High-dose loco-regional pattern of failure after primary radiotherapy in p16 positive and negative head and neck squamous cell carcinoma - A DAHANCA 19 study.

Introduction: Patients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status. Material and methods: Patients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12. Of 608 patients, 151 had loco-regional failure within five years, from whom 130 pairs of scans (planning-CT and diagnostic failure scan) were collected and deformably co-registered. Point of origin-based pattern of failure analysis was conducted, including distance to CTV1 and GTV, and estimated dose coverage of the point of origin. Results: Of 130 patients with pairs of scans, 104 (80 %) had at least one local or regional failure site covered by 95 % of prescribed dose and 87 (67 %) of the failures had point of origin within the high-dose CTV (CTV1). Of failures from primary p16 + OPSCC, the majority of both mucosal (84 %) and nodal (61 %) failures were covered by curative doses. For p16- tumors (oral cavity, OPSCC p16neg, hypopharynx and larynx), 75 % of mucosal and 66 % of nodal failures were high-dose failures. Conclusion: Radioresistance is the primary cause of failure after RT for HNSCC irrespective of HPV/p16 status. Thus, focus on predictors for the response to RT is warranted to identify patients with higher risk of high-dose failure that might benefit from intensified treatment regimens.

Tumor volume and cancer stem cell expression as prognostic markers for high-dose loco-regional failure in head and neck squamous cell carcinoma - A DAHANCA 19 study.

BACKGROUND AND PURPOSE: Reliable and accessible biomarkers for patients with Head and Neck Squamous Cell Carcinoma (HNSCC) are warranted for biologically driven radiotherapy (RT). This study aimed to investigate the prognostic value of putative cancer stem cell (CSC) markers, hypoxia, and tumor volume using loco-regional high-dose failure (HDF) as endpoint. MATERIALS AND METHODS: Tumor tissue was retrieved from patients treated with primary chemo-(C-)RT and nimorazole for HNSCC in the Danish Head and Neck Cancer Study Group (DAHANCA) 19 study. Tumor volume, hypoxic classification, and expression of CSC markers CD44, SLC3A2, and MET were analyzed. For patients with eligible data on all parameters (n = 340), the risk of HDF following primary chemo-(C-)RT were analyzed by these biomarkers as a whole and stratified for p16-positive oropharynx (p16 + OPSCC) vs p16-negative (p16-) tumors (oral cavity, p16- oropharynx, hypopharynx and larynx). RESULTS: Higher risk of HDF was seen for patients with larger primary and nodal volume (>25 cm3, Hazard Ratio (HR): 3.00 [95 % CI: 1.73-5.18]), high SLC3A2 (HR: 2.99 [1.28-6.99]), CD44 (>30 % positive, HR: 2.29 [1.05-5.00]), and p16- tumors (HR: 2.53 [1.05-6.11]). p16- tumors had a higher CSC marker expression than p16 + OPSCC. The factors associated with the highest risk of HDF were larger volume (HR: 3.29 [1.79-6.04]) for p16- tumors (n = 178) and high SLC3A2 (HR: 6.19 [1.58-24.23]) for p16 + OPSCC (n = 162). CONCLUSION: Tumor volume, p16, and CSC markers are potential biomarkers for HDF for patients with HNSCC treated with (C-)RT. Lower expression of CSC in p16 + OPSCC may contribute to better tumor control.

HPV testing versus p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: results from the DAHANCA 19 study.

INTRODUCTION: The prognosis after primary (chemo-)radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) is affected by Human Papillomavirus (HPV) status, with a better prognosis in HPV-positive OPSCC. HPV-status is routinely assessed by p16 immunohistochemistry (IHC), but additional HPV DNA testing is debated. Also, there are numerous HPV genotypes, which prognostic role may need clarification. The purpose of this study was: (1) to test a custom-made targeted HPV next generation sequencing (NGS) panel in OPSCC, (2) to determine correlation with p16 IHC, and (3) to assess the impact of HPV DNA testing on outcome in the prospectively randomized clinical trial DAHANCA 19. MATERIALS AND METHODS: We included 271 patients with OPSCC treated with primary (chemo-)radiotherapy in the DAHANCA 19 trial. Of these, 199 (73%) were p16-positive. HPV-status was determined by targeted HPV next generation sequencing (NGS), using a custom-made HPV genotyping panel. RESULTS: HPV was detected in 194 tumor samples. p16 IHC and NGS HPV status were concordant in 265 (98%) of 271 patients, whereas we did not detect HPV DNA in 5 p16-positive tumors. HPV16 accounted for 169 of 194 HPV-positive cases (87%). HPV genotypes 18, 31, 33, 35, and 59 were also detected.Loco-regional failure and overall survival were similar whether patients were separated by p16 IHC, or HPV DNA status (p < 0.0001 for all) and did not depend on HPV genotype (p = 0.9 and p = 0.7). CONCLUSION: In the present study, HPV DNA testing or typing in a Danish OPSCC cohort did not add additional information to p16 IHC, the most widely used and accepted prognostic indicator.

Socioeconomic position and the pre-diagnostic interval among patients diagnosed with head and neck squamous cell carcinoma - a population-based study from DAHANCA.

BACKGROUND: The socioeconomic differences in survival are pronounced for patients diagnosed with head and neck cancer; disease stage at diagnosis is suggested to be a main driver of this association. This nationwide, population-based study investigates socioeconomic differences in the pre-diagnostic interval and disease stage at diagnosis. MATERIAL AND METHODS: Information on patient-reported symptoms, symptom onset and disease-specific factors was obtained from the nationwide population-based Danish Head and Neck Cancer Group (DAHANCA) database for patients diagnosed with head and neck squamous cell carcinoma between 2008 and 2019 in Denmark. Socioeconomic position (SEP) was measured by individual-level education, income and cohabitation status obtained from administrative registers. Socioeconomic differences in the interval from symptom onset to diagnosis were investigated in general linear models with 95% confidence intervals (CIs); overall and by subsite, symptom and comorbidity score. Consultation patterns prior to diagnosis were examined using methods for change-point detection. Associations with advanced-stage disease were estimated in logistic regression models. RESULTS: Patients with low, medium and high SEP had a similar interval from patient-reported symptom onset to diagnosis of 10 weeks. Although this interval varied according to primary symptom and anatomical subsite, no apparent socioeconomic differences were observed within these subgroups. Aligned with the patient-reported symptom onset, a distinct increase in consultation rates was observed at 9 weeks (95% CI [7.3; 10.7]) for patients with low SEP and 7 weeks (95% CI [4.8; 9.2]) for patients with high SEP, with overlapping CIs. Patients with low compared to high SEP had increased odds for advanced-stage glottic and oral cavity squamous cell carcinoma. For the remaining subsites the association varied according to SEP-indicator and TNM-edition. CONCLUSION: The interval from symptom onset to diagnosis and consultation patterns were similar across SEP groups. Still, socioeconomic differences in stage at diagnosis were observed for some - but not all - subsites.

Association of Smoking, Comorbidity, Clinical Stage, and Treatment Intent With Socioeconomic Differences in Survival After Oropharyngeal Squamous Cell Carcinoma in Denmark.

Importance: The socioeconomic gap in survival after cancer is pronounced among patients with head and neck cancer. Understanding the mechanisms of this gap is crucial to target intervention strategies. Objective: To investigate socioeconomic differences in survival after oropharyngeal squamous cell carcinoma (OPSCC) according to human papillomavirus (HPV) status and the extent to which smoking, comorbidity, clinical stage, and treatment intent explain the survival gap. Design, Setting, and Participants: This nationwide, population-based cohort study was based on prospectively collected information on all patients with a diagnosis of OPSCC from the Danish Head and Neck Cancer Group database and administrative registries. The study included 4600 patients born in 1921 or later, aged 30 years or older, and residing in Denmark 1 year prior to OPSCC diagnosis. Patients with missing information (547 [12%]) were excluded. Patients were diagnosed between January 1, 2008, and December 31, 2019, and followed up until December 31, 2021. Data were analyzed from June 6 to October 4, 2022. Exposure: Socioeconomic position (educational level, disposable income, or cohabiting status). Main Outcomes and Measures: Socioeconomic differences in 5-year overall survival were estimated in Cox proportional hazards regression models by HPV status. The indirect effect and proportion mediated by smoking, comorbidity, clinical stage, and treatment intent were estimated based on a counterfactual approach. Results: The analyzed cohort comprised 4053 patients (1045 women [26%] and 3008 men [74%]). The median age was 61 years (IQR, 55-68 years), and 2563 patients (63%) had HPV-positive OPSCC while 1490 patients (37%) had HPV-negative OPSCC. The 5-year standardized overall survival was 10% to 15% lower among patients with a lower educational level, with low disposable income, or who were living alone (patients with HPV-positive OPSCC, 68%-71%; patients with HPV-negative OPSCC, 31%-34%) than patients with a higher educational level, high disposable income, or a cohabiting partner (patients with HPV-positive OPSCC, 81%-86%; patients with HPV-negative OPSCC, 43%-46%). Among patients with HPV-positive OPSCC, a considerable part of this survival gap was estimated to be associated with differences in smoking (27%-48%), comorbidity (10%-19%), clinical stage (8%-19%), and treatment intent (16%-28%). Among those with HPV-negative OPSCC, comorbidity (12%-22%) and treatment intent (16%-42%) were the primary potential mediators. Conclusions and Relevance: This cohort study suggests that, regardless of HPV status, patients with low socioeconomic position had 10% to 15% lower 5-year overall survival than patients with high socioeconomic position. A substantial part of this survival gap was associated with differences in smoking, comorbidity, clinical stage, or treatment intent at diagnosis.

Nasal vestibule squamous cell carcinoma: a population-based cohort study from DAHANCA.

BACKGROUND: Cancer of the nasal vestibule is a rare type of malignancy dominated by squamous cell carcinoma (SCC), and with poor survival. The treatment is either radiotherapy, surgery or a combination of both. Previous studies have shown a 5-year disease-specific survival of 74% and overall survival (OS) of 50%.Our objective was to describe the consecutive cohort of patients diagnosed with SCC of the nasal vestibule in Denmark from 2008 until 2018 and evaluate prognostic factors and treatment outcome using locoregional failure (LRF), disease-specific mortality (DSM), and OS as endpoints. METHODS: All patients diagnosed with SCC of the nasal vestibule from 2008 until 2018 were identified in the nationwide clinical database, DAHANCA and were followed for LRF and death (DSM and OS) until March 2021. OS was analysed using Kaplan-Meier estimator, and cumulative incidence of LRF and DSM were analysed using the Aalen-Johansen estimator. Analysis of prognostic factors was performed using Cox proportional hazard models. RESULTS: A total of 162 patients were identified. The median age was 71 years and 54% were male. Disease stage at the time of diagnosis were stage I (70%), II (17%), III (2%) and IV (11%). Curatively intended treatment was performed in 146 patients (90%), of which treatment failure occurred in 42 patients (29%). Most failures occurred at the primary tumour site (64%). Cancer Patient Pathways recommended time to treatment was fulfilled in 71% of patients. The 5-year OS and DSM in patients treated with curative intent were 65% and 11%, respectively. Stage was a significant independent prognostic factor. No difference in LRF, DSM or OS were shown between the applied treatments. CONCLUSIONS: Stage is the main independent prognostic factor, and failure most commonly appear at the primary tumour site.

Treatment outcomes and survival following definitive (chemo)radiotherapy in HPV-positive oropharynx cancer: Large-scale comparison of DAHANCA vs PMH cohorts.

We compare outcomes in two large-scale contemporaneously treated HPV-positive (HPV+) oropharynx cancer (OPC) cohorts treated with definitive radiotherapy/chemoradiotherapy (RT/CRT). p16-confirmed HPV+ OPC treated between 2007 and 2015 at PMH and DAHANCA were identified. Locoregional failure (LRF), distant metastasis (DM), and overall survival (OS) were compared. Multivariable analysis (MVA) calculated adjusted-hazard-ratio (aHR) with 95% confidence interval (95% CI), adjusting for cohort, age, gender, performance status, smoking pack-years, T-category and N-category and chemotherapy. Compared to PMH (n = 701), DAHANCA (n = 1174) contained lower TNM-8T-categories (T1-T2: 77% vs 56%), N-categories (N0-N1: 77% vs 67%) and stages (stage I: 63% vs 44% (all P < .001). PMH used standard-fractionation CRT in 69% (481) while 31% (220) received hypofractionated or moderately accelerated RT-alone. All DAHANCA patients were treated with moderately accelerated RT; 96% (1129) received nimorazole (NIM) and 73% (856) concurrent weekly cisplatin. DAHANCA had shorter overall-treatment-time (P < .001), lower gross tumor (66-68 vs 70 Gy) and elective neck (50 vs 56 Gy) doses. Median follow-up was 4.8 years. DAHANCA had higher 5-year LRF (13% vs 7%, aHR = 0.47 [0.34-0.67]), comparable DM (7% vs 12%, aHR = 1.32 [0.95-1.82]), but better OS (85% vs 80%, aHR = 1.30 [1.01-1.68]). CRT patients had a lower risk of LRF (aHR 0.56 [0.39-0.82]), DM (aHR 0.70 [0.50-1.00]) and death (aHR 0.39 [0.29-0.52]) vs RT-alone. We observed exemplary outcomes for two large-scale trans-Atlantic HPV+ OPC cohorts treated in a similar manner. Concurrent chemotherapy was a strong, independent prognostic factor for all endpoints. Our findings underscore the need for a very careful approach to de-intensification of treatment for this disease.

Sinonasal cancer in Denmark 2008-2015: a population-based phase-4 cohort study from DAHANCA.

BACKGROUND: Sinonasal cancer is considered a rare disease with poor survival. Its treatment has changed profoundly in recent years, primarily following the introduction of intensity-modulated radiation therapy (IMRT) and minimally invasive endoscopic surgery. Danish national guidelines on treatment of patients diagnosed with sinonasal carcinoma were introduced in 2007. The aim of this phase-4 study was to assess the effect of the implementation of guidelines by describing treatment outcomes in a consecutive nationwide cohort. METHODS: All patients diagnosed with sinonasal carcinoma in Denmark from 2008 to 2015 were identified in the nationwide clinical database, DAHANCA, and were followed until May 2020. Overall survival (OS) was analysed using Kaplan-Meier estimator. Cumulative incidence of locoregional failure (LRF) and disease-specific mortality (DSM) were analysed using the Aalen-Johansen estimator. Competing risks were death from other causes (DSM) and distant failure and death (LRF). Analysis of prognostic factors was performed using Cox proportional hazard analysis. Start of follow-up was time of diagnosis. The results are presented as estimates with 95% confidence intervals (95% CIs). RESULTS: A total of 331 patients were identified. Curatively intended treatment was performed in 264 patients (80%). Non-compliance with treatment guidelines was registered in 24 patients (9%). Non-compliance was associated with LRF (hazard ratio [HR], 2.0 [95% CI: 1.1-3.5]). Among patients qualified for curative treatment, failure occurred in 109 patients (41%), primarily at the primary tumour site (81%). Anatomical tumour site and disease stage were independent prognostic factors. The 5-year OS was 56% in patients treated with curative intent, and a combined treatment strategy showed reduced LRF (HR, 0.53 [95% CI: 0.30-0.92]) in a multivariate analysis. CONCLUSIONS: Guideline compliance and a combined treatment approach reduced the incidence of LRF and thereby increased OS. Our results confirm those of international studies. Treatment of sinonasal carcinoma remains a challenge that requires multidisciplinary team coordination.

Influence of FAZA PET hypoxia and HPV-status for the outcome of head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy: Long-term results from the DAHANCA 24 trial (NCT01017224).

PURPOSE: Hypoxic tumor volumes can be visualized with 18F-FAZA PET/CT. In head and neck squamous cell carcinoma (HNSCC), hypoxia is important for the clinical outcome after primary radiotherapy (RT). The outcome is furthermore heavily influenced by the HPV/p16-positivity of oropharyngeal tumors (OPCp16+ tumors). The study purposes were (1) to report on locoregional failures within five years after primary RT in a prospective cohort stratified by both HPV/p16-status and PET hypoxia and (2) to characterize the failure site and the spatial association to PET hypoxia. MATERIAL AND METHODS: From 2009 to 2011, 38 patients with non-metastatic SCC of the larynx, oro-, hypo- and nasopharynx completing primary RT were included in the prospective DAHANCA 24 trial (NCT01017224). Fifteen patients had OPCp16+ tumors. All were imaged with a static FAZA PET/CT prior to treatment. The hypoxia threshold was determined by a tumor-to-muscle ratio (TMR) of 1.6. Recurrences were documented histologically. Imaging of the recurrence was deformable fused with the pre-treatment FAZA PET/CT. The spatial information of recurrence- and hypoxic volumes were compared visually. RESULTS: Sixteen patients had more hypoxic tumors (high tracer uptake, TMR ≥1.6) before treatment (42%). With a median follow-up of 7.8 years, nine locoregional recurrences were observed, of which seven were in patients with high-uptake tumors (44% and 9%, respectively, HR 5.8 [1.2-28.2]). The risk of locoregional recurrence was highest among patients with more hypoxic, non-OPCp16+ tumors (57% [21-94%]), with a risk difference of 45% [4-86%], when comparing to less hypoxic, non-OPCp16+ tumors. Eight patients had sufficient imaging of the recurrence for co-registration with the FAZA PET/CT. Six had hypoxic primary tumors, and in two, the recurrence was overlapping the baseline hypoxic subvolume. CONCLUSION: HNSCC demonstrating a TMR ≥1.6 at baseline is significantly associated with treatment failure after primary RT. In addition to HPV/p16-status, FAZA PET/CT has potential for the selection of tumors requiring treatment intensification.

A prospective, multicenter DAHANCA study of hyperfractionated, accelerated radiotherapy for head and neck squamous cell carcinoma.

Background: The study aimed to evaluate Hyperfractionated, Accelerated Radiotherapy (HART) with nimorazole for patients with head and neck squamous cell carcinoma (HNSCC) using loco-regional failure (LRF), overall survival (OS), early and late morbidity as endpoints. Material and methods: From February 2007 to January 2018, 295 patients with unresected HNSCC, T1-T4, N0-N3, M0, were treated with HART prescribed as 76 Gy in 56 fractions (fx), 10 fx weekly. IMRT was used in >90% of patients. No chemotherapy was given. Patients were prospectively registered in the DAHANCA database. Results: The median age was 64 years, 75% of patients were males. Primary sites were larynx (25%), pharynx (64%) and oral cavity (11%). In total, 59% were stage III-IV (UICC 2002). Of the 150 oropharyngeal cancer (OPC) patients, 42% were p16+. The proportion of patients receiving HART as planned was 97%. The median follow-up time was 66 months. Three-year actuarial LRF was 19% and OS was 66%. LRF was significantly higher for stage III-IV patients compared to stage I-II (25% vs. 11%, HR 2.12 [1.21-3.74]). The site-specific LRF rates were: for larynx 22% [12-32], hypopharynx 30% [16-45], non-p16+ oropharynx 15% [8-23], p16+ oropharynx 7% [1-13] and oral cavity 35% [18-53]. During therapy, 51% reported severe dysphagia and 60% required feeding tubes. The peak incidence of late, severe dysphagia and xerostomia was 21% and 9%, respectively. A comparison to historical data from previous DAHANCA trials showed that tumor control and morbidity are comparable to treatment with acceleration and/or chemo-radiation. Conclusions: HART represents an attractive approach for patients with HNSCC where treatment intensification is indicated.

Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial.

PURPOSE: To study the associations between development of moderate to severe skin rash, clinical outcome, and single nucleotide polymorphisms (SNPs) in candidate genes in head and neck cancer patients from the DAHANCA 19 trial receiving the EGFR-inhibitor zalutumumab concurrently with radiation treatment. MATERIAL AND METHODS: 310 patients were included from the zalutumumab-arm of the DAHANCA 19 study. Nine SNPs in the candidate genes EGFR, EGF, AREG, FCGR2A, FCGR3A, and CCND1 were successfully determined in 294 patients. Clinical endpoints were moderate to severe skin rash within the first 3 weeks of treatment, loco-regional failure (LRF), disease-specific survival (DSS), and overall survival (OS). RESULTS: During the first 3 weeks of treatment, 86% of the patients experienced any grade of rash and 17% experienced a moderate to severe rash. Development of moderate to severe rash was not associated with LRF or DSS but was associated with improved OS, HR 0.40 (95% CI: 0.19-0.82). The effect was similar for patients with p16-negative or p16-positive tumors (p = .90). After adjustment for comorbidity and performance status, the minor alleles of SNPs rs9996584 and rs13104811 located near the AREG gene were significantly associated with increased risk of moderate to severe rash with per-allele odds ratios of 1.61 (1.01-2.54) and 1.56 (1.00-2.44). SNP rs11942466 located close to rs9996584 had a borderline significant association, and none of the other SNPS were significantly associated with risk of skin rash. CONCLUSIONS: Moderate to severe skin rash after zalutumumab during radiation treatment was associated with improved OS, independent of HPV/p16-status. Genetic variants in AREG (member of the EGF family) may be associated with increased risk of skin rash.

Oncocytic carcinoma of the salivary glands: A Danish national study.

OBJECTIVES: To present a Danish national series of oncocytic carcinoma (OC) patients, including data on treatment, recurrence and survival. METHODS: From the national Danish database of salivary gland carcinomas, all patients diagnosed with OC from 1990 to 2005 were identified and data concerning demographics, tumor site, clinical stage and treatment profiles were extracted. A follow-up was carried out. RESULTS: Of the 15 cases of salivary gland OC, eight were female. The incidence was 0.02/100.000 inhabitants per year in Denmark, 13 patients presented with OC in the parotid gland and two patients with OC in the submandibular gland. Eight patients had nodal involvement at the time of diagnosis. None of the patients had distant metastases at the time of diagnosis. All patients were treated with primary surgery and seven patients received adjuvant radiotherapy. Half of the patients had recurrence. Six patients were alive at 5 years follow up and one patient was alive without recurrence at 10 years follow up. CONCLUSIONS: This study is the first to report a national incidence of oncocytic carcinoma in the salivary glands. The results confirm oncocytic carcinoma to be a salivary gland carcinoma with a poor prognosis. All patients experiencing recurrence died of the disease. Treatment must be aggressive. National registries are necessary to achieve further knowledge for future treatment recommendations.

Progressive resistance training in head and neck cancer patients during concomitant chemoradiotherapy -- design of the DAHANCA 31 randomized trial.

BACKGROUND: Head and neck cancer patients undergoing concomitant chemoradiotherapy (CCRT) frequently experience loss of muscle mass and reduced functional performance. Positive effects of exercise training are reported for many cancer types but biological mechanisms need further elucidation. This randomized study investigates whether progressive resistance training (PRT) may attenuate loss of muscle mass and functional performance. Furthermore, biochemical markers and muscle biopsies will be investigated trying to link biological mechanisms to training effects. METHODS: At the Departments of Oncology at Herlev and Aarhus University Hospitals, patients with stage III/IV squamous cell carcinoma of the head and neck, scheduled for CCRT are randomized 1:1 to either a 12-week PRT program or control group, both with 1 year follow-up. Planned enrollment is 72 patients, and stratification variables are study site, sex, p16-status, and body mass index. Primary endpoint is difference in change in lean body mass (LBM) after 12 weeks of PRT, assessed by dual-energy X-ray absorptiometry (DXA). The hypothesis is that 12 weeks of PRT can attenuate the loss of LBM by at least 25%. Secondary endpoints include training adherence, changes in body composition, muscle strength, functional performance, weight, adverse events, dietary intake, self-reported physical activity, quality of life, labor market affiliation, blood biochemistry, plasma cytokine concentrations, NK-cell frequency in blood, sarcomeric protein content in muscles, as well as muscle fiber type and fiber size in muscle biopsies. Muscle biopsies are optional. DISCUSSION: This randomized study investigates the impact of a 12-week progressive resistance training program on lean body mass and several other physiological endpoints, as well as impact on adverse events and quality of life. Furthermore, a translational approach is integrated with extensive biological sampling and exploration into cytokines and mechanisms involved. The current paper discusses decisions and methods behind exercise in head and neck cancer patients undergoing concomitant chemoradiotherapy. TRIAL REGISTRATION: Approved by the Regional Ethics Committee for the Capital Region of Denmark (protocol id: H-15003725) and registered retrospectively at ClinicalTrials.gov ( NCT02557529 ) September 11th 2015.

Incidence of and survival after glottic squamous cell carcinoma in Denmark from 1971 to 2011-A report from the Danish Head and Neck Cancer Group.

AIM: To describe the incidence, disease-specific mortality (DSM), and overall survival (OS) of patients with glottic squamous cell carcinomas (SCC) in Denmark from 1971-2011 in a national population-based cohort of consecutive patients. MATERIALS AND METHODS: All patients diagnosed with glottic SCC stage I-IV between 1971 and 2011 in Denmark were included. Patients were identified from the Danish Head and Neck Cancer database, which has a coverage of approximately 100% of registered glottic cancer in Denmark. Information on vital status and cause of death were updated using patient charts and national registries. RESULTS: In total 5132 patients with glottic SCC were included. The yearly number of new cases increased from 107 in the 1970s to 139 in the 2000s. Overall, the incidence increased from 1.9 to 2.6 per 100,000, with a more prominent increase in men (3.5 to 4.7) compared with women (0.4 to 0.6). The 5-year DSM was 16% (15-17%) and the 5-year OS was 63% (61-64). The hazard rate of DSM adjusted for patient characteristics, tumour characteristics and waiting-time was significantly lower in the 2000s (p < 0.01), and the hazard rate of OS was significantly higher (p < 0.01) compared to the earlier decades. Longer waiting-time for treatment (>25 d) significantly increased DSM and reduced OS. CONCLUSION: Despite being highly avoidable with smoking cessation, the incidence of glottic SCC increased in Denmark from 1971-2011. The adjusted hazard rate of DSM and overall death after glottic SCC was significantly lower in the 2000s compared to previous decades. Waiting-time for treatment significantly influenced DSM and OS.

Polymorphous low-grade adenocarcinoma: A Danish national study.

OBJECTIVES: To present a national series of polymorphous low-grade adenocarcinoma (PLGA) patients, including survival rates and an analysis of prognostic factors. MATERIALS AND METHODS: By merging three Danish nationwide registries, 73 patients diagnosed with PLGA from 1990 to 2005 were identified. Histological slides were reviewed and data concerning demographics, tumour site, clinical stage, treatment profiles and follow-up were retrieved. Survival estimates and prognostic factors were evaluated by comparing Kaplan-Meier plots using the Mantel-Haenszel log-rank test. RESULTS: Of the 73 patients, 47 (64%) were female. Median age was 58years. The most common location was the palate (73%). Median latency was five months. Recurrence was seen in 13% of patients. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) rates after 10years were 73%, 99% and 83%, respectively. Univariate analyses suggested that free resection margins significantly improve RFS. CONCLUSION: PLGA usually has an excellent survival outcome even in cases of advanced stage disease and locoregional recurrence. Primary choice of treatment should be complete surgical excision. Although there is no convincing evidence for the efficacy of adjuvant radiotherapy, it should still be considered, particularly in cases of involved resection margins and advanced stage disease. Late recurrences are common and respond well to salvage therapy.

Pattern of failure in 5001 patients treated for glottic squamous cell carcinoma with curative intent - A population based study from the DAHANCA group.

PURPOSE: To describe the pattern of failure in a national consecutive cohort of patients with glottic squamous cell carcinomas (SCC) treated with primary radiotherapy (RT) with curative intent over a 41-year period. MATERIALS AND METHODS: All patients undergoing curative treatment for a glottic SCC diagnosed in Denmark between 1971 and 2011 were included and followed from the first contact with the oncology center to death or February 15, 2015. RESULTS: 5001 patients were identified of whom 98% had primary RT. The median follow-up was 9.1 years/5.7 years (patients alive/patients who died). Ten patients were lost to follow-up. In total 1511 failures were observed; of these 93%, 11% and 5% included T site, N site, and M site, respectively. For patients diagnosed in the 70s and the 00s, respectively, the five-year incidences were: local failure (32% vs 19%), loco-regional failure (34% vs 21%), laryngectomy (26% vs 10%), laryngectomy-free survival (48% vs 62%), disease-free survival (62% vs 68%), and overall survival (62% vs 68%). The five-year incidence of ultimate failure (13-16%) remained statistically unchanged. CONCLUSION: From the 70s to the 00s a continually improving primary disease-control was observed with a concurrent decrease in the incidence of laryngectomy. The survival rate was significantly higher in the 00s compared to the previous three decades.

Salivary duct carcinoma: a Danish national study.

BACKGROUND: To present the first national series of salivary duct carcinoma patients, including survival rates and an analysis of prognostic factors. METHODS: By merging three Danish nationwide registries that encompass an entire population, 34 patients diagnosed with salivary duct carcinoma from 1990 to 2005 were identified. Histological slides were reviewed, and data concerning demographics, tumour site, clinical stage, treatment profiles and follow-up were retrieved. Survival estimates and prognostic factors were evaluated by comparing Kaplan-Meier plots using the Mantel-Haenszel log-rank test. RESULTS: Salivary duct carcinoma showed an incidence of 0.04/100.000 inhabitants/year. Distant recurrence was seen in 52% of patients. Five-year overall survival, disease-specific survival and recurrence-free survival were 32%, 42% and 35%, respectively. Univariate analyses suggested that overall stage (III/IV) and vascular invasion have a negative impact on all survival measures. Involved resection margins correlated with a poorer overall survival and disease-specific survival, whereas adjuvant radiotherapy improved overall survival and recurrence-free survival. CONCLUSIONS: Salivary duct carcinoma incidence averages to two episodes per year in the entire Kingdom of Denmark. With half of patients in this study experiencing distant recurrences and only a third surviving at 5 years, prognosis is dismal. Advanced overall stage, vascular invasion and involved resection margins all seem to correlate with a poorer survival, while adjuvant radiotherapy significantly improved outcome. Extensive T-site surgery, neck dissection and adjuvant radiotherapy are therefore recommended.

Collagen fragment biomarkers as serological biomarkers of lean body mass - a biomarker pilot study from the DAHANCA25B cohort and matched controls.

BACKGROUND: Loss of muscle mass and function is an important complication to ageing and a range of pathologies, including, but not restricted to, cancer, organ failures, and sepsis. A number of interventions have been proposed ranging from exercise to anabolic pharmacological therapy, with varying success. Easily applicable serological biomarkers of lean and/or muscle mass and change therein would benefit monitoring of muscle mass during muscle atrophy as well as during recovery. We set out to validate if novel peptide biomarkers derived from Collagen III and VI were markers of lean body mass (LBM) or change therein in head and neck cancer patients in the Danish Head and Neck Cancer Group(DAHANCA) 25B cohort subjected to resistance training as well as in an age-matched and gender-matched control group. METHODS: Blood samples and dual X-ray absorptiometry data were measured at baseline, after 12 and 24 weeks in 41 HNSCC subjects of the DAHANCA 25B cohort of subjects recovering from neck and head cancer (stages provided in Table 1), and at baseline only in 21 healthy age-matched and gender-matched controls. Serum from blood was analyzed for the ProC3, IC6, and C6M peptide biomarkers and LBM were derived from the dual X-ray absorptiometry scans. RESULTS: We were not able to show any correlation between biomarkers and LBM or C6M and anabolic response to exercise in recovering head and neck cancer patients. However, we did find that the biomarkers IC6, IC6/C6M, and ProC3 are biomarkers of LBM in the control group subjects (R (2)/P of 0.249/0.035, 0.416/0.007 and 0.178 and P = 0.057, respectively). CONCLUSION: In conclusion, the IC6, ProC3, and IC6/C6M biomarkers are indeed biomarkers of LBM in healthy individuals of both genders, but not in HNSCC patients.

Salivary adenoid cystic carcinoma in Denmark 1990-2005: Outcome and independent prognostic factors including the benefit of radiotherapy. Results of the Danish Head and Neck Cancer Group (DAHANCA).

AIM: To describe outcome and prognostic factors, including the effect of radiotherapy, in a consecutive national series of salivary gland adenoid cystic carcinomas. METHODS: From the national Danish salivary gland carcinoma database in the structure of DAHANCA, 201 patients diagnosed with adenoid cystic carcinoma, and treated with a curative intent, were identified in the period between 1990 and 2005. Variables necessary for statistical analyses were extracted from the database. RESULTS: The 10-year crude survival and disease specific survival rates were 58% and 75%, respectively. The 10-year locoregional control rate was 70%, and 36% of patients experienced a recurrence during follow-up (median 7.5 years); 18% developed distant metastases (most commonly to the lungs). In multivariate analysis, stage and margin status were both important factors with regards to survival and locoregional control. Radiotherapy did not improve survival, but it did improve the locoregional control rate. CONCLUSIONS: The treatment of choice is surgery with as wide margins as possible including elective, selective neck dissection. Adjuvant radiotherapy should be considered in patients with incomplete tumor resection, high disease stages, and tumors with a solid growth pattern.