•Head and neck cancer patients at risk of distant metastases (DM) are difficult to identify.•We investigated the influence of initial tumor volume (cm3) on the risk of DM.•Gross tumor volumes (GTV) ...were extracted from treatment planning systems.•We found that GTV is an independent factor strongly associated with the risk of DM.•This may improve the selection of patients for intervention trials.
Distant metastases (DM) in head and neck squamous cell carcinomas (HNSCC) are in most circumstances non-curable. The TNM staging system is insufficient to predict the risk of DM. This study investigates if the DM risk can be predicted using a multivariate model including pre-treatment total tumor volume for both p16-positive oropharyngeal squamous cell carcinoma (OPSCC) and all other sites (other HNSCC).
The study includes patients with localized pharyngeal and laryngeal squamous cell carcinomas treated with primary radiotherapy from 2008-2017 from three head and neck cancer centers. Patients were identified in the Danish Head and Neck Cancer (DAHANCA) database. Total (nodal and primary) tumor volume (Gross Tumor Volume, GTV) was extracted from local treatment planning systems. The GTV was grouped by volume (cm3) in four intervals and included in a multivariate Cox proportional hazard regression controlled for pre-selected clinical values incl. stage.
The study includes 2,865 patients, of which 321 (11 %) had DM post-treatment. The risk of DM was assessed in a multivariate model based on 2,751 patients (p16-positive OPSCC: 1,032; and other HNSCC: 1,719). There was a significant association between GTV and the risk of DM, and in tumor volumes ≥ 50 cm3 hazard ratios of 7.6 (2.5–23.4) for p16-positive OPSCC and 4.1 (2.3–7.2) in other HNSCC were observed.
Tumor volume is an independent risk factor for DM. The addition of total tumor volume to a predictive model is important to identify subgroups of HNSCC patients at high risk of DM.
In this study we have determined the genome-wide relationship of JIL-1 kinase mediated H3S10 phosphorylation with gene expression and the distribution of the epigenetic H3K9me2 mark. We show in ...wild-type salivary gland cells that the H3S10ph mark is predominantly enriched at active genes whereas the H3K9me2 mark is largely associated with inactive genes. Comparison of global transcription profiles in salivary glands from wild-type and JIL-1 null mutant larvae revealed that the expression levels of 1539 genes changed at least 2-fold in the mutant and that a substantial number (49%) of these genes were upregulated whereas 51% were downregulated. Furthermore, the results showed that downregulation of genes in the mutant was correlated with higher levels or acquisition of the H3K9me2 mark whereas upregulation of a gene was correlated with loss of or diminished H3K9 dimethylation. These results are compatible with a model where gene expression levels are modulated by the levels of the H3K9me2 mark independent of the state of the H3S10ph mark, which is not required for either transcription or gene activation to occur. Rather, H3S10 phosphorylation functions to indirectly maintain active transcription by counteracting H3K9 dimethylation and gene silencing.
Abstract Background and purpose Tumour HPV-positivity is a favourable prognostic factor in the radiotherapy of HNSCC, but the optimal radiotherapy regimen for HPV-positive HNSCC is not yet defined. ...Reducing overall treatment time is known to improve outcome in the radiotherapy of HNSCC as was also demonstrated in the randomised DAHANCA 6&7 trial. We aimed to assess the influence of tumour HPV-status, expressed by p16, on the response to accelerated fractionated radiotherapy in HNSCC through evaluation of the DAHANCA 6&7 trial. Materials and methods Immunohistochemical detection of HPV-associated p16-expression was performed on FFPE-pre-treatment tumour-tissues from 794 patients enrolled in the DAHANCA 6&7 trial. The influence of tumour p16-status on loco-regional tumour control and survival as a function of fractionation schedule (5 Fx/week vs 6 Fx/week) was evaluated 5 years after the completion of radiotherapy. Results The significant and independent prognostic value of tumour p16-positivity in HNSCC radiotherapy was confirmed, with adjusted hazard ratios (HR) of 0.58 0.43–0.78, 0.47 0.33–0.67 and 0.54 0.42–0.68 for loco-regional control, disease-specific and overall survival, respectively. Accelerated radiotherapy significantly improved loco-regional tumour control compared to conventional radiotherapy, adjusted HR: 0.73 0.59–0.92 and the benefit of the 6 Fx/week regimen was observed both in p16-positive (HR: 0.56 0.33–0.96) as well as in p16-negative tumours (HR: 0.77 0.60–0.99). Disease-specific survival was also significantly improved with accelerated radiotherapy in the group of p16-positive tumours (adjusted HR: 0.43 0.22–0.82). Conclusion Accelerated radiotherapy significantly improves outcome in HNSCC compared to conventional fractionation. The observed benefit is independent of tumour p16-status and the use of a moderately accelerated radiotherapy regimen seems advantageous also for HPV/p16-positive HNSCC.
Abstract Purpose The DAHANCA 6 trial evaluated tumor response and morbidity after moderate accelerated radiotherapy compared to conventional fractionated radiotherapy in patients treated for glottic ...squamous cell carcinoma (SCC). Further, the failure pattern and incidence of new primary tumors were explored. Patients and methods Six hundred and ninety-four patients with non-metastatic glottic SCC were randomized between six or five weekly fractions (fx/w) of radiotherapy to the same total dose. The median treatment time was 38 and 46 days, respectively. The primary endpoint was loco-regional failure. Results Median follow-up time was 14.5 years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6 fx/w group and 29.3% in the 5 fx/w group and the corresponding hazard rate (HR) of LRF was 0.72 (CI: 0.53–0.97, p = 0.04). The effect of acceleration on LRF was especially evident in well differentiated tumors (HR = 0.42 (CI: 0.23–0.75) and in T1–2 tumors (HR = 0.60 (CI: 0.41–0.89)). The HR of laryngectomy was 0.72 (CI: 0.50–1.04) in the 6 fx/w group compared to the 5 fx/w group. The hazards of disease-specific death, event-free survival, and overall survival were comparable between the two groups. Significantly more patients experienced severe acute mucositis in the 6 fx/w group but the incidence of late morbidity was comparable between the groups. New primary tumors occurred in 22.5% of the patients. Conclusion Moderate accelerated radiotherapy significantly improved loco-regional control in patients with glottic SCC.
Abstract Background and purpose To develop a normal tissue complication probability (NTCP) model of radiation-induced biochemical hypothyroidism (HT) after primary radiotherapy for head and neck ...squamous cell carcinoma (HNSCC) with adjustment for latency and clinical risk factors. Patients and methods Patients with HNSCC receiving definitive radiotherapy with 66–68 Gy without surgery were followed up with serial post-treatment thyrotropin (TSH) assessment. HT was defined as TSH >4.0 mU/l. Data were analyzed with both a logistic and a mixture model (correcting for latency) to determine risk factors for HT and develop an NTCP model based on mean thyroid dose (MTD) and thyroid volume. Results 203 patients were included. Median follow-up: 25.1 months. Five-year estimated risk of HT was 25.6%. In the mixture model, the only independent risk factors for HT were thyroid volume (cm3 ) (OR = 0.75 95% CI: 0.64–0.85, p < 0.001) and MTD (Gy) (OR = 1.12 95% CI: 1.07–1.20, p < 0.001). From the mixture NTCP-model individual dose constraints for a 25% risk of HT were 26, 38, 48 and 61 Gy for thyroid volumes of 10, 15, 20 and 25 cm3 , respectively. Conclusions Comparing the logistic and mixture models demonstrates the importance of latent-time correction in NTCP-modeling. Thyroid dose constraints in treatment planning should be individualized based on thyroid volume.
Purpose
Salivary gland carcinoma is a rare disease and studies on epidemiology and outcome require data collection over many years. The aim of this study is to present an update of incidence rates, ...anatomical sites, histological subtypes, and survival rates based on the Danish national cohort of salivary gland carcinoma patients.
Methods
Data from all Danish patients with salivary gland carcinoma diagnosed from 1990 to 2015 (
n
= 1601) were included and analyzed following histological reevaluation and reclassification. Overall, disease-specific, and recurrence-free survival were evaluated. Prognostic factors were analyzed with multivariate Cox Hazard Regression.
Results
The study population consisted of 769 men and 832 women, median age 62 years (range 6–102). The most frequent anatomic site was the parotid gland (51.8%). Adenoid cystic carcinoma was the most common subtype (24.7%). The majority had tumor classification T1/T2 (65.3%). The mean crude incidence was 1.2/100.000/year with an increase of 1.5% per year. There was no increase in age-adjusted incidence. The 5-, 10-, and 20-year survival rates were for overall survival 68, 52, and 35%, for disease-specific survival, 77, 69, and 64%, and for recurrence-free survival, 75, 64, and 51%, respectively. Age, high-grade histological subtype, advanced T-classification, cervical lymph node metastases, vascular invasion, and involved surgical margins had significantly negative impact on survival rates.
Conclusion
The age-adjusted incidence has been stable for a period of 26 years. Multivariate analysis confirmed that histological grade, advanced stage, involved surgical margins and vascular invasion are independent negative prognostic factors. Survival rates were stationary compared to earlier reports.
Squamous cell carcinoma of the head and neck (HNSCC) comprises a variety of malignant tumors. Due to the rarity of each individual malignant entity, knowledge of epidemiological changes and trends ...over time may be derived from data compiled in regional and national registries. This study analyzed the development in incidence rates and mortality in elderly HNSCC patients in Denmark between 1980 and 2012 with specific attention to compliance to radiotherapy, the main treatment modality of HNSCC in Denmark.
HNSCC consisting of more than 25 patients per year over the age of 70 years were analyzed. This included cancer of the oral cavity defined as ICD-codes C00.3-4, C02-04, C05.0, C06; oropharynx as C01, C05.1-9, C09-10; and larynx as C32 recorded in the NORDCAN database. Additional data from the DAHANCA database was added to assess differences in compliance to treatment between younger and older patient groups.
HNSCC was predominant in younger patients. Only 17% were older than 70 years. The median age was 60 years. Generally, incidence rates rose for cancer of the oral cavity and oropharynx between 1980 and 2012 and stabilized for laryngeal cancer. Mortality rates had a shallower increase, especially in younger age groups, which translated into improved age-specific survival rates. Compliance to radiotherapy was high for all age groups. Failure to receive at least 60 Gy during radical radiation treatment was 2.3% despite a significant increase in patients with poor WHO performance status over time.
HNSCC is a rare disease in patients above 70 years accounting for only 17% of all HNSCC patients. Incidence rates increased over time, but age-specific survival rates improved, especially in younger patients. Failure rates to comply with radiation treatment, however, were low in both young and elderly patients.
Abstract
Introduction. Loss of lean body mass is common following radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) and may reduce maximal muscle strength and functional ...performance. However, the associations between lean body mass, muscle strength and functional performance are unclear and no studies in HNSCC patients have compared the levels of these variables to the levels seen in healthy individuals. Purpose. The purpose of the present study was to investigate the associations between lean body mass, maximal muscle strength and functional performance in HNSCC patients and to compare the levels of these variables after radiotherapy and after progressive resistance training with the levels in healthy individuals. Material and methods. Lean body mass (dual energy X-ray absorptiometry), maximal muscle strength (isokinetic dynamometry) and functional performance (10 m max gait speed, 30 s chair rise, 30 s arm curl, stair climb) from HNSCC patients from the DAHANCA 25 trials and data from 24 healthy individuals were included. Results. Lean body mass and maximal muscle strength were significantly associated according to the gender and age-adjusted linear regression model (p < 0.0001). In addition, maximal muscle strength were associated with 30 s arm curl performance, 10 m max gait speed and 30 s chair rise (p < 0.0001). Multiple regression analyses showed that HNSCC patients expressed significant lower levels of the investigated variables after radiotherapy than healthy individuals (p < 0.0001), and that all differences were evened out after training. Conclusions. Significant associations were found between lean body mass, maximal muscle strength and functional performance in HNSCC patients. Patients expressed lower levels of these variables compared with healthy individuals, suggesting that lean body mass is a clinically relevant health factor in HNSCC patients.
In head and neck cancer, distant metastases may be present at diagnosis (M1) or occur after treatment (DM). It is unknown whether M1 and DM follow the same clinical development and share prognosis, ...as population-based studies regarding outcomes are scarce. Therefore, we investigated the incidence, location of metastases and overall survival of patients with M1 and DM.
Patients diagnosed with squamous cell carcinoma of the pharynx and larynx in Denmark 2008-2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. We identified 7300 patients, of whom 197 (3%) had M1 and 498 (8%) developed DM during follow-up.
The 5-year cumulative incidence of DM was 8%. 1- and 2-year overall survival for DM (27% and 13%) vs. M1 (28% and 9%) were equally poor. There was no significant difference in location of metastases for M1 and DM and the most frequently involved organs were lungs, bone, lymph nodes and liver, in descending order. In oropharyngeal squamous cell carcinomas, the location of metastases did not differ by p16-status. For p16-positive patients, 21% of DM occurred later than three years of follow-up compared to 7% of p16-negative patients.
Incidence, location of metastases and prognosis of primary metastatic (M1) or post-treatment metastatic (DM) disease in pharyngeal and laryngeal squamous cell carcinoma are similar in this register-based study
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.
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).
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.
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.
PDF
