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Background: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas., Methods: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation., Findings: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC., Conclusions: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation., Funding: This work was funded by Oncode PoC 2018-P0003., Competing Interests: Declaration of interests H.C.’s full disclosure is given at https://www.uu.nl/staff/JCClevers/. H.C. is inventor of several patents related to organoid technology, is a co-founder of Xilis, Inc., and is currently an employee of Roche, Basel. E.D. is inventor on a patent related to head and neck organoid technology. R.M. is currently an employee of Roche Products, Welwyn. S.M.W. holds unrestricted research grants from Bayer, Pfizer, Roche, MSD, Amgen, and AstraZeneca, all paid to the UMCG., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called 'elective dose' in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary. Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment., Methods: UPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial. Patients to be treated with definitive radiation therapy for a newly diagnosed stage T 2-4  N 0-2  M 0 squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors. In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level. Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5 weeks. The primary endpoint is 'normalcy of diet' at 1 year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment (safety)., Discussion: The objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck., Trial Registration: ClinicalTrials.gov Identifier: NCT02442375 .

Background: GTV delineation is the first crucial step in radiotherapy and requires high accuracy, especially with the growing use of highly conformal and adaptive radiotherapy techniques. If GTV delineations of observers concord, they are considered to be of high accuracy. The aim of the study is to determine the interobserver agreement for GTV delineations of supraglottic laryngeal carcinoma on CT and on CT combined with MR-images and to determine the effect of adding MR images to CT-based delineation on the delineated volume and the interobserver agreement., Methods: Twenty patients with biopsy proven T1-T4 supraglottic laryngeal cancer, treated with curative intent were included. For all patients a contrast enhanced planning CT and a 1.5-T MRI with gadolinium were acquired in the same head-and-shoulder mask for fixation as used during treatment. For MRI, a two element surface coil was used as a receiver coil. Three dedicated observers independently delineated the GTV on CT. After an interval of 2 weeks, a set of co-registered CT and MR-images was provided to delineate the GTV on CT. Common volumes (C) and encompassing volumes (E) were calculated and C/E ratios were determined for each pair of observers. The conformity index general (CIgen) was used to quantify the interobserver agreement., Results: In general, a large variation in interobserver agreement was found for CT (range: 0.29-0.77) as well as for CT-MR delineations (range: 0.17-0.80). The mean CIgen for CT (0.61) was larger compared to CT-MR (0.57) (p = 0.032). Mean GTV volume delineated on CT-MR (6.6 cm(3)) was larger compared to CT (5.6 cm(3)) (p = 0.002)., Conclusion: Delineation on CT with co-registered MR-images resulted in a larger mean GTV volume and in a decrease in interobserver agreement compared to CT only delineation for supraglottic laryngeal carcinoma.

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&E in three dimensions. The overlap between the GTV and the tumorH&E was 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&E by the consensus GTV was 88%. tumorH&E tissue 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.

Purpose: To model locoregional recurrences of oropharyngeal squamous cell carcinomas (OSCC) treated with primary intensity modulated radiation therapy (IMRT) in order to find the origins from which recurrences grow and relate their location to original target volume borders., Methods and Materials: This was a retrospective analysis of OSCC treated with primary IMRT between January 2002 and December 2009. Locoregional recurrence volumes were delineated on diagnostic scans and coregistered rigidly with treatment planning computed tomography scans. Each recurrence was analyzed with two methods. First, overlapping volumes of a recurrence and original target were measured ('volumetric approach') and assessed as 'in-field', 'marginal', or 'out-field'. Then, the center of mass (COM) of a recurrence volume was assumed as the origin from where a recurrence expanded, the COM location was compared with original target volume borders and assessed as 'in-field', 'marginal', or 'out-field'., Results: One hundred thirty-one OSCC were assessed. For all patients alive at the end of follow-up, the mean follow-up time was 40 months (range, 12-83 months); 2 patients were lost to follow-up. The locoregional recurrence rate was 27%. Of all recurrences, 51% were local, 23% were regional, and 26% had both local and regional recurrences. Of all recurrences, 74% had imaging available for assessment. Regarding volumetric analysis of local recurrences, 15% were in-field gross tumor volume (GTV), and 65% were in-field clinical tumor volume (CTV). Using the COM approach, we found that 70% of local recurrences were in-field GTV and 90% were in-field CTV. Of the regional recurrences, 25% were volumetrically in-field GTV, and using the COM approach, we found 54% were in-field GTV. The COM of local out-field CTV recurrences were maximally 16 mm outside CTV borders, whereas for regional recurrences, this was 17 mm., Conclusions: The COM model is practical and specific for recurrence assessment. Most recurrences originated in the GTV. This suggests radioresistance in certain tumor parts., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To investigate the feasibility and accuracy of an automated method to validate gross tumor volume (GTV) delineations with pathology in laryngeal and hypopharyngeal cancer., Methods and Materials: High-resolution computed tomography (CT(HR)), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans were obtained from 10 patients before total laryngectomy. The GTV was delineated separately in each imaging modality. The laryngectomy specimen was sliced transversely in 3-mm-thick slices, and whole-mount hematoxylin-eosin stained (H&E) sections were obtained. A pathologist delineated tumor tissue in the H&E sections (GTV(PATH)). An automatic three-dimensional (3D) reconstruction of the specimen was performed, and the CT(HR), MRI, and PET were semiautomatically and rigidly registered to the 3D specimen. The accuracy of the pathology-imaging registration and the specimen deformation and shrinkage were assessed. The tumor delineation inaccuracies were compared with the registration errors., Results: Good agreement was observed between anatomical landmarks in the 3D specimen and in the in vivo images. Limited deformations and shrinkage (3% ± 1%) were found inside the cartilage skeleton. The root mean squared error of the registration between the 3D specimen and the CT, MRI, and PET was on average 1.5, 3.0, and 3.3 mm, respectively, in the cartilage skeleton. The GTV(PATH) volume was 7.2 mL, on average. The GTVs based on CT, MRI, and PET generated a mean volume of 14.9, 18.3, and 9.8 mL and covered the GTV(PATH) by 85%, 88%, and 77%, respectively. The tumor delineation inaccuracies exceeded the registration error in all the imaging modalities., Conclusions: Validation of GTV delineations with pathology is feasible with an average overall accuracy below 3.5 mm inside the laryngeal skeleton. The tumor delineation inaccuracies were larger than the registration error. Therefore, an accurate histological validation of anatomical and functional imaging techniques for GTV delineation is possible in laryngeal cancer patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To analyze the cranial distribution of level II lymph nodes in patients with laryngeal cancer to optimize the elective radiation nodal target volume delineation., Methods and Materials: The most cranially located metastatic lymph node was delineated in 67 diagnostic CT data sets. The minimum distance from the base of the skull (BOS) to the lymph node was determined., Results: A total of 98 lymph nodes were delineated including 62 ipsilateral and 36 contralateral lymph nodes. The mean ipsilateral and contralateral distance from the top of the most cranial metastatic lymph node to the BOS was 36 mm (range, -9-120; standard deviation [SD], 17.9) and 35 mm (range, 14-78; SD 15.0), respectively. Only 5% and 12% of the ipsilateral and 3% and 9% of the contralateral metastatic lymph nodes were located within 15 mm and 20 mm below the BOS, respectively. No significant differences were found between patients with only ipsilateral metastatic lymph nodes and patients with bilateral metastatic lymph nodes. Between tumors that do cross the midline and those that do not, no significant difference was found in the distance of the most cranial lymph node to the BOS and the occurrence ipsilateral or contralateral., Conclusions: Setting the cranial border of the nodal target volume 1.5 cm below the base of the skull covers 95% of the lymph nodes and should be considered in elective nodal irradiation for laryngeal cancer. Bilateral neck irradiation is mandatory, including patients with unilateral laryngeal cancer, when elective irradiation is advised.

Purpose: To analyze the exact location of the most cranial metastatic cervical lymph node in patients with oropharyngeal or hypopharyngeal carcinoma. This was done to specify the cranial border of the elective nodal target volume for improvement of parotid-sparing irradiation., Methods and Materials: The most cranial metastatic lymph node, ipsilateral and, when present, contralateral, was delineated on 58 diagnostic CT scans of patients with node-positive oropharyngeal or hypopharyngeal carcinoma. The distances from the delineated lymph node to the base of the skull were measured in all planes., Results: The mean ipsilateral and contralateral distance to the base of the skull in the coronal plane was 25.6 mm (range 2.6-73.8; SD 14.7) and 34.7 mm (range 10.4-78.9; SD 14.0), respectively (p = 0.002). Ipsilateral and contralateral metastatic lymph nodes were located within 20 mm below the base of the skull in 24 patients (41%) and 3 patients (5%), respectively., Conclusion: Contralateral metastatic lymph nodes are more caudally located than are ipsilateral metastatic lymph nodes. In elective irradiation, lowering the cranial border of the contralateral nodal target volume with 20 mm below the base of the skull should be considered.