Epidemiological trends and survival of oropharyngeal cancer in a high HPV-prevalent area: A Danish population-based study from 2000 to 2020.

Denmark, alongside other Scandinavian countries, the United States, Canada, and the United Kingdom, has high prevalence of human papillomavirus (HPV). Our oropharyngeal squamous cell carcinoma (OPSCC) database includes all diagnosed cases in Eastern Denmark during a period of more than two decades. We investigated the incidence, survival, and recurrence of patients with OPSCC with combined p16- and HPV testing covering a consecutive 21-year period. Age-adjusted incidence rate (AAIR) per 100,000, survival models, and Cox proportional-hazards model were employed. Two thousand eight hundred thirty-four patients were included (57.5% HPV positive (HPV+)/p16 positive (p16+), 33.7% HPV negative (HPV-)/p16 negative (p16-), 4% HPV+/p16-, and 4.8% HPV-/p16+). The AAIR for all patients increased from 1.8 to 5.1 per 100,000 from 2000 to 2020 linked to an increasing AAIR of HPV+/p16+ OPSCCs from 0.9 to 3.5 per 100,000 from 2000 to 2020. The AAIR for the HPV-/p16- OPSCCs decreased from 1.6 to 1.4 from 2017 to 2020. HPV+/p16+ OPSCCs had a higher 5-year overall survival (OS) of 79.2% compared to the other subgroups (HPV+/p16- OS: 50.4%; HPV-/p16+ OS: 49.4%; HPV-/p16- OS: 35.1%). The AAIR of the total OPSCC group increased from year 2000 to 2020, driven by a rise in the HPV+/p16+ group. A decreasing incidence rate was observed for the HPV-/p16- OPSCCs from 2017 to 2020. The OS for HPV+/p16+ OPSCCs was significantly higher compared to all other HPV/p16 subgroups. Therefore, we recommend testing for combined HPV and p16 status in patients with OPSCC when selecting patients for clinical trials, especially in case of de-escalating/escalating.

Efficacy of nivolumab as second line treatment for recurrent or metastatic head and neck squamous cell carcinoma: a national DAHANCA cohort study.

INTRODUCTION: The aim of this study was to investigate phase IV efficacy, of the PD-1 inhibitor nivolumab among an unselected and unbiased national cohort of recurrent/metastatic Head and Neck Squamous Cell Carcinoma (rmHNSCC) patients. MATERIAL AND METHODS: Inclusion criteria included histologically confirmed rmHNSCC and nivolumab as a second-line palliative treatment. Data were collected from patient files at the five Danish head and neck cancer centers and from the DAHANCA database. The iRECIST criteria were used for treatment evaluation.Endpoints were response rate (RR), overall survival (OS), and progression-free survival (PFS), calculated from the start of treatment to the date of event/censoring by the KM-method. Descriptive statistics were used to describe patients and treatment. Analyses were two-sided, with p < .05 considered significant. RESULTS: A total of 146 patients were identified in the period 2017-2020. They had a RR of 14%, median OS of 10.2 months [95% CI: 8.2-12.2] and median PFS of 3.1 months [95% CI: 2.3-4.2]. Patient age (≥ 70 years) or comorbidity did not significantly affect outcome. WHO performance status (PS) =1 was associated with an increased risk of death (HR: 2.1 [95% CI: 1.2-4.0], p = .02) and progression (HR: 1.9 [95% CI: 1.2-3.2], p = .01). Concomitant glucocorticoid-treatment during immunotherapy (≥ 50% of treatment time) appeared important for risk of death (HR: 6.4 [95% CI: 2.3-17.8], p < .001) and risk of progression (HR: 4.8 [95% CI: 1.8-12.5], p = .001). PD-L1 expression ≥ 20% was associated with a lowered risk of progression (HR: 0.5 [95% CI: 0.3-0.7], p = .001), but not lowered risk of death. CONCLUSION: In this unselected national cohort, outcome of second-line treatment reflects data from the registration studies. Furthermore, the results suggest that immunotherapy should be used with great care in treatment of rmHNSCC in patients with poor performance.

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.

Comparison of methods for estimating glomerular filtration rate in head and neck cancer patients treated with cisplatin.

Cisplatin is a chemotherapeutic agent widely used in the treatment of various solid tumors. Cisplatin induces nephrotoxicity and may lead to long-term reduction of kidney function. Consequently, determination of glomerular filtration rate (GFR) is used to monitor potential kidney damage. This study aimed to compare two commonly used algorithms for estimating GFR (eGFR) from plasma creatinine (PCr) with 51Cr-EDTA clearance (CrCl) as a reference method. This was a retrospective single center study of 94 head and neck cancer patients treated with cisplatin. CrCl was performed once before, during, and after treatment, and PCr was measured concurrently. eGFR was assessed from PCr applying the Cockcroft-Gault (CG) and the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations. Agreement was assessed applying the statistical methods of Bland and Altman. A predefined limit of clinically acceptable variation between CrCl and eGFR of 14% was applied. Comparison of CrCl and eGFRCKD revealed a positive slope of the linear regression line, suggesting proportional bias (p < 0.001). No systematic bias was found for eGFRCG. Pre-treatment, 42 (46%), 53 (56%) and 48 (53%) observations were within the clinically acceptable limit of variation for standardized eGFRCKD, BSA corrected eGFRCKD, and eGFRCG, respectively. The observed body weight changes were significant. In conclusion, estimated GFRCKD cannot sufficiently replace CrCl in the assessment of GFR during treatment with cisplatin due to systematic bias. Consequently, if CrCl is unavailable, then the CG equation is the better choice provided proper attention is paid to the large variation between methods.

Primary transoral robotic surgery with concurrent neck dissection for early stage oropharyngeal squamous cell carcinoma implemented at a Danish head and neck cancer center: a phase II trial on feasibility and tumour margin status.

There is an increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the western world due to human papillomavirus (HPV). According to the Danish Head and Neck Cancer Group guidelines, the current recommended treatment of patients with OPSCC in Denmark is primary radiation therapy (RT) with or without concomitant chemotherapy. This is the first study in Scandinavia from a head and neck cancer centre that aims to demonstrate the feasibility of performing primary transoral robotic surgery (TORS) and concurrent neck dissection for patients with early stage OPSCC. Between September 2014 and January 2016, 30 consecutive patients with clinical T1-T2, N0-N1 OPSCC underwent primary TORS and concurrent neck dissection. The patients were offered postoperative adjuvant therapy according to pathological risk parameters: pT >2, T-site margin <2 mm, pN >1 or extracapsular extension (ECE). Concomitant chemotherapy was offered to patients with the presence of ECE or involved margins. Twenty-nine patients had negative margins on T-site after primary resection. Only one patient had a close margin of 1 mm. Unilateral neck dissection was performed in 21 patients while nine patients underwent bilateral neck dissection. Due to an upstaging following surgery, 13 patients were referred to adjuvant therapy. Four of these patients received RT and two patients received concomitant chemo-radiation (CCR) therapy. Seven patients declined the recommended adjuvant therapy one of whom later developed an N-site recurrence and received salvage surgery with postoperative RT. In summary, 43% of the patients were referred to adjuvant therapy following primary surgery which was mainly due to N-site stage migration and ECE. Primary TORS and concurrent neck dissection is a safe and feasible procedure that may be an alternative to primary RT and CCR in a selected group of patients with early stage OPSCC.

Locally advanced head and neck cancer treated with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. Results from the DAHANCA 18 phase II study.

PURPOSE/OBJECTIVE: A phase II clinical trial evaluating the feasibility and outcome of treating locally advanced head and neck squamous cell carcinoma (HNSCC) with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. MATERIAL AND METHODS: A total of 227 patients with stage III or IV HNSCC of the larynx, oropharynx, hypopharynx, or oral cavity where included between January 2007 and December 2010. The prescribed radiotherapy (RT) dose was 66-68 Gy in 2 Gy fractions, 6 F/W. The hypoxic radiosensitiser nimorazole was given orally at a dose of 1200 mg/m(2) before each fraction. Concomitant cisplatin (40 mg/m(2)) i.v. was given once a week for a maximum of six cycles. Outcome data were evaluated in terms of loco-regional tumour control (LRC), event-free survival (EFS) and overall survival (OS). Morbidity data were evaluated based on the DAHANCA routine registration. Human papillomavirus (HPV)-status was estimated by immunohistochemical staining of p16. RESULTS: Included were 178 (78%) men and 49 (22%) women with a median age of 57 years. All except five patients received RT as prescribed. At least five series of cisplatin was given to 164 (72%) of the patients, and 149 patients (66%) received the full dose of nimorazole. The five-year actuarial LRC, EFS and OS rates were 80%, 67% and 72%, respectively. The LRC rates according to site were: oropharynx: 88%, larynx: 77%, hypopharynx 72% and oral cavity 49%, respectively. HPV/p16 staining was obtained in 141 of the 150 oropharyngeal cancers. Of these, 112 (79%) were p16 pos and 29 (21%) were p16 neg. LRC for the p16 neg oropharyngeal cancers was poorer than for the p16 pos (74% vs. 91%; p = 0.02). Tube feeding during treatment was necessary for 146 (64%) patients. At 12 months this number was reduced to 6%. CONCLUSION: The treatment was tolerable in this cohort of locally advanced HNSCC patients. Acute and late toxicity was comparable to similar studies of chemoradiotherapy, and the outcome superior to the data reported in the literature. This strongly indicates that RT of advanced head and neck cancer must include as well hypoxic modification, accelerated fractionation as chemoradiotherapy to yield optimal outcome.

Quality of life in thyroid cancer.

To explore the impact of differentiated thyroid cancer (DTC) on quality of life (QoL) a clinical analytical framework was developed. Based on the clinical analytical framework, a systematic literature search was performed to identify studies applying patient-reported outcomes (PRO) instruments among patients with DTC. Subsequently, the scope was narrowed down to studies comparing scores on the Medical Outcomes Study (MOS) Short form 36 (SF-36) to a reference population (clinical interpretability criterion). Further, the currently available thyroid cancer (TC) specific QoL PROs were review in accordance with the standards of the International Society of Quality of Life Research. In the initial search, 213 studies were included. The additional 'clinical interpretability'-criteria, limited the final study sample to 16 studies, 13 cross-sectional and 3 longitudinal. QoL was impacted across all SF-36 scales. The impact was generally modest and the impact was impeded by time since diagnosis and treatment. Four TC specific instruments were identified. Generally, the documentation of their measurement properties, particularly content validity and clinical validity, including substantial quantitative validation, was scarce. As was the cross-cultural applicability of the currently available instruments. This restricted, focused, clinically founded review showed an impact on a broad range of QoL issues. There is a need for large-scale measurement of QoL outcome longitudinally, using well-validated PRO instruments in order to identify with certainty the impact on subgroups.

Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? - results from the randomized DAHANCA 5 and 7 trials.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of hemoglobin often have a poor response to radiation that may be related to hypoxia-induced radioresistance. We have previously published the importance of hemoglobin level and the effect of transfusion by the results from the randomized DAHANCA 5 trial, including 414 patients in the analysis. Aim of the current analysis was to gain additional power by adding patients from the continued subrandomization in the DAHANCA 7 trial, now including a total of almost 1200 patients. MATERIAL AND METHODS: Patients were randomized to treatment in the DAHANCA 5 and 7 study (nimorazole vs. placebo and five fx/week vs. six fx/week), and in addition, patients with "low" pre-irradiation hemoglobin values (females <13 g/dl; males <14.5 g/dl) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a hemoglobin level in the "high" value range. RESULTS: A total of 1166 patients were included, 701 patients had high hemoglobin levels and 465 had low hemoglobin levels. Among the low hemoglobin patients, 235 were randomized to receive transfusion. Patient characteristics and treatment arms were well balanced. In the majority of patients, transfusion resulted in increased hemoglobin levels although this decreased slightly throughout treatment as in the non-transfused patients. Overall, the patients with low hemoglobin level had a significant reduced probability of locoregional control, disease-specific and overall survival. In the low hemoglobin group, transfusion did not improve the outcome in locoregional control, disease-specific or overall survival. In multivariate analyses, HPV/p16 status, T and N classification were significant factors for all outcome measures, whereas there was no significant influence of transfusion or hemoglobin level on endpoints. CONCLUSION: Transfusion prior to and during radiation treatment did not improve the outcome in patients with HNSCC and low hemoglobin values, but may have a negative impact on survival.

Treatment outcomes in patients with supraglottic laryngeal cancer: a single centre study.

BACKGROUND: Treatment of squamous cell carcinoma of the supraglottic larynx (SCCSL) in Denmark has changed in several ways from the year 2000 to 2014, including the introduction of IMRT radiation technique and the addition of concurrent chemotherapy (CRT), as well as systematic reduction in waiting times until treatment initiation. AIM/OBJECTIVES: Our aim is to investigate the effect of the abovementioned factors on overall survival (OS) and locoregional control (LC) for SCCSL patients. MATERIALS AND METHODS: Retrospective cohort study with data from the DAHANCA database. We used the Kaplan-Meier and Cumulative Incidence plots as well as Cox regression analysis. RESULTS: We found a statistically significant improvement of the 5-year OS of 19.3 percentage points (pp). Cox regression found LC was not improved in patients receiving CRT compared to radiotherapy (RT) alone. CONCLUSIONS AND SIGNIFICANCE: Introduction of CRT treatment for head and neck cancers in general is known to improve LC. We could not demonstrate this effect for SCCSL specifically, as our results were not statistically significant on this point. OS was significantly improved.

Nasopharyngeal malignancies in Denmark diagnosed from 1980 to 2014.

OBJECTIVES: Nasopharyngeal malignancies are reported having decreasing incidence and reduced mortality. This study provides a nationwide update of the incidence and survival in Denmark. MATERIALS AND METHODS: The Danish Cancer Registry (DCR) and Central Population Register (CPR) were used to identify all patients registered with nasopharyngeal malignancies between 1980 and 2014 in Denmark. We evaluated the age-adjusted incidence rate (AAIR), average annual percent change (AAPC) and relative survival (RS) and also constructed age-population-cohort (APC) models. RESULTS: 911 patients were identified with a male:female ratio of 2.2:1, a median age of 57.7 years (range 2.8-98.3 years) and an overall median follow-up time of 2.7 years (range 0-37 years). The AAIR was 0.39 cases per 100 000 in 1980 and 0.28 cases per 100 000 in 2014 with an AAPC of -3.2 (95% CI: -7.5; 1.2, p = 0.1). The overall 1-year and 5-year RS rates were 76.3% and 42.1%, respectively. We found a significant age effect in the APC model for the incidence of nasopharyngeal malignancies, but no significant cohort or period effects. CONCLUSION: The incidence of nasopharyngeal carcinomas has slightly decreased over the last four decades, however insignificantly. Meanwhile, the relative survival has increased significantly in Denmark since 1980. The cause of improved relative survival might be attributed to altered treatment practices.

Carcinoma of the nasal cavity and paranasal sinuses in Denmark 1995-2004.

OBJECTIVE: To evaluate the treatment outcome for sino-nasal carcinomas in Denmark from 1995-2004 and compare the results to the previous Danish survey covering 1982-1991. DESIGN: Retrospective follow-up. MATERIALS AND METHODS: In the five Danish head and neck oncology centres, charts of all consecutive patients with sino-nasal carcinomas were reviewed and data extracted to a common database. Altogether 242 patients from the period 1995-2004 were identified. Of these 162 (67%) were male and 80 (33%) female. Histologies included squamous cell carcinoma (55%), adenocarcinoma (28.5%), adenoid-cystic carcinoma (5.0%), undifferentiated carcinoma (4.5%), transitiocellular carcinoma (1.7%), mucoepidermoid carcinoma (0.8%), neuroendocrine carcinoma (2.5%), small cell carcinomas (1.2%) and carcinomas not otherwise specified (0.8%). Treatments included radiotherapy alone 79 (33%), surgery alone 29 (12%), combined surgery and radiotherapy 96 (40%), palliative/no treatment 38 (16%). A total of 204 (86%) patients were treated with curative intent. RESULTS: Of the 204 patients treated with curative intent, 94 (46%) relapsed. Most failures were in T-site (63, 30%). N-site failures were 10 (5%) and M-site failures six (3%). Failure occurring in T+N-site, T+M-site, N+M-site and T+N+M-site were seven (3%), two (1%), one (0.5%) and five (3%) respectively. The 5-year actuarial local, nodal and loco-regional control rates were 55 + or - 4%, 86 + or - 3%, 49 + or - 4%, respectively. The overall 5-year actuarial survival rate for the entire cohort was 47 + or - 3%, and the corresponding cancer-specific 5-year actuarial survival rate was 57 + or - 3%. Female gender, nasal cavity tumour, adenocarcinoma and low clinical stage were significant positive prognostic factors in univariate analysis. A Cox multivariate analysis showed that only tumour site and clinical stage were independent significant prognostic factors. CONCLUSION: The current series has confirmed stage and tumour site as independent prognostic factors. Compared to the previous Danish survey covering the period 1982-1991, the overall survival and cancer-specific survival rates have improved significantly.

The Nephroprotective Effect of Mannitol in Head and Neck Cancer Patients Receiving Cisplatin Therapy.

INTRODUCTION: Cisplatin is used as treatment for several different malignancies and a well-known complication is irreversible kidney damage. To protect the kidneys, this treatment is often combined with mannitol infusion to promote osmotic diuresis. Earlier studies investigating the nephroprotective effect of mannitol have shown conflicting results. OBJECTIVE: To investigate changes in kidney function in head and neck cancer patients treated with cisplatin with and without additional mannitol infusion. METHODS: A single center, retrospective cohort study of patients with squamous cell carcinoma of the head and neck receiving radiotherapy with cisplatin. Patient data were collected from November 2013 to December 2014. RESULTS: After exclusion, a total of 78 patients were considered evaluable. They were equally distributed between a mannitol and a non-mannitol group and anthropomorphometrically similar. 51Cr-EDTA clearance declined in the mannitol group from 99.7 (19.9) to 96.4 (20.8) mL/min and in the non-mannitol group from 102.2 (17.8) to 92.3 (23.1) mL/min. CONCLUSIONS: There was a significantly smaller decrease in 51Cr-EDTA clearance in the mannitol group indicating a nephroprotective effect of mannitol.

Risk of Thyroid Cancer in 1,504 Patients Referred for Thyroid Surgery with Assumed Benign Histology.

OBJECTIVES: The aims of this study were to report the risk of thyroid malignancy in cases of either benign fine-needle aspiration (FNA) or without FNA performed, and to investigate possible predictive factors for thyroid malignancy in a population with recent moderately low iodine intake. METHODS: All patients referred for thyroid surgery in a tertiary cancer centre between 2000 and 2016 were included (n = 3,703). After excluding cases indicating malignant histology, we included group 1: patients with benign FNA (n = 764), and group 2: patients without FNA (n = 740), leaving 1,504 eligible for further investigation. Information on age, gender, tracheal compression or dislocation, thyroid specimen weight, scintigraphy, ultrasound, medically treated thyrotoxicosis, serum stimulating thyroid hormone, indication for surgery, TNM classification, stage, and outcome were retrieved. RESULTS: The malignancy risk was 7.6% (58/764) in group 1 and 6.8% (50/740) in group 2. Patients with T2-4 tumours constituted 2.2% (33/1,504). In the combined groups, ultrasound verified that solitary solid tumour was predictive for malignancy (p = 0.01 by χ2, and OR = 1.69, p = 0.02 in multiple logistic regression). For group 1 patients, thyrotoxicosis (which in this case was medically treated) was a significant predictive factor for malignancy (p = 0.04). CONCLUSIONS: The risk of malignancy of 7.6% and 6.8% was high, considering that patients with malignant FNA, suspicious FNA, or clinical findings indicating malignancy were excluded, and 2.2% of these malignancies were stages T2-4. In cases with solitary solid tumour on ultrasound, the risk of malignancy should not be ignored, even with benign FNA.

Incidental and Non-incidental Papillary Thyroid Microcarcinoma in Denmark 1996-2015: A national study on incidence, outcome and thoughts on active surveillance.

BACKGROUND: Incidental and non-incidental papillary microcarcinomas (PMC) are associated with different outcomes and treatment options may vary. The least favourable outcome is typically seen when carcinoma is suspected prior to surgery. Only a few studies have addressed the prognosis based on the way of detection for PMC, and they have been limited to retrospective single-center studies. We hypothesize that the "way of detection" may predict prognosis. The aim was to calculate the incidence and outcome of PMC based on the way of detection and to identify patients that may be suitable for active surveillance. METHOD: This national cohort study consists of 803 patients diagnosed with PMC in Denmark from 1996 to 2015. Patients were identified from the DATHYRCA database and allocated into groups according to the way of detection leading to surgery: Incidental at surgery (n = 527), non-incidental with symptoms suspected from the index tumor (n = 134) and non-incidental with symptoms suspected from a metastasis (n = 142). RESULTS: Age-standardized incidence rates increased from 0.35 per 100,000 per year in 1996 to 1.19 per 100,000 per year in 2015. A significant rise in incidence was found for both the incidental group and non-incidental group with symptoms suspected from a metastasis. Recurrence free survival was significantly worse for patients with suspicion of metastasis prior to surgery than patient groups without. No difference in mortality was found between groups. CONCLUSION: PMC patients without suspicion of metastasis have the same low risk of recurrence as incidental cases and may be candidates for active surveillance.

Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997-2013: a nationwide study.

BACKGROUND: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested. METHODS: The study included 200 patients identified from the nationwide Danish MTC cohort 1997-2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994-2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested. RESULTS: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81-0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76-0.88; 131/158). Completeness was 88% (95% CI: 0.75-0.95; 42/48) and 81% (95% CI: 0.72-0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested. CONCLUSION: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study.

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38-4.57) vs 3.04 (95% CI: 1.38-6.67) for stage II, 2.06 (95% CI: 0.45-9.39) vs 3.59 (95% CI: 1.61-8.03) for stage III and 5.87 (95% CI: 2.02-17.01) vs 59.26 (20.53-171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997-2014: A Nationwide Study.

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure. METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used. RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure. CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

High serum levels of YKL-40 in patients with squamous cell carcinoma of the head and neck are associated with short survival.

YKL-40 is a glycoprotein secreted by macrophages, neutrophils and malignant tumor cells. Elevated serum levels of YKL-40 are associated with poor prognosis in several malignancies. In this study, we examined the prognostic value of serum YKL-40 before treatment and during follow-up in patients with squamous cell carcinoma of the head and neck (HNSCC). YKL-40 was determined by ELISA retrospectively in serum from 173 patients with primary HNSCC before treatment and up to 2 years after treatment. Median follow-up time was 7.9 years. YKL-40 protein expression in tumor biopsies was assessed by immunohistochemistry in 50 patients. Pretreatment serum YKL-40 was elevated in 53%. Patients with high serum YKL-40 had shorter survival than patients with normal serum YKL-40 (33 vs. 84 months; p = 0.008). Multivariate Cox analysis including pretreatment serum YKL-40, age, sex, primary tumor site, TNM classification and treatment demonstrated that TNM classification (HR = 2.61, p = 0.02) and serum YKL-40 (log-transformed continuous variable: HR = 1.55, p < 0.0001) were independent prognostic variables of overall survival (OS). Multivariate Cox analysis demonstrated that TNM classification (HR = 5.77, p = 0.001) and serum YKL-40 (dichotomous variable: HR = 2.75, p = 0.01) were independent predictors of recurrence-free survival. During follow-up after radiotherapy, a high serum YKL-40 (log-transformed continuous variable) in patients with TNM Stage III and IV disease predicted poorer OS within 6 months (HR = 1.95, p < 0.0001). Immunohistochemical analysis showed YKL-40 expression in the malignant tumor cells. In conclusion, serum YKL-40 was demonstrated to be an independent prognostic biomarker of recurrence-free and overall survival in patients with HNSCC.

A Non Platinum Regimen for the Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Region. Results From an Extended Phase II Study With Paclitaxel and Capecitabine.

BACKGROUND: This study presents the results of an extended phase II study originally published in 2007, regarding the antitumor activity and toxicity of a non-platinum containing regimen with paclitaxel and capecitabine for the treatment of recurrent or disseminated squamous cell carcinoma of the head and neck region. Fifty patients were included in the original study. MATERIALS AND METHODS: A total of 183 patients with recurrent or disseminated squamous cell carcinoma were eventually included in the extended study. There were 37 women and 146 men. The mean age was 56 years. Performance status (WHO) was as follows: WHO 0:31, WHO 1:107, and WHO 2:45 patients. The treatment consisted of paclitaxel 175 mg/m2, once every third week and capecitabine 825 mg/m2 p.o. b.i.d for 2 weeks. RESULTS: The overall response rate (complete response and partial response) according to the WHO criteria was: 33% (CI 26-40). The median progression-free survival was 4.8 (CI 4.2-5.4) months. The median overall survival (OS) was 8.9 (CI 7.6-9.5) months. Compliance was good. Of the 1,131 cycles, only 13% had to be administered with a reduced dose and/or postponed to a later date. Toxicity was mild and grades 3 and 4 toxicities were uncommon. Two toxic deaths were registered though. CONCLUSION: The response rate and the OS for this low toxicity regimen makes it a feasible alternative for not cisplatin eligible patients.

Trends in thyroid cancer: Retrospective analysis of incidence and survival in Denmark 1980-2014.

BACKGROUND: Thyroid cancer incidence has been reported to be increasing since the 1970 s. The aim of this study was to investigate the change in incidence and survival from 1980 to 2014 in Denmark. METHODS: We identified patients registered with thyroid cancer in the period 1980-2014. We evaluated the age-adjusted incidence rate (AAIR) and the average annual percentage change (AAPC), constructed age-period-cohort models (APCs), and evaluated relative survival (RS). RESULTS: We included 5139 patients. The AAIR was 1.6 cases per 100,000 in 1980 and 4.5 cases in 2014 with an AAPC of 3.4%. The AAIR for papillary carcinomas (n = 2864) quintupled in the study period, and accounts for most of the observed increase in incidence with an AAPC of 4.9%. Follicular carcinomas (n = 920) nearly tripled in AAIR and had the second greatest increase in AAPC. Papillary carcinomas had the best prognosis with 1-year and 5-year RSs of 95% and 91%, followed by the follicular carcinomas with 1-year and 5-year RSs of 90% and 80%, respectively. Anaplastic carcinomas (n = 320) had the worst prognosis with 1-year and 5-year RSs of 18% and 12%. We found a significant age effect in the APC model for the incidence of thyroid cancer but no significant cohort or period effects. CONCLUSION: The incidence of thyroid cancer is rising. This is primarily attributable to an increase in papillary carcinomas. The relative survival has improved significantly in Denmark since 1980. The cause of the increasing incidence remains to be established, but enhanced diagnostic scrutiny and increased iodine intake may be influential.