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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.

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).

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.

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. 13 people with HNC who were successfully treated in the Department of Radiation Oncology at the Erasmus MC Cancer Institute in Rotterdam, the Netherlands. Two focus groups and six individual interviews; data were analyzed with directed content analysis. 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. 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.

IntroductionThe 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 analysisThis 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 disseminationThe 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 numberNL8458.

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 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.

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.

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.

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 (AUCbaseline) and fentanyl AUC in the presence of mucositis grade ≥2. The secondary endpoint was the RD between AUCbaseline 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.