Cost-effectiveness analysis of (accelerated) pre-operative versus (conventional) post-operative radiotherapy for patients with oral cavity cancer in Sweden.

BACKGROUND: Treatment for resectable oral cavity cancer (OCC) often includes combinations of surgery and radiotherapy (RT), but there is no conclusive information on the preferred treatment order. The aim of this study was to assess the costs and cost-effectiveness of two alternative treatment regimens for patients with OCC, reflecting pre- and post-operative RT, from a societal perspective. METHODS: The study used data from the ARTSCAN 2 randomised controlled trial, which compares pre-operative accelerated RT with post-operative conventionally fractionated RT. Two-hundred-forty patients were included in the analysis of treatment outcomes. Direct costs were retrieved from the hospital's economic systems, while indirect costs were obtained from national registries. Cost-effectiveness was assessed and a sensitivity analysis was performed. Overall survival (OS) at 5 years, was used as effect measure in the analysis. RESULTS: Two-hundred-nine patients completed the treatments and had retrievable data on costs. Mean direct costs (inpatient and outpatient care) were € 47,377 for pre-operative RT and € 39,841 for post-operative RT (p = 0.001), while corresponding indirect costs were € 19,854 and € 20,531 (p = 0.89). The incremental cost, i.e., the mean difference in total cost between the treatment regimens, was € 6859 paralleled with a 14-percentage point lower OS-rate at 5 years for pre-operative RT (i.e., 58 vs. 72%). Thus, pre-operative RT was dominated by post-operative RT. CONCLUSIONS: From a societal perspective, post-operative RT for patients with resectable OCC is the dominant strategy compared to pre-operative RT.

Squamous cell carcinoma of the mobile tongue in young adults: A Swedish head & neck cancer register (SweHNCR) population-based analysis of prognosis in relation to age and stage.

Increased incidence of squamous cell carcinoma (SCC) of the tongue has been reported in young adults (YA) in several countries since the 1980s and confirmed in later studies. The etiology is unclear, the prognosis has been debated, and conflicting results have been published. Some studies show better survival in young adults than in older patients, some worse, and others no difference. Most studies are based on selected series or include other sites in the oral cavity. The definition of "YA" is arbitrary and varies between studies. It is thus difficult to use in general conclusions. This work uses data from the population-based Swedish Head and Neck Cancer register (SweHNCR), which has > 98% coverage. SweHNCR data includes age, gender, TNM, treatment intention, treatment given, lead times, performance status, and to a lesser degree, smoking habits. The current Swedish population is around 10 million. We analyzed outcomes for 1416 patients diagnosed with SCC of the oral tongue from 2008 to 2017 using 18-39 years to define YA age because it is the range most commonly used. We found no significant difference in relative survival (a proxy for diagnosis-specific survival) between age groups of patients treated with curative intent for SCC of the oral tongue. The stage at time of diagnosis was equally distributed among the age groups. Excess mortality rate correlated mainly with stage, subsite of the tongue, performance status, and lead time to treatment.

A practical and environmentally friendly protocol for synthesis of α-deuterated carboxylic acids.

α-deuterated carboxylic acids have been synthesized from the corresponding malonic acids via hydrogen/deuterium exchange and decarboxylation in presence of D2 O. The method is general, mild and efficient and does not require organic solvents or other additives. Yields range between 83% and 94% and purification was not necessary. Starting materials were easy accessible and the α-deuterated carboxylic acids may easily be transformed to other labeled compounds such as alcohols, aldehydes, esters, and amides. Characterization with NMR confirmed purity and isotopic purity.

Base of tongue squamous cell carcinomas, outcome depending on treatment strategy and p16 status. A population-based study from the Swedish Head and Neck Cancer Register.

BACKGROUND: The base of tongue squamous cell carcinoma (BOTSCC) is mainly an HPV-related tumor. Radiotherapy (EBRT) ± concomitant chemotherapy (CT) is the backbone of the curatively intended treatment, with brachytherapy (BT) boost as an option. With four different treatment strategies in Sweden, a retrospective study based on the population-based Swedish Head and Neck Cancer Register (SweHNCR) was initiated. MATERIAL AND METHODS: Data on tumors, treatment and outcomes in patients with BOTSCC treated between 2008 and 2014 were validated through medical records and updated as needed. Data on p16 status were updated or completed with immunohistochemical analysis of archived tumor material. Tumors were reclassified according to the UICC 8th edition. RESULTS: Treatment was EBRT, EBRT + CT, EBRT + BT or EBRT + CT + BT in 151, 145, 82 and 167 patients respectively (n = 545). A p16 analysis was available in 414 cases; 338 were p16+ and 76 p16-. 5-year overall survival (OS) was 68% (95% CI: 64-72%), with76% and 37% for p16+ patients and p16- patients, respectively. An increase in OS was found with the addition of CT to EBRT for patients with p16+ tumors, stages II-III, but for patients with tumor stage I, p16+ (UICC 8) none of the treatment strategies was superior to EBRT alone. CONCLUSION: In the present retrospective population-based study of BOTSCC brachytherapy was found to be of no beneficial value in curatively intended treatment. An increase in survival was found for EBRT + CT compared to EBRT alone in patients with advanced cases, stages II and III (UICC 8), but none of the regimes was significantly superior to EBRT as a single treatment modality for stage I (UICC 8), provided there was p16 positivity in the tumor. In the small group of patients with p16- tumors, a poorer prognosis was found, but the small sample size did not allow any comparisons between different treatment strategies.

Results from a prospective, randomised study on (accelerated) preoperative versus (conventional) postoperative radiotherapy in treatment of patients with resectable squamous cell carcinoma of the oral cavity - The ARTSCAN 2 study.

BACKGROUND AND PURPOSE: An earlier prospective randomised multicentre study (ARTSCAN) in head and neck cancer patients that compared conventionally fractionated radiotherapy (CF) with accelerated radiotherapy (AF) was inconclusive. In the subgroup of oral cavity squamous cell cancer (OCSCC) a large absolute, but not statistically significant, difference in local control was seen in favour of AF. This difference was more pronounced in resectable tumours. The finding raised the hypothesis that AF could be beneficial for OCSCC patients. In addition, the longstanding controversy on pre- or postoperative radiotherapy was addressed. MATERIALS AND METHODS: Patients with OCSCC, judged to withstand and likely benefit from combined therapy, were recruited. Subjects were randomised to either preoperative AF with 43 fractions given as a concomitant boost with two fractions/day to the tumour bearing volume to a total dose of 68 Gy in 4.5 weeks followed by surgery, or primary surgery with postoperative CF, total dose 60 or 66 Gy in 6-7 weeks. For patients whose tumours had high-risk features, 66 Gy and concomitant cisplatin was prescribed. RESULTS: 250 patients were randomised. Median follow-up was 5 years for locoregional control (LRC) and 9 years for overall survival (OS). There were no statistically significant differences between the two treatment arms regarding LRC and OS. LRC at five years was 73% (95% CI, 65-82) in preoperative AF and 78% (95% CI, 70-85) in postoperative CF. Toxicity was more pronounced in preoperative AF. CONCLUSION: This study does not support that AF prior to surgery improves outcome in oral cavity cancer compared with postoperative CF.

A longitudinal study of the Swedish MD Anderson Dysphagia Inventory in patients with oral cancer.

OBJECTIVE: The aim of this study was to investigate whether the Swedish MD. Anderson Dysphagia Inventory (MDADI) is able to detect changes in dysphagia symptoms over time for patients with head and neck cancer (HNC). METHODS: One hundred and forty-two patients with resectable tumors of the oral cavity were included prior to treatment. The patients filled out the MDADI, European Organization for Research and Treatment of Cancer Quality of Life questionnaire Core 30 (EORTC QLQ-C30) and the HNC module (H&N35) at baseline and at least one follow-up at 6 and/or 12 months after oncologic treatment. A control group without dysphagia (n = 115) was included. RESULTS: Self-perceived swallowing function decreased in all domains at 6 months, and improved between 6 and 12 months. The changes were similar to the changes of the EORTC domains, indicating a sensitivity to change. However, even if improvements were seen at 12 months, the values were still inferior compared to baseline values, and the values of a control group without dysphagia. Convergent validity was found with values of the MDADI and EORTC domains producing similar results, and moderate correlations as hypothesized. Patients with moderate-severe dysphagia according to the MDADI (<60 points) demonstrated inferior values of the EORTC domains compared to patients with scores above 60 points. CONCLUSION: The Swedish MDADI was found to be sensitive to change, and showed convergent results when compared to other established instruments. The threshold value for the MDADI (<60 points) indicating moderate-severe dysphagia may be a valuable addition in the clinical use. LEVEL OF EVIDENCE: 1.

Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is one of the most malignant tumors, with a median survival of only a few months. The tumorigenic processes of this disease have not yet been completely unraveled. Here, we report an mRNA expression and DNA methylation analysis of fourteen primary ATCs. ATCs clustered separately from normal thyroid tissue in unsupervised analyses, both by RNA expression and by DNA methylation. In expression analysis, enrichment of cell-cycle-related genes as well as downregulation of genes related to thyroid function were seen. Furthermore, ATC displayed a global hypomethylation of the genome but with hypermethylation of CpG islands. Notably, several cancer-related genes displayed a correlation between RNA expression and DNA methylation status, including MTOR, NOTCH1, and MAGI1. Furthermore, TSHR and SLC26A7, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, displayed low expression as well as aberrant gene body DNA methylation. This study is the largest investigation of global DNA methylation in ATC to date. It shows that aberrant DNA methylation is common in ATC and likely contributes to tumorigenesis in this disease. Future explorations of novel treatments should take this into consideration.

EGFR modulates complement activation in head and neck squamous cell carcinoma.

BACKGROUND: The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR signalling is also involved in diverse innate immune functions in epithelia. We previously found a role for EGFR in modulating the complement system in skin, this prompted an investigation into EGFR role in complement modulation in HNSCC. METHODS: We used patient derived HNSCC cell lines with varying sensitivities to EGFR inhibitors, and generated EGFR inhibition resistant cell lines to study the role of EGFR in modulating complement in HNSCC. RESULTS: We found that HNSCC cell lines activate the complement system when incubated with human serum. This complement activation was increased in cell lines sensitive to EGFR inhibition following the use of the tyrosine kinase inhibitor Iressa. Sensitive cell line made resistant to EGFR-inhibitors displayed complement activation and a decrease in complement regulatory proteins even in the absence of EGFR-inhibitors. Complement activation did not cause lysis of HNSCC cells, and rather led to increased extracellular signal-regulated kinase (ERK) phosphorylation in one cell line. CONCLUSION: These data indicate that EGFR has a complement modulatory role in HNSCC, and that a prolonged EGFR-inhibition treatment in sensitive cancer cells increases complement activation. This has implications in understanding the response to EGFR inhibitors, in which resistance and inflammatory skin lesions are two major causes for treatment cessation.

Substantial intrinsic variability in chemoradiosensitivity of newly established anaplastic thyroid cancer cell-lines.

Background: Well characterized human cell lines are needed for preclinical treatment studies of anaplastic thyroid cancer (ATC).Aims/Objectives: The aim was to establish, verify and characterize a panel of ATC cell lines.Material and methods: Cell lines were established from ATC fine-needle aspiration biopsies and characterized genetically and functionally regarding treatment sensitivities.Results: Eight cell lines were established in vitro and the anaplastic thyroid origin was verified. Seven of the cell lines were also grown as xenografts. The cell lines harboured complex karyotypes with modal numbers in hyperdiploid to near-pentaploid range. Five were TP53 mutated and three carried the BRAFV600E mutation. None had rearrangements of RET. For doxorubicin, IC50 ranged from 0.42 to 46 nmol/L and for paclitaxel from 1.6 to 196 nmol/L. Radiation sensitivity varied between 2.6 and 6.3 Gy. Two of the BRAF mutated cell lines displayed high sensitivity to vemurafenib, while the third was similar to the wild-type ones.Conclusions and significance: We describe a series of new ATC cell lines demonstrating large heterogeneity in the response to cytostatic drugs and the BRAF inhibitor vemurafenib. The observations are relevant to future attempts to optimize treatment combinations for ATC.

Societal cost of oropharyngeal cancer by human papillomavirus status, cancer stage, and subsite.

BACKGROUND: The incidence of oropharyngeal cancer (OPC) is increasing, particularly human papillomavirus (HPV)-associated OPC. The aim of this study was to specify the total societal cost of OPC by HPV status, cancer stage, and subsite using a bottom-up cost-of-illness approach. METHODS: We analyzed 121 consecutive patients with OPC from the Southern Health Care Region of Sweden. We estimated the direct medical costs and indirect costs (e.g., disease-related morbidity and premature death) from 1 month prior to OPC diagnosis until 3 years after treatment completion. RESULTS: The mean total cost per patient was €103 386 for HPV-positive and €120 244 for HPV-negative OPC. Eighty-one percent of the patients analyzed were HPV-positive: Accordingly, HPV-positive OPC represented 79% of the total cost of OPC. The mean total cost of stage I, II, III, IVA, IVB, and IVC, regardless of HPV status, was €59 424, €57 000, €69 246, €115 770, €234 459, and €21 930, respectively, of which indirect costs were estimated at €22 493 (37.8%), €14 754 (25.9%), €28 681 (41.4%), €67 107 (58%), €166 280 (70.9%), and €0. Tonsillar cancer represented 64% of OPC, with a mean total cost of €117 512 per patient. CONCLUSION: The societal cost of OPC is substantial. HPV-associated OPC comprises 79% of the total cost of this disease. The data presented in this study may be used in analytical models to aid decision makers in determining the potential value of gender-neutral HPV vaccination.

Identification of Targetable Lesions in Anaplastic Thyroid Cancer by Genome Profiling.

Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor with no available cure. The genetic landscape of this malignancy has not yet been fully explored. In this study, we performed whole exome sequencing and the RNA-sequencing of fourteen cases of ATC to delineate copy number changes, fusion gene events, and somatic mutations. A high frequency of genomic amplifications was seen, including 29% of cases having amplification of CCNE1 and 9% of CDK6; these events may be targetable by cyclin dependent kinase (CDK) inhibition. Furthermore, 9% harbored amplification of TWIST1, which is also a potentially targetable lesion. A total of 21 fusion genes in five cases were seen, none of which were recurrent. Frequent mutations included TP53 (55%), the TERT promoter (36%), and ATM (27%). Analyses of mutational signatures showed an involvement of processes that are associated with normal aging, defective DNA mismatch repair, activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity, failure of DNA double-strand break repair, and tobacco exposure. Taken together, our results shed new light on the tumorigenesis of ATC and show that a relatively large proportion (36%) of ATCs harbor genetic events that make them candidates for novel therapeutic approaches. When considering that ATC today has a mortality rate of close to 100%, this is highly relevant from a clinical perspective.

A novel human in vitro papillomavirus type 16 positive tonsil cancer cell line with high sensitivity to radiation and cisplatin.

BACKGROUND: Human papillomavirus (HPV) is an established risk factor for oropharyngeal squamous cell carcinoma (OSCC). The aim was to establish cell lines from HPV-positive tonsil carcinomas to be used for treatment development. METHODS: Fresh samples from 23 HPV-positive tonsil carcinomas were cultivated in vitro. The established cell line was analyzed for viral characteristics, cell karyotype, TP53 status, and growth capabilities in nude mice. In vitro studies of sensitivities to radiation, cisplatin and cetuximab were performed. RESULTS: After 19 months (eight passages), one cell line, LU-HNSCC-26, was established in vitro and also grew as xenografts. The tumor was from a 48 year old non-smoking man with non-keratinizing, p16 positive tonsil OSCC, stage T2N0M0 with HPV16. It contained 19.5 (CV% 3.7) HPV16 copies/cell (passage 8). The complete HPV16 genome sequence was obtained. Episomal HPV16 was present with an E2/E7 ratio of 1.1 (CV% 2.6). In addition, HPV16 mRNA specific for the intact E2 gene was detected. The viral expression manifested 1.0 (CV% 0.1) E7 mRNA copies per HPV16 genome. The karyotype was determined and the cell line demonstrated wild type TP53. The ID50 for radiation was 0.90 Gy and the IC50 for cisplatin was 0.99 µmol/L. The cell line was inhibited to a maximum of 18% by cetuximab. CONCLUSIONS: We established an in vitro tonsil carcinoma cell line containing episomal HPV16. This is an important step towards efficient treatment development.

GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression.

The ETS family transcription factor GABPA is suggested as an oncogenic element, which is further supported by the recent reporting of it as the sole ETS member to activate the mutant TERT promoter in thyroid carcinomas (TC). However, it remains unclear how GABPA contributes to TC pathogenesis. The present study is designed to address this issue. TERT expression was significantly diminished in TERT promoter-mutated TC cells upon GABPA inhibition. Surprisingly, GABPA depletion led to robustly increased cellular invasion independently of TERT promoter mutations and TERT expression. DICER1, a component of the microRNA machinery, was identified as a downstream effector of GABPA. GABPA facilitated Dicer1 transcription while its depletion reduced Dicer1 expression. The mutation of the GABPA binding site in the DICER1 promoter led to diminished basal levels of DICER1 promoter activity and abolishment of GABPA-stimulated promoter activity as well. The forced DICER1 expression abrogated the invasiveness of GABPA-depleted TC cells. Consistently, the analyses of 93 patients with papillary thyroid carcinoma (PTC) revealed a positive correlation between GABPA and DICER1 expression. GABPA expression was negatively associated with TERT expression and promoter mutations, in contrast to published observations in cancer cell lines. Lower GABPA expression was associated with distant metastasis and shorter overall/disease-free survival in PTC patients. Similar results were obtained for PTC cases in the TCGA dataset. In addition, a positive correlation between GABPA and DICER1 expression was seen in multiple types of malignancies. Taken together, despite its stimulatory effect on the mutant TERT promoter and telomerase activation, GABPA may itself act as a tumor suppressor rather than an oncogenic factor to inhibit invasion/metastasis in TCs and be a useful predictor for patient outcomes.

Short half-life of HPV16 E6 and E7 mRNAs sensitizes HPV16-positive tonsillar cancer cell line HN26 to DNA-damaging drugs.

Here we show that treatment of the HPV16-positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan-induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down-regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1-negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half-life of the HPV16 E6 and E7 mRNAs renders HPV16-driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.

Correction: The economic burden of human papillomavirus-related precancers and cancers in Sweden.

[This corrects the article DOI: 10.1371/journal.pone.0179520.].

The DNA damage response activates HPV16 late gene expression at the level of RNA processing.

We show that the alkylating cancer drug melphalan activated the DNA damage response and induced human papillomavirus type 16 (HPV16) late gene expression in an ATM- and Chk1/2-dependent manner. Activation of HPV16 late gene expression included inhibition of the HPV16 early polyadenylation signal that resulted in read-through into the late region of HPV16. This was followed by activation of the exclusively late, HPV16 splice sites SD3632 and SA5639 and production of spliced late L1 mRNAs. Altered HPV16 mRNA processing was paralleled by increased association of phosphorylated BRCA1, BARD1, BCLAF1 and TRAP150 with HPV16 DNA, and increased association of RNA processing factors U2AF65 and hnRNP C with HPV16 mRNAs. These RNA processing factors inhibited HPV16 early polyadenylation and enhanced HPV16 late mRNA splicing, thereby activating HPV16 late gene expression.

Development and external validation of a risk-prediction model to predict 5-year overall survival in advanced larynx cancer.

OBJECTIVES/HYPOTHESIS: TNM-classification inadequately estimates patient-specific overall survival (OS). We aimed to improve this by developing a risk-prediction model for patients with advanced larynx cancer. STUDY DESIGN: Cohort study. METHODS: We developed a risk prediction model to estimate the 5-year OS rate based on a cohort of 3,442 patients with T3T4N0N+M0 larynx cancer. The model was internally validated using bootstrapping samples and externally validated on patient data from five external centers (n = 770). The main outcome was performance of the model as tested by discrimination, calibration, and the ability to distinguish risk groups based on tertiles from the derivation dataset. The model performance was compared to a model based on T and N classification only. RESULTS: We included age, gender, T and N classification, and subsite as prognostic variables in the standard model. After external validation, the standard model had a significantly better fit than a model based on T and N classification alone (C statistic, 0.59 vs. 0.55, P < .001). The model was able to distinguish well among three risk groups based on tertiles of the risk score. Adding treatment modality to the model did not decrease the predictive power. As a post hoc analysis, we tested the added value of comorbidity as scored by American Society of Anesthesiologists score in a subsample, which increased the C statistic to 0.68. CONCLUSIONS: A risk prediction model for patients with advanced larynx cancer, consisting of readily available clinical variables, gives more accurate estimations of the estimated 5-year survival rate when compared to a model based on T and N classification alone. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:1140-1145, 2018.

Cell line dependent expression of EpCAM influences the detection of circulating tumor cells with CellSearch.

OBJECTIVES: The existence of circulating tumor cells has emerged as an important factor for prognosis and survival. The CellSearch method is the only circulating tumor cell detection method approved by the US Food and Drug Administration for clinical use. It relies on the detection of EpCAM (epithelial cell adhesion molecule) and is approved for colon cancer, breast cancer and prostate cancer. We now investigated whether CellSearch can be used to quantify circulating tumor cells in head and neck squamous cell cancer. STUDY DESIGN AND METHODS: In this study, we investigated the expression of EpCAM in 12 head and neck squamous cell cancer cell lines using Western blot and how this affected their detectability with CellSearch in peripheral blood. RESULTS: We found a great variation in the expression of EpCAM between our head and neck squamous cell cancer cell lines. This was accompanied by variations in counting efficiency. CONCLUSION: We suggest that for reliable quantification of circulating tumor cells in blood from patients with head and neck squamous cell cancer cell, an epitope independent method is preferable. LEVEL OF EVIDENCE: NA.

The economic burden of human papillomavirus-related precancers and cancers in Sweden.

BACKGROUND: High-risk (HR) human papillomavirus (HPV) infection is an established cause of malignant disease. We used a societal perspective to estimate the cost of HR HPV-related cervical, vulvar, vaginal, anal, and penile precancer and cancer, and oropharyngeal cancer in Sweden in 2006, 1 year before HPV vaccination became available in the country. MATERIALS AND METHODS: This prevalence-based cost-of-illness study used diagnosis-specific data from national registries to determine the number of HR HPV-related precancers and cancers. The HR HPV-attributable fractions of these diseases were derived from a literature review and applied to the total burden to estimate HR HPV-attributable costs. Direct costs were based on health care utilization and indirect costs on loss of productivity due to morbidity (i.e., sick leave and early retirement) and premature mortality. RESULTS: The total annual cost of all HR HPV-attributable precancers and cancers was €94 million (€10.3/inhabitant). Direct costs accounted for €31.3 million (€3.4/inhabitant) of the total annual cost, and inpatient care amounted to €20.7 million of direct costs. Indirect costs made up €62.6 million (€6.9/inhabitant) of the total annual cost, and premature mortality amounted to €36 million of indirect costs. Cervical precancer and cancer was most costly (total annual cost €58.4 million). Among cancers affecting both genders, anal precancer and cancer, and oropharyngeal cancer were the most costly (€11.2 million and €11.9 million, respectively). For oropharyngeal cancer, males had the highest health care utilization and represented 71% of the total annual cost. Penile precancer and cancer was least costly (€2.6 million). CONCLUSION: The economic burden of HR HPV-related precancers and cancers is substantial. The disease-related management and treatment costs we report are relevant as a point of reference for future economic evaluations investigating the overall benefits of HPV vaccination in females and males in Sweden.