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BACKGROUND: To explore variation in numbers and treatment between hospitals that treat head and neck cancer (HNC) in the Netherlands. MATERIAL AND METHODS: Patient, tumor and treatment characteristics were collected from the Netherlands Cancer Registry, while histopathological features were obtained by linkage to the national pathology record register PALGA. Inter-hospital variation in volume, stage, treatment, pathologically confirmed loco-regional recurrence and overall survival rate was evaluated by tumor site. RESULTS: In total, 2094 newly diagnosed patients were included, ranging from 65 to 417 patients in participating hospitals treating HNC in 2008. Oral cavity cancer was mainly treated by surgery only, ranging from 46 to 82% per hospital, while the proportion of surgery with (chemo)radiotherapy ranged from 18 to 40%. Increasing age, male sex, and high stage were associated with a higher hazard of dying. In oropharynx cancer, the use of (chemo)radiotherapy varied from 31 to 82% between hospitals. We found an indication that higher volume was associated with a lower overall hazard of dying for the total group, but not by subsite. Low numbers, e.g. for salivary gland, nasopharynx, nasal cavity and paranasal sinus, did not permit all desired analyses. CONCLUSION: This study revealed significant interhospital variation in numbers and treatment of especially oropharyngeal and oral cavity cancer. This study is limited because we had to rely on data recorded in the past for a different purpose. To understand whether this variation is unwanted, future research should be based on prospectively collected data, including detailed information on recurrences, additional case-mix information and cause of death.

Background. The radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) phase III trial compared intra-arterial (IA) to intravenous (IV) cisplatin-based chemoradiation for head and neck cancer. Long-term efficacy and toxicity are reported after a median follow-up of 7.5 years.Methods. Patients with inoperable squamous cell carcinoma (SCC) of the oropharynx, oral cavity, or hypopharynx, were randomized between radiotherapy (RT) + IA cisplatin 150 mg/m(2), followed by systemic rescue or RT + I. V. cisplatin 100 mg/m(2). RT consisted of 46 Gy to the affected and elective areas, followed by a boost of 24 Gy.Results. Among 237 patients, 57 recurred locally, 35 regionally, and 80 locoregionally. There were 32 second primary tumors, 65 distant metastases, and 154 deaths. Locoregional control and overall survival were not different between the treatment arms. Late dysphagia was worse in the I.V. arm (log-rank p=.014).Conclusion. IA cisplatin did not improve tumor control compared to I.V. administered cisplatin, despite the higher dose in IA delivery of the drug. (C) 2015 Wiley Periodicals, Inc.

Background. The purpose of this study was to evaluate the long-term results of primary radiotherapy treatment for squamous cell carcinoma (SCC) of the nasal vestibule.Methods. Eighty-one patients were treated with external beam radiotherapy (EBRT) and/or interstitial radiotherapy (IRT) for a primary, localized, Wang classified SCC of the nasal vestibule.Results. Median follow-up was 38 months. T1 tumors were treated with IRT: we observed 1 local failure (at 13 months) among 48 patients (5-year local control rate of 97%). Most T2 tumors (20 of 26) were treated with EBRT. There were 8 local recurrences among 26 patients (5-year local control rate of 68%). For the T3 tumors (n = 7; all treated with EBRT), we observed local recurrence in 2 patients (5-year local control rate of 53%). The late-term side effects were relatively mild.Conclusion. Local primary radiotherapy (either IRT for T1 or EBRT for T2/3) is an adequate treatment for SCC of the nasal vestibule with little late sequelae. (C) 2015 Wiley Periodicals, Inc.

BackgroundBoth radiotherapy (RT) and cisplatin-based chemoradiotherapy (CRT) in patients with head and neck cancer may cause sensorineural hearing loss (SNHL). The purpose of this review was to provide more insight into SNHL because of CRT compared to RT.MethodsComprehensive search of Medline and Embase with the terms radiotherapy combined with ototoxicity, head and neck squamous cell carcinoma, and synonyms.ResultsOf the 2507 studies found, 21 were included in this study. Pooled analysis could not be committed because of heterogeneity. Incidence rates of SNHL after RT and CRT varied considerably, with percentages ranging from 0% to 43% and 17% to 88%, respectively. Factors that influenced the risk of SNHL were radiation dose to the cochlea, follow-up time, age, baseline hearing level, and cisplatin dose.ConclusionThe wide range of SNHL incidence rates makes it impossible to draw any conclusions on the severity of RT- and CRT-induced ototoxicity. To allow for future comparison of study outcomes, development of uniform criteria is of utmost importance. (c) 2014 Wiley Periodicals, Inc. Head Neck37: 281-292, 2015

Objectives/HypothesisThe purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not.Study DesignLong-term (LT) follow-up study.MethodsBetween 1999 and 2004, 158 patients with head and neck cancer were treated with intravenous (IV) CCRT (n = 80) or intraarterial CCRT (n = 78). Audiometry was performed before, short-term (ST), and LT posttreatment. Differences in hearing were assessed with a multivariable linear regression analysis, incorporating the effect of aging.ResultsLong-term audiometry (median 4.5 years) was available in 67 patients (42%). At ST follow-up, a deterioration of 21.6 decibel was seen compared to baseline at pure-tone averages (PTA) 8-10-12.5 kHz. At LT follow-up, this deterioration further increased with 5 decibel (P = 0.005). Only in CCRT-IV patients was a significant progressive treatment-induced hearing loss seen, at PTA 8-10-12.5 kHz (P = 0.005), PTA 1-2-4 kHz air conduction (P = 0.014), and PTA 0.5-1-2 kHz bone conduction (P = 0.045).ConclusionCCRT-induced hearing impairment was progressive over time, especially in higher frequencies and only in CCRT-IV patients, with a modest deterioration of 5 decibel 4.5 years post-treatment.

In patients with oral or oropharyngeal cancer the functionality of the tongue may become severely affected by the treatment of the cancer. In order plan tongue cancer treatment with minimal loss of functionality, the patient’s tongue functionality after treatment can be estimated by biomechanical modelling. This model is constructed from post-mortem data of a different individual. However, the biomechanical model should be personalised using information of the tongue’s muscular architecture in order to better estimate the port-treatment functionality. Therefore, we applied the MRI method constrained spherical deconvolution (CSD) to the tongue, which resulted in accurate in-vivo reconstructions of the tongue’s muscular architecture. Subsequently, using a CSD-based registration algorithm we generated population averages of CSD images of in-vivo tongues. These averages served as the template from which we were able to automatically generate personalised biomechanical models of the tongue. These models predicted the range-of-motion of the tongues more accurately than a generic model. Although promising, the largest draw-back of CSD MRI is the long scan time, which increases the chance of motion artefacts distorting the images. Therefore, we designed and built a custom MRI receiver coil for tongue imaging. Using this coil, we were able to halve the scan time of a CSD scan. Furthermore, this acceleration provided by the custom coil allowed us to develop a real-time MRI sequence, resulting in three-dimensional videos of swallowing at a frame rate of 12 frames per second.

Salivary gland tumor research is hampered by low incidence and high diversity of tumors. By using nationwide data and a new imaging technique, some problems can be bypassed.In this thesis, some epidemiological questions were answered, regarding salivary gland pleomorphic adenoma (SGPA) incidence, recurrence rate and risk of malignant transformation in 3.506 Dutch patients. Subsequently, in a systematic review on natural history of recurrent pleomorphic adenoma, 9.003 Dutch and Danish patients were analyzed. The third paper for the first time reported all steps of malignant transformation of SGPA on a genetical level. In a paper on the risk of breast cancer after salivary gland cancer or SGPA, an increased risk in both cases was reported, based on Dutch data in over 3.600 patients.The second part of the thesis first systematically described the use of molecular imaging of salivary glands based on presence of prostate-specific membrane antigen (PSMA). Subsequently the potential use of PSMA PET/CT for head neck radiotherapy is described by showing how it can assess and guide salivary gland radiotherapy. Finally, presence of a large bilateral macroscopic collection of salivary gland tissue in the human nasopharynx was suspected on PSMA PET/CT, histologically and radiologically described and 3D-reconstructed in human cadaver tissue (n=2) and PSMA PET/CT scans of 100 patients. The gland collections were named “tubarial glands”. Subsequently, the effect of radiotherapy on these glands in 723 patients with head and neck cancer was evaluated, showing increased xerostomia and dysphagia. The paper was discussed is several published comments.

This thesis provides new insights in diagnostics and therapy of cutaneous head and neck melanoma. The concept of cutaneous melanoma treatment has changed significantly over the past two decades. The first part of this thesis, entitled ‘Diagnostics’, focuses on the evaluation of the new 8th AJCC cancer staging manual, including the application of new technologies in sentinel lymph node biopsy and selection of prognostic factors for individualized treatment. Improved knowledge of molecular biology, especially in the field of cancer immunology, has contributed to the innovative designs of curative immunotherapy trials in stage III cutaneous melanoma patients. This potentially curative treatment option positions the role of therapeutic regional dissections from a different perspective, marked by a shift from extensive dissections to more limited salvage operations for removal of residual lymph node metastases. The second part of this thesis, entitled ‘Therapy’, focuses on the value of standard curative surgical protocols for stage III head and neck cutaneous melanoma and on the role of new oncolytic immunotherapy in stage III-IV cutaneous melanoma. This thesis seeks to increase awareness of the effects of diagnostics and limited surgery in the pre-immunological era.

This thesis offers a detailed analysis of nodal disease characteristics in a large cohort of 3664 differentiated thyroid cancer patients managed at a single quaternary cancer institution. Developments in imaging technology have resulted in increased use of neck ultrasound to detect nodal disease. We demonstrate that preoperative neck ultrasonography has resulted in more comprehensive neck dissections and reduced salvage neck dissections in thyroid cancer. Details of prognostic nodal features are analyzed to stratify outcomes. Lymph node characteristics, particularly presence of extracapsular nodal spread and high lymph node burden are predictors of poorer outcome. Significantly improved nodal recurrence outcomes are reported in a modern cohort of differentiated thyroid cancer patients. The need for risk-stratified and cost-effective surveillance approaches to patients is addressed in the context of increasing thyroid cancer diagnosis around the world.This is a detailed study of lymph node metastases in thyroid cancer. The increased understating of nodal prognostic features dictates more accurate risk stratification, subsequent individualized management, and more cost-effective long-term surveillance.

This thesis shows the complexity and multidimensional concept of quality of care in head and neck cancer. The selected topics represent examples of quality assessment using structure [centralization (Chapter 2) and variation of care (Chapter 3)], process [waiting time (Chapter 4) and pathologic specimen handling (Chapter 5, 6)] and outcome indicators [influence of volume and variation of care on outcome (Chapter 3) and specific outcome of rare head and neck tumors arising in the salivary gland (Chapter 7, 8)]. Head and neck cancer care in the Netherlands is centralized in specific head and neck cancer centers, but nonetheless the care given varied per head and neck center. We showed that volume may play a role in this variation, but several other quality related aspects of head and neck cancer care are of influence as well. For instance: waiting time differences, as we showed that waiting time has significant influence on outcome. What we also showed is that pathology specimen handling is another key factor, and that non-standardized workflow leads to differences and non-uniformity.For the more rare types of head and neck cancer, like salivary gland tumors, the low volume in the Netherlands makes quality assurance almost impossible. For proper quality assessment and thereby quality assurance, based upon this thesis, redistribution of rare head and neck cancers appears inevitable. The variation in numbers and treatment we found could have been biased by case-mix factors we did not include. The relatively small sample size of our study population limited us regarding some statistics.

The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable of detecting this tracers. In part one, the reader is introduced to the concept of fluorescence image-guided surgery and the evolution thereof. Furthermore the hybrid approach for image-guided surgical guidance is presented. Part two describes the clinical evaluation of the hybrid approach using the hybrid tracer indocyanine green-technetium 99m-nanocolloid. To further refine the hybrid approach for surgical guidance, part three of this thesis describes the development and evaluation of different types of (hybrid) imaging modalities.

Ototoxicity is a common adverse event after cisplatin treatment and radiotherapy to the head and neck area. Counseling patients about this adverse event is important. The thesis main objective is to improve our knowledge ototoxicity in patients with head and neck cancer. A systematic review showed that it is impossible to draw unambiguous conclusions about the incidence of (C)RT-induced ototoxicity, since different definitions of ototoxicity are used in the literature. Existing standards to score hearing impairment are available, but not consistently used. By developing a new grading system we facilitate a nuanced system, that may be used to assess the impact of hearing loss in specific situations in daily life. Furthermore, we developed a model to predict the treatment-induced hearing loss per individual. Based on pre-treatment hearing levels, radiation dose, and cisplatin dose, the model predicts the post-treatment hearing level at PTA 1-2-4 kHz. This model is a step towards improving counseling of patients. In a long-term follow-up study we found significant CRT-induced hearing loss at long-term. Patients treated with CRT intra-arterial showed significantly less hearing loss at both short-term and long-term post-treatment measurements compared to patients treated with CRT intravenous. Another follow-up study showed that patients treated with IMRT suffer from modest treatment-induced hearing loss, provided that the radiation dose to the cochlea is limited. In a study regarding hearing loss due to radiotherapy for head and neck rhabdomysarcoma in children, we concluded that 19% developed clinically relevant hearing loss at speech frequencies. Less hearing loss was seen after AMORE-based treatment compared to EBRT-based treatment.

In de afgelopen decennia zijn er opmerkelijke veranderingen opgetreden in de epidemiologie van het plaveiselcelcarcinoom in het hoofd-halsgebied (HNSCC). Naast de typische HNSCC patiënt (man, 60-70 jaar, nicotine- en alcohol-abusus) is er meer aandacht gekomen voor de jonge HNSCC patiënt (