Calabresi K12 Scholars Program, 9/1/2020-8/31/2022 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB [2020-1231] of University of Texas, MD Anderson Cancer Center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.