Christian Grønhøj

The global incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing, mainly due to a rise in human papillomavirus-positive (HPV+) cases. In Denmark, this group now constitutes more than 70% of newly diagnosed patients with OPSCC, making HPV+ OPSCC an increasing health issue. Approximately 10–15% of patients experience recurrence after treatment, and 30% die within five years of diagnosis. Detecting recurrence can be challenging, as it relies on either visible findings during clinical examination or symptoms reported by the patient. However, recent studies have shown that circulating tumor HPV-DNA (ctHPV-DNA) is a promising biomarker for detecting recurrence. The aim of the study presented in this protocol is to investigate whether prospective and systematic ctHPV-DNA testing can improve the standard follow-up program by detecting recurrence earlier than, or simultaneously with, clinical or radiological examination. This study is a prospective diagnostic accuracy study aiming to include 200 newly diagnosed patients with HPV+ OPSCC. Patients will be followed systematically with blood samples at baseline before treatment initiation and at every standard follow-up visit after treatment completion for up to three years. If a sample after treatment completion is positive for ctHPV-DNA, the patient will be referred for clinical ENT examination and a PET/CT scan to assess if the patient has detectable recurrence. This study will provide novel knowledge of the sensitivity and specificity of ctHPV-DNA testing for detecting recurrence in patients with HPV+ OPSCC, based on a large, prospectively and systematically followed cohort in which positive ctHPV-DNA findings will be acted upon clinically.

Denmark's publicly funded routine HPV vaccination program includes boys born from 2005 onward, leaving earlier birth cohorts of young men potentially unprotected. A published deterministic dynamic transmission metapopulation model was adapted to evaluate the impacts of a 3-year male catch-up vaccination program on the cases, deaths, and costs of HPV-associated diseases in Denmark over a 100-year time horizon. Routine gender-neutral HPV vaccination of adolescents with a nonavalent vaccine was modeled with and without a male catch-up program, at 4 catch-up vaccination coverage rates (VCRs) from 40% to 70%. Adding a temporary catch-up program for men born in 1997-2005 was projected to avert 253 HPV-associated cancer cases and 89 deaths at a VCR of 40%. Increasing coverage to 70% was estimated to avert 359 cases and 128 deaths. Catch-up vaccination may be considered cost-effective at all modeled VCRs, with incremental cost-effectiveness ratios of €35,584- 35,755 per quality-adjusted life year compared to routine adolescent vaccination alone. Expanding Denmark's male catch-up HPV vaccination program to include all men born in 1997-2005 would reduce the burden of HPV-associated cancers and diseases and may represent a cost-effective public health strategy.

Human papillomavirus (HPV) is the main cause of the rapidly increasing incidence of oropharyngeal squamous cell carcinoma (OPC) in high-income countries, particularly in men. Studies have shown a lower awareness of HPV-associated cancers, particularly OPC, in men. This study assessed the information provided by health authorities on HPV-induced OPC in multiple high-income countries. A standardized search for HPV information was conducted on health authority websites. Webpages were categorized as high, moderate-to-low or no awareness according to the extent of patient information that was provided on the link between HPV and OPC. Seven health authorities demonstrated high awareness of the link between HPV and the development of OPC, 24 showed moderate-to-low awareness, and three exhibited no awareness. In European Medicines Agency Member countries, only 17.4% of the population had access to the high awareness content through their public health bodies. Only seven out of the 39 health authorities analyzed provided high awareness content on the link between HPV and OPC. This demonstrates the general lack of public awareness of this important link, suggesting public health bodies currently fail to prioritize this matter and do not provide relevant information to the public.

The clinical influence of COVID-19 on patients with oropharyngeal squamous cell carcinoma (OPSCC) in Denmark is unclear. To investigate the impact of COVID-19 on frequency of diagnosed cases, treatment regimens, time to treatment (TTT), and prognosis for OPSCC patients in Eastern Denmark. All patients with OPSCC in Eastern Denmark during COVID-19 lockdown periods in 2019 and 2020 were included. Primary outcomes were TTT and changes in treatment regimens. Secondary outcomes were three-year overall survival (OS), three-year recurrence-free interval (RFI), and pattern of recurrence. Two hundred and ninety-seven patients were included. Most patients received chemoradiotherapy (CRT), with 82% in the COVID-19 period vs. 70% in the non-COVID-19 period, p = 0.06. Primary surgery was allocated to 7% in the COVID-19 period vs. 11% in the non-COVID-19 period, p = 0.06. The TTT was significantly shorter for primary surgery during the pandemic (20 vs. 28 days, p = 0.04). No differences in three-year OS or three-year RFI were observed. We found a significantly decreased TTT for primary surgery during the pandemic alongside a notable decline in primary surgery and a corresponding increase in CRT. Lockdown periods of the COVID-19 pandemic did not impact the frequency or prognosis of OPSCC in Eastern Denmark.

Comparing included patients to the OPSCC database

HPV VisionArray scans of tumor samples in patients with HPV-negative pre-treatment plasma samples.

Figure S2: Copies of HPV DNA per ml plasma in the pretreatment sample in follow-up serial samples in patients with an HPV+ follow-up sample but with no clinical or radiological evidence of recurrence or residual disease. Red dots denote an HPV+ sample, black dots denote an HPV- sample measured by ddPCR. Size of yellow RT rectangle indicates time (days) of radiotherapy with curative intent.

Figure S3: Copies of HPV DNA per ml plasma in follow-up samples for patients with residual disease. A black dot denotes a cell-free HPV-DNA negative plasma sample, while a red dot denotes a cell-free HPV-DNA positive plasma sample measured by ddPCR. Missing samples are marked in grey. Size and placement of yellow rectangles and yellow lines indicates time and type of treatment. A red line indicates the date of the recurrence. RT: radiotherapy; OP: Operation; Re-OP: Re-resection and re-operation.

Overall survival of patients in the OPSCC database compared to patients included in the project