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Background: Evidence on the risk of second primary cancer (SPC) following primary laryngeal squamous cell carcinoma (LSCC) is limited, especially in Europe. Methods: Patients diagnosed with primary LSCC from 1953-2018 were retrieved from the Finnish Cancer Registry. A total of 6241 LSCC patients were identified adding to 49,393 person-years (PY) of follow-up until the end of 2019. Only one patient emigrated and was lost to follow-up. Both standardized incidence ratios (SIR) and excess absolute risk (EAR) per 1000 person-years at risk (PYR) of second primary cancer (SPC) were calculated relative to the general population. Only non-laryngeal SPCs diagnosed six months after diagnosis of primary LSCC were included. Results: A SPC was diagnosed in 1244 LSCC patients (20% of all LSCC patients) over the 65-year period, predominantly in men (92%, n=1170). Out of all SPCs, 34% were diagnosed within 0.5 to 5 years and 66% after 5 years from primary LSCC. Among male patients, the overall SIR for SPC at any location was 1.61 (95% CI: 1.52-1.71), corresponding to 9.49 excess SPCs per 1000 PYR (95% CI: 8.19-11). The corresponding SIR for women was 1.47 (95% CI: 1.15-1.84), yielding 4.82 excess SPCs per 1000 PYR (95% CI: 2.36-9.84). The risk remained significant even after 20 years of follow-up (SIR for all 1.73, 95% CI: 1.49-2.01 and EAR 16.8 per 1000 PY, 11.88-23.75). The risk for SPC was also significantly elevated in all age groups, except <40. The highest SIRs were for SPCs arising in the mouth/pharynx (SIR for all 3.08, 95% CI: 2.36-3.95 and EAR 0.80 per 1000 PY, 0.55-1.15) and lungs (3.02, 2.75-3.30 and 5.90 per 1000, 5.13-6.78). Conclusion: Patients with LSCC as primary cancer have a 60% excess risk for an SPC, especially for tobacco-associated cancers, remaining significantly elevated even decades after treatment. NOVELTY & IMPACT Although prior research on the risk of second primary cancer (SPC) among laryngeal squamous cell carcinoma (LSCC) patients has been conducted in other regions, the European perspective remains notably underrepresented. Moreover, studies on the subject focusing especially on LSCC are, even globally, only a few. The present study, with over 6000 LSCC patients followed-up over six decades, consists of the largest reported cohort of LSCC patients in Europe, and with the longest follow-up. Patients with LSCC as a primary cancer have a 60% excess risk for an SPC, which remains significantly elevated even 20 years after the diagnosis of the first primary cancer, especially for those with a tobacco/alcohol-related cancer. Healthcare professionals should be aware of the SPC risk among LSCC survivors who should be counseled about this phenomenon. [ABSTRACT FROM AUTHOR]

This study aims to report on the effectiveness of voice rehabilitation following radiotherapy for laryngeal cancer in a long-term perspective, i.e., up to three years after completion of radiotherapy. The study included a total of 74 patients that were randomised into an intervention group (n = 37) or a control group (n = 37). Voice recordings with blinded assessment of voice quality with the GRBAS protocol (Grade, Roughness, Breathiness, Asthenia, Strain) and acoustic analysis was performed at baseline, 12 and 36 months following radiotherapy. Voice rehabilitation was performed in 10 sessions immediately following completion of radiotherapy. Patients also filled out the Swedish Self-Evaluation of Communication Experiences after Laryngeal cancer. The S-SECEL demonstrated statistically significant improvements in the intervention group when comparing baseline and 36 months, and no changes in the control group. Acoustic measures did not reveal any significant changes. The perceptual analysis demonstrated that when comparing the changes within the groups between baseline and 36 months there were statistically significant differences between the intervention and control group regarding the voice qualities Roughness, Breathiness and Strain. In the control group, 50% demonstrated deterioration in roughness, while in the intervention group only 7% deteriorated during this time. In Breathiness and Strain, 57 and 50%, respectively, improved in the intervention group, while only 32% and 23% improved, respectively, in the control group. Voice rehabilitation following radiotherapy for laryngeal cancer demonstrate positive effects in patient reported outcomes and perceptual measures of voice quality, and the effects remain up to three years following radiotherapy. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Objectives: Glottic precursor lesion (GPL) is a well-known premalignant condition, but the existing knowledge of incidence and malignant potential is based on subpopulation studies. In this first, nationwide study we report data from all verified cases of GPL in Denmark during a 10-year period with focus on incidence and malignant transformation of GPL. Methods: Patients were identified by a search for GPL in the time period from 01.01.2000 to 31.12.2009 using the Danish Pathology Data Base, Patobank, which is a nationwide source of all cyto- and histopathological data obtained in Denmark. Data were validated and supplemented by medical chart review. Results: A 10-year national cohort of 965 patients (median age 60 years, male-female ratio 2:1) with histologically verified GPL was analyzed. The overall malignant transformation rate was 18.3% (mild dysplasia 7.7%, moderate dysplasia 19.8%, severe dysplasia 28.5%, and carcinoma in situ 40.3%) with a median progression time of 29 months. Eighty-eight percent of patients were active or former smokers. A significantly larger proportion of male patients (24.1%) experienced malignant transformation compared to females (6.6%) (p <.001). Conclusion: This nationwide population-based study of GPL patients confirmed a stable incidence of GPL in Denmark from January 2000 to December 2009 and a considerable malignant potential, correlated to the grading of GPL according to the World Health Organization classification of laryngeal precursor lesions from 2005, WHOC2005. The recent update, WHOC2017, of low-grade versus high-grade lesions may thus contain less nuanced prognostic information than WHOC2005. Level of evidence: 2b retrospective cohort study [ABSTRACT FROM AUTHOR]

The article focuses on correlation and prognostic impact of human papilloma virus and p16-expression in advanced hypopharynx and larynx cancer treated with definitive radiotherapy. Topics include the human papilloma virus (HPV) is a well-established aetiological factor in oropharynx cancer (OPC), the global variation in the incidence of HPV plus OPC is considerable, and the countries with high age standardized incidence rates of the disease are located in Northern America and Europe.

Background: The purpose of this registry study was to evaluate trends in incidence and survival of laryngeal cancer in the Danish population from 1980 to 2014. Methods: This study includes all patients with laryngeal cancer registered in the Danish Cancer Registry (DCR) in the period 1980–2014. The age-adjusted incidence rate (AAIR) per 100,000 and average annual percent change (AAPC) were calculated. We evaluated the relative survival at five years in relation to gender, anatomical location, year at diagnosis, and histological type. Further, an age-period-cohort (APC) model of incidence was constructed. Results: A total of 8748 patients (82% males) were included. The median age at diagnosis was 60 years, range 18–101 years. The AAIR decreased from 3.6 per 100,000 in 1980 to 2.3 per 100,000 in 2014 with an AAPC of –0.8% (p <.008). Considering the anatomic location, we found that glottic cancer had a significantly better survival at five years compared to the other locations. We observed no significant difference in survival for supraglottic, subglottic and larynx unspecified cancer during the observation period. During the period 1980–2014, we found no improvement in five year relative survival. Conclusions: This nation-wide study reports a significant decrease in the incidence of laryngeal cancer. Glottic cancer had a significantly better survival at five years compared to other locations. [ABSTRACT FROM AUTHOR]

Previous studies reported that cigarette smoking during radiation therapy was associated with unfavorable outcomes in various cancers using medical interviewing or monitoring of cotinine. Here, we evaluated the effect of smoking cessation on definitive radiation therapy for early stage glottic carcinoma by monitoring expiratory carbon monoxide (CO). We enrolled 103 patients with early glottic carcinoma (T1N0/T2N0 = 79/24) who underwent conventional radiotherapy between 2005 and 2016. The median age was 70 years. Pathologically, all patients had squamous cell carcinoma. Since 2009, we confirmed smoking cessation before radiation therapy by medical interviews. Since 2014, we measured expiratory CO to strictly monitor smoking cessation. The patients were divided according to diagnosis years: 'no cessation' (2005–2008), 'incomplete cessation' (2009–2013), and 'complete cessation' (2014–2016). We retrospectively analyzed the local recurrence rate and disease-free survival (DFS). The median follow-up period was 60.1 months (range, 1.9–110.0 months). The 2-year local recurrence rate in the 'complete cessation' group was 5.3% and tended to be lower than that in the 'incomplete cessation' group (13.7%) and 'no cessation' group (21.2%). Multivariate analysis revealed that 'no cessation' was a risk factor for DFS (hazard ratio [HR] = 4.25) and local recurrence rate (HR = 16.5, p <.05) compared to 'complete cessation.' We confirmed that the 'complete cessation' group had better prognosis than the 'no cessation' group by monitoring expiratory CO during radiation therapy for early stage glottic carcinoma. Moreover, monitoring expiratory CO was easier and more suitable than conventional methods for evaluating smoking cessation because it provided real-time measurements. [ABSTRACT FROM AUTHOR]

The article informs about a study on subglottic squamous cell carcinoma. Topics discussed include the clinical course of a complete national cohort of consecutive patients diagnosed with subglottic; laryngectomy-free survival (LFS), an event was defined as death or laryngectomy regardless of cause; and the effect of modern-RT compared to old-RT was adjusted for age, disease stage and differentiation.

Background: The purpose of the study was to determine trends in age-adjusted incidence rates (AAIR) and survival probability in head and neck cancers (HNCs) in the Danish population from 1980 to 2014. Material and methods: All patients registered with HNC in the nationwide Danish Cancer Registry from 1980 to 2014 were included. We evaluated the AAIR per 100,000 and the average annual percent change (AAPC). The relative survival probability at 5 years was calculated in relation to gender, anatomical location and histology, and we constructed age-period-cohort models of incidence. Results: About 34,606 patients were included (64.7% men). The AAIR increased from 9.1 per 100,000 in 1980 to 17.4 per 100,000 in 2014 with an AAPC of 2.1%. The greatest incidence increase was observed in oropharyngeal cancer (AAPC: 5.4%) followed by hypopharyngeal cancer (AAPC: 4.2%). Adenocarcinomas had the highest AAPC (5.0%) followed by squamous cell carcinomas (AAPC: 2.0%). The AAPC was significantly higher in women (2.4%) compared with men (1.6%). For all HNC patients, the relative survival at 5 years rose significantly from 49.0% in 1980-1984 to 62.4% in 2010-2014. Women had a significantly higher survival than men with a relative survival of 61.7% compared to 50.0% in men. Laryngeal cancer had the best survival probability of cancers in the upper aerodigestive tract with hypopharyngeal cancer having the poorest survival. Conclusion: This nation-wide study showed a significant rise in incidence of HNC for men and women along with a significant increase in relative survival. Oropharyngeal cancer had the highest increase in incidence followed by hypopharyngeal cancer which showed the poorest survival of HNCs. [ABSTRACT FROM AUTHOR]

Background.To investigate the dose-volume factors in mastication muscles that are implicated as possible causes of trismus in patients following treatment with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy for head and neck cancers. Material and methods.All evaluable patients treated at our institution between January 2004 and April 2009 with chemotherapy and IMRT for squamous cell cancers of the oropharynx, nasopharynx, hypopharynx or larynx were included in this analysis (N = 421). Trismus was assessed using CTCAE 4.0. Bi-lateral masseter, temporalis, lateral pterygoid and medial pterygoid muscles were delineated on axial computed tomography (CT) treatment planning images, and dose-volume parameters were extracted to investigate univariate and multimetric correlations. Results.Forty-six patients (10.9%) were observed to have chronic trismus of grade 1 or greater. From analysis of baseline patient characteristics, toxicity correlated with primary site and patient age. From dose-volume analysis, the steepest dose thresholds and highest correlations were seen for mean dose to ipsilateral masseter (Spearman's rank correlation coefficient Rs = 0.25) and medial pterygoid (Rs = 0.23) muscles. Lyman-Kutcher-Burman modeling showed highest correlations for the same muscles. The best correlation for multimetric logistic regression modeling was withV68Gyto the ipsilateral medial pterygoid (Rs = 0.29). Conclusion.Chemoradiation-induced trismus remains a problem particularly for patients with oropharyngeal carcinoma. Strong dose-volume correlations support the hypothesis that limiting dose to the ipsilateral masseter muscle and, in particular, the medial pterygoid muscle may reduce the likelihood of trismus. [ABSTRACT FROM PUBLISHER]

Background and purpose.To determine the spatial correspondence between the gross tumor volume (GTV) delineated on computer tomography (CT) and the actual tumor on histopathology. Material and methods.Sixteen patients with T3 or T4 laryngeal or hypopharyngeal cancer underwent a CT scan before total laryngectomy. The GTV was delineated on CT by three independent observers and by consensus between the three observers. After surgery, whole-mount hematoxylin-eosin stained (H&E) sections were obtained. One pathologist delineated the tumor in the H&E sections (tumorH&E). The reconstructed specimen was registered to the CT scan in order to compare the GTV to the tumorH&Ein three dimensions. The overlap between the GTV and the tumorH&Ewas calculated and the distance between the volumes was determined. Results.Tumor tissue was delineated in 203 of 516 H&E sections. For 14 patients a detailed analysis could be performed. The GTV volume was on average 1.7 times larger than the volume of the tumorH&E. The mean coverage of the tumorH&Eby the consensus GTV was 88%. tumorH&Etissue was found at 1.6 mm to 12.9 mm distance outside the GTV depending on observer and patient. Conclusions.GTVs delineated on CT for laryngeal and hypopharyngeal cancer were 1.7 times larger than the tumor. Complete coverage of the tumor by the GTV was, however, not obtained. [ABSTRACT FROM AUTHOR]

BackgroundSquamous 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. Material and methodsHNSCC 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. ResultsHNSCC 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. ConclusionHNSCC 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 FROM PUBLISHER]

Objective. This study aims to assess the effect of voice rehabilitation on health-related quality of life (HRQL) and communication experience for laryngeal cancer patients treated with radiotherapy. Method. This prospective randomised controlled trial included 74 patients with Tis-T4 laryngeal cancer treated curatively by radiotherapy, of which 37 constituted the intervention group receiving voice rehabilitation and 37 patients as a control group. Patients were followed at one and six months post-radiotherapy, with voice rehabilitation conducted between these time-points. Endpoints included patient reported outcomes, including HRQL as measured by European Organisation for Research and Treatment of Cancer (EORTC) Core30 (C30) and Head & Neck35 (H&N35) as well as communication function as measured by Swedish Self-Evaluation of Communication Experiences after Laryngeal cancer (S-SECEL). Results. The intervention group reported statistically significant improvements in communication experience as measured by S-SECEL environmental, attitudinal and total score domains compared to the control group. Similar improvements were seen in EORTC H&N35 Speech domain and the EORTC C30 domain Global quality of life. Moderate correlations were noted (r = 0.51-0.59) between three of four S-SECEL domains and the EORTC domains Speech and Global quality of life. Conclusion. Laryngeal cancer patients treated with radiotherapy who receive voice rehabilitation appear to experience beneficial effects on communication function and selected HRQL domains. Voice rehabilitation following radiotherapy is recommended but further research investigating potential target groups and long-term effects is required. [ABSTRACT FROM AUTHOR]

Background. Many cancer patients who are smokers when starting cancer therapy continue smoking despite evidence of tobacco smoking as a risk factor for poor treatment response and secondary primary cancers. Small samples and inconsistent results in previous studies warrant further research to identify predictors of being a continuous smoker during and after radiotherapy. Material and methods. In the clinical database of the Danish Head and Neck Cancer Group (DAHANCA), we identified 1455 patients diagnosed with laryngeal cancer between 2000 and 2010, who were all smokers at date of diagnosis and treated with primary radiotherapy. Information on the socio-economic characteristics of the study cohort was obtained from Statistics Denmark the year prior to diagnosis. Logistic regression analyses were applied. Results. In the cohort of laryngeal cancer patients smoking before starting radiotherapy, 50% still smoked one year after radiotherapy similar to the percentage of smokers during treatment. Being younger than 60 years (OR 1.39, 95% CI 1.00-1.91), commenced smoking before the age of 15 (OR 1.77, 95% CI 1.32-2.38), having a poor WHO Performance status (OR 3.09, 95% CI 1.71-5.61), low income (OR 2.21, 95% CI 1.23-3.98) and living alone (OR 1.56, 95% CI 1.13-2.14) were associated with increased risk of continuous smoking during treatment. Similar findings were found two months and one year after radiotherapy, however, no association with living alone (OR 1.08, 95% CI 0.73-1.59) at the one-year follow-up. Tumor stage and the average number of cigarettes smoked per day before radiotherapy were not associated with being a continuous smoker. Conclusion. Younger patients, who had an early smoking initiation, a poor performance status, low income and lived alone, were most likely to continue smoking. Continuous smoking was not related to the extent of disease. [ABSTRACT FROM AUTHOR]

Background. To provide further information about short-term effects on voice quality and health-related quality of life (HRQL) following radiotherapy for laryngeal cancer, comparing glottic and supraglottic tumours. Material and methods. Sixty-seven male patients who received radiotherapy for glottic and supraglottic tumours were included. Voice recordings were performed and patient reported outcome questionnaires filled in before radiotherapy and one-month post-completion. Acoustic and temporal measures were produced from the recordings and compared to an age-matched, vocally healthy control group (n = 23). Results. Deterioration of HRQL post-radiotherapy was noted for both the glottic and supraglottic cohort. Pre- radiotherapy the glottic cohort demonstrated acoustic and temporal measures that were statistically different from healthy controls, with improvements post-radiotherapy where several measures showed no statistically significant differences compared to healthy controls. The supraglottic cohort revealed voice measures comparable to the healthy controls but demonstrated statistically significant impairments in HRQL compared to the glottic cohort following radiotherapy. Conclusion. Patients with supraglottic tumours may experience more eating and swallowing related problems prior to radiotherapy compared to glottic tumours and demonstrate a more significant reduction in HRQL following treatment. However, in terms of voice measurements, subjective measures correlate poorly with objective acoustic parameters, thereby emphasising the importance of patient-reported outcomes as part of treatment evaluation. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate a single institution's outcome for patients with advanced laryngeal cancer treated with accelerated radiotherapy (RT). Fifty-eight patients with advanced laryngeal cancer (T3/T4N0/N + M0) were treated with curative intent with accelerated RT during the period 1990 - 1998. Patients received radiotherapy alone or with induction chemotherapy. The 5-year local control (LC) and loco-regional control (LRC) probabilities were both 49% for T3 and 75% for T4 tumors. The 5-year disease-free survival probability was 46% and 68% and overall survival probability was 30% and 39% for T3 and T4 tumors respectively. No significant statistical difference in outcome was found, either between T3 and T4 tumors, or between patients who received induction chemotherapy and those who did not. The treatment results for advanced laryngeal cancer at this institution were comparable to those reported in the literature. The results for T3 and T4 were similar. T4 classification alone should not be an exclusion criterion for larynx preservation. Overall survival was poor, partly because of a high incidence of deaths from intercurrent diseases. [ABSTRACT FROM AUTHOR]

Introduction: Objective measurements of levels of physical activity and fitness in patients with head and neck cancer (HNC) are lacking. Furthermore, demographic, clinical and lifestyle-related correlates of low levels of physical activity and fitness in patients with HNC are unknown. This study aims to investigate the levels of accelerometer that assessed physical activity and fitness in patients with HNC and to identify their demographical, clinical and lifestyle-related correlates. Methods: Two hundred and fifty-four patients who were recently diagnosed with HNC and participated in the NETherlands QUality of life and Biomedical cohort studies In head and neck Cancer (NET-QUBIC) study were included. Physical activity (accelerometer), cardiorespiratory fitness (Chester Step Test), hand grip strength (hand dynamometer) and lower body muscle function (30-second chair-stand test) were assessed. Multivariable linear regression analyses with a stepwise forward selection procedure were used. Results: Patients spent 229 min/d in physical activity of which 18 min/d in moderate-to-vigorous physical activity. The mean predicted VO2max was 27.9 ml/kg/min, the mean hand grip strength was 38.1 kg and the mean number of standings was 14.3. Patients with lower educational level, more comorbidity and higher tumor stage spent significantly less time in physical activity. Older patients, females and patients with a higher tumor stage had significantly lower cardiorespiratory fitness levels. Older patients, females, patients with more comorbidity, patients with normal weight and patients who have never smoked had significantly lower hand grip strength. Older patients, patients with lower educational level, smokers and patients with more comorbidity had a significantly lower function of lower body muscle. Conclusions: Pre-treatment levels of physical activity, cardiorespiratory fitness and lower body muscle function are low in patients with HNC. Based on this study, exercise programs targeted and tailored to patients with low levels of physical activity and fitness can be developed. [ABSTRACT FROM AUTHOR]

Background:Validation of magnetic resonance imaging (MRI) and development of guidelines for the delineation of the gross tumor volume (GTV) is of utmost importance to benefit from the visibility of anatomical details on MR images and to achieve an accurate GTV delineation. In the ideal situation, the GTV delineation corresponds to the histopathologically determined ‘true tumor volume’. Consequently, we developed guidelines for GTV delineation of laryngeal and hypopharyngeal tumors on MRI and determined the accuracy of the resulting delineation of the tumor outline on histopathology as gold standard. Material and methods:Twenty-seven patients with T3 or T4 laryngeal/hypopharyngeal cancer underwent a MRI scan before laryngectomy. Hematoxylin and eosin sections were obtained from surgical specimens and tumor was delineated by one pathologist. GTV was delineated on MR images by three independent observers in two sessions. The first session (del1) was performed according to clinical practice. In the second session (del2) guidelines were used. The reconstructed specimen was registered to the MR images for comparison of the delineated GTVs to the tumor on histopathology. Volumes and overlap parameters were analyzed. A target margin needed to assure tumor coverage was determined. Results:The median GTVs (del1: 19.4 cm3, del2: 15.8 cm3) were larger than the tumor volume on pathology (10.5 cm3). Comparable target margins were needed for both delineation sessions to assure tumor coverage. By adding these margins to the GTVs, the target volumes for del1 (median: 81.3 cm3) were significantly larger than for del2 (median: 64.2 cm3) (p ≤ 0.0001) with similar tumor coverage. Conclusions:In clinical radiotherapy practice, the delineated GTV on MRI is twice as large as the tumor volume. Validated delineation guidelines lead to a significant decrease in the overestimation of the tumor volume. [ABSTRACT FROM PUBLISHER]

Background:Factors influencing survival after head and neck cancer (HNC) include among others stage, age, and sex. More recently, human papillomavirus (HPV) positivity has been described as a favorable prognostic factor in relation to some HNCs. Material and methods:In this nationwide register-based cohort study of all 20 925 individuals diagnosed with squamous cell carcinoma of the head and neck (HNSCC) in Denmark 1978–2010, we investigate secular trends in all-cause five-year mortality after HNSCC according to the anticipated degree of association with HPV using a Cox proportional hazards model. Furthermore, we examine whether any trend over time differed according to sex, stage, and age at diagnosis. Results:All-cause five-year mortality after HNSCC has decreased over time. The greatest decrease was seen in the last decade (2000–2010) among patients with HNSCC at sites estimated to be strongly associated with HPV, i.e. the base of the tongue and the tonsils, where a 28% decrease per five years (e.g. HRbase of tongue/tonsils=0.72; 95% CI 0.64–0.81) was observed. When examining sex- and age-specific time trends, the decrease in mortality was most pronounced among male patients and patients below 60 years at diagnosis. In contrast, no clear pattern was observed when examining five-year all-cause mortality trends according to stage. Conclusion:All-cause five-year mortality after HNSCC has decreased significantly in Denmark from 1978 to 2010, especially for HNSCCs at sites anticipated to be strongly associated with HPV, possibly due to an increasing proportion of HPV-positive HNSCCs. [ABSTRACT FROM PUBLISHER]

PurposeThe aim of the study was to test the hypothesis that head and neck cancer (HNC) patients benefit from specialized follow-up (FU), as this strategy ensures timely detection of relapses for successful salvage treatment. This was done by evaluation of the pattern of failure, the temporal distribution of recurrences, and the outcome of salvage treatment in a contemporary cohort of HNC patients. MethodsThe study evaluated a cohort of 2062 consecutive patients treated with curative intent at Aarhus University Hospital from 1 January 2000 to 31 December 2013. The database of DAHANCA contained recordings of recurrent disease in 567 patients with primary tumors of the larynx, pharynx, oral cavity, nasal cavity, paranasal sinuses and salivary glands. A review of medical records was performed in order to update and supplement the database. ResultsFailures of the 567 patients were primarily in T-site (65%) followed by N-site (36%) and M-site (22%). The vast majority of the first recurrences occurred within the first years after primary treatment; 62%, 82%, and 91% within the first, second and third year, respectively. Totally, 51% were amenable for salvage treatment, and 44% benefited from salvage in terms of a complete response. Permanent tumor control was observed in 128 patients (23%) after one or two salvage attempts. The highest salvage rate was recorded in patients with primary glottic carcinoma (41%) and the lowest among hypopharyngeal cancers (2%). Asymptomatic recurrence was recorded in 12% of all recurrences and this was found to be a positive prognostic factor for disease-specific survival, as they had significantly better outcome after salvage. ConclusionOur data support the usefulness of specialized FU in terms of early detection of recurrent disease. In particular patients with silent recurrences benefited from early detection, as they had a significantly lower risk ratio of death from primary HNC. [ABSTRACT FROM PUBLISHER]

Objective.To develop a methodology for using FDG PET/CT in adaptive dose painting by numbers (DPBN) in head and neck squamous cell carcinoma (HNSCC) patients. Issues related to noise in PET and treatment robustness against geometric errors are addressed. Methods.Five patients with locally advanced HNSCC scheduled for chemo-radiotherapy were imaged with FDG-PET/CT at baseline and 2–3 times during radiotherapy (RT). The GTVPETwas segmented with a gradient-based method. A double median filter reduces the impact of noise in the PET uptake-to-dose conversion. Filtered FDG uptake values were linearly converted into a voxel-by-voxel prescription from 70 (median uptake) to 86 Gy (highest uptake). A PTVPETwas obtained by applying a dilation of 2.5 mm to the entire prescription. Seven iso-uptake thresholds led to seven sub-levels compatible with the Tomotherapy HiArt®Treatment Planning System. Planning aimed to deliver a median dose of 56 Gy and 70 Gy in 35 fractions on the elective and therapeutic PTVs, respectively. Plan quality was assessed with quality volume histogram (QVH). At each time point, plans were generated with a total of 3–4 plans for each patient. Deformable image registration was used for automatic contour propagation and dose summation of the 3 or 4 treatment plans (MIMvista®). Results.GTVPETsegmentations were performed successfully until week 2 of RT but failed in two patients at week 3. QVH analysis showed high conformity for all plans (mean VQ = 0.9593%; mean VQ = 1.053.9%; mean QF 2.2%). Good OAR sparing was achieved while keeping high plan quality. Conclusion.Our results show that adaptive FDG-PET-based escalated dose painting in patients with locally advanced HNSCC is feasible while respecting strict dose constraints to organs at risk. Clinical studies must be conducted to evaluate toxicities and tumor response of such a strategy. [ABSTRACT FROM PUBLISHER]

Integration of molecular imaging PET techniques into therapy selection strategies and radiation treatment planning for head and neck squamous cell carcinoma (HNSCC) can serve several purposes. First, pre-treatment assessments can steer decisions about radiotherapy modifications or combinations with other modalities. Second, biology-based objective functions can be introduced to the radiation treatment planning process by co-registration of molecular imaging with planning computed tomography (CT) scans. Thus, customized heterogeneous dose distributions can be generated with escalated doses to tumor areas where radiotherapy resistance mechanisms are most prevalent. Third, monitoring of temporal and spatial variations in these radiotherapy resistance mechanisms early during the course of treatment can discriminate responders from non-responders. With such information available shortly after the start of treatment, modifications can be implemented or the radiation treatment plan can be adapted tailing the biological response pattern. Currently, these strategies are in various phases of clinical testing, mostly in single-center studies. Further validation in multicenter set-up is needed. Ultimately, this should result in availability for routine clinical practice requiring stable production and accessibility of tracers, reproducibility and standardization of imaging and analysis methods, as well as general availability of knowledge and expertise. Small studies employing adaptive radiotherapy based on functional dynamics and early response mechanisms demonstrate promising results. In this context, we focus this review on the widely used PET tracer 18F-FDG and PET tracers depicting hypoxia and proliferation; two well-known radiation resistance mechanisms. [ABSTRACT FROM AUTHOR]

Background and purpose. Anatomic changes during head and neck radiotherapy require replanning. The primary aim of this study is the definition of the agreement among experts in the head and neck automatic delineation frame to use as benchmark. The secondary goal is to assess the reliability of automatic delineation for nasopharynx radiotherapy and time saving. Material and methods. A computed tomography (CT) scan was acquired in 10 nasopharynx patients along intensity-modulated radiotherapy (IMRT) treatment for replanning. Deformable registration with replanning autocontouring of the structures was performed using VelocityAI 2.3© software defining Structure Set A. The optimization of these contours was obtained through revision by a skilled operator, drawing Structure Set B. An ex novo Structure Set C was segmented on the replanning CT-scan by an expert delineation team. The mean Dice's Similarity Index (mDSI) was calculated between Structure Set A and B, A and C, and between B and C for each volume. All segmentation times for organs at risk (OARs) and clinical target volume (CTV) were recorded and compared. Results. We validated the replanning autocontoured Structure Sets for 10 patients. For volumetric analysis we observed mDSI values of 0.87 for the OARs, 0.70 for nodes, 0.90 for CTV in the Structure Set A-B comparison and respectively of 0.74, 0.63 and 0.78 for the Structure Set A-C one, and 0.78, 0.78 and 0.85 for Structure Set B-C, which represents the existing expert based benchmark. We calculated a mean saved time in Structure Set B of 30 minutes. Conclusions. Autocontouring procedures offer considerable segmentation time saving with acceptable reliability of the contours, even if an independent check procedure for their optimization is still required to increase their adherence to referential benchmark gold standard among experts, which stands at a 0.80 DSI value. [ABSTRACT FROM AUTHOR]

Background. Predictive models for swallowing dysfunction were developed previously and showed the potential of improved intensity-modulated radiotherapy to reduce the risk of swallowing dysfunction. Still the risk is high. The aim of this study was to determine the potential of swallowing-sparing (SW) intensity-modulated proton therapy (IMPT) in head and neck cancer (HNC) for reducing the risk of swallowing dysfunction relative to currently used photon therapy. Material and methods. Twenty-five patients with oropharyngeal (n = 21) and hypopharyngeal (n = 4) cancer received primary radiotherapy, including bilateral neck irradiation, using standard (ST) intensity-modulated photon therapy (IMRT). Prophylactic (54 Gy) and therapeutic (70 Gy) target volumes were defined. The dose to the parotid and submandibular glands was reduced as much as possible. Four additional radiotherapy plans were created for each patient: SW-IMRT, ST-IMPT, 3-beam SW-IMPT (3B-SW-IMPT) and 7-beam SW-IMPT (7B-SW-IMPT). All plans were optimized similarly, with additional attempts to spare the swallowing organs at risk (SWOARs) in the SW plans. Probabilities of swallowing dysfunction were calculated with recently developed predictive models. Results. All plans complied with standard HNC radiotherapy objectives. The mean parotid gland doses were similar for the ST and SW photon plans, but clearly lower in all IMPT plans (ipsilateral parotid gland ST-IMRT: 46 Gy, 7B-SW-IMPT: 29 Gy). The mean dose in the SWOARs was lowest with SW-IMPT, in particular with 7B-SW-IMPT (supraglottic larynx ST-IMRT: 60 Gy, 7B-SW-IMPT: 40 Gy). The observed dose reductions to the SWOARs translated into substantial overall reductions in normal tissue complication risks for different swallowing dysfunction endpoints. Compared with ST-IMRT, the risk of physician-rated grade 2-4 swallowing dysfunction was reduced on average by 8.8% (95% CI 6.5-11.1%) with SW-IMRT, and by 17.2% (95% CI: 12.7-21.7%) with 7B-SW-IMPT. Conclusion. SWOAR-sparing with proton therapy has the potential to substantially reduce the risk of swallowing dysfunction compared to similar treatment with photons. [ABSTRACT FROM AUTHOR]

Aspiration and aspiration pneumonia has been reported with a high incidence in head and neck cancer populations treated with chemo-radiotherapy. The aim of this study was to investigate the incidence and mortality of aspiration pneumonia in an unselected series of head and neck cancer patients treated with curative radiotherapy with or without concurrent weekly cisplatin. Material and methods. A total of 324 consecutive patients treated with curative intended radiotherapy for head and neck cancer in a single Danish referral center in Aarhus from 2006 to 2008 were included and followed for a median of 4.3 years. Data on patient, tumor and treatment characteristics were obtained from the DAHANCA database. Data on hospital admissions were obtained from the National Patient Registry. Data from the National Registry of Causes of Death were obtained on all deaths and causes of death. Results. Severe dysphagia occurred in 32% of the 324 patients included. A total of 18 patients developed aspiration pneumonia, corresponding to an incidence rate of 29 (95% CI 17-46) per 1000 person-years and an incidence proportion of 5.3% (95% CI 3.1-8.3%) in the first year after radiotherapy; significant risk factors included tube feeding, clinical stage, severe dysphagia and incomplete response to treatment. Three of the 18 patients with aspiration pneumonia died from this complication. Conclusion. Dysphagia-related aspiration and aspiration pneumonia are serious and potentially fatal treatment complications to accelerated radiotherapy, but occur less frequent than previously reported. [ABSTRACT FROM AUTHOR]

Background. Characterization of textural features (spatial distributions of image intensity levels) has been considered as a tool for automatic tumor segmentation. The purpose of this work is to study the variability of the textural features in PET images due to different acquisition modes and reconstruction parameters. Material and methods. Twenty patients with solid tumors underwent PET/CT scans on a GE Discovery VCT scanner, 45–60 minutes post-injection of 10 mCi of [18F]FDG. Scans were acquired in both 2D and 3D modes. For each acquisition the raw PET data was reconstructed using five different reconstruction parameters. Lesions were segmented on a default image using the threshold of 40% of maximum SUV. Fifty different texture features were calculated inside the tumors. The range of variations of the features were calculated with respect to the average value. Results. Fifty textural features were classified based on the range of variation in three categories: small, intermediate and large variability. Features with small variability (range ≤ 5%) were entropy-first order, energy, maximal correlation coefficient (second order feature) and low-gray level run emphasis (high-order feature). The features with intermediate variability (10% ≤ range ≤ 25%) were entropy-GLCM, sum entropy, high gray level run emphsis, gray level non-uniformity, small number emphasis, and entropy-NGL. Forty remaining features presented large variations (range > 30%). Conclusion. Textural features such as entropy-first order, energy, maximal correlation coefficient, and low-gray level run emphasis exhibited small variations due to different acquisition modes and reconstruction parameters. Features with low level of variations are better candidates for reproducible tumor segmentation. Even though features such as contrast-NGTD, coarseness, homogeneity, and busyness have been previously used, our data indicated that these features presented large variations, therefore they could not be considered as a good candidates for tumor segmentation. [ABSTRACT FROM AUTHOR]

The article offers a cost benefit analysis on the future of image guided radiotherapy (IGRT). According to the authors, the benefits of IGRT for patients are higher rates of local control and lower toxicity. However, they admit little high level scientific evidence has been provided by radiation oncologists that IGRT is superior to traditional radiotherapy. They believe this makes it hard to assess the cost-benefit of this treatment based on the principles of evidence based medicine.

The UICC classification (TNM) represents the validated standard tool to describe tumor extent and includes prognostic information on the probability of disease control. The American Joint Committee on Cancer (AJCC) stage grouping is based on the evaluation of treatment and outcome. Gross tumor volume (GTV) might be more relevant than pure description (TNM) or stage grouping as prognostic factor for local control in head and neck cancer (HNC). Based on the observation of GTV-correlated outcome in our initial HNC patient cohort treated with IMRT, we tested the hypothesis that the GTV is the most reliable predictive tool in HNC outcome. A GTV based volumetric staging system (VS) was introduced, using two volumetric cut-off values (15 and 70 cm3). VS, TNM, and AJCC stages were assessed and correlated with outcome following primary radiation in 172 HNC patients. Analyses were based on Kaplan-Meier survival curves. VS proved to be superior to the TNM/AJCC in predicting outcome. In addition, VS enabled to stratify high- and low-risk patients in advanced TN stages. GTV represented the most important prognostic indicator in HNC treated with IMRT and is recommended to be considered for therapeutic decisions and estimation of outcome. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the head and neck is a devastating illness with a severe impact on affected individuals. Several mechanisms may lead to oxidative stress in tumor-bearing patients, among others chronic inflammation. Inflammatory cells, especially macrophages and neutrophil leukocytes, may produce reactive oxygen species (ROS) which participate in carcinogenesis and tumor-associated immunosuppression. The aim of the study presented in this paper was to compare the production of reactive oxygen species (ROS)—superoxide anion (O2-) and hydrogen peroxide (H2O2)—by neutrophils isolated from the blood of 16 patients with larynx carcinoma and 15 healthy controls. The serum activity of superoxide dismutase and catalase as well as the total peroxidase activity in serum have also been estimated. The production of ROS, especially spontaneous and phorbol 12-myristate 13-acetate (PMA)-induced O2-, was relatively higher in the patients with larynx carcinoma than in the healthy controls and increased parallel with the tumor stage (tumor, node, metastasis—TNM staging). The serum activity of catalase and peroxidase was also highest in the patients with stage T3 and T4 larynx carcinoma. After partial or total laryngectomy, a significant decrease in ROS production and the serum activity of catalase and peroxidase was observed. In contrast, the serum level of superoxide dismutase, which had been low prior to surgery, especially in the patients with advanced tumor stages (T3–T4), increased significantly afterwards. The results indicate the existence of oxidative stress in the blood of patients with larynx carcinoma and its significant decrease after partial or total laryngectomy. [ABSTRACT FROM AUTHOR]

Experimental studies have shown an almost 2-fold increase in effectiveness if accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) was compared with standard radiotherapy. This combination was chosen in order to overcome repopulation of clonogens during radiotherapy and to minimize tumour hypoxia. Analysis of microenvironmental parameters is required to identify tumours that can benefit from these new treatment approaches. In this study 124 patients with stage III or IV head and neck squamous cell carcinomas received ARCON treatment. Vascular architecture, perfusion, proliferation and oxygenation were studied in two human laryngeal squamous cell carcinoma xenograft lines and the effects of carbogen and nicotinamide were analysed. Loco-regional control for stage III-IV larynx carcinomas was 85%, for hypopharynx carcinomas 50% and for oral cavity and oropharynx carcinomas 65%. In the experimental studies, carbogen treatment resulted in one tumour line in a decrease of blood perfusion, which was reversed if nicotinamide was added. The other tumour line showed no perfusion changes after carbogen or nicotinamide treatment. Both tumour lines showed a drastic reduction of hypoxia after carbogen breathing only or carbogen breathing plus nicotinamide. The ARCON schedule results in high loco-regional tumour control rates. Analysis of tumour microenvironmental parameters showed differences in response to carbogen and nicotinamide between different tumour lines of similar histology and site of origin. This indicates that it may be advantageous to base the selection of patients for oxygenation modifying treatment on microenvironmental tumour characteristics. [ABSTRACT FROM AUTHOR]