Objectives: HPV‐positive oropharyngeal squamous cell carcinoma (OPSCC) and head and neck carcinoma of unknown primary (HNCUP) are increasing. Despite good prognosis, recurrence rates range from 10% to 25%. Surveillance with clinical controls and imaging is not always reliable. Circulating tumour human papillomavirus DNA (ctHPV‐DNA) has emerged as a potential biomarker for treatment evaluation and detection of recurrence. We aimed to investigate the correlation between ctHPV‐DNA in HPV+ OPSCC/HNCUP and radiologic tumour burden. Additionally, we sought to assess whether ctHPV‐DNA could serve as a tool in treatment evaluation.Design: A prospective observational cohort study.Setting: This multicenter study involved three otolaryngology units located in central Sweden. We utilised HPV genotype‐specific assays for droplet digital PCR (ddPCR) to detect ctHPV‐DNA in plasma at diagnosis and follow‐up. ctHPV‐DNA levels were correlated to radiological tumour burden and radiological response using the Kendall Rank correlation coefficient and the Kruskal–Wallis test.Participants: Patients with HPV+ OPSCC/HNCUP undergoing definitive (chemo)radiotherapy and enrolled in the CIRCOS study.Results: Out of 54 patients, 51 were eligible for analyses. At baseline, ctHPV‐DNA was detectable in 88%. A majority of patients with a favourable radiological evaluation according to RECIST had a corresponding undetectable ctHPV‐DNA at follow‐up. The levels of ctHPV‐DNA at baseline correlated with total tumour volume and nodal volume (rτ = 0.39, p < 0.01, respectively rτ = 0.26, p < 0.01).Conclusion: ctHPV‐DNA shows correlation with tumour burden. This study strengthens the role of ctHPV‐DNA as a promising biomarker for treatment evaluation in HPV‐related OPC/HNCUP. With further research on serial plasma sampling, ctHPV‐DNA could complement radiological treatment evaluation in HPV+ OPSCC/HNCUP. Trial Registration: NCT05904327 [ClinicalTrials.gov]

Objectives HPV-positive Oropharyngeal squamous cell carcinoma (OPSCC) and Head and neck carcinoma of unknown primary (HNCUP) is increasing. Despite good prognosis, recurrence rates range from 10- to 25%. Surveillance with clinical controls and imaging are not always reliable. Circulating tumour human papillomavirus DNA (ctHPV-DNA) has emerged as a potential biomarker for treatment evaluation and detection of recurrence. We aimed to investigate the correlation between ctHPV-DNA in HPV+ OPSCC/HNCUP and radiologic tumour burden. Additionally, we sought to assess whether ctHPV-DNA could serve as a tool in treatment evaluation. Design A prospective observational cohort study. Setting This multicenter study involved three otolaryngology units located in central Sweden. We utilised HPV genotype-specific assays for droplet digital PCR (ddPCR) to detect ctHPV-DNA in plasma at diagnosis and follow-up. ctHPV-DNA levels were correlated to radiological tumour burden and radiological response using Kendall Rank correlation coefficient and Kruskal Wallis test. Participants Patients with HPV+ OPSCC/HNCUP undergoing definitive (chemo)radiotherapy. Results Out of 54 patients, 51 were eligible for analyses. At baseline, ctHPV-DNA was detectable in 88%. The majority of patients with a favourable radiological evaluation according to RECIST, had a corresponding undetectable ctHPV-DNA at follow-up. The levels of ctHPV-DNA at baseline correlated with Total Tumour Volume and Nodal Volume (r τ = 0.39, p<0.01, respectively r τ =0.26, p<0.01). Conclusion ctHPV-DNA shows correlation with tumour burden. This study strengthens the role of ctHPV-DNA as a promising biomarker for diagnosing and monitoring HPV-related OPC/HNCUP. With further research on serial plasma sampling, ctHPV-DNA could complement radiological treatment evaluation in HPV+ OPSCC/HNCUP.