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Objective. To improve hyperthermia in clinical practice, pre-clinical hyperthermia research is essential to investigate hyperthermia effects and assess novel treatment strategies. Translating pre-clinical hyperthermia findings into clinically viable protocols requires laboratory animal treatment techniques similar to clinical hyperthermia techniques. The ALBA micro8 electromagnetic heating system (Med-logix SRL, Rome, Italy) has recently been developed to provide the targeted locoregional tumour heating currently lacking for pre-clinical research. This study evaluates the heat focusing properties of this device and its ability to induce robust locoregional tumour heating under realistic physiological conditions using simulations. Approach. Simulations were performed using the Plan2Heat treatment planning package (Amsterdam UMC, the Netherlands). First, the specific absorption rate (SAR) focus was characterised using a homogeneous phantom. Hereafter, a digital mouse model was used for the characterisation of heating robustness in a mouse. Device settings were optimised for treatment of a pancreas tumour and tested for varying circumstances. The impact of uncertainties in tissue property and perfusion values was evaluated using polynomial chaos expansion. Treatment quality and robustness were evaluated based on SAR and temperature distributions. Main results. The SAR distributions within the phantom are well-focused and can be adjusted to target any specific location. The focus size (full-width half-maximum) is a spheroid with diameters 9 mm (radially) and 20 mm (axially). The mouse model simulations show strong robustness against respiratory motion and intestine and stomach filling ( ∆ T 90 ≤ 0.14 °C ). Mouse positioning errors in the cranial-caudal direction lead to ∆ T 90 ≤ 0.23 °C. Uncertainties in tissue property and perfusion values were found to impact the treatment plan up to 0.56 °C (SD), with a variation on T 90 of 0.32 °C (1 SD). Significance. Our work shows that the pre-clinical phased-array system can provide adequate and robust locoregional heating of deep-seated target regions in mice. Using our software, robust treatment plans can be generated for pre-clinical hyperthermia research. [ABSTRACT FROM AUTHOR]

Background: Hyperthermia treatment planning is increasingly used in clinical applications and recommended in quality assurance guidelines. Assistance in phase-amplitude steering during treatment requires dedicated software for on-line visualization of SAR/temperature distributions and fast re-optimization in response to hot spots. As such software tools are not yet commercially available, we developed Adapt2Heat for on-line adaptive hyperthermia treatment planning and illustrate possible application by different relevant real patient examples. Methods: Adapt2Heat was developed as a separate module of the treatment planning software Plan2Heat. Adapt2Heat runs on a Linux operating system and was developed in Cþþ, using the open source Qt, Qwt and VTK libraries. A graphical user interface allows interactive and flexible on-line use of hyperthermia treatment planning. Predicted SAR/temperature distributions and statistics for selected phase-amplitude settings can be visualized instantly and settings can be re-optimized manually or automatically in response to hot spots. Results: Pretreatment planning E-Field, SAR and temperature calculations are performed with Plan2Heat and imported in Adapt2Heat. Examples show that Adapt2Heat can be helpful in assisting with phase-amplitude steering, e.g., by suppressing indicated hot spots. The effects of phaseamplitude adjustments on the tumor and potential hot spot locations are comprehensively visualized, allowing intuitive and flexible assistance by treatment planning during locoregional hyperthermia treatments. Conclusion: Adapt2Heat provides an intuitive and flexible treatment planning tool for on-line treatment planning-assisted hyperthermia. Extensive features for visualization and (re-)optimization during treatment allow practical use in many locoregional hyperthermia applications. This type of tools are indispensable for enhancing the quality of hyperthermia treatment delivery. [ABSTRACT FROM AUTHOR]

Objective: The in-house developed 70 MHz AMC-4 locoregional hyperthermia system has been in clinical use since 1984. This device was recently commercialized as the Alba 4D (MedlogixVR, Rome, Italy), with a similar geometrical 4-waveguide design. At the time of this study a hybrid Alba 4D was installed at our center, which incorporated elements of the AMC-4. This study aims to compare clinical performance of both devices. Methods: During one year after clinical acceptance of the hybrid Alba 4D, both devices were used for treatment delivery in patients scheduled for locoregional hyperthermia. Each patient started with the AMC4, next sessions were allocated to either device. Possible differences between Alba 4D and AMC-4 sessions in power, achieved temperature T0, T10, T50, T90, T100, treatment time and complaints per session, were evaluated using linear mixed models (LMMs) for repeated measures with patient as random effect. Results: From March 2018 to April 2019, eleven patients with cervical, pancreatic, vaginal carcinoma and uterine leiomyosarcoma received 27 locoregional hyperthermia sessions with the Alba 4D and 34 sessions with the AMC-4. Median number of sessions per patient was 5 (range 3–13). Treatment results for both devices were not significantly different: T50 was 40.5 ± 1.0 (C vs. 40.8 ± 0.7 (C, applied power was 500 ± 79 W vs. 526 ± 108 W, for the Alba 4D vs. AMC-4, respectively. Conclusion: Results of the first patients treated with the hybrid Alba 4D demonstrated comparable clinical performance of the Alba 4D and AMC-4 locoregional hyperthermia systems, and both devices are expected to yield similar favorable clinical results. [ABSTRACT FROM AUTHOR]

Background: The success of cancer hyperthermia (HT) treatments is strongly dependent on the temperatures achieved in the tumor and healthy tissues as it correlates with treatment efficacy and safety, respectively. Hyperthermia treatment planning (HTP) simulations have become pivotal for treatment optimization due to the possibility for pretreatment planning, optimization and decision making, as well as real-time treatment guidance. Materials and methods: The same computational methods deployed in HTP are also used for in silico studies. These are of great relevance for the development of new HT devices and treatment approaches. To aid this work, 3 D patient models have been recently developed and made available for the HT community. Unfortunately, there is no consensus regarding tissue properties, simulation settings, and benchmark applicators, which significantly influence the clinical relevance of computational outcomes. Results and discussion: Herein, we propose a comprehensive set of applicator benchmarks, efficacy and safety optimization algorithms, simulation settings and clinical parameters, to establish benchmarks for method comparison and code verification, to provide guidance, and in view of the 2021 ESHO Grand Challenge (Details on the ESHO grand challenge on HTP will be provided at https://www. esho.info/). Conclusion: We aim to establish guidelines to promote standardization within the hyperthermia community such that novel approaches can quickly prove their benefit as quickly as possible in clinically relevant simulation scenarios. This paper is primarily focused on radiofrequency and microwave hyperthermia but, since 3 D simulation studies on heating with ultrasound are now a reality, guidance as well as a benchmark for ultrasound-based hyperthermia are also included. [ABSTRACT FROM AUTHOR]

Hyperthermia (i.e. heating of tumor tissue to 40–43°C) is used in clinical oncology to enhance the therapeutic effect of chemotherapy and radiotherapy. Many tumor sites are heated either by a single RF or MW antenna positioned on the tumor location, or by a phased array positioned around the patient. Superficial tumors are generally heated with MW antennas (434–2450 MHz) and deep-seated tumors with RF antennas (70–150 MHz). These devices cover the major, more common tumor sites, but more rare locations require more dedicated applicators. We discuss dedicated RF systems aiming for heating semi-deep-seated tumors in the leg, breast, and upper thorax. Clinical results show that adequate heating is possible with these systems, with achieved temperatures in the therapeutic range. [ABSTRACT FROM AUTHOR]

Moderate hyperthermia at temperatures between 40 and 44°C is a multifaceted therapeutic modality. It is a potent radiosensitizer, interacts favorably with a host of chemotherapeutic agents, and, in combination with radiotherapy, enforces immunomodulation akin to " in situ tumor vaccination." By sensitizing hypoxic tumor cells and inhibiting repair of radiotherapy-induced DNA damage, the properties of hyperthermia delivered together with photons might provide a tumor-selective therapeutic advantage analogous to high linear energy transfer (LET) neutrons, but with less normal tissue toxicity. Furthermore, the high LET attributes of hyperthermia thermoradiobiologically are likely to enhance low LET protons; thus, proton thermoradiotherapy would mimic 12C ion therapy. Hyperthermia with radiotherapy and/or chemotherapy substantially improves therapeutic outcomes without enhancing normal tissue morbidities, yielding level I evidence reported in several randomized clinical trials, systematic reviews, and meta-analyses for various tumor sites. Technological advancements in hyperthermia delivery, advancements in hyperthermia treatment planning, online invasive and non-invasive MR-guided thermometry, and adherence to quality assurance guidelines have ensured safe and effective delivery of hyperthermia to the target region. Novel biological modeling permits integration of hyperthermia and radiotherapy treatment plans. Further, hyperthermia along with immune checkpoint inhibitors and DNA damage repair inhibitors could further augment the therapeutic efficacy resulting in synthetic lethality. Additionally, hyperthermia induced by magnetic nanoparticles coupled to selective payloads, namely, tumor-specific radiotheranostics (for both tumor imaging and radionuclide therapy), chemotherapeutic drugs, immunotherapeutic agents, and gene silencing, could provide a comprehensive tumor-specific theranostic modality akin to "magic (nano)bullets." To get a realistic overview of the strength (S), weakness (W), opportunities (O), and threats (T) of hyperthermia, a SWOT analysis has been undertaken. Additionally, a TOWS analysis categorizes future strategies to facilitate further integration of hyperthermia with the current treatment modalities. These could gainfully accomplish a safe, versatile, and cost-effective enhancement of the existing therapeutic armamentarium to improve outcomes in clinical oncology. [ABSTRACT FROM AUTHOR]

Intravenous chemotherapy plus abdominal locoregional hyperthermia is explored as a noninvasive alternative to hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment of peritoneal carcinomatosis (PC). First clinical results demonstrate feasibility, but survival data show mixed results and for pancreatic and gastric origin results are not better than expected for chemotherapy alone. In this study, computer simulations are performed to compare the effectiveness of peritoneal heating for five different locoregional heating systems. Simulations of peritoneal heating were performed for a phantom and two pancreatic cancer patients, using the Thermotron RF8, the AMC-4/ALBA-4D system, the BSD Sigma-60 and Sigma-Eye system, and the AMC-8 system. Specific absorption rate (SAR) distributions were optimized and evaluated. Next, to provide an indication of possible enhancement factors, the corresponding temperature distributions and thermal enhancement ratio (TER) of oxaliplatin were estimated. Both phantom and patient simulations showed a relatively poor SAR coverage for the Thermotron RF8, a fairly good coverage for the AMC-4/ALBA-4D, Sigma-60, and Sigma-Eye systems, and the best and most homogeneous coverage for the AMC-8 system. In at least 50% of the peritoneum, 35–45 W/kg was predicted. Thermal simulations confirmed these favorable peritoneal heating properties of the AMC-8 system and TER values of ∼1.4–1.5 were predicted in at least 50% of the peritoneum. Locoregional peritoneal heating with the AMC-8 system yields more favorable heating patterns compared to other clinically used locoregional heating devices. Therefore, results of this study may promote the use of the AMC-8 system for locoregional hyperthermia in future multidisciplinary studies for treatment of PC. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose)polymerase1 (PARP1) is an important enzyme in regulating DNA replication. Inhibition of PARP1 can lead to collapsed DNA forks which subsequently causes genomic instability, making DNA more susceptible in developing fatal DNA double strand breaks. PARP1-induced DNA damage is generally repaired by homologous recombination (HR), in which BRCA2 proteins are essential. Therefore, BRCA2-deficient tumour cells are susceptible to treatment with PARP1-inhibitors (PARP1-i). Recently, BRCA2 was shown to be down-regulated by hyperthermia (HT) temporarily, and this consequently inactivated HR for several hours. In this study, we investigated whether HT exclusively interferes with HR by analysing thermal radiosensitisation of BRCA2-proficient and deficient cells. After elucidating the equitoxicity of PARP1-ion BRCA2-proficient and deficient cells, we studied the cell survival, apoptosis, DNA damage (γ-H2AX foci and comet assay) and cell cycle distribution after different treatments. PARP1-isensitivity strongly depends on the BRCA2 status. BRCA2-proficient and deficient cells are radiosensitised by HT, indicating that HT does not exclusively act by inhibition of HR. In all cell lines, the addition of HT to radiotherapy and PARP1-iresulted in the lowest cell survival, the highest levels of DNA damage and apoptotic levels compared to duo-modality treatments. Concluding, HT not only inhibits HR, but also has the capability of radiosensitising BRCA2-deficient cells. Thus, in case of BRCA2-mutation carriers, combining HT with PARP1-imay boost the treatment efficacy. This combination therapy would be effective for all patients with PARP1-iregardless of their BRCA status. [ABSTRACT FROM PUBLISHER]

Background: Combined radiotherapy and hyperthermia is a well-established alternative to chemoradiotherapy for advanced stage cervical cancer patients with a contraindication for chemotherapy. Pre-clinical evidence suggests that the radiosensitizing effect of hyperthermia decreases substantially for time intervals between radiotherapy and hyperthermia as short as 1-2 h, but clinical evidence is limited. The purpose of this study is to determine the effect of the time interval between external beam radiotherapy (EBRT) and same-day hyperthermia on in-field recurrence rate, overall survival and late toxicity in women with advanced stage cervical cancer.Methods: Patients with advanced stage cervical cancer who underwent a full-course of curative daily EBRT and (4-5) weekly hyperthermia sessions between 1999 and 2014 were included for retrospective analysis. The mean time interval between EBRT fractions and same-day hyperthermia was calculated for each patient; the median thereof was used to divide the cohort in a 'short' and 'long' time-interval group. Kaplan-Meier analysis and stepwise Cox regression were used to compare the in-field recurrence and overall survival. Finally, high-grade (≥3) late toxicity was compared across time-interval groups. DNA repair suppression is an important hyperthermia mechanism, DNA damage repair kinetics were therefore studied in patient biopsies to support clinical findings.Results: Included were 58 patients. The 3-year in field recurrence rate was 18% and 53% in the short (≤79.2 min) and long (>79.2 min) time-interval group, respectively (p = 0.021); the 5-year overall survival was 52% and 17% respectively (p = 0.015). Differences between time-interval groups remained significant for both in-field recurrence (HR = 7.7, p = 0.007) and overall survival (HR = 2.3, p = 0.012) in multivariable Cox regression. No difference in toxicity was observed (p = 1.00), with only 6 and 5 events in the short and long group, respectively. The majority of DNA damage was repaired within 2 h, potentially explaining a reduced effectiveness of hyperthermia for long time intervals.Conclusions: A short time interval between EBRT and hyperthermia is associated with a lower risk of in-field recurrence and a better overall survival. There was no evidence for difference in late toxicity. [ABSTRACT FROM AUTHOR]

Purpose:To evaluate the enhancement effect of two combined radiation-sensitizing agents in mammalian cells at small doses as compared to large doses using the linear-quadratic (LQ) mathematical model. Methods and materials:Data on clonogenic assays concerning the radio-enhancement effects of combined halogenated pyrimidines and hyperthermia or combined cisplatin and hyperthermia, as published in earlier reports, were analyzed according to the LQ-formula: S(D)/S(0) = exp−(αD + βD2). Effects of sensitizing agents on the linear parameter α and the quadratic parameter β are compared in order to evaluate differences depending on the applied dose, the possible relations to mechanisms of radiation sensitization and to derive suggestions for applications. Results:The values of the linear parameter α, which determines the effectiveness at low doses, are for all cell lines and all conditions more increased than the values of the parameter β which has a higher contribution at larger radiation doses. The combination of hyperthermia with halogenated pyrimidines to radiation as well as the combination of hyperthermia and cisplatin to radiation significantly increases the value of the linear parameter α, as compared to radiation alone or radiation combined with a single agent. Conclusions:The radiation enhancement factors of the values of linear and quadratic parameters demonstrate that the sensitizing agents have a larger effect on the linear parameter which is dominant at low radiation doses as is used in fractionated-radiation treatment in the clinic. Moreover, the effect is even further increased when two radiation sensitizers are used. [ABSTRACT FROM PUBLISHER]

Planning of combined radiotherapy and hyperthermia treatments should be performed taking the synergistic action between the two modalities into account. This work evaluates the available experimental data on cytotoxicity of combined radiotherapy and hyperthermia treatment and the requirements for integration of hyperthermia and radiotherapy treatment planning into a single planning platform. The underlying synergistic mechanisms of hyperthermia include inhibiting DNA repair, selective killing of radioresistant hypoxic tumour tissue and increased radiosensitivity by enhanced tissue perfusion. Each of these mechanisms displays different dose-effect relations, different optimal time intervals and different optimal sequences between radiotherapy and hyperthermia. Radiosensitisation can be modelled using the linear-quadratic (LQ) model to account for DNA repair inhibition by hyperthermia. In a recent study, an LQ model-based thermoradiotherapy planning (TRTP) system was used to demonstrate that dose escalation by hyperthermia is equivalent to ∼10 Gy for prostate cancer patients treated with radiotherapy. The first step for more reliable TRTP is further expansion of the data set of LQ parameters for normally oxygenated normal and tumour tissue valid over the temperature range used clinically and for the relevant time intervals between radiotherapy and hyperthermia. The next step is to model the effect of hyperthermia in hypoxic tumour cells including the physiological response to hyperthermia and the resulting reoxygenation. Thermoradiotherapy planning is feasible and a necessity for an optimal clinical application of hyperthermia combined with radiotherapy in individual patients. [ABSTRACT FROM AUTHOR]

Reliable temperature information during clinical hyperthermia and thermal ablation is essential for adequate treatment control, but conventional temperature measurements do not provide 3D temperature information. Treatment planning is a very useful tool to improve treatment quality, and substantial progress has been made over the last decade. Thermal modelling is a very important and challenging aspect of hyperthermia treatment planning. Various thermal models have been developed for this purpose, with varying complexity. Since blood perfusion is such an important factor in thermal redistribution of energy in in vivo tissue, thermal simulations are most accurately performed by modelling discrete vasculature. This review describes the progress in thermal modelling with discrete vasculature for the purpose of hyperthermia treatment planning and thermal ablation. There has been significant progress in thermal modelling with discrete vasculature. Recent developments have made real-time simulations possible, which can provide feedback during treatment for improved therapy. Future clinical application of thermal modelling with discrete vasculature in hyperthermia treatment planning is expected to further improve treatment quality. [ABSTRACT FROM AUTHOR]

Simple Summary: When treatment limiting hot spots occur during locoregional hyperthermia (i.e., heating tumors to 40–44 °C for ~1 h), system settings are adjusted based on experience. In this study, we developed and evaluated treatment planning with temperature-based re-optimization and compared the predicted effectiveness to clinically applied protocol/experience-based steering. Re-optimization times were typically ~10 s; sufficiently fast for on-line use. Effective hot spot suppression was predicted, while maintaining adequate tumor heating. Inducing new hot spots was avoided. Temperature-based re-optimization to suppress treatment limiting hot spots seemed feasible to match the effectiveness of long-term clinical experience and will be further evaluated in a clinical setting. When numerical algorithms are proven to match long-term experience, the overall treatment quality within hyperthermia centers can significantly improve. Implementing these strategies would then imply that treatments become less dependent on the experience of the center/operator. Background: Experience-based adjustments in phase-amplitude settings are applied to suppress treatment limiting hot spots that occur during locoregional hyperthermia for pelvic tumors. Treatment planning could help to further optimize treatments. The aim of this research was to develop temperature-based re-optimization strategies and compare the predicted effectiveness with clinically applied protocol/experience-based steering. Methods: This study evaluated 22 hot spot suppressions in 16 cervical cancer patients (mean age 67 ± 13 year). As a first step, all potential hot spot locations were represented by a spherical region, with a user-specified diameter. For fast and robust calculations, the hot spot temperature was represented by a user-specified percentage of the voxels with the largest heating potential (HPP). Re-optimization maximized tumor T90, with constraints to suppress the hot spot and avoid any significant increase in other regions. Potential hot spot region diameter and HPP were varied and objective functions with and without penalty terms to prevent and minimize temperature increase at other potential hot spot locations were evaluated. Predicted effectiveness was compared with clinically applied steering results. Results: All strategies showed effective hot spot suppression, without affecting tumor temperatures, similar to clinical steering. To avoid the risk of inducing new hot spots, HPP should not exceed 10%. Adding a penalty term to the objective function to minimize the temperature increase at other potential hot spot locations was most effective. Re-optimization times were typically ~10 s. Conclusion: Fast on-line re-optimization to suppress treatment limiting hot spots seems feasible to match effectiveness of ~30 years clinical experience and will be further evaluated in a clinical setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma multiforme (GBM) is the most lethal brain tumor. Combining hyperthermia with chemotherapy and/or radiotherapy improves survival of GBM patients. For radio frequency (RF)-induced hyperthermia, the RF signals' power and phase need to be supervised to achieve a precise formation of the power deposition focal point, accurate thermal dose control, and safety management. Patient position during treatment also needs to be monitored to ensure the efficiency of the treatment and to avoid adverse effects in healthy tissue. This work demonstrates the development, implementation, evaluation, validation, and application of a multi-channel RF supervision module that meets the technical requirements of hyperthermia and provides a cost-effective solution for broad-band RF signal supervision and patient monitoring. It is a key component for a hyperthermia hardware system and facilitates future thermal magnetic resonance applications that integrate RF-induced heating, in vivo temperature mapping, and anatomic and functional imaging in a single RF applicator. Glioblastoma multiforme (GBM) is the most lethal and common brain tumor. Combining hyperthermia with chemotherapy and/or radiotherapy improves the survival of GBM patients. Thermal magnetic resonance (ThermalMR) is a hyperthermia variant that exploits radio frequency (RF)-induced heating to examine the role of temperature in biological systems and disease. The RF signals' power and phase need to be supervised to manage the formation of the energy focal point, accurate thermal dose control, and safety. Patient position during treatment also needs to be monitored to ensure the efficacy of the treatment and avoid damages to healthy tissue. This work reports on a multi-channel RF signal supervision module that is capable of monitoring and regulating RF signals and detecting patient motion. System characterization was performed for a broad range of frequencies. Monte-Carlo simulations were performed to examine the impact of power and phase errors on hyperthermia performance. The supervision module's utility was demonstrated in characterizing RF power amplifiers and being a key part of a feedback control loop regulating RF signals in heating experiments. Electromagnetic field simulations were conducted to calculate the impact of patient displacement during treatment. The supervision module was experimentally tested for detecting patient motion to a submillimeter level. To conclude, this work presents a cost-effective RF supervision module that is a key component for a hyperthermia hardware system and forms a technological basis for future ThermalMR applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Several randomized controlled trials have shown that the concurrent use of hyperthermia with radiotherapy results in a significant increase in local control rates. However, in studies that analyzed thermal parameters, the radiosensitizing effect required a favorable increase in tumor temperature. A good temperature increase is more difficult to achieve in deep-seated tumors than in superficial tumors. In this study, the reduction of subcutaneous fat overheating, which is a weak point of the deep heating of a capacitively coupled heating system, and the optimization of temperature distribution in the deep regional hyperthermia in the pelvis were investigated using electromagnetic field numerical simulations. In conclusion, the use of overlay boluses, the salt solution concentration in the overlay boluses, and the intergluteal cleft bolus insertion were found to be important for optimizing the temperature distribution. Further studies with numerical simulations based on the patient's body shape and tumor location are expected. Background: The purpose of this study was to evaluate the effectiveness of the clinical setting for deep regional hyperthermia of an 8 MHz radiofrequency (RF) capacitively coupled device in the pelvis by using numerical simulations of the electromagnetic field. Methods: A three-dimensional patient model of cervical cancer of the uterus in an obese patient was reconstructed with computed tomography data. The specific absorption rate (SAR) and temperature distributions among the various heating settings were evaluated using numerical simulations. Results: The averaged SAR value of the deep target tumor was similar between with or without overlay boluses (OBs), and that of the subcutaneous fat (SF) at the edges of cooling boluses with OBs was lower than that of the SF without OBs. The use of OBs reduced the overheating of the SF. The 0.5% salt solution in the OB produced the least overheated areas outside the deep target tumor compared with the other concentrations. The insertion of the intergluteal cleft (IGC) bolus could improve the temperature concentration of the deep target tumor. Conclusions: The use of OBs and the salt solution concentration in the OB were important to optimize the temperature distribution. IGC bolus might contribute to temperature optimization. Further studies with individualized numerical simulations in each patient are expected. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-muscle invasive bladder cancer is a disease that frequently recurs, despite standard bladder instillations with chemotherapeutic agents or immunotherapy. When the disease recurs despite treatment with standard bladder instillations, urology guidelines recommend surgical removal of the bladder. This major operation often comes with complications or even death. Therefore, patients are often unfit or unwilling to undergo this operation. In this study, we present the treatment outcome of "radiofrequency-induced hyperthermia combined with intravesical chemotherapy", which are bladder instillations with a chemotherapeutic agent, while simultaneously heating the bladder wall with microwave radiation to fever temperature. We compare the outcomes of two tumor subtypes of non-muscle invasive bladder cancer and two doses of chemotherapeutic agent. We conclude that this therapy is effective and safe in both types of non-muscle invasive bladder cancer patients in whom standard bladder treatments have failed. The high dose should be used if patients have a tumor at therapy onset. Background: The recurrence rate of non-muscle invasive bladder cancer (NMIBC) is high, despite intravesical treatments. Importantly, patients are frequently unfit or unwilling to undergo a recommended radical cystectomy when standard intravesical treatments fail, due to the substantial risk of morbidity and mortality. For these patients, radiofrequency-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We aim to determine treatment outcomes and assess the effect of (ablative) dose. Methods: 299 intensively pretreated patients treated with RF-CHT were included in safety analysis. Of these, 274 patients who fulfilled induction treatments were included in efficacy analysis. Six-month complete response (CR) and durable response were reported for (concomitant) carcinoma in situ (CIS) patients and recurrence-free survival (RFS) for papillary patients. Results: For CIS, six-month CR-rate was 56.0%; and durable response rates were 79.7%, 66.5%, and 40.3% at one-, two- and five-year, respectively. RFS rates for papillary patients were 77.9%, 57.5%, and 37.2%, respectively. Patients treated with ablative dose are less likely to develop recurrence (adjusted Hazard Ratio 0.54, p = 0.01), compared to adjuvant dose. Conclusions: RF-CHT is effective in NMIBC patients in whom standard intravesical treatments have failed and should be considered in patients who are unwilling or unfit to undergo radical cystectomy. Patients with CIS or residual papillary tumor at baseline benefit from ablative dose. [ABSTRACT FROM AUTHOR]

Electric permeabilization of cell membranes is the main mechanism of irreversible electroporation (IRE), an ablation technique for treatment of unresectable cancers, but the pulses also induce a significant temperature increase in the treated volume. To investigate the therapeutically thermal contribution, a preclinical setup is required to apply IRE at desired temperatures while maintaining stable temperatures. This study's aim was to develop and test an electroporation device capable of maintaining a pre-specified stable and spatially homogeneous temperatures and electric field in a tumor cell suspension for several clinical-IRE-settings. A hydraulically controllable heat exchange electroporation device (HyCHEED) was developed and validated at 37 °C and 46 °C. Through plate electrodes, HyCHEED achieved both a homogeneous electric field and homogenous-stable temperatures; IRE heat was removed through hydraulic cooling. IRE was applied to 300 μL of pancreatic carcinoma cell suspension (Mia PaCa-2), after which cell viability and specific conductivity were determined. HyCHEED maintained stable temperatures within ±1.5 °C with respect to the target temperature for multiple IRE-settings at the selected temperature levels. An increase of cell death and specific conductivity, including post-treatment, was found to depend on electric-field strength and temperature. HyCHEED is capable of maintaining stable temperatures during IRE-experiments. This provides an excellent basis to assess the contribution of thermal effects to IRE and other bio-electromagnetic techniques. [ABSTRACT FROM AUTHOR]

Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment with curative intent for peritoneal metastasis of colorectal cancer (CRC). Currently, there is no standardized HIPEC protocol: choice of drug, perfusate temperature, and duration of treatment vary per institute. We investigated the temperature-dependent effectiveness of drugs often used in HIPEC. Methods: The effect of temperature on drug uptake, DNA damage, apoptosis, cell cycle distribution, and cell growth were assessed using the temperature-dependent IC50 and Thermal Enhancement Ratio (TER) values of the chemotherapeutic drugs cisplatin, oxaliplatin, carboplatin, mitomycin-C (MMC), and 5-fluorouracil (5-FU) on 2D and 3D CRC cell cultures at clinically relevant hyperthermic conditions (38–43 °C/60 min). Results: Hyperthermia alone decreased cell viability and clonogenicity of all cell lines. Treatment with platinum-based drugs and MMC resulted in G2-arrest. Platinum-based drugs display a temperature-dependent synergy with heat, with increased drug uptake, DNA damage, and apoptosis at elevated temperatures. Apoptotic levels increased after treatment with MMC or 5-FU, without a synergy with heat. Conclusion: Our in vitro results demonstrate that a 60-min exposure of platinum-based drugs and MMC are effective in treating 2D and 3D CRC cell cultures, where platinum-based drugs require hyperthermia (>41 °C) to augment effectivity, suggesting that they are, in principle, suitable for HIPEC. [ABSTRACT FROM AUTHOR]

This paper describes a method to reconstruct bendable superficial hyperthermia applicators for routine clinical patient-specific treatment planning. The reconstruction uses a CT scan with a flexible silicone dummy applicator positioned on the patient. The curvature was approximated by two second-degree polynomial functions. A realistic treatment series was mimicked using a standard Alderson radiation therapy phantom and a treatment planning model was reconstructed from a CT scan. The variation among treatment curvatures was compared to the modelled curvature. The mathematical approximation of the applicator curvature was validated for this phantom experiment, as well as for clinical treatments. The average maximum variation among the successive mimicked sessions was 3.67 ± 0.69 mm (range 2.98–4.60 mm). The maximum deviation between the treatment curvature and the modelled curvature was 4.35 mm. Comparing the treatment and approximated curvature yielded a maximum deviation between 2.98 mm and 4.12 mm. For clinical treatments the maximum deviation of the treatment and approximated curvature varied between 0.48 mm and 1.98 mm. These results allow adequate reconstruction of bendable hyperthermia applicators for treatment planning, which can further improve treatment quality, for example by optimizing the water bolus temperature for patient-specific tumor depths. Predictive parameters for hyperthermia treatment outcome can easily be evaluated and compared for various input parameters. [ABSTRACT FROM AUTHOR]

Cervical cancers are almost exclusively caused by an infection with the human papillomavirus (HPV). When patients suffering from cervical cancer have contraindications for chemoradiotherapy, radiotherapy combined with hyperthermia is a good treatment option. Radiation-induced DNA breaks can be repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Hyperthermia can temporarily inactivate homologous recombination. Therefore, combining radiotherapy with hyperthermia can result in the persistence of more fatal radiation-induced DNA breaks. However, there is no consensus on the optimal sequence of radiotherapy and hyperthermia and the optimal time interval between these modalities. Moreover, the temperature of hyperthermia and HPV-type may also be important in radiosensitization by hyperthermia. In this study we thoroughly investigated the impact of different temperatures (37–42 °C), and the sequence of and time interval (0 up to 4 h) between ionizing radiation and hyperthermia on HPV16+: SiHa, Caski; HPV18+: HeLa, C4I; and HPV−: C33A, HT3 cervical cancer cell lines. Our results demonstrate that a short time interval between treatments caused more unrepaired DNA damages and more cell kill, especially at higher temperatures. Although hyperthermia before ionizing radiation may result in slightly more DNA damage, the sequence between hyperthermia and ionizing radiation yielded similar effects on cell survival. [ABSTRACT FROM AUTHOR]

Hyperthermia (HT) and molecular targeting agents can be used to enhance the effect of radiotherapy (RT). The purpose of this paper is to evaluate radiation sensitization by HT and different molecular targeting agents (Poly [ADP-ribose] polymerase 1 inhibitor, PARP1-i; DNA-dependent protein kinase catalytic subunit inhibitor, DNA-PKcs-i and Heat Shock Protein 90 inhibitor, HSP90-i) in cervical cancer cell lines. Survival curves of SiHa and HeLa cells, concerning the combined effects of radiation with hyperthermia and PARP1-i, DNA-PKcs-i or HSP90-i, were analyzed using the linear-quadratic model: S(D)/S(0) = exp − (αD + βD2). The values of the linear-quadratic (LQ) parameters α and β, determine the effectiveness at low and high doses, respectively. The effects of these sensitizing agents on the LQ parameters are compared to evaluate dose-dependent differences in radio enhancement. Combination of radiation with hyperthermia, PARP1-i and DNA-PKcs-i significantly increased the value of the linear parameter α. Both α and β were significantly increased for HSP90-i combined with hyperthermia in HeLa cells, though not in SiHa cells. The Homologous Recombination pathway is inhibited by hyperthermia. When hyperthermia is combined with DNA-PKcs-i and PARP1-i, the Non-Homologous End Joining or Alternative Non-Homologous End Joining pathway is also inhibited, leading to a more potent radio enhancement. The observed increments of the α value imply that significant radio enhancement is obtained at clinically-used radiotherapy doses. Furthermore, the sensitizing effects of hyperthermia can be even further enhanced when combined with other molecular targeting agents. [ABSTRACT FROM AUTHOR]

• Postoperative re-irradiation and hyperthermia is effective in recurrent breast cancer. • CEM43T50 incorporates both hyperthermia treatment duration and median temperature. • Thermal dose CEM43T50 was significantly associated with better locoregional control. • Three-year locoregional control was 92% vs. 74% for high vs. low thermal dose group. • Grade 3-4 late toxicity was similar for the low and high thermal dose subgroups. To investigate the impact of hyperthermia thermal dose (TD) on locoregional control (LRC), overall survival (OS) and toxicity in locoregional recurrent breast cancer patients treated with postoperative re-irradiation and hyperthermia. In this retrospective study, 112 women with resected locoregional recurrent breast cancer treated in 2010–2017 with postoperative re-irradiation 8frx4Gy (n = 34) or 23frx2Gy (n = 78), combined with 4–5 weekly hyperthermia sessions guided by invasive thermometry, were subdivided into 'low' (n = 56) and 'high' TD (n = 56) groups by the best session with highest median cumulative equivalent minutes at 43 °C (Best CEM43T50) < 7.2 min and ≥7.2 min, respectively. Actuarial LRC, OS and late toxicity incidence were analyzed. Backward multivariable Cox regression and inverse probability weighting (IPW) analysis were performed. TD subgroups showed no significant differences in patient/treatment characteristics. Median follow-up was 43 months (range 1–107 months). High vs. low TD was associated with LRC (p = 0.0013), but not with OS (p = 0.29) or late toxicity (p = 0.58). Three-year LRC was 74.0% vs. 92.3% in the low and high TD group, respectively (p = 0.008). After three years, 25.0% and 0.9% of the patients had late toxicity grade 3 and 4, respectively. Multivariable analysis showed that distant metastasis (HR 17.6; 95%CI 5.2–60.2), lymph node involvement (HR 2.9; 95%CI 1.2–7.2), recurrence site (chest wall vs. breast; HR 4.6; 95%CI 1.8–11.6) and TD (low vs. high; HR 4.1; 95%CI 1.4–11.5) were associated with LRC. TD was associated with LRC in IPW analysis (p = 0.0018). High thermal dose (best CEM43T50 ≥ 7.2 min) was associated with significantly higher LRC for patients with locoregional recurrent breast cancer treated with postoperative re-irradiation and hyperthermia, without augmenting toxicity. [ABSTRACT FROM AUTHOR]

• Fluid model gives accurate hyperthermia treatment planning. • In hyperthermic temperature range, errors < 0.1 °C. • 0.25 cm mesh results in fast & sufficiently accurate planning. Accurate hyperthermia treatment planning, monitoring, and evaluation of temperatures in and near fluid volumes in the body requires realistic modelling of heat transport within fluids, which is currently not implemented in available treatment planning packages. Aim of this study is to assess the accuracy of a thermophysical fluid model, developed for treatment planning near fluid volumes. A cubic phantom with inner dimensions of (7 cm)3 was filled with deionised water. The front, back, top and bottom walls of the cube consisted of PVC, the side walls of stainless steel. The left wall was kept at a constant temperature of 25 or 37 °C, the right wall at 1, 2, 5, 10, or 15 °C higher. Thermal probes mapped the temperature profile in the central vertical plane perpendicular to the cold and hot walls with a spatial resolution of 5–10 mm. The temperature distributions were compared to simulations using a finite volume-based thermophysical fluid model implementing the Boussinesq approximation to the Navier-Stokes equations, developed as an extension to our in-house developed hyperthermia treatment planning suite. The simulations were performed using three meshes at different resolutions. The fluid model predicts the temperature distribution accurately (random and systematic error <0.1 °C, at least 95% of absolute errors <0.2 °C) for hyperthermic temperature differences (<5 °C within the fluid volume). When the temperature differences reach 15 °C, the random and systematic errors increase to 0.3 °C and 0.1 °C, respectively, with absolute errors up to 1.1 °C. The thermophysical fluid model predicts temperature distributions in a convective fluid with sufficient accuracy for hyperthermia treatment planning in and near fluid regions. A mesh with a resolution of 0.25 cm combines accurate results with acceptable computation times. [ABSTRACT FROM AUTHOR]