Search

Purpose: Osteoradionecrosis of the jaw (ORNJ) is a severe iatrogenic disease characterized by bone death after radiation therapy (RT) to the head and neck. With over 9 published definitions and at least 16 classification systems, the true incidence and severity of ORNJ are obscured by lack of a standard for disease definition and severity assessment, leading to inaccurate estimation of incidence, reporting ambiguity, and likely under-diagnosis worldwide. This study aimed to achieve consensus on an explicit definition and phenotype of ORNJ and related precursor states through data standardization to facilitate effective diagnosis, monitoring, and multidisciplinary management of ORNJ., Methods: The ORAL Consortium comprised 69 international experts, including representatives from medical, surgical, radiation oncology, and oral/dental disciplines. Using a web-based modified Delphi technique, panelists classified descriptive cases using existing classification systems, reviewed systems for feature extraction and specification, and iteratively classified cases based on clinical/imaging feature combinations., Results: The Consortium ORNJ definition was developed in alignment with SNOMED-CT terminology and recent ISOO-MASCC-ASCO guideline recommendations. Case review using existing ORNJ classification systems showed high rates of inability to classify (up to 76%). Ten consensus statements and nine minimum data elements (MDEs) were outlined for prospective collection and classification of precursor/ORNJ disease states., Conclusion: This study provides an international, consensus-based definition and MDE foundation for standardized ORNJ reporting in cancer survivors treated with RT. Head and neck surgeons, radiation, surgical, medical oncologists, and dental specialists should adopt MDEs to enable scalable health information exchange and analytics. Work is underway to develop both a human- and machine-readable knowledge representation for ORNJ (i.e., ontology) and multidisciplinary resources for dissemination to improve ORNJ reporting in academic and community practice settings., Competing Interests: Declaration of competing interest The individual contributors/collaborators declare the following competing interests: National Institutes of Health (grants, travel, honoraria); Padagis (honoraria); NPi (honoraria); Castle Biosciences (consulting); Galera Therapeutics (consulting, grants); EMD Serono (advisory board, in-kind support, consulting, grants); UpToDate Inc (royalties); Cardinal Health (grants, consulting); Guy's and St Thomas' NHS Foundation Trust (grants); King's College London (grants); Canadian Institutes of Health Research (grants); Canadian Foundation for Innovation (grants);Cancer Research Society (grants); Merck (advisory service, consulting, honoraria, travel, grants); Pfizer (stock, consulting, honoraria). Moderna (stock); Healthcare Services Group (stock); Dr. Reddy's Laboratories (stock); CVS Health (stock). Organon (stock); Myomo (stock); Rewalk Robotics (stock); Elekta AB (grants, in-kind support, honoraria, travel); Philips Medical System (honoraria, travel); Varian/Siemens Healthineers (honoraria, travel). Kallsio, Inc. (royalties, licenses);Nanobiotix (consulting); LEO SAB (consulting, stock options);Shanghai JoAnn Medical Company(consulting); Yingming (consulting); Sanofi-Regeneron (honoraria); Merck Sharp & Dohme (honoraria); Glaxo Smith Kline (honoraria); Merus (honoraria); Sun Pharma (honoraria); Angelini (honoraria, consulting); MeiraGtx (grants);PCCA (grants); Mureva (grants); K pharmaceuticals (honoraria, consulting); Lipella Pharmaceuticals (honoraria, consulting); Amgen (honoraria, consulting); Bristol Myers Squibb (grants); Debiopharm (grants);ACI Clinical (consulting);Genentech (consulting); Astellas (consulting); Immunitas (consulting, stock); SIRPant (consulting); LEK (consulting); Burns and White (expert testimony); Doximity (stock)., (Copyright © 2025. Published by Elsevier Inc.)

Radiotherapy in the head-and-neck area is one of the main curative treatment options. However, this comes at the cost of varying levels of normal tissue toxicity, affecting up to 80% of patients. Mucositis can cause pain, weight loss and treatment delays, leading to worse outcomes and a decreased quality of life. Therefore, there is an urgent need for an approach to predicting normal mucosal responses in patients prior to treatment. We here describe an assay to detect irradiation responses in healthy oral mucosa tissue. Mucosa specimens from the oral cavity were obtained after surgical resection, cut into thin slices, irradiated and cultured for three days. Seven samples were irradiated with X-ray, and three additional samples were irradiated with both X-ray and protons. Healthy oral mucosa tissue slices maintained normal morphology and viability for three days. We measured a dose-dependent response to X-ray irradiation and compared X-ray and proton irradiation in the same mucosa sample using standardized automated image analysis. Furthermore, increased levels of inflammation-inducing factors-major drivers of mucositis development-could be detected after irradiation. This model can be utilized for investigating mechanistic aspects of mucositis development and can be developed into an assay to predict radiation-induced toxicity in normal mucosa.

Objectives: Long-term health-related quality of life (HRQOL) is frequently affected in head and neck cancer (HNC) survivors. Due to the shortage of studies investigating long-term patient-reported outcomes, we investigated long-term HRQOL using the novel FACE-Q HNC Module., Methods: A retrospective cross-sectional single-center study was performed, including all patients who underwent curative treatment for HNC between 2006 and 2013. All eligible patients (n = 863) were invited to participate of whom 540 completed the questionnaires. Additionally, a prospective longitudinal cohort of 43 HNC patients treated between 2020 and 2022 was included who preoperatively filled in the FACE-Q, and at three, six, and 12 months postoperatively. HRQOL domain scores were analyzed to visualize group characteristics by tumor site and type of surgical resection., Results: Both surgical and non-surgical HNC treatments predominantly affected long-term functional HRQOL domains (eating, salivation, speech, and swallowing), eating distress, and speaking distress, with distinct profiles depending on tumor site and type of treatment. In contrast, few long-term intergroup differences between HNC patients were observed for appearance, smiling, drooling distress, and smiling distress. Longitudinal data showed significant deterioration across all functional HRQOL domains in the short-term following treatment. Patients predominantly reported long-lasting negative treatment effects at 12 months follow-up for functional domains, whereas psychological domains showed near-complete recovery at group level., Conclusions: At long-term, various function-related and psychosocial HRQOL domains still are affected in head and neck cancer survivors. The results may serve to better inform patients with regard to specific treatments and highlight HRQOL domains which may potentially be optimized., 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 Ltd.. All rights reserved.)

Background and Purpose: Diffusion-weighted imaging (DWI) is a promising technique for response assessment in head-and-neck cancer. Recently, we optimized Non-Gaussian Intravoxel Incoherent Motion Imaging (NG-IVIM), an extension of the conventional apparent diffusion coefficient ( ADC ) model, for the head and neck. In the current study, we describe the first application in a group of patients with human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma. The aim of this study was to relate ADC and NG-IVIM DWI parameters to HPV status and clinical treatment response., Materials and Methods: Thirty-six patients (18 HPV-positive, 18 HPV-negative) were prospectively included. Presence of progressive disease was scored within one year. The mean pre-treatment ADC and NG-IVIM parameters in the gross tumor volume were compared between HPV-positive and HPV-negative patients. In HPV-negative patients, ADC and NG-IVIM parameters were compared between patients with and without progressive disease., Results: ADC , the NG-IVIM diffusion coefficient D , and perfusion fraction f were significantly higher, while pseudo-diffusion coefficient D* and kurtosis K were significantly lower in the HPV-negative compared to HPV-positive patients. In the HPV-negative group, a significantly lower D was found for patients with progressive disease compared to complete responders. No relation with ADC was observed., Conclusion: The results of our single-center study suggest that ADC is related to HPV status, but not an independent response predictor. The NG-IVIM parameter D, however, was independently associated to response in the HPV-negative group. Noteworthy in the opposite direction as previously thought based on ADC ., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was funded by a research grant from Elekta AB (Stockholm, Sweden) and a research grant from The Dutch Cancer Society (KWF 2019-12141). Erasmus MC Cancer Institute also has a research collaboration with Accuray Inc (Sunnyvale, CA, USA) and Varian, a Siemens Healthineers Company (Palo Alto, CA, USA)., (© 2024 The Authors.)

Objectives: Patients with head and neck cancer are routinely screened for dental foci prior to radiotherapy (RT) to prevent post- RT tooth extractions associated with an increased risk of osteoradionecrosis. We evaluated the risk factors for post-RT tooth extraction to personalise dental screening and prevention protocols prior to RT., Materials and Methods: This retrospective cohort study included dentulous patients diagnosed with oropharyngeal cancer who had undergone radiation therapy at doses 60-70 Gy and achieved a disease-free survival of ≥ 1 year (N = 174). Risk factors were assessed using Cox regression models., Results: The cumulative incidence of post-RT tooth extraction was 30.7 % at 5 years. Main indications for extraction (n = 62) were radiation caries (n = 20) and periodontal disease (n = 27). Risk factors associated (p < 0.05) with radiation caries-related extractions included active smoking, alcohol abuse, poor oral hygiene, parotid gland irradiation, and mandibular irradiation. A high-dose volume in the mandible was associated with periodontal disease events., Conclusion: Post-RT extractions due to radiation caries were influenced by lifestyle factors and RT dose in the mandible and parotid glands. Periodontal disease-related extractions were primarily associated with the mandibular dose. During dental screening these post-RT risk factors should be taken into account to prevent osteoradionecrosis., 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 The Author(s).)

Introduction: Tumor biopsy tissue response to ex vivo irradiation is potentially an interesting biomarker for in vivo tumor response, therefore, for treatment personalization. Tumor response ex vivo can be characterized by DNA damage response, expressed by the large-scale presence of DNA damage foci in tumor nuclei. Currently, characterizing tumor nuclei and DNA damage foci is a manual process that takes hours per patient and is subjective to inter-observer variability, which is not feasible in for clinical decision making. Therefore, our goal was to develop a method to automatically segment nuclei and DNA damage foci in tumor tissue samples treated with radiation ex vivo to characterize the DNA damage response, as potential biomarker for in vivo radio-sensitivity., Methods: Oral cavity tumor tissue of 21 patients was irradiated ex vivo (5 or 0 Gy), fixated 2 h post-radiation, and used to develop our method for automated nuclei and 53BP1 foci segmentation. The segmentation model used both deep learning and conventional image-analysis techniques. The training (22 %), validation (22 %), and test set (56 %) consisted of thousands of manually segmented nuclei and foci. The segmentations and number of foci per nucleus in the test set were compared to their ground truths., Results: The automatic nuclei and foci segmentations were highly accurate (Dice = 0.901 and Dice = 0.749, respectively). An excellent correlation (R 2  = 0.802) was observed for the foci per nucleus that outperformed reported inter-observation variation. The analysis took ∼ 8 s per image., Conclusion: This model can replace manual foci analysis for ex vivo irradiation of head-and-neck squamous cell carcinoma tissue, reduces the image-analysis time from hours to minutes, avoids the problem of inter-observer variability, enables assessment of multiple images or conditions, and provides additional information about the foci size. Thereby, it allows for reliable and rapid ex vivo radio-sensitivity assessment, as potential biomarker for response in vivo and treatment personalization., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was funded by a research grant of The Dutch Cancer Society (KWF 2019-12141). The Erasmus MC Cancer Institute also has research collaborations with Varian, a Siemens Healthineers Company, Elekta AB, Stockholm, Sweden, and Accuray Inc, Sunnyvale, USA., (© 2024 The Authors.)

Background and Purpose: Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy (RT). With a renewed interest in hypofractionation for head and neck radiotherapy, more information concerning ORN development after high fraction doses is important. The aim of this explorative study was to develop a model for ORN risk prediction applicable across different fractionation schemes using Equivalent Uniform Doses (EUD)., Material and Methods: We performed a retrospective cohort study in 334 oropharyngeal squamous cell carcinoma (OPSCC) patients treated with either a hypofractionated Stereotactic Body Radiation Therapy (HF-SBRT) boost or conventional Intensity Modulated Radiation Therapy (IMRT). ORN was scored with the CTCAE v5.0. HF-SBRT and IMRT dose distributions were converted into equivalent dose in 2 Gy fractions (α/β = 0.85 Gy) and analyzed using EUD. The parameter a that led to an EUD that best discriminated patients with and without grade ≥ 2 ORN was selected. Patient and treatment-related risk factors of ORN were analyzed with uni- and multivariable regression analysis., Results: A total of 32 patients (9.6%) developed ORN grade ≥ 2. An EUD(a = 8) best discriminated between ORN and non-ORN (AUC = 0.71). In multivariable regression, pre-RT extractions (SHR = 2.34; p = 0.012), mandibular volume (SHR = 1.04; p = 0.003), and the EUD(a = 8) (SHR = 1.14; p < 0.001) were significantly associated with ORN., Conclusion: Risk models for ORN based on conventional DVH parameters cannot be directly applied to HF-SBRT fractionation schemes and dose distributions. However, after correcting for fractionation and non-uniform dose distributions using EUD, a single model can distinguish between ORN and non-ORN after conventionally fractionated radiotherapy and hypofractionated boost treatments., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [The department of radiotherapy has research collaborations with Elekta AB, Stockholm, Sweden, Accuray Inc., Sunnyvale, CA, USA, and Varian, Palo Alto, CA, USA and has received a research grant from the Dutch Cancer Society.]., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy of the head and neck, but not all regions of the mandible may be equally at risk. Therefore our goal was to explore a local dose response relationship for subregions of the mandible., Materials and Methods: All oropharyngeal cancer patients treated at our hospital between 2009 and 2016 were reviewed. Follow-up was cut-off at 3 years. For patients that developed ORN, the ORN volume was delineated on the planning CT. Each mandible was divided into 16 volumes of interest (VOIs) based on the location of the dental elements and the presence of ORN in each was scored. Generalized estimating equations were used to build a model for the probability of developing ORN in an element VOI., Results: Of the 219 included patients, 22 developed ORN in 89 element VOIs. Mean dose to the element VOI (odds ratio (OR) = 1.05 per Gy, 95% confidence interval (CI): (1.04,1.07)), pre-radiotherapy extractions of an element ipsilateral to element of interest (OR = 2.81, 95% CI: (1.12,7.05)), and smoking at start of radiotherapy (OR = 3.37, 95% CI: (1.29,8.78)) were significantly associated with an increased probability of ORN in the VOI., Conclusion: The developed dose-response model indicates that the probability of ORN varies within the mandible and strongly depends on the local dose, the location of extractions, and smoking., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Perfusion MRI is promising for the assessment, prediction, and monitoring of radiation toxicity in organs at risk in head and neck cancer. Arterial spin labeling (ASL) may be an attractive alternative for conventional perfusion MRI, that does not require the administration of contrast agents. However, currently, little is known about the characteristics and performance of ASL in healthy tissues in the head and neck region. Therefore, the purpose of this study was to optimize and evaluate multidelay pseudocontinuous ASL (pCASL) for the head and neck region and to explore nominal values and measurement repeatability for the blood flow (BF), and the transit time and T1 values needed for BF quantification in healthy tissues. Twenty healthy volunteers underwent a scan session consisting of four repeats of multidelay pCASL (postlabel delays: 1000, 1632, 2479 ms). Regions of interest were defined in the parotid glands, submandibular glands, tonsils, and the cerebellum (as a reference). Nominal values of BF were calculated as the average over four repeats per volunteer. The repeatability coefficient and within-subject coefficient of repeatability (wCV) of BF were calculated. The effect of T1 (map vs. cohort average) and transit time correction on BF was investigated. The mean BF (± SE) was 55.7 ± 3.1 ml/100 g/min for the parotid glands, 41.2 ± 2.8 ml/100 g/min for the submandibular glands, and 32.3 ± 2.2 ml/100 g/min for the tonsils. The best repeatability was found in the parotid glands (wCV = 13.3%-16.1%), followed by the submandibular glands and tonsils (wCV = 20.0%-24.6%). On average, the effect of T1 and transit time correction on BF was limited, although substantial bias occurred in individual acquisitions. In conclusion, we demonstrated the feasibility of BF measurements in the head and neck region using multidelay pCASL and reported on nominal BF values, BF repeatability, the effect of T1, and transit time in various tissues in the head and neck region., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient's immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA)., Methods: The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included., Discussion: In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA's expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy., Trial Registration: The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022)., (© 2023. The Author(s).)

Background: Head and neck squamous cell carcinoma (HNSCC) displays a large heterogeneity in treatment response, and consequently in patient prognosis. Despite extensive efforts, no clinically validated model is available to predict tumor response. Here we describe a functional test for predicting tumor response to radiation and chemotherapy on the level of the individual patient., Methods: Resection material of 17 primary HNSCC patients was cultured ex vivo, irradiated or cisplatin-treated, after which the effect on tumor cell vitality was analyzed several days after treatment., Results: Ionizing radiation (IR) affected tumor cell growth and viability with a clear dose-response relationship, and marked heterogeneity between tumors was observed. After a single dose of 5Gy, proliferation in IR-sensitive tumors dropped below 30% of the untreated level, while IR-resistant tumors maintained at least 60% of proliferation. IR-sensitive tumors showed on average a twofold increase in apoptosis, as well as an increased number and size of DNA damage foci after treatment. No differences in the homologous recombination (HR) proficiency between IR-sensitive and -resistant tumors were detected. Cisplatin caused a decrease in proliferation, as well as induction of apoptosis, again with marked variation between the samples., Conclusions: Our functional ex vivo assay discriminated between IR-sensitive and IR-resistant HNSCC tumors, and may also be suitable for predicting response to cisplatin. Its predictive value is currently under investigation in a prospective clinical study.

Background/purpose: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC., Material and Methods: We performed a retrospective cohort study ( N  = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) ( N  = 180), or 24 Gy IMRT (2 Gy fractions) ( N  = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT., Results: All cases of PRMU ( N  = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% ( N  = 46) vs. 12% ( N  = 18) for conventional fractionation ( p  = 0.003). Most PRMU developed within nine months ( N  = 48). PRMU occurring > nine months ( N  = 16) were mainly observed in the SBRT boost group ( N  = 15). Sex ( p  = 0.048), acute tube feeding ( p = < 0.001), tumor subsite tonsil ( p  = 0.001), and N stage ( p  = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions., Conclusion: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

Objective: Osteoradionecrosis (ORN) is a severe late complication after radiotherapy but current knowledge on ORN risks in the setting of postoperative radiotherapy (PORT) is limited. We studied the incidence and risk factors of ORN in patients with oral cavity cancers (OCC, treated with PORT., Patients and Methods: A retrospective cohort study was conducted including OCC patients (mainly squamous cell) treated with postoperative intensity modulated radiotherapy between 2010 and 2018 with > 1 year disease-free survival. Cumulative incidences of ORN were computed using the Kaplan Meier method. Clinical and dosimetric risk factors for mandibular ORN were evaluated using Cox regression models., Results: Within our cohort (N = 227, median follow-up 49 months) we observed 46 cases of ORN, mainly in the mandible (n = 41). The cumulative incidence of mandibular ORN was 15.9 % (SE 2.5 %) at three years and 19.8 % (SE 3.0 %) at five years. At univariable analysis, smoking, mandibular mandibulotomy or segment resection, mean dose to the mandible, and mandible volume (%) ≥ 60 Gy (V60) were significantly associated with increased ORN risks. At multivariable analysis, smoking (HR 2.13, 95 %CI 1.12-4.06) and V60 (HR 1.02 per 1 % increase, 95 %CI 1.01-1.04) remained predictive factors. For active smokers with a high V60 ≥ 40 % we observed rapid ORN development with a 1-year incidence of 29 % vs 6 % for others (p < 0.01)., Conclusion: OCC Patients treated with PORT are at high risk for mandibular ORN. We identified the mandibular volume receiving ≥ 60 Gy as the dominant risk factor, especially in active smokers. Limiting high-dose volumes at treatment planning may decrease ORN risks., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The aim of this article is to establish a comprehensive contouring guideline for treatment planning using only magnetic resonance images through an up-to-date set of organs at risk (OARs), recommended organ boundaries, and relevant suggestions for the magnetic resonance imaging (MRI)-based delineation of OARs in the head and neck (H&N) region., Methods and Materials: After a detailed review of the literature, MRI data were collected from the H&N region of healthy volunteers. OARs were delineated in the axial, coronal, and sagittal planes on T2-weighted sequences. Every contour defined was revised by 4 radiation oncologists and subsequently by 2 independent senior experts (H&N radiation oncologist and radiologist). After revision, the final structures were presented to the consortium partners., Results: A definitive consensus was reached after multi-institutional review. On that basis, we provided a detailed anatomic and functional description and specific MRI characteristics of the OARs., Conclusions: In the era of precision radiation therapy, the need for well-built, straightforward contouring guidelines is on the rise. Precise, uniform, delineation-based, automated OAR segmentation on MRI may lead to increased accuracy in terms of organ boundaries and analysis of dose-dependent sequelae for an adequate definition of normal tissue complication probability., (© 2022 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.)

Introduction: The locoregional failure (LRF) rate in human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) remains disappointingly high and toxicity is substantial. Response prediction prior to or early during treatment would provide opportunities for personalised treatment. Currently, there are no accurate predictive models available for correct OPSCC patient selection. Apparently, the pivotal driving forces that determine how a OPSCC responds to treatment, have yet to be elucidated. Therefore, the holistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts study focuses on a holistic approach to gain insight in novel potential prognostic biomarkers, acquired before and early during treatment, to predict response to treatment in HPV-negative patients with OPSCC., Methods and Analysis: This single-centre prospective observational study investigates 60 HPV-negative patients with OPSCC scheduled for primary radiotherapy (RT) with cisplatin or cetuximab, according to current clinical practice. A holistic approach will be used that aims to map the macroscopic (with Intra Voxel Incoherent Motion Diffusion Kurtosis Imaging (IVIM-DKI); before, during, and 3 months after RT), microscopic (with biopsies of the primary tumour acquired before treatment and irradiated ex vivo to assess radiosensitivity), and molecular landscape (with circulating tumour DNA (ctDNA) analysed before, during and 3 months after treatment). The main end point is locoregional control (LRC) 2 years after treatment. The primary objective is to determine whether a relative change in the mean of the diffusion coefficient D (an IVIM-DKI parameter) in the primary tumour early during treatment, improves the performance of a predictive model consisting of tumour volume only, for 2 years LRC after treatment. The secondary objectives investigate the potential of other IVIM-DKI parameters, ex vivo sensitivity characteristics, ctDNA, and combinations thereof as potential novel prognostic markers., Ethics and Dissemination: The study was approved by the Medical Ethical Committee of Erasmus Medical Center. The main results of the trial will be presented in international meetings and medical journals., Trial Registration Number: NL8458., Competing Interests: Competing interests: The department of radiotherapy has research collaborations with Elekta AB, Stockholm, Sweden and with Accuray, Sunnyvale, California, USA and Varian, Palo Alto, California, USA., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The supportive needs for head and neck cancer (HNC) patients during the vulnerable period after treatment are not always met. Therefore, more professional support regarding physical, social, and psychological care as well as lifestyle is recommended., Objective: This study is an evaluation of a nurse-led aftercare intervention to support patients recovering from HNC treatment., Methods: Intervention group (IG) participants received 2 extra consultations from a nurse practitioner 3 and 9 months after treatment of HNC. A holistic conversational tool, the Self-Management Web, was developed to guide the nurse through the conversation. Primary outcomes were health-related quality of life (HRQoL) and quality of patient-centered care. A secondary outcome was self-management skills., Results: Twenty-seven patients were included in the IG, and 28 were included in the control group. Differences in HRQoL and self-management between the IG and the control group were not statistically significant. For the IG, all domains of the Self-Management Web were perceived important and addressed by the nurse practitioner., Conclusion: This holistic nurse-led aftercare intervention was highly appreciated by HNC patients. Although the intervention met the need for support in recovery after treatment, it did not improve HRQoL or self-management skills., Implications of Practice: For both nurses and patients, the intervention is feasible and acceptable in daily practice. Self-management support for patients after their cancer treatment is of added value and has potential to improve the quality of regular follow-up care., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To define metastatic categories based on their prognostic significance. We hypothesized that oligometastasis in patients with head and neck squamous cell carcinoma (HNSCC) is associated with better post-distant metastasis disease specific survival (post-DM DSS) compared to patients with polymetastasis. Furthermore, the impact on survival of synchronous versus metachronous distant metastasis (DM) occurrence was assessed., Materials and Methods: Retrospective cohort study in which patients with DM were stratified into three groups: oligometastasis (maximum of 3 metastatic foci in ≤2 anatomic sites), explosive metastasis (≥4 metastatic foci at one anatomic site) and explosive-disseminating metastasis (spread to ≥3 anatomic sites or >3 metastatic foci in 2 anatomic sites). In addition, patients were divided into synchronous versus metachronous DM., Results: Between January 1, 2006 and December 31, 2013, a total of 2687 patients with HNSCC were identified, of which 324 patients developed DM. In this group, 115 (35.5%) patients had oligometastasis, 64 (19.8%) patients had explosive metastasis and 145 (44.8%) patients had explosive-disseminating metastasis. Their median post-DM DSS were 4.7 months, 4.1 months and 1.7 months respectively (p < .001). Synchronous DM was associated with more favorable survival rates in univariable and multivariable analyses than metachronous DM with recurrence of the index tumor (6-month post-DM DSS probability of 0.51 vs 0.17, p < .001)., Conclusion: Oligometastasis in HNSCC signifies a better prognosis than a polymetastatic pattern. Metachronous DM occurrence with recurrence of the primary index tumor is associated with an unfavorable prognosis., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To compare the impact on survival and late radiation toxicity of patients with squamous cell carcinoma of unknown primary who were treated with ipsilateral neck dissection and ipsilateral postoperative radiotherapy (PORT) and patients treated with ipsilateral neck dissection and PORT to both sides of the neck plus the pharyngeal axis., Methods: Retrospective cohort study performed at the Erasmus University Medical Center in which 78 patients with squamous cell carcinoma of unknown primary were identified. Thirty-nine patients received PORT to both sides of the neck plus the pharyngeal axis (BILAX) and another 39 patients were irradiated on the ipsilateral neck (IPSI) only. The endpoints of the present study were 3-year overall survival (OS), 3-year disease-free survival (DFS), and overall late radiation toxicity., Results: The 3-year OS rate of the entire group of 78 patients was 74.2% and the 3-year DFS rate was 72.7%. The 3-year OS rates for the IPSI and the BILAX groups were 74.4% and 74.1%, respectively ( P = .654). The most common late radiation toxicity experienced was xerostomia (64.8%), which was significantly more often seen in the BILAX group than in the IPSI group (83.8% and 44.1%, respectively, P = .001). Overall late radiation toxicity was significantly higher in the BILAX group ( P = .003)., Conclusion: There was no significant difference in OS and DFS rates between the IPSI and the BILAX group. Late radiation toxicity was significantly higher in the BILAX group., Level of Evidence: Level 2b: Individual retrospective cohort study., Competing Interests: 6The authors declare no potential conflict of interest., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Purpose: To optimize the diffusion-weighting b values and postprocessing pipeline for hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region., Methods: Optimized diffusion-weighting b value sets ranging between 5 and 30 b values were constructed by optimizing the Cramér-Rao lower bound of the hybrid intravoxel incoherent motion diffusion kurtosis imaging model. With this model, the perfusion fraction, pseudodiffusion coefficient, diffusion coefficient, and kurtosis were estimated. Sixteen volunteers were scanned with a reference b value set and 3 repeats of the optimized sets, of which 1 with volunteers swallowing on purpose. The effects of (1) b value optimization and number of b values, (2) registration type (none vs. intervolume vs. intra- and intervolume registration), and (3) manual swallowing artifact rejection on the parameter precision were assessed., Results: The SD was higher in the reference set for perfusion fraction, diffusion coefficient, and kurtosis by a factor of 1.7, 1.5, and 2.3 compared to the optimized set, respectively. A smaller SD (factor 0.7) was seen in pseudodiffusion coefficient. The sets containing 15, 20, and 30 b values had comparable repeatability in all parameters, except pseudodiffusion coefficient, for which set size 30 was worse. Equal repeatability for the registration approaches was seen in all parameters of interest. Swallowing artifact rejection removed the bias when present., Conclusion: To achieve optimal hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region, b value optimization and swallowing artifact image rejection are beneficial. The optimized set of 15 b values yielded the optimal protocol efficiency, with a precision comparable to larger b value sets and a 50% reduction in scan time., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma (OPSCC). Materials and methods: We performed a retrospective cohort study in 195 consecutive OPSCC patients with T1-small T3 disease, treated at Erasmus MC between 2009 and 2016 with a SBRT (3 × 5.5 Gy) boost after 46 Gy IMRT. Primary endpoints were disease-specific survival (DSS) and Grade ≥3 toxicity (Common Terminology Criteria). The Kaplan-Meier method and Cox regression model were applied to determine rates and risk factors. Results: The median follow-up was 4.3 years. Treatment compliance was high (100%). Rates of 5-year DSS and late grade ≥3 toxicity were 85% and 28%, respectively. Five-year overall survival was 67%. The most frequently observed toxicities were mucosal ulceration or soft tissue necrosis ( n  = 30, 5 year 18%), dysphagia or weight loss ( n  = 18, 5 year 12%) and osteoradionecrosis ( n  = 11, 5 year 9%). Current smoker status (hazard ratio [HR] = 2.9, p  = .001) and Charlson Comorbidity Index ≥2 (HR = 1.9, p  = .03) were was associated with increased toxicity risk. Tooth extraction prior to RT was associated with increased osteoradionecrosis risk (HR = 6.4, p  = .006). Conclusion: We reported on outcomes in the largest patient series to date treated with a hypofractionated boost for OPSCC. Efficacy was good with survival rates comparable to conventionally fractionated (chemo)radiotherapy. Grade ≥3 toxicity profiles showed high rates of soft tissue necrosis and osteoradionecrosis. Strategies to mitigate severe toxicity risks are under investigation to improve the tolerability of the SBRT boost.

Background: The objectives of this study are to determine the incidence and survival rate of patients with head and neck squamous cell carcinoma (HNSCC) with multiple primary tumors (MPT) in the HN-region, lung, or esophagus., Methods: Patient and tumor specific data of 1372 patients with HNSCC were collected from both the national cancer registry and patient records to ensure high-quality double-checked data., Results: The total incidence of MPTs in the HN-region, lung, and esophagus in patients with HNSCC was 11% (149/1372). Patients with lung MPTs and esophageal MPTs had a significant worse 5-year survival than patients with HN-MPTs (29%, 14%, and 67%, respectively, P < 0.001). The 5-year survival rate for synchronous HN MPTs was only 25%, whereas it was surprisingly high for patients with metachronous HN MPT (85%, P < 0.001)., Conclusions: One of 10 patients with HNSCC develop MPTs in the HN-region, lung, or esophagus. The 5-year survival of patients with metachronous HN MPTs was surprisingly favorable., (© 2019 The Authors. Head & Neck published by Wiley Periodicals, Inc.)

Purpose: Accelerated partial breast irradiation is a treatment option for selected patients with early-stage breast cancer. Some accelerated partial breast irradiation techniques lead to skin toxicity with the skin dose as a main risk factor. Biodegradable spacers are effective and safe in prostate brachytherapy to protect the rectum. We hypothesize that a subcutaneous spacer injection reduces the skin dose in breast brachytherapy., Methods and Materials: Ultrasound-guided spacer injections, either hyaluronic acid (HA) or iodined polyethylene glycol (PEG), were performed on fresh mastectomy specimens. Success was defined as a spacer thickness of ≥5 mm in the high-dose skin area. Usability was scored using the system usability scale. Pre and postinjection CT scans were used to generate low-dose-rate seed brachytherapy treatment plans after defining a clinical target volume. Maximum dose to small skin volumes (D 0.2cc ) and existence of hotspots (isodose ≥90% on 1 cm 2 of skin) were calculated as skin toxicity indicators., Results: We collected 22 mastectomy specimens; half had HA and half had PEG injection. Intervention success was 100% for HA and 90.9% for PEG (p = NS). Hydrodissection was feasible in 81.8% with HA and 63.6% with PEG. Median system usability scale score was 97.5 for HA and 82.5 for PEG (p < 0.001). Mean D 0.2cc was 80.8 Gy without spacer and 53.7 Gy with spacer (p < 0.001). Skin hotspots were present in 40.9% without spacer but none with spacer (p < 0.001)., Conclusions: A spacer injection in mastectomy specimens is feasible. An extra 5 mm space is always achieved, thereby potentially reducing the skin dose dramatically in low-dose-rate seed breast brachytherapy., (Copyright © 2018 American Brachytherapy Society. All rights reserved.)

Background and Purpose: During oncoplastic breast-conserving surgery (BCS), the surgical cavity is closed to reduce seroma formation. This makes the radiotherapy target definition using clips challenging, leading to poor inter-observer agreement and potentially geographical misses. We hypothesize that injecting a radiopaque hydrogel in the lumpectomy cavity before closure improves radiotherapy target definition and agreement between observers., Materials and Methods: Women undergoing BCS in a single university hospital were prospectively accrued in the study. Three to 9 ml of iodined PolyEthylene Glycol (PEG) hydrogel and clips were inserted in the lumpectomy cavity. A CT-scan was performed at 4 to 6 weeks. CT images of BCS patients with standard clips only were used as control group, matched on age, specimen weight, and distance between clips. Six radiation oncologists delineated the tumor bed volumes and rated the cavity visualization scores (CVS). The primary endpoint was the agreement between observers measured using a Conformity Index (Cx)., Results: Forty-two patients were included, 21 hydrogel procedures and 21 controls, resulting in 315 observer pairs. The feasibility of the intervention was 100%. The median Cx was higher in the intervention group (Cx = 0.70, IQR [0.54-0.79]) than in the control group (Cx = 0.54, IQR [0.42-0.66]), p < 0.00, as were the CVS (3.5 [2.5-4.5] versus 2.5 [2-3.5], p < 0.001). The rate of surgical site infections was similar to literature., Conclusions: The use of radiopaque PEG enables to identify the lumpectomy cavity, resulting in a high inter-observer agreement for radiotherapy target definition. This intervention is easy to perform and blend well into current practice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To investigate the effect of patient specific vessel cooling on head and neck hyperthermia treatment planning (HTP). Methods and materials: Twelve patients undergoing radiotherapy were scanned using computed tomography (CT), magnetic resonance imaging (MRI) and contrast enhanced MR angiography (CEMRA). 3D patient models were constructed using the CT and MRI data. The arterial vessel tree was constructed from the MRA images using the 'graph-cut' method, combining information from Frangi vesselness filtering and region growing, and the results were validated against manually placed markers in/outside the vessels. Patient specific HTP was performed and the change in thermal distribution prediction caused by arterial cooling was evaluated by adding discrete vasculature (DIVA) modeling to the Pennes bioheat equation (PBHE). Results: Inclusion of arterial cooling showed a relevant impact, i.e., DIVA modeling predicts a decreased treatment quality by on average 0.19 °C ( T 90), 0.32 °C ( T 50) and 0.35 °C ( T 20) that is robust against variations in the inflow blood rate (|Δ T | < 0.01 °C). In three cases, where the major vessels transverse target volume, notable drops (|Δ T | > 0.5 °C) were observed. Conclusion: Addition of patient-specific DIVA into the thermal modeling can significantly change predicted treatment quality. In cases where clinically detectable vessels pass the heated region, we advise to perform DIVA modeling.

Background: Accelerated partial breast irradiation (APBI) is a treatment option for selected early stage breast cancer patients. Some APBI techniques lead to skin toxicity with the skin dose as main risk factor. We hypothesize that a spacer injected between the skin and target volume reduces the skin dose and subsequent toxicity in permanent breast seed implant (PBSI) patients., Methods: In this parallel-group, single-center, randomized controlled trial, the effect of a subcutaneous spacer injection on skin toxicity among patients treated with PBSI is tested. Eligibility for participation is derived from international guidelines for suitable patients for partial breast radiotherapy, e.g. women aged ≥ 50 years with a histologically proven non-lobular breast carcinoma and/or ductal carcinoma in situ (DCIS), tumor size ≤ 3 cm, node-negative, and PBSI technically feasible. Among exclusion criteria are neoadjuvant chemotherapy, lymphovascular invasion, and allergy for hyaluronic acid. For the patients allocated to receive spacer, after the PBSI procedure, 4-10 cc of biodegradable hyaluronic acid (Barrigel™, Palette Life Sciences, Santa Barbara, CA, USA or Restylane SubQ®, Galderma Benelux, Breda, the Netherlands) is injected directly under the skin using ultrasound guidance to create an extra 0.5-1 cm space between the treatment volume and the skin. The primary outcome is the rate of telangiectasia at two years, blindly assessed using Bentzen's 4-point scale. Secondary outcomes include: local recurrence; disease-free and overall survival rates; adverse events (pain, redness, skin/subcutaneous induration, radiation dermatitis, pigmentation, surgical site infection); skin dose; cosmetic and functional results; and health-related quality of life. A Fisher's exact test will be used to test differences between groups on the primary outcome. Previous studies found 22.4% telangiectasia at two years. We expect the use of a spacer could reduce the occurrence of telangiectasia to 7.7%. A sample size of 230 patients will allow for a 10% lost to follow-up rate., Discussion: In this study, the effect of a subcutaneous spacer injection on the skin dose, late skin toxicity, and cosmetic outcome is tested in patients treated with PBSI in the setting of breast-conserving therapy. Our results will be relevant for most forms of breast brachytherapy as well as robotic radiosurgery, as skin spacers could protect the skin with these other techniques., Trial Registration: Netherlands Trial Register, NTR6549 . Registered on 27 June 2017.

Over 90% of patients treated for head and neck cancer with curatively aimed chemo or bioradiotherapy will develop painful mucositis and xerostomia. Sublingually delivered fentanyl (SDL) is a rapid acting opioid to treat breakthrough pain. It is unclear how SDL is absorbed by the mucosa of these patients. Therefore, the aim of this study was to investigate the effects of mucositis and xerostomia on the absorption of SDL. Thirteen patients who received chemo or bioradiotherapy (RT), were given a single dose of fentanyl: Before start of RT, 3 and 6 weeks after start of RT, and 6 weeks after finishing RT. Pharmacokinetic samples were taken. The primary endpoint was the relative difference (RD) between systemic exposure to fentanyl (area under the curve; AUC) at baseline (AUC baseline ) and fentanyl AUC in the presence of mucositis grade ≥2. The secondary endpoint was the RD between AUC baseline and fentanyl AUC in the presence of xerostomia, which were analyzed by means of a paired t -test on log-transformed data. Mucositis resulted in a 12.7% higher AUC ( n = 13; 95% CI: -10.7% to +42.2%, p = 0.29) compared to baseline levels and xerostomia resulted in a 22.4% lower AUC ( n = 8; 95% CI: -51.9% to +25.3%, p = 0.25) compared to baseline levels. Mucositis grade ≥2 or xerostomia caused by chemo or bioradiotherapy does not significantly alter the systemic exposure to SDL. Patients with pain during and after chemo or bioradiotherapy may be safely treated with SDL.

Purpose: Radiotherapy (RT) treatment of locally-advanced and recurrent head and neck carcinoma (HNC) results in disappointing outcomes. Combination of RT with cisplatin or cetuximab improves survival but the increased toxicity and patient's comorbidity warrant the need for a less-toxic radiosensitizer. Stimulated by several randomized studies demonstrating the radio-sensitizing effect of hyperthermia, we developed the HYPERcollar. Here, we report early experience and toxicity in patients with advanced HNC., Methods and Materials: 119 hyperthermia treatments given to 27 patients were analyzed. Hyperthermia was applied once a week by the HYPERcollar aimed at achieving 39-43 °C in the target area, up to patients' tolerance. Pre-treatment planning was used to optimize treatment settings. When possible, invasive thermometry catheters were placed., Results: Mean power applied during the 119 hyperthermia treatments ranged from 120 to 1007 W (median 543 W). 15 (13%) hyperthermia treatments were not fully completed due to: pain allocated to hyperthermia (6/15), dyspnea from sticky saliva associated with irradiation (2/15) and unknown reasons (7/15). No severe complications or enhanced thermal or mucosal toxicities were observed. Excluding post-operative treatment, response rates after 3 months were 46% (complete) and 7% (partial)., Conclusion: Hyperthermia with the HYPERcollar proved to be safe and feasible with good compliance and promising outcome.

Objectives/hypothesis: This study aimed to analyze the effect of human papillomavirus (HPV)-associated T1-2 node-positive oropharyngeal squamous cell carcinoma (OPSCC) on nodal response, recurrent disease, and survival in patients treated according to the Rotterdam protocol., Study Design: Retrospective cohort study., Methods: In total, 77 patients with T1-2 OPSCC with nodal disease, treated between 2000 and 2012, were included in this study. Patients were treated according to the Rotterdam protocol: 46 Gy of IMRT followed by a local boost using cyberknife or brachytherapy (22 Gy) and neck dissection. The presence of HPV was determined by p16 INK4A immunostaining. Outcomes were overall survival, disease-free survival, and the extent of nodal response. Nodal stage was determined following the 7th and 8th American Joint Cancer Committee/Union for International Cancer Control classification., Results: Overall, 68.4% of patients had p16-positive disease, and 35.4% of all patients achieved complete nodal response (pN0) after 46 Gy of intensity-modulated radiotherapy (IMRT). Based on the 7th TNM classification, nodal response (partial or complete) was significantly associated with HPV status (P = .002). Patients with p16-positive OPSCC had an odds ratio (OR) of 4.6 to achieve complete nodal response. However, smoking interacted with this effect. Applying the 8th TNM classification, complete or partial response was associated with HPV status but was not significant (OR: 1.7, P = .138). Complete nodal response led to 100% overall survival in p16-positive OPSCC patients., Conclusions: HPV-related OPSCCs are associated with complete nodal response after 46 Gy of IMRT. Patients with full regional control (pN0) after IMRT and subsequent neck dissection show a significantly better overall survival, but smoking negatively interacts with this effect., Level of Evidence: 4. Laryngoscope, 128:2333-2340, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To provide insight into people's experiences in dealing with the consequences of head and neck cancer (HNC) in daily life and their needs for self-management support., Sample & Setting: 13 people with HNC who were successfully treated in the Department of Radiation Oncology at the Erasmus MC Cancer Institute in Rotterdam, the Netherlands., Methods & Variables: Two focus groups and six individual interviews; data were analyzed with directed content analysis., Results: Most patients wished to receive professional support for dealing with post-treatment consequences. Apart from physical complaints, patients had difficulties in dealing with the emotional aspects of HNC and its treatment and struggled with building self-confidence to move on with their lives. Patients mentioned the importance of relatives being there for them but complained that their needs were not always met. Support from fellow patients was valued for their empathetic capacity., Implications for Nursing: Nurses must provide self-management support that meets people's integral needs inherent in living with the consequences of HNC, particularly in the initial post-treatment period. Practical interventions could be useful.

Purpose: Hyperthermia (40-44 °C) effectively sensitises tumours to radiotherapy by locally altering tumour biology. One of the effects of heat at the cellular level is inhibition of DNA repair by homologous recombination via degradation of the BRCA2-protein. This suggests that hyperthermia can expand the group of patients that benefit from PARP-inhibitors, a drug exploiting homologous recombination deficiency. Here, we explore whether the molecular mechanisms that cause heat-mediated degradation of BRCA2 are conserved in cell lines from various origins and, most importantly, whether, BRCA2 protein levels can be attenuated by heat in freshly biopted human tumours., Experimental Design: Cells from four established cell lines and from freshly biopsied material of cervical (15), head- and neck (9) or bladder tumours (27) were heated to 42 °C for 60 min ex vivo. In vivo hyperthermia was studied by taking two biopsies of the same breast or cervical tumour: one before and one after treatment. BRCA2 protein levels were measured by immunoblotting., Results: We found decreased BRCA2-levels after hyperthermia in all established cell lines and in 91% of all tumours treated ex vivo. For tumours treated with hyperthermia in vivo, technical issues and intra-tumour heterogeneity prevented obtaining interpretable results., Conclusions: This study demonstrates that heat-mediated degradation of BRCA2 occurs in tumour material directly derived from patients. Although BRCA2-degradation may not be a practical biomarker for heat deposition in situ, it does suggest that application of hyperthermia could be an effective method to expand the patient group that could benefit from PARP-inhibitors.

Background: Keloids are a burden for patients due to physical, aesthetic and social consequences. Treatment remains a challenge due to therapy resistance and high recurrence rates. The main goals of treatment are to improve scar appearance and symptoms and patients' quality of life (QoL)., Methods: Two multicentre, randomised controlled open trials that compared 1) intralesional cryotherapy with excision and corticosteroid injections for primary keloids, and 2) intralesional cryotherapy with excision and brachytherapy for therapy resistant keloids. Primary outcome was scar appearance assessed with the Patient and Observer Scar Assessment Scale. Secondary outcomes were patient reported QoL (Skindex-29, SF-36, EQ-5D-5L), recurrence rates and scar volume reduction. For analysis, a linear mixed model was used. Power analysis indicated 33 patients in each group were needed., Results: The trial was prematurely terminated after inclusion of 26 patients due to unexpectedly inferior outcomes after intralesional cryotherapy. For primary keloids no convincing difference between treatments was found, but surgery improved scar appearance while cryotherapy did not. For resistant keloids, excision followed by brachytherapy improved scar appearance (POSAS) and scar symptoms (itch and pain) significantly (p < 0.001, p < 0.001 and p = 0.006 respectively) while cryotherapy did not. Neither of the treatments caused indisputable improvements in QoL., Conclusions: Intralesional cryotherapy is inferior to keloid excision followed by brachytherapy for resistant keloids. In primary keloids, intralesional cryotherapy reduced keloid volume and, therefore, may be used in these patients and specific cases. Primary keloid group size was too small to draw valid conclusions, further research on the efficacy of intralesional cryotherapy for primary keloids is warranted., (Copyright © 2018 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: To determine the optimal brachytherapy dose and fractionation scheme for keloid treatment., Methods and Materials: Patient cohorts from 3 centers treated with keloid excision followed by 2 × 9 Gy, 3 × 6 Gy, or 2 × 6 Gy high-dose-rate brachytherapy were retrospectively compared regarding recurrence (after at least 12 months' follow-up) and complications (after at least 1 month's follow-up), using logistic regression analyses., Results: A total of 238 keloids were treated. An overall full recurrence rate of 8.3% was found. After correction for confounders (sex, skin color, keloid location, keloid duration) no statistically significant differences in recurrence rates could be discerned between fractionation schemes. There were 12.8% major and 45.6% minor complication rates. Lower radiation dose resulted in significantly fewer complications (odds ratio 0.35, P=.015)., Conclusions: After excision of resistant keloids, high-dose-rate brachytherapy with a biological equivalent dose of approximately 20 Gy is recommended, on the basis of low recurrence and complication rates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Previously, we have proposed Erasmus-iCycle, an algorithm for fully automated IMRT plan generation based on prioritised (lexicographic) multi-objective optimisation with the 2-phase ϵ-constraint (2pϵc) method. For each patient, the output of Erasmus-iCycle is a clinically favourable, Pareto optimal plan. The 2pϵc method uses a list of objective functions that are consecutively optimised, following a strict, user-defined prioritisation. The novel lexicographic reference point method (LRPM) is capable of solving multi-objective problems in a single optimisation, using a fuzzy prioritisation of the objectives. Trade-offs are made globally, aiming for large favourable gains for lower prioritised objectives at the cost of only slight degradations for higher prioritised objectives, or vice versa. In this study, the LRPM is validated for 15 head and neck cancer patients receiving bilateral neck irradiation. The generated plans using the LRPM are compared with the plans resulting from the 2pϵc method. Both methods were capable of automatically generating clinically relevant treatment plans for all patients. For some patients, the LRPM allowed large favourable gains in some treatment plan objectives at the cost of only small degradations for the others. Moreover, because of the applied single optimisation instead of multiple optimisations, the LRPM reduced the average computation time from 209.2 to 9.5 min, a speed-up factor of 22 relative to the 2pϵc method.

The benefit of hyperthermia as a potent modifier of radiotherapy has been well established and more recently also the combination with chemotherapy was shown beneficial. Also for head and neck cancer, the impact of hyperthermia has been clinically demonstrated by a number of clinical trials. Unfortunately, the technology applied in these studies provided only limited thermal dose control, and the devices used only allowed treatment of target regions close to the skin. Over the last decade, we developed the technology for deep and controlled hyperthermia that allows treatment of the entire head and neck region. Our strategy involves focused microwave heating combined with 3D patient-specific electromagnetic and thermal simulations for conformal, reproducible and adaptive hyperthermia application. Validation of our strategy has been performed by 3D thermal dose assessment based on invasively placed temperature sensors combined with the 3D patient specific simulations. In this paper, we review the phase III clinical evidence for hyperthermia in head and neck tumors, as well as the heating and dosimetry technology applied in these studies. Next, we describe the development, clinical implementation and validation of 3D guided deep hyperthermia with the HYPERcollar, and its second generation, i.e. the HYPERcollar3D. Lastly, we discuss early clinical results and provide an outlook for this technology.

The eye is considered to be a critical organ when determining safety standards for radio frequency (RF) radiation. Experimental data obtained using animals showed that RF heating of the eye, particularly over a specific threshold, can induce cataracts. During the treatment of cancer in the head and neck by hyperthermia, the eyes receive a considerable dose of RF radiation due to stray radiation from the prolonged (60 min) and intense exposure at 434 MHz of this region. In the current study, we verified the exposure guidelines for humans by determining the association between the electromagnetic and thermal dose in the eyes with the reported ocular effects. We performed a simulation study to retrospectively assess the specific absorption rate (SAR) and temperature increase in the eyes of 16 selected patients (encompassing a total of 74 treatment sessions) whose treatment involved high power delivery as well as a minimal distance between the tumor site and the eye. Our results show that the basic restrictions on the peak 10 g spatial-averaged SAR (10 W kg(-1)) and peak tissue temperature increase (1 °C) are exceeded by up to 10.4 and 4.6 times, on average, and by at least 6.2 and 1.8 times when considering the lower limit of the 95% confidence interval. Evaluation of the acute effects according to patients' feedback (all patients), the common toxicity criteria scores (all patients) and an ophthalmology investigation (one patient with the highest exposure) revealed no indication of any serious acute ocular effect, even though the eyes were exposed to high electromagnetic fields, leading to a high thermal dose. We also found that, although there is a strong correlation (R (2) =  0.88) between the predicted induced SAR and temperature in the eye, there are large uncertainties regarding the temperature-SAR relationship. Given this large uncertainty (129%) compared with the uncertainty of 3D temperature simulations (61%), we recommend using temperature simulations as a dosimetric measure in electromagnetic exposure risk assessments.

Purpose: To report, from a retrospective analysis of prospectively collected data, on the feasibility, outcome, toxicity, and voice-handicap index (VHI) of patients with T1a glottic cancer treated by a novel intensity modulated radiation therapy technique developed at our institution to treat only the involved vocal cord: single vocal cord irradiation (SVCI)., Methods and Materials: Thirty patients with T1a glottic cancer were treated by means of SVCI. Dose prescription was set to 16 × 3.63 Gy (total dose 58.08 Gy). The clinical target volume was the entire vocal cord. Setup verification was done by means of an online correction protocol using cone beam computed tomography. Data for voice quality assessment were collected prospectively at baseline, end of treatment, and 4, 6, and 12 weeks and 6, 12, and 18 months after treatment using VHI questionnaires., Results: After a median follow-up of 30 months (range, 7-50 months), the 2-year local control and overall survival rates were 100% and 90% because no single local recurrence was reported and 3 patients died because of comorbidity. All patients have completed the intended treatment schedule; no treatment interruptions and no grade 3 acute toxicity were reported. Grade 2 acute dermatitis or dysphagia was reported in only 5 patients (17%). No serious late toxicity was reported; only 1 patient developed temporary grade 2 laryngeal edema, and responded to a short-course of corticosteroid. The VHI improved significantly, from 33.5 at baseline to 9.5 and 10 at 6 weeks and 18 months, respectively (P<.001). The control group, treated to the whole larynx, had comparable local control rates (92.2% vs 100%, P=.24) but more acute toxicity (66% vs 17%, P<.0001) and higher VHI scores (23.8 and 16.7 at 6 weeks and 18 months, respectively, P<.0001)., Conclusion: Single vocal cord irradiation is feasible and resulted in maximal local control rate at 2 years. The deterioration in VHI scores was slight and temporary and subsequently improved to normal levels. Long-term follow-up is needed to consolidate these promising results., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To assess whether deformable registration between CT and MR images can be used to avoid patient immobilization, we compared registration accuracy in various scenarios, with and without immobilization equipment. Whereas both deformable registration and the use of immobilization equipment improved the registration accuracy, the combination gave the best alignment., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

To provide an adequate level of protection for humans from exposure to radio-frequency (RF) electromagnetic fields (EMF) and to assure that any adverse health effects are avoided. The basic restrictions in terms of the specific energy absorption rate (SAR) were prescribed by IEEE and ICNIRP. An example of a therapeutic application of non-ionizing EMF is hyperthermia (HT), in which intense RF energy is focused at a target region. Deep HT in the head and neck (H&N) region involves inducing energy at 434 MHz for 60 min on target. Still, stray exposure of the brain is considerable, but to date only very limited side-effects were observed. The objective of this study is to investigate the stringency of the current basic restrictions by relating the induced EM dose in the brain of patients treated with deep head and neck (H&N) HT to the scored acute health effects. We performed a simulation study to calculate the induced peak 10 g spatial-averaged SAR (psSAR₁₀g) in the brains of 16 selected H&N patients who received the highest SAR exposure in the brain, i.e. who had the minimum brain-target distance and received high forwarded power during treatment. The results show that the maximum induced SAR in the brain of the patients can exceed the current basic restrictions (IEEE and ICNIRP) on psSAR₁₀g for occupational environments by 14 times. Even considering the high local SAR in the brain, evaluation of acute effects by the common toxicity criteria (CTC) scores revealed no indication of a serious acute neurological effect. In addition, this study provides pioneering quantitative human data on the association between maximum brain SAR level and acute adverse effects when brains are exposed to prolonged RF EMF.

Purpose: Dosimetry during deep local hyperthermia treatments in the head and neck currently relies on a limited number of invasively placed temperature sensors. The purpose of this study was to assess the feasibility of 3D dosimetry based on patient-specific temperature simulations and sensory feedback., Materials and Methods: The study includes 10 patients with invasive thermometry applied in at least two treatments. Based on their invasive thermometry, we optimised patient-group thermal conductivity and perfusion values for muscle, fat and tumour using a 'leave-one-out' approach. Next, we compared the accuracy of the predicted temperature (ΔT) and the hyperthermia treatment quality (ΔT50) of the optimisations based on the patient-group properties to those based on patient-specific properties, which were optimised using previous treatment measurements. As a robustness check, and to enable comparisons with previous studies, we optimised the parameters not only for an applicator efficiency factor of 40%, but also for 100% efficiency., Results: The accuracy of the predicted temperature (ΔT) improved significantly using patient-specific tissue properties, i.e. 1.0 °C (inter-quartile range (IQR) 0.8 °C) compared to 1.3 °C (IQR 0.7 °C) for patient-group averaged tissue properties for 100% applicator efficiency. A similar accuracy was found for optimisations using an applicator efficiency factor of 40%, indicating the robustness of the optimisation method. Moreover, in eight patients with repeated measurements in the target region, ΔT50 significantly improved, i.e. ΔT50 reduced from 0.9 °C (IQR 0.8 °C) to 0.4 °C (IQR 0.5 °C) using an applicator efficiency factor of 40%., Conclusion: This study shows that patient-specific temperature simulations combined with tissue property reconstruction from sensory data provides accurate minimally invasive 3D dosimetry during hyperthermia treatments: T50 in sessions without invasive measurements can be predicted with a median accuracy of 0.4 °C.

Purpose: In current clinical practice, head and neck (H&N) hyperthermia treatment planning (HTP) is solely based on computed tomography (CT) images. Magnetic resonance imaging (MRI) provides superior soft-tissue contrast over CT. The purpose of the authors' study is to investigate the relevance of using MRI in addition to CT for patient modeling in H&N HTP., Methods: CT and MRI scans were acquired for 11 patients in an immobilization mask. Three observers manually segmented on CT, MRI T1 weighted (MRI-T1w), and MRI T2 weighted (MRI-T2w) images the following thermo-sensitive tissues: cerebrum, cerebellum, brainstem, myelum, sclera, lens, vitreous humor, and the optical nerve. For these tissues that are used for patient modeling in H&N HTP, the interobserver variation of manual tissue segmentation in CT and MRI was quantified with the mean surface distance (MSD). Next, the authors compared the impact of CT and CT and MRI based patient models on the predicted temperatures. For each tissue, the modality was selected that led to the lowest observer variation and inserted this in the combined CT and MRI based patient model (CT and MRI), after a deformable image registration. In addition, a patient model with a detailed segmentation of brain tissues (including white matter, gray matter, and cerebrospinal fluid) was created (CT and MRIdb). To quantify the relevance of MRI based segmentation for H&N HTP, the authors compared the predicted maximum temperatures in the segmented tissues (Tmax) and the corresponding specific absorption rate (SAR) of the patient models based on (1) CT, (2) CT and MRI, and (3) CT and MRIdb., Results: In MRI, a similar or reduced interobserver variation was found compared to CT (maximum of median MSD in CT: 0.93 mm, MRI-T1w: 0.72 mm, MRI-T2w: 0.66 mm). Only for the optical nerve the interobserver variation is significantly lower in CT compared to MRI (median MSD in CT: 0.58 mm, MRI-T1w: 1.27 mm, MRI-T2w: 1.40 mm). Patient models based on CT (Tmax: 38.0 °C) and CT and MRI (Tmax: 38.1 °C) result in similar simulated temperatures, while CT and MRIdb (Tmax: 38.5 °C) resulted in significantly higher temperatures. The SAR corresponding to these temperatures did not differ significantly., Conclusions: Although MR imaging reduces the interobserver variation in most tissues, it does not affect simulated local tissue temperatures. However, the improved soft-tissue contrast provided by MRI allows generating a detailed brain segmentation, which has a strong impact on the predicted local temperatures and hence may improve simulation guided hyperthermia.

Background and Purpose: Hyperthermia treatment planning (HTP) is used in the head and neck region (H&N) for pretreatment optimization, decision making, and real-time HTP-guided adaptive application of hyperthermia. In current clinical practice, HTP is based on power-absorption predictions, but thermal dose-effect relationships advocate its extension to temperature predictions. Exploitation of temperature simulations requires region- and temperature-specific thermal tissue properties due to the strong thermoregulatory response of H&N tissues. The purpose of our work was to develop a technique for patient group-specific optimization of thermal tissue properties based on invasively measured temperatures, and to evaluate the accuracy achievable., Patients and Methods: Data from 17 treated patients were used to optimize the perfusion and thermal conductivity values for the Pennes bioheat equation-based thermal model. A leave-one-out approach was applied to accurately assess the difference between measured and simulated temperature (∆T). The improvement in ∆T for optimized thermal property values was assessed by comparison with the ∆T for values from the literature, i.e., baseline and under thermal stress., Results: The optimized perfusion and conductivity values of tumor, muscle, and fat led to an improvement in simulation accuracy (∆T: 2.1 ± 1.2 °C) compared with the accuracy for baseline (∆T: 12.7 ± 11.1 °C) or thermal stress (∆T: 4.4 ± 3.5 °C) property values., Conclusion: The presented technique leads to patient group-specific temperature property values that effectively improve simulation accuracy for the challenging H&N region, thereby making simulations an elegant addition to invasive measurements. The rigorous leave-one-out assessment indicates that improvements in accuracy are required to rely only on temperature-based HTP in the clinic.

Background and Purpose: Evaluation of the variation in tumor growth rate and the influence of tumor growth rate on disease free survival (DFS) and overall survival (OS) in laryngeal squamous cell carcinoma (LSCC)., Material and Methods: We delineated tumor volume on a diagnostic and planning CT scan in 131 patients with laryngeal squamous cell carcinoma and calculated the tumor growth rate. Primary endpoint was DFS. Follow up data were collected retrospectively., Results: A large variation in tumor growth rate was seen. When dichotomized with a cut-off point of -0.3 ln(cc/day), we found a significant association between high growth rate and worse DFS (p = 0.008) and OS (p = 0.013). After stepwise adjustment for potential confounders (age, differentiation and tumor volume) this significant association persisted. However, after adjustment of N-stage association disappeared. Exploratory analyses suggested a strong association between N-stage and tumor growth rate., Conclusions: In laryngeal squamous cell carcinoma, there is a large variation in tumor growth rate. This tumor growth rate seems to be an important factor in disease free survival and OS. This tumor growth rate is independent of age, differentiation and tumor volume associated with DFS, but N-stage seems to be a more important risk factor., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Clinical trials have shown that hyperthermia, as adjuvant to radiotherapy and/or chemotherapy, improves treatment of patients with locally advanced or recurrent head and neck (H&N) carcinoma. Hyperthermia treatment planning (HTP) guided H&N hyperthermia is being investigated, which requires patient specific 3D patient models derived from Computed Tomography (CT)-images. To decide whether a recently developed automatic-segmentation algorithm can be introduced in the clinic, we compared the impact of manual- and automatic normal-tissue-segmentation variations on HTP quality., Material and Methods: CT images of seven patients were segmented automatically and manually by four observers, to study inter-observer and intra-observer geometrical variation. To determine the impact of this variation on HTP quality, HTP was performed using the automatic and manual segmentation of each observer, for each patient. This impact was compared to other sources of patient model uncertainties, i.e. varying gridsizes and dielectric tissue properties., Results: Despite geometrical variations, manual and automatic generated 3D patient models resulted in an equal, i.e. 1%, variation in HTP quality. This variation was minor with respect to the total of other sources of patient model uncertainties, i.e. 11.7%., Conclusions: Automatically generated 3D patient models can be introduced in the clinic for H&N HTP., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The objective of the presented study is to report on retrospectively collected data on long-term outcome and toxicity and prospective assessment of quality of life (QoL) and Voice-Handicap Index (VHI) of patients with T1a glottic cancer treated with radiotherapy. Between 1985 and 2011, 549 patients were treated. Endpoints were local control (LC), toxicity, QoL and VHI. After a median follow-up of 93 months, the actuarial rates of LC were 91, and 90 % at 5- and 10-years, respectively. Continuing smoking (p < 0.001) and anaemia (p = 0.02) were significantly correlated with poor LC on univariate analysis and fractionation schedule did not show significant correlation (p = 0.08). On multivariate analysis, only continuing smoking retained significance (p = 0.001). These patients had also significantly increased incidence of second primary tumour and lower overall survival rates. The incidence of grade ≥2 late xerostomia and dysphagia were 10 and 6 %, respectively. Slight and temporary deterioration of QoL-scores was reported. The scores on the EROTC-QOL-H&N35 dysphagia and xerostomia at 24 months were -2 and -3, compared to baseline, respectively. VHI improved significantly from 34 at baseline to 21 at 24 months. Patients who continued smoking had significantly worse VHI. In conclusion, excellent outcome with good QoL and VHI were reported. Patients who continued smoking after radiotherapy had significantly poor LC and worse VHI. The current study emphasizes the importance of smoking cessation and the non-inferiority of hypofractionated schemes in terms of outcome and VHI. At our institution, phase II study is going to evaluate the role of single vocal cord irradiation with high fraction dose.

Background: Keloids are a burden for patients due to physical, aesthetic and social complaints and treatment remains a challenge because of therapy resistance and high recurrence rates. The main goal of treatment is to improve the quality of life (QoL); this implies that, apart from surgical outcomes, patient-reported outcome measures (PROMs) need to be taken into account. Decision making in keloid treatment is difficult due to heterogeneity of the condition and the lack of comparative studies., Methods/design: This is a multicentre, randomised controlled open trial that compares 1) intralesional cryotherapy versus excision and corticosteroids for primary keloids, and 2) intralesional cryotherapy versus excision and brachytherapy for therapy-resistant keloids. The primary outcome is the Patient and Observer Scar Assessment Scale (POSAS), a 12-item scale (with score 12 indicating the best and 120 indicating the worst scar imaginable). A difference of six points on the total score is considered to be of clinical importance. Secondary outcomes are recurrence rates, volume reduction, Skindex-29 scores, SF-36 scores and complication rates. Primary and secondary outcome measurements are taken at baseline, and at 2, 12, 26 and 52 weeks postoperatively. For analysis, a linear mixed model is used. A total of 176 patients will be included over a period of 2.5 years. The protocol is approved by the Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam and follows good clinical practice guidelines., Discussion: The outcomes of this study will improve evidence-based decision making for the treatment of keloids, as well as patient education., Trial Registration: Dutch Trial Register NTR4151.

Objectives: To compare outcome, toxicity and QoL of two boost modalities for T1-2 oropharyngeal carcinoma (OPC)., Materials and Methods: Between 2000 and 2012, 250 consecutive patients with T1-2N0-3 were treated with 46-Gy of IMRT followed by boost using brachytherapy (BTB) or stereotactic body radiotherapy (CKB). Endpoints were local control (LC), disease-free survival (DFS), overall survival (OS), toxicity and prospective QoL-assessment., Results: The 3-year actuarial incidence of LC were 97% and 94% for the CKB and BTB, respectively (p=0.33). The figures for DFS were 92% and 86% (p=0.15) and for OS were 81% and 83% (p=0.82), respectively. The incidence of tube feeding were 17% and 20%, respectively (p=0.47). The figures for grade ⩾2 late dysphagia were 11% and 8% (p=0.34) and for xerostomia were 16% and 12% (p=0.28), respectively. For both modalities, clinically relevant deteriorations were seen on all scales at end of treatment but the scores returned to almost baseline levels within 6-12months, with exception of QLQ-H&N35-xerostomia. The difference on that scale was neither statistically significant nor clinically relevant between both modalities., Conclusion: Comparable outcome, toxicity and QoL-scores were achieved with both modalities. In the light of the logistical hassle around the implantation, the need of dexterity, and the risk of anaesthesia and peri-operative complications associated with BTB, CKB might be regarded as the optimal option to boost early-stage OPC. However, in radiotherapy departments where no facilities are available for stereotactic radiotherapy, BTB is an elegant option to achieve excellent outcome with low toxicity profile and good QoL., (Copyright © 2013 Elsevier Ltd. All rights reserved.)