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Objective: This study aims to determine the added value of a geometrically accurate diffusion-weighted (DW-) MRI sequence on the accuracy of gross tumor volume (GTV) delineations, using pathological tumor delineations as a ground truth., Methods: Sixteen patients with laryngeal or hypopharyngeal carcinoma were included. After total laryngectomy, the specimen was cut into slices. Photographs of these slices were stacked to create a 3D digital specimen reconstruction, which was registered to the in vivo imaging. The pathological tumor (tumor HE ) was delineated on the specimen reconstruction. Six observers delineated all tumors twice: once with only anatomical MR imaging, and once (a few weeks later) when DW sequences were also provided. The majority voting delineation of session one (GTV MRI ) and session two (GTV DW-MRI ), as well as the clinical target volumes (CTVs), were compared to the tumor HE ., Results: The mean tumor HE volume was 11.1 cm 3 , compared to a mean GTV MRI volume of 18.5 cm 3 and a mean GTV DW-MRI volume of 15.7 cm 3 . The median sensitivity (tumor coverage) was comparable between sessions: 0.93 (range: 0.61-0.99) for the GTV MRI and 0.91 (range: 0.53-1.00) for the GTV DW-MRI . The CTV volume also decreased when DWI was available, with a mean CTV MR of 47.1 cm 3 and a mean CTV DW-MRI of 41.4 cm 3 . Complete tumor coverage was achieved in 15 and 14 tumors, respectively., Conclusion: GTV delineations based on anatomical MR imaging tend to overestimate the tumor volume. The availability of the geometrically accurate DW sequence reduces the GTV overestimation and thereby CTV volumes, while maintaining acceptable tumor coverage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Individual elective lymph node irradiation instead of elective neck irradiation is a new concept for head-and-neck cancer (HNC) patients developed for the Magnetic Resonance Image guided linear accelerator (MR-linac). To prepare this, the detectability, volume changes and intra-fraction motion of elective lymph nodes on the MR-linac was assessed., Materials and Methods: A total of 15 HNC patients underwent diagnostic pre-treatment MRI. Additionally, two MR-linac scans were obtained with a 10-minute time difference in the first week of radiation treatment. Elective lymph node contours inside lymph node levels (Ib-V) were segmented on the pre-treatment MRI and the MR-linac scans and compared on number and maximal transversal diameter. Intra-fraction motion of elective lymph nodes on the MR-linac was estimated using Center of Mass (COM) distances and incremental isotropic expansion of lymph node segmentations., Results: Of all 679 detected lymph nodes on the pre-treatment MRI, eight lymph nodes were not detectable on the first MR-linac scan and 16 new lymph nodes were detected. Lymph node diameters between the pre-treatment MRI scan and the MR-linac scan varied from -0.19 to + 0.13 mm. COM distances varied from 1.2 to 1.7 mm and lymph node contours had to be expanded with 3 mm., Conclusions: Nearly all elective lymph nodes were detectable on the 1.5T MR-linac scan with no major changes in target volumes compared to the pre-treatment MRI. Simulated intra-fraction motion during the MR-linac scans was smaller than the 5-mm margin that will be used in the first elective lymph node radiation treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Background: The aim of this prospective cohort study was to investigate swallowing function in relation to personal and clinical factors among patients with head and neck cancer (HNC) from diagnosis up to 2 years after treatment., Methods: The 100 ml water swallow test was measured before treatment, and 3, 6, 12, and 24 months after treatment. Linear mixed-effects model analysis was conducted to investigate changes over time and the association with personal (sex and age) and clinical (tumor site, tumor stage, and treatment modality) factors., Results: Among 128 included patients, number of swallows increased from baseline to 3 months after treatment and decreased to baseline again at 6 months after treatment. The number of swallows was associated with age and treatment modality., Conclusions: In patients with HNC, swallowing (dys)function changes over time with the worst score 3 months after treatment. A higher age and being treated with surgery are factors associated with swallowing dysfunction over time., (© 2022 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

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 and Purpose: To decrease the impact of radiotherapy to healthy tissues in the head and neck region, we propose to restrict the elective neck irradiation to elective lymph nodes at risk of containing micro metastases instead of the larger lymph node volumes. To assess whether this new concept is achievable in the clinic, we determined the number, volume changes and displacement of elective lymph nodes during the course of radiotherapy., Materials and Methods: MRI scans of 10 head and neck cancer (HNC) patients were acquired before radiotherapy and in week 2, 3, 4 and 5 during radiotherapy. The weekly delineations of elective lymph nodes inside the lymph node levels (Ib/II/III/IVa/V) were rigidly registered and analyzed regarding number and volume. The displacement of elective lymph nodes was determined by center of mass (COM) distances, vector-based analysis and the isotropic contour expansion of the lymph nodes of the pre-treatment scan or the scan of the previous week in order to geographically cover 95% of the lymph nodes in the scans of the other weeks., Results: On average, 31 elective lymph nodes in levels Ib-V on each side of the neck were determined. This number remained constant throughout radiotherapy in most lymph node levels. The volume of the elective lymph nodes reduced significantly in all weeks, up to 50% in week 5, compared to the pre-treatment scan. The largest median COM displacements were seen in level V, for example 5.2 mm in week 5 compared to the pre-treatment scan. The displacement of elective lymph nodes was mainly in cranial direction. Geographical coverage was obtained when the lymph node volumes were expanded with 7 mm in case the pre-treatment scan was used and 6.5 mm in case the scan of the previous week was used., Conclusion: Elective lymph nodes of HNC patients remained visible on MRI and decreased in size during radiotherapy. The displacement of elective lymph nodes differ per lymph node level and were mainly directed cranially. Weekly adaptation does not seem to improve coverage of elective lymph nodes. Based on our findings we expect elective lymph node irradiation is achievable in the clinic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Reinders, Stijnman, de Ridder, Doornaert, Raaijmakers and Philippens.)

Introduction: Head and neck cancer (HNC) and its treatment often negatively impact swallowing function. The aim was to investigate the course of patient-reported swallowing problems from diagnosis to 3, 6, 12, and 24 months after treatment, in relation to demographic, clinical, and lifestyle factors., Methods: Data were used of the Netherlands Quality of Life and Biomedical Cohort Study in head and neck cancer research (NET-QUBIC). The primary outcome measures were the subscales of the Swallowing Quality of Life Questionnaire (SWAL-QOL). Linear mixed-effects models (LMM) were conducted to investigate changes over time and associations with patient, clinical, and lifestyle parameters as assessed at baseline., Results: Data were available of 603 patients. There was a significant change over time on all subscales. Before treatment, 53% of patients reported swallowing problems. This number increased to 70% at M3 and decreased to 59% at M6, 50% at M12, and 48% at M24. Swallowing problems (i.e., longer eating duration) were more pronounced in the case of female, current smoking, weight loss prior to treatment, and stage III or IV tumor, and were more prevalent at 3 to 6 months after treatment. Especially patients with an oropharynx and oral cavity tumor, and patients receiving (C)RT following surgery or CRT only showed a longer eating duration after treatment, which did not return to baseline levels., Conclusion: Half of the patients with HNC report swallowing problems before treatment. Eating duration was associated with sex, smoking, weight loss, tumor site and stage, and treatment modality, and was more pronounced 3 to 6 months after treatment., (© 2022. The Author(s).)

In recent years, MRI-guided radiotherapy (MRgRT) has taken an increasingly important position in image-guided radiotherapy (IGRT). Magnetic resonance imaging (MRI) offers superior soft tissue contrast in anatomical imaging compared to computed tomography (CT), but also provides functional and dynamic information with selected sequences. Due to these benefits, in current clinical practice, MRI is already used for target delineation and response assessment in patients with head and neck squamous cell carcinoma (HNSCC). Because of the close proximity of target areas and radiosensitive organs at risk (OARs) during HNSCC treatment, MRgRT could provide a more accurate treatment in which OARs receive less radiation dose. With the introduction of several new radiotherapy techniques (i.e., adaptive MRgRT, proton therapy, adaptive cone beam computed tomography (CBCT) RT, (daily) adaptive radiotherapy ensures radiation dose is accurately delivered to the target areas. With the integration of a daily adaptive workflow, interfraction changes have become visible, which allows regular and fast adaptation of target areas. In proton therapy, adaptation is even more important in order to obtain high quality dosimetry, due to its susceptibility for density differences in relation to the range uncertainty of the protons. The question is which adaptations during radiotherapy treatment are oncology safe and at the same time provide better sparing of OARs. For an optimal use of all these new tools there is an urgent need for an update of the target definitions in case of adaptive treatment for HNSCC. This review will provide current state of evidence regarding adaptive target definition using MR during radiotherapy for HNSCC. Additionally, future perspectives for adaptive MR-guided radiotherapy will be discussed.

Purpose: After treatment for head and neck cancer (HNC), patients often experience major problems in masticatory function. The aim of this prospective cohort study among patients with HNC was to investigate which personal and clinical factors are associated with masticatory function from diagnosis up to 2 years after treatment with curative intent., Methods: Masticatory function was measured using the Mixing Ability Test (MAT) before treatment (baseline), and 3, 6, 12, and 24 months after treatment. A linear mixed-effects model with a random intercept and slope was conducted to investigate changes over time and the association with personal (sex, age) and clinical (tumor site, tumor stage, treatment modality) factors as measured at baseline., Result: One-hundred-twenty-five patients were included. The prevalence of masticatory dysfunction was estimated at 29% at M0, 38% at M3, 28% at M6, 26% at M12, and 36% at M24. A higher (worse) MAT score was associated with age, tumor stage, tumor site, timing of assessment, and the interaction between assessment moment and tumor site., Conclusion: In patients with HNC, masticatory function changed over time and dysfunction was associated with a higher age, a tumor in the oral cavity, a higher tumor stage, and a shorter time since treatment. The prevalence of masticatory dysfunction ranged from 26 to 38%., (© 2022. The Author(s).)

Purpose: Before and after treatment for head and neck cancer (HNC), many patients have problems with mastication, swallowing, and salivary flow. The aim of this study was to investigate the association between objective test outcomes of mastication, swallowing, and salivary flow versus patient-reported outcomes (PROs) measuring mastication-, swallowing-, and salivary flow-related quality of life., Methods: Data of the prospective cohort "Netherlands Quality of Life and Biomedical Cohort Study" was used as collected before treatment, and 3 and 6 months after treatment. Spearman's rho was used to test the association between objective test outcomes of the mixing ability test (MAT) for masticatory performance, the water-swallowing test (WST) for swallowing performance, and the salivary flow test versus PROs (subscales of the EORTC QLQ-H&N35, Swallow Quality of Life questionnaire (SWAL-QoL-NL) and Groningen Radiation-Induced Xerostomia (GRIX))., Results: Data of 142 patients were used, and in total, 285 measurements were performed. No significant correlations were found between the MAT or WST and subscales of the EORTC QLQ-H&N35. Significant but weak correlations were found between the MAT or WST and 4 subscales of the SWAL-QoL-NL. Weak to moderate correlations were found between the salivary flow test and GRIX at 3 and 6 months after treatment, with the highest correlation between salivary flow and xerostomia during the day (Spearman's rho =  - 0.441, p = 0.001)., Conclusion: The association between objective test outcomes and PROs is weak, indicating that these outcome measures provide different information about masticatory performance, swallowing, and salivary flow in patients with HNC., (© 2021. The Author(s).)

Background and Purpose: Conventional elective neck irradiation (ENI) in head and neck cancer consists of radiotherapy (RT) to the regional lymph node (LN) levels contoured on computed tomography. Hybrid Magnetic Resonance (MR) - RT modalities, such as combined magnetic resonance imaging - linear accelerators (MRLs), might enable new ENI strategies in which individual non-suspect lymph nodes (i-LNs) are targeted. In this treatment planning study, new MR-based strategies targeting i-LNs (i-ENI) were compared to conventional treatment., Materials and Methods: All i-LNs were delineated on MR images of ten retrospectively selected patients with T2-4aN0M0 laryngeal cancer. Three strategies were considered. Strategy A: Conventional ENI delivered with a conventional linear accelerator (35x 1.55 Gy). Strategy B: MRL-based i-ENI (35x 1.55 Gy) to the individual lymph nodes including a background dose to the conventional elective neck volumes (35x 1.03 Gy). Strategy C: Same as Strategy B, but without background dose. In all plans the dose prescription to the primary tumor was 35x 2 Gy. Mean dose ( D mean ) reductions in the organs at risk (OAR) were compared using the Wilcoxon signed rank test., Results: Compared to conventional ENI (strategy A), significant D mean reductions of 6.0 Gy and 8.0 Gy were observed in the submandibular glands, of 9.4 Gy and 13 Gy in the carotid arteries and of 9.9 Gy and 19.4 Gy in the thyroid for strategy B and C, respectively. Large inter-patient variations of D mean reductions were observed in all OARs., Conclusion: MRL-based i-ENI is a new promising concept that could reduce the mean dose to OARs in the neck significantly for patients with laryngeal cancer., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Dysphagia may occur in up to 44% of patients with head and neck cancer (HNC) treated with radiation therapy and up to 84% of patients treated with surgery. To test the extent of dysphagia, the 100 mL water swallow test (WST) was developed. In this study, reliability of the 100 mL WST was determined in patients with HNC and healthy subjects., Methods: Thirty-three patients and 40 healthy subjects performed the WST twice on the same day. To assess reliability, the intraclass correlation coefficient (ICC 2,1 ), standard error of measurement, smallest detectable change, and limits of agreement were calculated., Results: Good to excellent correlations were found for patients with HNC (number of swallows; ICC = 0.923, duration; ICC = 0.893), and excellent correlations for healthy subjects (number of swallows; ICC = 0.950, duration; ICC = 0.916)., Conclusion: The 100 mL WST has a good to excellent reliability in patients with HNC and healthy subjects., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Treatment of patients with head and neck cancer can result in disrupted mastication. To measure masticatory performance in people with compromised mastication, the mixing ability test (MAT) was developed., Objective: In this study, the reliability of the MAT was evaluated in patients with head and neck cancer and healthy controls., Methods: Thirty-four patients with head and neck cancer and 42 healthy controls performed the MAT twice on the same day. To assess reliability, the intra-class correlation coefficient (ICC 2,1 ), standard error of measurement (SEM), smallest detectable change (SDC) and limits of agreement (LoA) were calculated., Results: A good (ICC = 0.886) and moderate correlation (ICC = 0.525) were found for patients and healthy controls, respectively. Patients had a worse mixing ability (mean = 19.12, SD = 4.56) in comparison with healthy controls (mean = 16.42, SD = 2.04). The SEM was 0.76 in patients and 1.45 in healthy controls, with a SDC of 2.12 and 4.02, respectively. The LoA was -4.46 to 4.42 in patients and -3.65 to 4.59 in healthy controls., Conclusion: The MAT has a good reliability in patients with head and neck cancer and a moderate reliability in healthy controls., (© 2020 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Advances in diagnostic imaging create opportunities for improved therapeutic targeting of cancer but conceptual thinking about radiotherapy target volume definition and dose-prescription is not keeping up. In this opinion paper we discuss how modern imaging can contribute to new concepts for radiotherapy dose-prescription and target volume definition illustrated by the example of head and neck cancer. These new insights have the potential to significantly reduce radiation associated toxicity and may have important impact on the combination of radiotherapy with systemic cancer therapies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To benchmark and improve, through means of a targeted intervention, the quality of intensity modulated radiation therapy treatment planning for locally advanced head and neck cancer (HNC) in the Netherlands. The short and long-term impact of this intervention was assessed., Methods and Materials: A delineated computed tomography-scan of an oropharynx HNC case was sent to all 15 Dutch radiation therapy centers treating HNC. Aims for planning target volume and organ-at-risk (OAR) dosimetry were established by consensus. Each center generated a treatment plan. In a targeted intervention, OAR sparing of all plans was discussed, and centers with the best OAR sparing shared their planning strategies. Impact of the intervention was assessed by (1) short-term (half a year after intervention) replanning of the original case and (2) long-term (1 and 3 years after intervention) planning of new cases., Results: Benchmarking revealed substantial difference in OAR doses. Initial mean doses were 22 Gy (range, 15-31 Gy), 35 Gy (18-49 Gy), and 37 Gy (20-46 Gy) for the contralateral parotid gland, contralateral submandibular gland, and combined swallowing structures, respectively. Replanning after targeted intervention significantly reduced mean doses and variation, but clinically relevant differences still remained: 18 Gy (14-22 Gy), 28 Gy (17-45 Gy), and 29 Gy (18-39 Gy), respectively. One and 3 years later the variation remained stable., Conclusions: Despite many years of HNC intensity modulated radiation therapy experience, initial treatment plans showed surprisingly large variations. The simple targeted intervention used in this analysis improved OAR sparing, and its impact was durable; however, fairly large dose differences still continue to exist. Additional work is needed to understand these variations and to minimize them. A national radiation oncology platform can be instrumental for developing and maintaining high-quality planning protocols., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In brain/head-and-neck radiotherapy (RT), thermoplastic immobilization masks guarantee reproducible patient positioning in treatment position between MRI, CT, and irradiation. Since immobilization masks do not fit in the diagnostic MR head/head-and-neck coils, flexible surface coils are used for MRI imaging in clinical practice. These coils are placed around the head/neck, in contact with the immobilization masks. However, the positioning of these flexible coils is technician dependent, thus leading to poor image reproducibility. Additionally, flexible surface coils have an inferior signal-to-noise-ratio (SNR) compared to diagnostic coils. The aim of this work was to create a new immobilization setup which fits into the diagnostic MR coils in order to enhance MR image quality and reproducibility. For this purpose, a practical immobilization setup was constructed. The performances of the standard clinical and the proposed setups were compared with four tests: SNR, image quality, motion restriction, and reproducibility of inter-fraction subject positioning. The new immobilization setup resulted in 3.4 times higher SNR values on average than the standard setup, except directly below the flexible surface coils where similar SNR was observed. Overall, the image quality was superior for brain/head-and-neck images acquired with the proposed RT setup. Comparable motion restriction in feet-head/left-right directions (maximum motion ≈1 mm) and comparable inter-fraction repositioning accuracy (mean inter-fraction movement 1 ± 0.5 mm) were observed for the standard and the new setup.

Purpose: To quantify intrafractional motion to determine population-based radiotherapy treatment margins for head-and-neck tumors., Methods: Cine MR imaging was performed in 100 patients with head-and-neck cancer on a 3T scanner in a radiotherapy treatment setup. MR images were analyzed using deformable image registration (optical flow algorithm) and changes in tumor contour position were used to calculate the tumor motion. The tumor motion was used together with patient setup errors (450 patients) to calculate population-based PTV margins., Results: Tumor motion was quantified in 84 patients (12/43/29 nasopharynx/oropharynx/larynx, 16 excluded). The mean maximum (95th percentile) tumor motion (swallowing excluded) was: 2.3 mm in superior, 2.4 mm in inferior, 1.8 mm in anterior and 1.7 mm in posterior direction. PTV margins were: 2.8 mm isotropic for nasopharyngeal tumors, 3.2 mm isotropic for oropharyngeal tumors and 4.3 mm in inferior-superior and 3.2 mm in anterior-posterior for laryngeal tumors, for our institution., Conclusions: Intrafractional head-and-neck tumor motion was quantified and population-based PTV margins were calculated. Although the average tumor motion was small (95th percentile motion <3.0 mm), tumor motion varied considerably between patients (0.1-12.0 mm). The intrafraction motion expanded the CTV-to-PTV with 1.7 mm for laryngeal tumors, 0.6 mm for oropharyngeal tumors and 0.2 mm for nasopharyngeal tumors., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Current standard radiotherapy for oropharynx cancer (OPC) is associated with high rates of severe toxicities, shown to adversely impact patients' quality of life. Given excellent outcomes of human papilloma virus (HPV)-associated OPC and long-term survival of these typically young patients, treatment de-intensification aimed at improving survivorship while maintaining excellent disease control is now a central concern. The recent implementation of magnetic resonance image - guided radiotherapy (MRgRT) systems allows for individual tumor response assessment during treatment and offers possibility of personalized dose-reduction. In this 2-stage Bayesian phase II study, we propose to examine weekly radiotherapy dose-adaptation based on magnetic resonance imaging (MRI) evaluated tumor response. Individual patient's plan will be designed to optimize dose reduction to organs at risk and minimize locoregional failure probability based on serial MRI during RT. Our primary aim is to assess the non-inferiority of MRgRT dose adaptation for patients with low risk HPV-associated OPC compared to historical control, as measured by Bayesian posterior probability of locoregional control (LRC)., Methods: Patients with T1-2 N0-2b (as per AJCC 7th Edition) HPV-positive OPC, with lymph node <3 cm and <10 pack-year smoking history planned for curative radiotherapy alone to a dose of 70 Gy in 33 fractions will be eligible. All patients will undergo pre-treatment MRI and at least weekly intra-treatment MRI. Patients undergoing MRgRT will have weekly adaptation of high dose planning target volume based on gross tumor volume response. The stage 1 of this study will enroll 15 patients to MRgRT dose adaptation. If LRC at 6 months with MRgRT dose adaptation is found sufficiently safe as per the Bayesian model, stage 2 of the protocol will expand enrollment to an additional 60 patients, randomized to either MRgRT or standard IMRT., Discussion: Multiple methods for safe treatment de-escalation in patients with HPV-positive OPC are currently being studied. By leveraging the ability of advanced MRI techniques to visualize tumor and soft tissues through the course of treatment, this protocol proposes a workflow for safe personalized radiation dose-reduction in good responders with radiosensitive tumors, while ensuring tumoricidal dose to more radioresistant tumors. MRgRT dose adaptation could translate in reduced long term radiation toxicities and improved survivorship while maintaining excellent LRC outcomes in favorable OPC., Trial Registration: ClinicalTrials.gov ID: NCT03224000; Registration date: 07/21/2017.

Background: For accurate target definition, we determined margins for the clinical target volume (CTV) for laryngeal and hypopharyngeal cancer in computed tomography (CT, 4.3 mm), magnetic resonance imaging (MR, 6.1 mm) and fluorodeoxyglucose (FDG)-positron emission tomography (PET, 5.2 mm). Previously, we used Hematoxylin-eosin (HE) stained whole-mount sections of total laryngectomy specimens as gold standard to define CTV margins. In the present study, we verified the HE-based tumor delineation with staining for pan-cytokeratin, specific for squamous cell carcinoma., Methods: Twenty-seven patients with a T3/T4 laryngeal hypopharyngeal tumor were included. From each patient, a total laryngectomy specimen was obtained. Four subsequent 3-mm thick slices containing tumor were selected of which 4-µm thick whole-mount sections were obtained and stained with HE and for pan-cytokeratin CK-AE1/3. Tumors were microscopically delineated on both sections by an experienced head-and-neck pathologist. Tumor delineations were compared using the conformity index (CI) and the distance between both contours., Results: The CI between HE-based and CK-AE1/3-based tumor delineations was 0.87. The maximum and 95th percentile (p95) extent of the HE-based tumor delineations from the CK-AE1/3-based tumor delineations were 1.7 mm and 0.7 mm, respectively. The maximum and p95 extent of the CK-AE1/3-based tumor delineations from the HE-based tumor delineations was 1.9 mm and 0.8 mm, respectively., Conclusions: Histopathological assessment of tumor outline on standard HE-stained sections is comparable to microscopic tumor extent based on squamous cell specific pan-cytokeratin staining. Therefore, CTV margins based on HE based tumor contour will be adequate.

Background and Purpose: The goal of this study was to improve target definition by deriving modality-specific margins for clinical target volumes (CTV) for laryngeal and hypopharyngeal cancer on CT, MRI and 18-FDG-PET., Material and Methods: Twenty-five patients with T3/T4 laryngeal/hypopharyngeal cancer underwent CT, MRI and 18-FDG-PET scans before laryngectomy. HE-sections were obtained from the surgical specimen and tumor was delineated (tumor HE ). The GTVs on CT and MRI were delineated in consensus. PET-based GTVs were automatically segmented. The three-dimensionally reconstructed specimen was registered to the various images. Modality-specific CTV margins were derived and added to the GTVs to achieve adequate tumor coverage. The resulting CTVs were compared with each other, to tumor HE , and to CTV CT10 constructed on CT with the clinical margin of 10mm., Results: CTV margins of 4.3mm (CT), 6.1mm (MRI) and 5.2mm (PET) were needed to achieve adequate tumor coverage. The median volumes of the resulting modality-specific CTVs were 44ml (CT), 48ml (MRI) and 39ml (PET), while the CTV 10mm was 80ml., Conclusion: For laryngohypopharyngeal tumors, 45-52% target volume reduction compared with CTV 10mm is achievable when modality-specific CTV margins are used. PET-based CTVs were significantly smaller compared to CT- and MRI-based CTVs., (Copyright © 2017 The Authors. Published by Elsevier B.V. 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.

Background and Purpose: Since lymph nodes volumes are generally four times the volume of the primary PTV, the advantage of using tight margins around the primary PTV is not clear. Therefore treatment margins of T2-T4 laryngeal carcinoma for IMRT are generally chosen in such a way that the PTV is comparable to that in conventional radiotherapy. The aim of this study is to quantify the effect of volume reduction of the primary PTV of T2-T4 laryngeal carcinoma with regard to late toxicity despite elective irradiation of lymph node levels II to IV., Methods: Two treatment plans based on conservative (GTV-PTV = 15 mm and 20 mm cranial), and on evidence-based tight margins (GTV-PTV = 8 mm) were calculated for 16 patients. Toxicity effects were estimated based on the dose distributions., Results: Compared to conservative margins, using tight margins resulted in: 1) significant reduction of the normal tissue complication probability (NTCP) for swallowing muscles and submandibular glands, 2) significant reduction of the mean dose in all organs at risk (OAR), 3) a mean dose smaller than 60 Gy for all OARs except for the laryngeal cartilages. When the lymph node levels II to IV were prescribed with an elective dose, an NTCP reduction of 53% for the swallowing muscles and of 23% for the submandibular glands was found by using tight instead of conservative margins. When positive nodes were present, NTCP reduction amounted to 29% and 15%, respectively., Conclusions: There is a potential benefit in realizing evidence-based tight margins for laryngeal cancer patients despite elective irradiation of lymph node levels II to IV.

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 compare patient-reported xerostomia during daytime and during nighttime with objectively measured parotid and submandibular gland function in a cohort of head-and-neck cancer (HNC) patients treated with RT., Materials and Methods: A cohort of 138 HNC patients underwent objective measurements of parotid (PF) and submandibular (SMF) gland function and completed a xerostomia questionnaire (XQ) before RT, at 6 weeks, 6 months and 1 year after RT. No attempt was made to spare the submandibular gland(s). The XQ contained specific questions concerning the sensation of dry mouth during day- (XD) and nighttime (XN), scored on a 5-point Likert scale. Patients with no or mild (grade 1-3) xerostomia and patients with more severe (grade 4-5) complaints were grouped together., Results: Before RT, no association existed between dry mouth complaints and PF or SMF. At 6 weeks, 6 months and 1 year after RT; 37%, 51% and 36% had grade 4-5 XD and 65%, 64% and 56% had grade 4-5 XN, respectively. Patients with grade 4-5 XD and XN had significantly worse SMF at all time points after RT compared to patients with grade 1-3 XD and XN, while PF was significantly worse only at 6 weeks after RT. In multivariate analyses, SMF was consistently the most important factor related to XN after treatment. PF significantly influenced XD at 6 weeks and 1 year after RT., Conclusions: Differentiating between complaints during day- and nighttime in xerostomia research is necessary. Dry mouth at night is a frequent problem after (parotid-sparing) RT for HNC and is explained by submandibular gland dysfunction. Sparing of the contralateral submandibular gland, in addition to parotid gland sparing, may result in improved patient-reported xerostomia., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The salivary mucin MUC5B, present in (sero)mucous secretions including submandibular gland (SMG) saliva, plays an important role in the lubrication of the oral mucosa and is thought to be related to the feeling of dry mouth. We investigated if MUC5B levels in SMG saliva could distinguish between the presence or absence of severe dry mouth complaints 12  months after radiotherapy (RT) for head-and-neck cancer (HNC)., Findings: Twenty-nine HNC patients with a residual stimulated SMG secretion rate of ≥ 0.2 ml/10 min at 12  months after RT were analyzed. MUC5B (in U; normalized to 1) and total protein levels (mg/ml) were measured in SMG saliva at baseline and 12 months after RT using ELISA and BCA protein assay, respectively. Overall, median MUC5B levels decreased after RT from 0.12 to 0.03 U (p = 0.47). Patients were dichotomized into none/mild xerostomia (n = 12) and severe xerostomia (n = 17) based on a questionnaire completed at 12 months. SMG and whole saliva flow rates decreased after RT but were comparable in both groups. The median MUC5B level was higher in patients with no or mild xerostomia compared to patients with severe xerostomia (0.14 vs 0.01 U, p = 0.22). Half of the patients with severe xerostomia had no detectable MUC5B at 12 months after RT. No differences in total protein levels were observed., Conclusions: Qualitative saliva parameters like MUC5B need further investigation in RT-induced xerostomia. This pilot study showed a trend towards lower MUC5B levels in the SMG saliva of patients with severe xerostomia 12 months after RT for HNC.

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: We investigated radiation-induced changes in the salivary glands, 6 weeks after RT, using MRI., Materials and Methods: Eighteen oropharyngeal cancer patients were treated with salivary gland sparing IMRT. All patients received a 3T MRI exam before and 6 weeks after the end of RT, including a T(1)-weighted (T(1)w), a T(2)-weighted (T(2)w), and a dynamic contrast-enhanced (DCE) MRI. For both time points separately, the parotid and submandibular glands were delineated on the MR images. Differences in median signal intensity and signal variation within the glands were tested for significance. Correlations were studied between the MR changes and the planned RT dose., Results: The volume of the glands reduced significantly by 25%. The T(1)w signal decreased by 10% and the T(2)w signal increased by 23%. The k(ep) value decreased, while the v(e) increased. A correlation of the changes in T(2)w signal with the mean dose was found in both glands., Conclusions: Overall radiation-induced changes and volume loss were observed in the parotid and submandibular gland using MR. The observed differences indicated an increased water content such as found in oedema. The overall changes could be related to the mean dose, with a slightly greater impact in the high dose area., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Besides sparing the parotid gland, sparing the submandibular gland is considered to be important in preventing xerostomia in head-and-neck cancer patients. Delineation of the submandibular gland at CT, and even on T(1)- and T(2)-weighted MR images, is difficult, due to low contrast with the surrounding tissues. MR sialography might be used for delineation., Methods and Materials: Sixteen oropharyngeal cancer patients received a CT and MRI exam as part of the standard treatment imaging protocol. Patients were scanned in their five-point RT immobilization mask. The MRI exam included T(1)- and T(2)-weighted MRI scans and an MR sialography scan. Thirty submandibular glands were delineated on only CT, on the combined CT and T(1)- and T(2)-weighted MRI scans and on all MR images. A Wilcoxon signed-rank test was performed to test if the delineated volumes were significantly different., Results: The delineated volume of the submandibular gland was 7.3mL in the CT-delineation, 7.1mL in the CT/MRI-delineation and 8.1mL in the MRI-delineation. The MRI-delineation was significantly larger than the other delineations (p<0.001). The differences were mainly located in the cranial direction., Conclusion: The delineation of the submandibular gland was improved in the cranial direction by using T(1)- and T(2)-weighted MRI and MR sialography, compared to the other delineations., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To analyze the combined and updated results from the University of Michigan and University Medical Center Utrecht on normal tissue complication probability (NTCP) of the parotid gland 1 year after radiotherapy (RT) for head-and-neck (HN) cancer., Patients and Methods: A total of 222 prospectively analyzed patients with various HN malignancies were treated with conventional and intensity-modulated RT. Stimulated individual parotid gland flow rates were measured before RT and 1 year after RT using Lashley cups at both centers. A flow ratio <25% of pretreatment was defined as a complication. The data were fitted to the Lyman-Kutcher-Burman model., Results: A total of 384 parotid glands (Michigan: 157; Utrecht: 227 glands) was available for analysis 1 year after RT. Combined NTCP analysis based on mean dose resulted in a TD(50) (uniform dose leading to 50% complication probability) of 39.9 Gy and m (steepness of the curve) of 0.40. The resulting NTCP curve had good qualitative agreement with the combined clinical data. Mean doses of 25-30 Gy were associated with 17-26% NTCP., Conclusions: A definite NTCP curve for parotid gland function 1 year after RT is presented, based on mean dose. No threshold dose was observed, and TD(50) was equal to 40 Gy., (2010 Elsevier Inc. All rights reserved.)

The benefits of a patient-specific head support, developed to improve immobilization during radiotherapy, were determined in head and neck cancer patients. Cone-beam CTs were registered to the planning CT in five regions. Compared to the standard head support, the individual head support decreased the systematic and random errors of the inter- and intrafraction displacements and reduced deformations., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy., Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulated salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC)., Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD(50) in these models was approximately 39 Gy., Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To optimize the use of MRI for delineation of gross tumor volume for radiotherapy treatment planning purposes in hypopharyngeal and laryngeal tumors., Methods and Materials: Magnetic resonance images (T1 weighted and T2 weighted) of a healthy volunteer were acquired using a 1.5 T and 3.0 T MR scanner. Various receiver coils were investigated that were compatible with the immobilization mask needed for reliable coregistration with computed tomography data. For the optimal receiver coil, the influence of resolution, slice thickness, and strength of magnetic field on the signal-to-noise ratio (SNR) was studied. Feasibility of the definitive protocol was tested on patients with hypopharyngeal (n = 19) and laryngeal (n = 42) carcinoma., Results: Large differences in SNR were obtained for the various coils. The SNR values obtained using surface coils that were compatible with the immobilization mask were three times higher than those obtained using a standard head-and-neck coil and five times higher than those obtained using a body coil. High-resolution images (0.4 x 0.4 x 4 mm(3)) showed superior anatomic detail and resulted in a 4-min scan time. Image quality at 3.0 T was not significantly better compared with 1.5 T. In 3 patients the MR study could not be performed; for 5 patients images were severely deteriorated by motion artefacts. High-quality MR images were obtained in 53 patients., Conclusions: High-resolution MR images of the hypopharynx and larynx can be obtained in the majority of patients using surface receiver coils in combination with the radiotherapy mask. These MR images can be successfully used for tumor delineation in radiotherapy.

Purpose: To compare parotid gland dose-volume response relationships in a large cohort of patients treated with intensity-modulated (IMRT) and conventional radiotherapy (CRT)., Methods and Materials: A total of 221 patients (64 treated with IMRT, 157 with CRT) with various head-and-neck malignancies were prospectively evaluated. The distribution of tumor subsites in both groups was unbalanced. Stimulated parotid flow rates were measured before and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from computed tomography-based treatment planning. The normal tissue complication probability (NTCP) model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow ratio <25% of the pretreatment flow rate. The relative risk of complications was determined for IMRT vs. CRT and adjusted for the mean parotid gland dose using Poisson regression modeling., Results: One year after radiotherapy, NTCP curves for IMRT and CRT were comparable with a TD(50) (uniform dose leading to a 50% complication probability) of 38 and 40 Gy, respectively. Until 6 months after RT, corrected for mean dose, different complication probabilities existed for IMRT vs. CRT. The relative risk of a complication for IMRT vs. CRT after 6 weeks was 1.42 (95% CI 1.21-1.67), after 6 months 1.41 (95% CI; 1.12-1.77), and at 1 year 1.21 (95% CI 0.87-1.68), after correcting for mean dose., Conclusions: One year after radiotherapy, no difference existed in the mean dose-based NTCP curves for IMRT and CRT. Early after radiotherapy (up to 6 months) mean dose based (Lyman) models failed to fully describe the effects of radiotherapy on the parotid glands.

Background and Purpose: The submandibular glands are proposed to be important in preventing xerostomia in head-and-neck cancer patients. We investigated the feasibility of sparing the contralateral submandibular gland (cSMG) by reducing the dose to the contralateral planning target volume (PTV) and by reducing the clinical target volume (CTV)-to-PTV margin., Materials and Methods: Ten oropharyngeal cancer patients with a contralateral elective PTV were included in this planning study, using intensity modulated radiotherapy (IMRT). The effect on the mean dose to the cSMG of reducing the dose coverage to the contralateral elective PTV from 95 to 90% of the prescribed dose (54Gy in 1.8Gy daily fractions) was determined. The influence of reducing the margin for position uncertainty from 5 to 2mm was investigated., Results: The mean dose to the cSMG was reduced from 54Gy to approximately 40Gy if the dose coverage to the contralateral PTV was reduced to 90% of the prescribed dose. The estimated normal tissue complication probability (NTCP) was reduced below 50%. Reducing the margin from 5 to 2mm resulted in a decrease in the mean dose to the cSMG of approximately 6Gy., Conclusions: Reducing the mean dose to the cSMG below 40Gy is possible with a reasonable dose coverage of the contralateral elective PTV.

Purpose: To evaluate whether magnetic-resonance (MR) sialography can be used to investigate radiation-induced xerostomia. Preradiotherapy (pre-RT) and postradiotherapy (post-RT) MR sialographic images of the major salivary ducts (parotid and submandibular) were compared., Methods and Materials: Magnetic-resonance sialography was performed pre-RT, and 6 weeks and 6 months post-RT on 9 patients with T1-4N0-2M0 naso- or oropharyngeal tumors, on a 1.5-T MR scanner. Patients were positioned in the scanner, using a radiotherapy immobilization mask. Image registration of the MR sialograms pre- and post-RT with each other and with the CT and consequently the dose distribution was performed. A categorical scoring system was used to compare the visibility of ducts pre-RT and post-RT., Results: Good-quality MR sialographic images were obtained, and image registration was successful in all cases. The visibility score of the parotid ducts and submandibular ducts was reduced at 6 weeks post-RT, which means that the full trajectory of the salivary ducts, from the intraglandular space to the mouth cavity, was only partially visualized. For some of the parotid ducts, the visibility score improved at 6 months post-RT, but not for the submandibular ducts. The mean dose for the parotid glands was 35 Gy (1 standard deviation [SD] 3 Gy), and for the submandibular glands it was 62 Gy (SD, 8 Gy)., Conclusion: Three-dimensional MR sialography is a promising approach for investigating xerostomia, because radiation-induced changes to the saliva content of the ducts can be visualized.

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.

Background: To describe long-term changes in time of quality of life (QOL) and the relation with parotid salivary output in patients with head-and-neck cancer treated with radiotherapy., Methods: Forty-four patients completed the EORTC-QLQ-C30(+3) and the EORTC-QLQ-H&N35 questionnaires before treatment, 6 weeks, 6 months, 12 months, and at least 3.5 years after treatment. At the same time points, stimulated bilateral parotid flow rates were measured., Results: There was a deterioration of most QOL items after radiotherapy compared with baseline, with gradual improvement during 5 years follow-up. The specific xerostomia-related items showed improvement in time, but did not return to baseline. Global QOL did not alter significantly in time, although 41% of patients complained of moderate or severe xerostomia at 5 years follow-up. Five years after radiotherapy the mean cumulated parotid flow ratio returned to baseline but 20% of patients had a flow ratio <25%. The change in time of xerostomia was significantly related with the change in flow ratio (p = 0.01)., Conclusion: Most of the xerostomia-related QOL scores improved in time after radiotherapy without altering the global QOL, which remained high. The recovery of the dry mouth feeling was significantly correlated with the recovery in parotid flow ratio.

Purpose: Xerostomia is a severe complication after radiotherapy for oropharyngeal cancer, as the salivary glands are in close proximity with the primary tumor. Intensity-modulated radiotherapy (IMRT) offers theoretical advantages for normal tissue sparing. A Phase II study was conducted to determine the value of IMRT for salivary output preservation compared with conventional radiotherapy (CRT)., Methods and Materials: A total of 56 patients with oropharyngeal cancer were prospectively evaluated. Of these, 30 patients were treated with IMRT and 26 with CRT. Stimulated parotid salivary flow was measured before, 6 weeks, and 6 months after treatment. A complication was defined as a stimulated parotid flow rate <25% of the preradiotherapy flow rate., Results: The mean dose to the parotid glands was 48.1 Gy (SD 14 Gy) for CRT and 33.7 Gy (SD 10 Gy) for IMRT (p < 0.005). The mean parotid flow ratio 6 weeks and 6 months after treatment was respectively 41% and 64% for IMRT and respectively 11% and 18% for CRT. As a result, 6 weeks after treatment, the number of parotid flow complications was significantly lower after IMRT (55%) than after CRT (87%) (p = 0.002). The number of complications 6 months after treatment was 56% for IMRT and 81% for CRT (p = 0.04)., Conclusions: IMRT significantly reduces the number of parotid flow complications for patients with oropharyngeal cancer.

Purpose: To determine the most adequate parameter to measure the consequences of reducing the parotid gland dose., Methods and Materials: One hundred eight patients treated with radiotherapy for various malignancies of the head and neck were prospectively evaluated using three methods. Parotid gland function was objectively determined by measuring stimulated parotid flow using Lashley cups and scintigraphy. To assess xerostomia-related quality of life, the head-and-neck cancer module European Organization for Research and Treatment of Cancer QLQ (Quality of Life Questionnaire) H&N35 was used. Measurements took place before radiotherapy and 6 weeks and 12 months after the completion of radiotherapy. Complication was defined for each method using cutoff values. The correlation between these complications and the mean parotid gland dose was investigated to find the best measure for parotid gland function., Results: For both flow and scintigraphy data, the best definition for objective parotid gland toxicity seemed to be reduction of stimulated parotid flow to < or =25% of the preradiotherapy flow. Of all the subjective variables, only the single item dry mouth 6 weeks after radiotherapy was found to be significant. The best correlation with the mean parotid gland dose was found for the stimulated flow measurements. The predictive ability was the highest for the time point 1 year after radiotherapy. Subjective findings did not correlate with the mean parotid dose., Conclusions: Stimulated flow measurements using Lashley cups, with a complication defined as flow < or =25% of the preradiotherapy output, correlated best with the mean parotid gland dose. When reduction of the mean dose to the parotid gland is intended, the stimulated flow measurement is the best method for evaluating parotid gland function.

Background and Purpose: To determine the interobserver variability of clinical target volume delineation of glandular breast tissue and of boost volume in tangential breast irradiation., Patients and Methods: Eighteen consecutive patients with left sided breast cancer treated by breast conserving surgery agreed to participate in our study. Volumes of the glandular breast tissue (CTV breast) and of the boost (CTV boost) were delineated by five observers. We determined 'conformity indices' (CI) and the ratio between the volume of each CTV and the mean volume of all CTVs (CTV ratio). Subsequently we determined the most medial, lateral, anterior, posterior, cranial and caudal extensions both of CTV breast and CTV boost for all observers separately., Results: The mean CI breast was 0.87. For one observer we noted the highest CTV ratio in 17 out of 18 cases. No association was noted between CI breast and menopausal status. The mean CI boost was 0.56. We did not find a relation between the presence or absence of clips and the CI boost. For another observer we noted the lowest CTV boost ratio in 10 out of 17 cases., Conclusions: We recommend that each institute should determine its interobserver variability with respect to CTV breast and CTV boost before implementing the delineation of target volumes by planning CT in daily practice.

Purpose: The goal of this planning study was to compare step-and-shoot intensity-modulated radiotherapy (IMRT) plans with helical dynamic IMRT plans for oropharynx patients on the basis of dose distribution., Methods and Materials: Five patients with oropharynx cancer had been previously treated by step-and-shoot IMRT at the University Medical Centre Utrecht, The Netherlands, applying five fields and approximately 60-90 segments. Inverse planning was carried out using Plato, version 2.6.2. For each patient, an inverse IMRT plan was also made using Tomotherapy Hi-Art System, version 2.0, and using the same targets and optimization goals. Statistical analysis was performed by a paired t test., Results: All tomotherapy plans compared favorably with the step-and-shoot plans regarding sparing of the organs at risk and keeping an equivalent target dose homogeneity. Tomotherapy plans in particular realized sharper dose gradients compared with the step-and-shoot plans. The mean dose to all parotid glands (n = 10) decreased on average 6.5 Gy (range, -4 to 14; p = 0.002). The theoretical reduction in normal tissue complication probabilities in favor of the tomotherapy plans depended on the parotid normal tissue complication probability model used (range, -3% to 32%)., Conclusion: Helical tomotherapy IMRT plans realized sharper dose gradients compared with the clinically applied step-and shoot plans. They are expected to be able to reduce the parotid normal tissue complication probability further, keeping a similar target dose homogeneity.

Purpose: Irradiation of the parotid glands causes salivary dysfunction, resulting in reduced salivary flow. Recovery can be seen with time; however, long-term prospective data are lacking. The objective of this study was to analyze the long-term parotid gland function after irradiation for head-and-neck cancer., Methods and Materials: A total of 52 patients with head-and-neck cancer and treated with radiotherapy (RT) were prospectively evaluated. Stimulated bilateral parotid salivary flow rates were measured before RT and 6 weeks, 6 months, 12 months, and at least 3.5 years after RT completion. A complication was defined as a stimulated parotid flow rate of <25% of the pre-RT flow rate. The normal tissue complication probability model proposed by Lyman was fit to the data. Multilevel techniques were used to model the patterns of flow rates with time., Results: The mean stimulated flow rate of the parotid glands before RT was 0.31 mL/min (standard deviation [SD], 0.21). This was reduced to 0.14 mL/min (SD, 0.15) at 6 weeks after RT and recovered to 0.20 mL/min (SD, 0.22) at 6 months and 0.19 mL/min (SD, 0.21) at 12 months after RT. The mean stimulated flow rate was 0.25 mL/min (SD, 0.28) 5 years after RT. The mean dose to the parotid gland resulting in a 50% complication probability increased from 34 Gy at 6 weeks to 40 Gy at 6 months, 42 Gy at 12 months, and 46 Gy at 5 years after RT. Multilevel modeling indicated that both dose and time were significantly associated with the flow ratio., Conclusion: Salivary output can still recover many years after RT. At 5 years after RT, we found an increase in the salivary flow rate of approximately 32% compared with at 12 months after RT.

Purpose: To investigate the effect of random setup uncertainties on the highly conformal dose distributions produced by intensity-modulated radiotherapy (IMRT) for clinical head-and-neck cancer patients and to determine adequate margins to account for those uncertainties., Methods and Materials: We have implemented in our clinical treatment planning system the possibility of simulating normally distributed patient setup displacements, translations, and rotations. The planning CT data of 8 patients with Stage T1-T3N0M0 oropharyngeal cancer were used. The clinical target volumes of the primary tumor (CTV(primary)) and of the lymph nodes (CTV(elective)) were expanded by 0.0, 1.5, 3.0, and 5.0 mm in all directions, creating the planning target volumes (PTVs). We performed IMRT dose calculation using our class solution for each PTV margin, resulting in the conventional static plans. Then, the system recalculated the plan for each positioning displacement derived from a normal distribution with sigma = 2 mm and sigma = 4 mm (standard deviation) for translational deviations and sigma = 1 degrees for rotational deviations. The dose distributions of the 30 fractions were summed, resulting in the actual plan. The CTV dose coverage of the actual plans was compared with that of the static plans., Results: Random translational deviations of sigma = 2 mm and rotational deviations of sigma = 1 degrees did not affect the CTV(primary) volume receiving 95% of the prescribed dose (V(95)) regardless of the PTV margin used. A V(95) reduction of 3% and 1% for a 0.0-mm and 1.5-mm PTV margin, respectively, was observed for sigma = 4 mm. The V(95) of the CTV(elective) contralateral was approximately 1% and 5% lower than that of the static plan for sigma = 2 mm and sigma = 4 mm, respectively, and for PTV margins <5.0 mm. An additional reduction of 1% was observed when rotational deviations were included. The same effect was observed for the CTV(elective) ipsilateral but with smaller dose differences than those for the contralateral side. The effect of the random uncertainties on the mean dose to the parotid glands was not significant. The maximal dose to the spinal cord increased by a maximum of 3 Gy., Conclusions: The margins to account for random setup uncertainties, in our clinical IMRT solution, should be 1.5 mm and 3.0 mm in the case of sigma = 2 mm and sigma = 4 mm, respectively, for the CTV(primary). Larger margins (5.0 mm), however, should be applied to the CTV(elective), if the goal of treatment is a V(95) value of at least 99%.