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BackgroundDuring resonance frequency (RF) hyperthermia treatment, the temperature of the tumor tissue is elevated to the range of 39–44°C. Accurate temperature monitoring is essential to guide treatments and ensure precise heat delivery and treatment quality. Magnetic resonance (MR) thermometry is currently the only clinical method to measure temperature noninvasively in a volume during treatment. However, several studies have shown that this approach is not always sufficiently accurate for thermal dosimetry in areas with motion, such as the pelvic region. Model-based temperature estimation is a promising approach to correct and supplement 3D online temperature estimation in regions where MR thermometry is unreliable or cannot be measured. However, complete 3D temperature modeling of the pelvic region is too complex for online usage.PurposeThis study aimed to evaluate the use of proper orthogonal decomposition (POD) model reduction combined with Kalman filtering to improve temperature estimation using MR thermometry. Furthermore, we assessed the benefit of this method using data from hyperthermia treatment where there were limited and unreliable MR thermometry measurements.MethodsThe performance of POD–Kalman filtering was evaluated in several heating experiments and for data from patients treated for locally advanced cervical cancer. For each method, we evaluated the mean absolute error (MAE) concerning the temperature measurements acquired by the thermal probes, and we assessed the reproducibility and consistency using the standard deviation of error (SDE). Furthermore, three patient groups were defined according to susceptibility artifacts caused by the level of intestinal gas motion to assess if the POD–Kalman filtering could compensate for missing and unreliable MR thermometry measurements.ResultsFirst, we showed that this method is beneficial and reproducible in phantom experiments. Second, we demonstrated that the combined method improved the match between temperature prediction and temperature acquired by intraluminal thermometry for patients treated for locally advanced cervical cancer. Considering all patients, the POD–Kalman filter improved MAE by 43% (filtered MR thermometry = 1.29°C, POD–Kalman filtered temperature = 0.74°C). Moreover, the SDE was improved by 47% (filtered MR thermometry = 1.16°C, POD–Kalman filtered temperature = 0.61°C). Specifically, the POD–Kalman filter reduced the MAE by approximately 60% in patients whose MR thermometry was unreliable because of the great amount of susceptibilities caused by the high level of intestinal gas motion.ConclusionsWe showed that the POD–Kalman filter significantly improved the accuracy of temperature monitoring compared to MR thermometry in heating experiments and hyperthermia treatments. The results demonstrated that POD–Kalman filtering can improve thermal dosimetry during RF hyperthermia treatment, especially when MR thermometry is inaccurate.

Background: Organ-sparing treatment for muscle-invasive bladder cancer by maximal transurethral removal of the tumor (TURB) followed by chemoradiation (CRT) has shown promising results in recent studies, and is therefore considered to be an acceptable alternative for the standard of radical cystectomy (RC) in selected patients. We report on outcomes in a single-center, retrospective CRT cohort in comparison to a RC and radiotherapy only (RT) cohort. Patients and methods: The patient population included n = 84 CRT patients, n = 93 RC patients, and n = 95 RT patients. Primary endpoints were local control (LC) up to 2 years and overall survival (OS) up to 5 years. Cox regression was performed to determine risk factors for LC and OS in the CRT group. Acute genito-urinary (GU) and gastro-intestinal (GI) toxicity were scored with CTCAE version 4 for the RT and CRT cohort. Logistic regression was used to determine risk factors for toxicity. We followed the EQUATOR guidelines for reporting, using the STROBE checklist for observational research. Results: Baseline characteristics were different between the treatment groups with in particular worse comorbidity scores and higher age in the RT cohort. The CRT schedule was completed by 96% of the patients. LC at 2 years was 83.4% (90% CI 76.0–90.8) for CRT vs. 70.9% (62.2–79.6) for RC and 67.0% (56.8–77.2) for RT. OS at 5 years was 48.9% (38.4–59.4) for CRT vs. 46.6% (36.4–56.8) for RC, and 27.6% (19.4–35.8) for RT. High T stage was significantly associated with worse LC and OS in the CRT group. GU/GI toxicity grade ≥2 occurred in 43 (48.3%) RT patients and 38 (45.2%) CRT patients. Conclusions: The organ-preserving strategy with CRT was feasible and tolerable in this patient population, and the achieved LC and OS were satisfactory in comparison to the RC cohort and literature.

Simple Summary Following radiotherapy for head and neck cancer, patients are at risk for developing a recurrent or second tumor. Often reirradiation is required in these patients, which is hampered in dose by the previous irradiation. Besides chemotherapy, hyperthermia can potentially increase the effectivity of the radiotherapy. In this study we have used a new hyperthermia applicator in order to increase the effectivity of the radiotherapy in patients requiring reirradiation. We show that the added hyperthermia treatment is tolerated by patients and that we reach a higher hyperthermia dose to the tumor compared to the previous applicator. In addition, we show that the tumor control and survival as well as toxicity are similar compared to what has been reported in literature using chemotherapy as an additive to reirradiation in head and neck cancer patients. Abstract (1) Background: Head and neck cancer (HNC) patients with recurrent or second primary (SP) tumors in previously irradiated areas represent a clinical challenge. Definitive or postoperative reirradiation with or without sensitizing therapy, like chemotherapy, should be considered. As an alternative to chemotherapy, hyperthermia has shown to be a potent sensitizer of radiotherapy in clinical studies in the primary treatment of HNC. At our institution, we developed the Hypercollar3D, as the successor to the Hypercollar, to enable improved application of hyperthermia for deeply located HNC. In this study, we report on the feasibility and clinical outcome of patients treated with the Hypercollar3D as an adjuvant to reirradiation in recurrent or SP HNC patients; (2) Methods: We retrospectively analyzed all patients with a recurrent or SP HNC treated with reirradiation combined with hyperthermia using the Hypercollar3D between 2014 and 2018. Data on patients, tumors, and treatments were collected. Follow-up data on disease specific outcomes as well as acute and late toxicity were collected. Data were analyzed using Kaplan Meier analyses; (3) Results: Twenty-two patients with recurrent or SP HNC were included. The average mean estimated applied cfSAR to the tumor volume for the last 17 patients was 80.5 W/kg. Therefore, the novel Hypercollar3D deposits 55% more energy at the target than our previous Hypercollar applicator. In patients treated with definitive thermoradiotherapy a complete response rate of 81.8% (9/11) was observed at 12 weeks following radiotherapy. Two-year local control (LC) and overall survival (OS) were 36.4% (95% CI 17.4–55.7%) and 54.6% (95% CI 32.1–72.4%), respectively. Patients with an interval longer than 24 months from their previous radiotherapy course had an LC of 66.7% (95% CI 37.5–84.6%), whereas patients with a time interval shorter than 24 months had an LC of 14.3% (95% CI 0.7–46.5%) at 18 months (p = 0.01). Cumulative grade 3 or higher toxicity was 39.2% (95% CI 16.0–61.9%); (4) Conclusions: Reirradiation combined with deep hyperthermia in HNC patients using the novel Hypercollar3D is feasible and deposits an average cfSAR of 80.5 W/kg in the tumor volume. The treatment results in high complete response rates at 12 weeks post-treatment. Local control and local toxicity rates were comparable to those reported for recurrent or SP HNC. To further optimize the hyperthermia treatment in the future, temperature feedback is warranted to apply heat at the maximum tolerable dose without toxicity. These data support further research in hyperthermia as an adjuvant to radiotherapy, both in the recurrent as well as in the primary treatment of HNC patients.

IntroductionBreast cancer is the most frequently diagnosed malignancy worldwide but almost half of the patients have an excellent prognosis with a 5-year survival rate of 98%–99%. These patients could potentially be treated with thermal ablation to avoid surgical excision, reduce treatment-related morbidity and increase patients’ quality of life without jeopardising treatment effectiveness. Previous studies showed highest complete ablation rates for radiofrequency, microwave and cryoablation. However, due to heterogeneity among studies, it is unknown which of these three techniques should be selected for a phase 3 comparative study.Methods and analysisThe aim of this phase 2 screening trial is to determine the efficacy rate of radiofrequency, microwave and cryoablation with the intention to select one treatment for further testing in a phase 3 trial. Additionally, exploratory data are obtained for the phase 3 trial. The design is a multicentre open-label randomised phase 2 screening trial. Patients with unifocal, invasive breast cancer with a maximum diameter of 2 cm without lymph node or distant metastases are included. Triple negative, Bloom-Richardson grade 3 tumours and patients with an indication for neoadjuvant chemotherapy will be excluded. Included patients will be allocated to receive one of the three thermal ablation techniques. Three months later surgical excision will be performed to determine the efficacy of thermal ablation. Treatment efficacy in terms of complete ablation rate will be assessed with CK 8/18 and H&E staining. Secondary outcomes include feasibility of the techniques in an outpatient setting, accuracy of MRI for complete ablation, patient satisfaction, adverse events, side effects, cosmetic outcome, system usability and immune response.Ethics and disseminationThis study protocol was approved by Medical Research Ethics Committee of the Erasmus Medical Center, Rotterdam, the Netherlands. Study results will be submitted for publication in peer-reviewed journals.Trial registration numberNL9205 (www.trialregister.nl); Pre-results.

Purpose: Thermal dose-effect relations have demonstrated that clinical effectiveness of hyperthermia would benefit from more controlled heating of the tumor. Hyperthermia treatment planning (HTP) is a potent tool to study strategies enabling target conformal heating, but its accuracy is affected by patient modeling approximations. Homogeneous phantoms models are being used that do not match the body shape of patients in treatment position and often have unrealistic target volumes. As a consequence, simulation accuracy is affected, and performance comparisons are difficult. The aim of this study is to provide the first step toward standardization of HTP simulation studies in terms of patient modeling by introducing the Erasmus Virtual Patient Repository (EVPR): a virtual patient model database.Methods: Four patients with a tumor in the head and neck or the pelvis region were selected, and corresponding models were created using a clinical segmentation procedure. Using the Erasmus University Medical Center standard procedure, HTP was applied to these models and compared to HTP for commonly used surrogate models.Results: Although this study was aimed at presenting the EVPR database, our study illustrates that there is a non-negligible difference in the predicted SAR patterns between patient models and homogeneous phantom-based surrogate models. We further demonstrate the difference between actual and simplified target volumes being used today.Conclusion: Our study describes the EVPR for the research community as a first step toward standardization of hyperthermia simulation studies.

The efficacy of a hyperthermia treatment depends on the delivery of well-controlled heating, hence, accurate temperature monitoring is essential for ensuring effective treatment. For deep pelvic hyperthermia, there are no comprehensive and systematic reports on MR thermometry. Moreover, data inclusion generally lacks objective selection criteria leading to a high probability of bias when comparing results. Herein, we studied whether imaging-based data inclusion predicts accuracy and could serve as a tool for prospective patient selection. The accuracy of the MR thermometry in patients with locally advanced cervical cancer was benchmarked against intraluminal temperature. We found that gastrointestinal air motion at the start of the treatment, quantified by the Jaccard similarity coefficient, was a good predictor for MR thermometry accuracy. The results for the group that was selected for low gastrointestinal air motion improved compared to the results for all patients by 50% (accuracy), 26% (precision), and 80% (bias). We found an average MR thermometry accuracy of 2.0 °C when all patients were considered and 1.0 °C for the selected group. These results serve as the basis for comprehensive benchmarking of novel technologies. The Jaccard similarity coefficient also has good potential to prospectively determine in which patients the MR thermometry will be valuable.

Background and purpose: To investigate the accuracy of dwell position detection with a combined electromagnetic tracking (EMT) brachytherapy (BT) system for treatment verification, by quantifying positional errors due to EM field interference in typical pelvic BT clinical settings. Materials and methods: Dedicated prostate and cervix BT phantoms were imaged with CT. For the cervix phantom, the Utrecht applicator + interstitial catheters were used. The implants were reconstructed and treatment plans were created with 270/65 dwell positions for the prostate/cervix phantom. Next, EMT experiments were performed in clinical BT settings using a prototype of a combined EMT/BT system. We quantified positional errors due to EM field interference from surrounding equipment by comparing planned and EMT-measured dwell positions. The mean residual error between planned and EMT-measured dwell positions was calculated in the prostate interstitial catheters and in the whole cervix implant including the applicator. For the cervix phantom, the analysis was repeated for only the interstitial catheters. Results: Mean residual errors of less than 0.5/0.4 mm in the prostate/cervix catheters were found. For the whole cervix implant including the applicator, large deviations up to 2.4 mm were found. Compared to the interference free set-up, the CT and patient bed environments showed larger residual errors in the interstitial catheters, but residual errors remained

Simple Summary Hyperthermia is a treatment for cancer patients, which consists of heating the body to 43 °C. The temperature during treatment is usually measured by placing temperature probes intraluminal or invasively. The only clinically used option to measure temperature distributions non-invasively and in 3D is by MR thermometry (MRT). However, in order to be able to replace conventional temperature probes, MRT needs to become more reliable. In this review paper, we propose standardized performance thresholds for MRT, based on our experience of treating nearly 4000 patients. We then review the literature to assess to what extent these requirements are already being met in the clinic today and identify common problems. Lastly, using pre-clinical results in the literature, we assess where the biggest potential is to solve the problems identified. We hope that by standardizing MRT parameters as well as highlighting current and promising developments, progress in the field will be accelerated. Abstract Hyperthermia treatments in the clinic rely on accurate temperature measurements to guide treatments and evaluate clinical outcome. Currently, magnetic resonance thermometry (MRT) is the only clinical option to non-invasively measure 3D temperature distributions. In this review, we evaluate the status quo and emerging approaches in this evolving technology for replacing conventional dosimetry based on intraluminal or invasively placed probes. First, we define standardized MRT performance thresholds, aiming at facilitating transparency in this field when comparing MR temperature mapping performance for the various scenarios that hyperthermia is currently applied in the clinic. This is based upon our clinical experience of treating nearly 4000 patients with superficial and deep hyperthermia. Second, we perform a systematic literature review, assessing MRT performance in (I) clinical and (II) pre-clinical papers. From (I) we identify the current clinical status of MRT, including the problems faced and from (II) we extract promising new techniques with the potential to accelerate progress. From (I) we found that the basic requirements for MRT during hyperthermia in the clinic are largely met for regions without motion, for example extremities. In more challenging regions (abdomen and thorax), progress has been stagnating after the clinical introduction of MRT-guided hyperthermia over 20 years ago. One clear difficulty for advancement is that performance is not or not uniformly reported, but also that studies often omit important details regarding their approach. Motion was found to be the common main issue hindering accurate MRT. Based on (II), we reported and highlighted promising developments to tackle the issues resulting from motion (directly or indirectly), including new developments as well as optimization of already existing strategies. Combined, these may have the potential to facilitate improvement in MRT in the form of more stable and reliable measurements via better stability and accuracy.

Simple Summary Hyperthermia treatment planning is the process of optimizing treatment quality using pre-treatment simulations. Although it has become a powerful tool, prediction accuracy is strongly dependent on the patient model. For deep hyperthermia in the pelvis, it is common that only four tissue categories are discriminated (bone, fat, muscle-like, and tumor). For the head and neck region, more tissues have been shown to be required for good prediction accuracy. Delineating is a labor-intensive and difficult process. Hence, it is important to find the optimum between accuracy and labor, but for deep pelvic hyperthermia, there are no published studies showing the impact of the number of tissues. We studied the trade-off between the segmentation detail needed and segmentation feasibility. Our findings indicate that including high water content tissues can impact simulation accuracy. Although our results, in general, underline the suitability of our current clinical protocol, they help to prioritize improvements for specific cases. Abstract In hyperthermia, the general opinion is that pre-treatment optimization of treatment settings requires a patient-specific model. For deep pelvic hyperthermia treatment planning (HTP), tissue models comprising four tissue categories are currently discriminated. For head and neck HTP, we found that more tissues are required for increasing accuracy. In this work, we evaluated the impact of the number of segmented tissues on the predicted specific absorption rate (SAR) for the pelvic region. Highly detailed anatomical models of five healthy volunteers were selected from a virtual database. For each model, seven lists with varying levels of segmentation detail were defined and used as an input for a modeling study. SAR changes were quantified using the change in target-to-hotspot-quotient and maximum SAR relative differences, with respect to the most detailed patient model. The main finding of this study was that the inclusion of high water content tissues in the segmentation may result in a clinically relevant impact on the SAR distribution and on the predicted hyperthermia treatment quality when considering our pre-established thresholds. In general, our results underline the current clinical segmentation protocol and help to prioritize any improvements.

Background: Addition of deep hyperthermia results in improved local control (LC) and overall survival (OS) compared to radiotherapy alone in patients with cervical carcinoma. Previously, we showed that the thermal dose of hyperthermia significantly correlates with LC and disease specific survival (DSS). Over the last decade, new radiation techniques were introduced resulting in improved LC.Aim: To validate the effect of thermal dose in a more recent cohort of patients treated with modern radiotherapy techniques, including image guided brachytherapy (IGBT).Methods: We analyzed primary cervical carcinoma patients treated with a combination of radiotherapy and deep hyperthermia between 2005 and 2016 at our institute. Data on patient, tumor and treatment were collected including the thermal dose parameters TRISE and CEM43T90. Follow-up data on LC, disease free survival, DSS, OS as well as late toxicity data were collected. Data were analyzed using the Cox proportional hazard and Kaplan-Meier analyses.Results: 227 patients were included. In multivariate analysis, histology, FIGO stage, lymphadenopathy, TRISE, CEM43T90 and IGBT had a significant effect on LC. In the patients treated with IGBT, the thermal dose parameter TRISE remained to have a significant effect on LC in univariate analysis.Conclusions: The positive association between thermal dose and clinical outcome is replicated in an independent, recent cohort of cervical carcinoma patients. Importantly, in patients receiving IGBT, the effect of thermal dose on clinical outcome is still observed. (C) 2019 Elsevier B.V. All rights reserved.

OBJECTIVES: To compare MR imaging with or without DWI and clinical response evaluation (CRE) in the local control evaluation of cervical carcinoma after radiotherapy. METHODS: In a multicentre university setting, we prospectively included 107 patients with primary cervical cancer treated with radiotherapy. Sensitivity and specificity for CRE and MR imaging (with pre-therapy MR imaging as reference) (2 readers) were evaluated using cautious and strict criteria for identifying residual tumour. Nested logistic regression models were constructed for CRE, subsequently adding MR imaging with and without DWI as independent variables, as well as the pre- to post-treatment change in apparent diffusion coefficient (delta ADC). RESULTS: Using cautious criteria, CRE and MR imaging with DWI (reader 1/reader 2) have comparable high specificity (83% and 89%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (63%/53%) than CRE. Using strict criteria, CRE and MR imaging with DWI both showed very high specificity (99% and 92%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (89%/77%) than CRE. All sensitivities were not significantly different. Addition of MR imaging with DWI to CRE has statistically significant incremental value in identifying residual tumour (reader 1: estimate, 1.06; p = 0.001) (reader 2: estimate, 0.62; p = 0.02). Adding the delta ADC did not have significant incremental value in detecting residual tumour. CONCLUSIONS: DWI significantly increases the specificity of MR imaging in the detection of local residual tumour. Furthermore, MR imaging with DWI has significant incremental diagnostic value over CRE, whereas adding the delta ADC has no incremental diagnostic value. KEY POINTS: • If MR imaging is used for response evaluation, DWI should be incorporated • MR imaging with DWI has diagnostic value comparable/complementary to clinical response evaluation • Inter-reader agreement is moderate to fair for two experienced radiologist readers • Quantitative measurements of ADC early post-therapy have limited diagnostic value. ispartof: EUROPEAN RADIOLOGY vol:29 issue:1 pages:309-318 ispartof: location:Germany status: published

Clinical outcome of hyperthermia depends on the achieved target temperature, therefore target conformal heating is essential. Currently, invasive temperature probe measurements are the gold standard for temperature monitoring, however, they only provide limited sparse data. In contrast, magnetic resonance thermometry (MRT) provides unique capabilities to non-invasively measure the 3D-temperature. This study investigates MRT accuracy for MR-hyperthermia hybrid systems located at five European institutions while heating a centric or eccentric target in anthropomorphic phantoms with pelvic and spine structures. Scatter plots, root mean square error (RMSE) and Bland&ndash, Altman analysis were used to quantify accuracy of MRT compared to high resistance thermistor probe measurements. For all institutions, a linear relation between MRT and thermistor probes measurements was found with R2 (mean &plusmn, standard deviation) of 0.97 &plusmn, 0.03 and 0.97 &plusmn, 0.02, respectively for centric and eccentric heating targets. The RMSE was found to be 0.52 &plusmn, 0.31 &deg, C and 0.30 &plusmn, 0.20 &deg, C, respectively. The Bland-Altman evaluation showed a mean difference of 0.46 &plusmn, C and 0.13 &plusmn, 0.08 &deg, C, respectively. This first multi-institutional evaluation of MR-hyperthermia hybrid systems indicates comparable device performance and good agreement between MRT and thermistor probes measurements. This forms the basis to standardize treatments in multi-institution studies of MR-guided hyperthermia and to elucidate thermal dose-effect relations.

Hyperthermia, i.e. heating the tumor to a temperature of 40–43 °C is considered by many a valuable treatment to sensitize tumor cells to radiotherapy and chemotherapy. In recent randomized trials the great potential of adding hyperthermia to chemotherapy was demonstrated for treatment of high risk soft tissue sarcoma: +11.4% 5 yrs. overall survival (OS) and for ovarian cancer with peritoneal involvement nearly +12 months OS gain. As a result interest in combining chemotherapy with hyperthermia, i.e. thermochemotherapy, is growing. Extensive biological research has revealed that hyperthermia causes multiple effects, from direct cell kill to improved oxygenation, whereby each effect has a specific temperature range. Thermal sensitization of the tumor cell for chemotherapy occurs for many drugs at temperatures ranging from 40 to 42 °C with little additional increase of sensitization at higher temperatures. Increasing perfusion/oxygenation and increased extravasation are two other important hyperthermia induced mechanisms. The combination of free drug and hyperthermia has not been found to increase tumor drug concentration. Hence, enhanced effectiveness of free drug will depend on the thermal sensitization of the tumor cells for the applied drug. In contrast to free drugs, experimental animal studies combining hyperthermia and thermo-sensitive liposomal (TSL) drugs delivery have demonstrated to result in a substantial increase of the drug concentration in the tumor. For TSL based chemotherapy, hyperthermia is critical to both increase perfusion and extravasation as well as to trigger TSL drug release, whereby the temperature controlled induction of a local high drug concentration in a highly permeable vessel is driving the enhanced drug uptake in the tumor. Increased drug concentrations up to 26 times have been reported in rodents. Good control of the tissue temperature is required to keep temperatures below 43 °C to prevent vascular stasis. Further, careful timing of the drug application relative to the start of heating is required to benefit optimal from the combined treatment. From the available experimental data it follows that irrespective whether chemotherapy is applied as free drug or using a thermal sensitive liposomal carrier, the optimal thermal dose for thermochemotherapy should be 40–42 °C for 30–60 min, i.e. equivalent to a CEM43 of 1–15 min. Timing is critical: most free drug should be applied simultaneous with heating, whereas TSL drugs should be applied 20–30 min after the start of hyperthermia.

Background: Addition of deep hyperthermia to radiotherapy results in improved local control (LC) and overall survival compared to radiotherapy alone in cervical carcinoma patients. Based on preclinical data, the time interval between radiotherapy, and hyperthermia is expected to influence treatment outcome. Clinical studies addressing the effect of time interval are sparse. The repercussions for clinical applications are substantial, as the time between radiotherapy and hyperthermia should be kept as short as possible. In this study, we therefore investigated the effect of the time interval between radiotherapy and hyperthermia on treatment outcome.Methods: We analyzed all primary cervical carcinoma patients treated between 1996 and 2016 with thermoradiotherapy at our institute. Data on patients, tumors and treatments were collected, including the thermal dose parameters TRISE and CEM43T90. Follow-up data on tumor status and survival as well as late toxicity were collected. Data was analyzed using Cox proportional hazards analysis and Kaplan Meier analysis.Results: 400 patients were included. Kaplan Meier and univariate Cox analysis showed no effect of the time interval (range 30-230 min) on any clinical outcome measure. Besides known prognostic factors, thermal dose parameters TRISE and CEM43T90 had a significant effect on LC. In multivariate analysis, the thermal dose parameter TRISE (HR 0.649; 95% CI 0.501-0.840) and the use of image guided brachytherapy (HR 0.432; 95% CI 0.214-0.972), but not the time interval, were significant predictors of LC and disease specific survival.Conclusions: The time interval between radiotherapy and hyperthermia, up to 4 h, has no effect on clinical outcome. These results are re-ensuring for our current practice of delivering hyperthermia within maximal 4 h after radiotherapy.

Hyperthermia has a number of biological effects that sensitize tumors to radiotherapy in the range between 40-44 °C. One of these effects is heat-induced degradation of BRCA2 that in turn causes reduced RAD51 focus formation, which results in an attenuation of DNA repair through homologous recombination. Prompted by this molecular insight into how hyperthermia attenuates homologous recombination, we now quantitatively explore time and temperature dynamics of hyperthermia on BRCA2 levels and RAD51 focus formation in cell culture models, and link this to their clonogenic survival capacity after irradiation (0-6 Gy). For treatment temperatures above 41 °C, we found a decrease in cell survival, an increase in sensitization towards irradiation, a decrease of BRCA2 protein levels, and altered RAD51 focus formation. When the temperatures exceeded 43 °C, we found that hyperthermia alone killed more cells directly, and that processes other than homologous recombination were affected by the heat. This study demonstrates that optimal inhibition of HR is achieved by subjecting cells to hyperthermia at 41-43 °C for 30 to 60 minutes. Our data provides a guideline for the clinical application of novel combination treatments that could exploit hyperthermia's attenuation of homologous recombination, such as the combination of hyperthermia with PARP-inhibitors for non-BRCA mutations carriers.

IntroductionBladder cancer (urothelial carcinoma) is a common malignancy characterized by high recurrence rates and intense clinical follow-up, indicating the necessity for more effective therapies. Current treatment regimens include intra-vesical administration of mitomycin C (MMC) for non-muscle invasive disease and systemic cisplatin for muscle-invasive or metastatic disease. Hyperthermia, heating a tumor to 40-44 degrees C, enhances the efficacy of these chemotherapeutics by various modes of action, one of which is inhibition of DNA repair via homologous recombination. Here, we explore whether ex vivo assays on freshly obtained bladder tumors can be applied to predict the response towards hyperthermia.Material and methodsThe cytochrome C release assay (apoptosis) and the RAD51 focus formation assay (DNA repair) were first established in the bladder cancer cell lines RT112 and T24 as measurements for hyperthermia efficiency, and subsequently tested in freshly obtained bladder tumors (n = 59).ResultsHyperthermia significantly increased the fraction of apoptotic cells after cisplatin or MMC treatment in both RT112 and T24 cells and in most of the bladder tumors (8/10). The RAD51 focus formation assay detected both morphological and numerical changes of RAD51 foci upon hyperthermia in the RT112 and T24 cell lines. In 64% of 37 analyzed primary bladder tumor samples, hyperthermia induced similar morphological changes in RAD51 foci.ConclusionThe cytochrome C assay and the RAD51 focus formation assay are both feasible on freshly obtained bladder tumors, and could serve to predict the efficacy of hyperthermia together with cytotoxic agents, such as MMC or cisplatin.

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.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.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).Hyperthermia with the HYPERcollar proved to be safe and feasible with good compliance and promising outcome.

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.

BACKGROUND: Radiofrequency (RF) mild hyperthermia (40 °C-44 °C for 60 minutes) is an effective adjuvant treatment for several types of cancer. To ensure treatment efficacy, quality assurance (QA) is necessary. This study presents the first systematic 3D characterisation of the heating performance of the commonly used Pyrexar BSD2000-3D MR-compatible hyperthermia applicator using magnetic resonance temperature imaging (MRTI).METHODS: A reproducibly positioned phantom was heated with a power of 1000 watts during the 12.4 min needed to measure eight temperature distributions using MRTI. The target heating location was systematically varied between experiments. We analysed focus shape characteristics, steering accuracy, focus deformation due to steering, presence of off-target heating and reproducibility.RESULTS: The mean maximum temperature increase was 5.9 ± 0.4 °C. The mean full width half maximum (FWHM) was 14.4 ± 0.5 cm in the XY plane and 24.5 ± 0.8 cm in Z-direction. The mean steering error was 0.4 ± 0.2 cm. The focus shape slightly varied between experiments, depending on steering distance in Y-direction. Off-target heating was not detected. Reproducibility of the focus amplitude and shape was determined by comparing the mean deviation from the mean temperature in the central slice was 0.3 ± 0.2 °C.CONCLUSION: The Pyrexar BSD2000-3D MR-compatible applicator provides robust and reproducible heating. The upper boundary of the 95% confidence interval of the spatial steering accuracy is 0.9 cm, i.e. sufficient to fulfil the criterion of ≤0.2 °C temperature variation due to positioning errors as defined by Canters et al.

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.

Confining treatment to the tumor to improve therapeutic outcome and reduce toxicity, is a hot issue in cancer research. Hyperthermia is recognized as a strong sensitizer for radiotherapy and chemotherapy enhancing tumor control without increasing toxicity. Today's electromagnetic hyperthermia systems heat large tissue volumes with limited ability to selectively heat the tumor. Fortunately, tremendous improvements in 3-dimensional electromagnetic & temperature modelling provide an exciting opportunity to design advanced multi-element electromagnetic applicator systems. Together with feedback control using MR non-invasive thermometry and smart E-field sensors, this paves the way for selective tumor heating and potentially prescription of a thermal dose. A technological advanced hyperthermia system, with guaranteed delivery of high quality hyperthermia lowers the threshold for newcomers to apply hyperthermia. Combined with recent proof that hyperthermia blocks DNA repair and new, exciting, ways for controlled drug delivery using temperature sensitive liposome encapsulated drugs, this is expected to increase interest of the medical community in hyperthermia.

To investigate the clinical benefit of replacing the BSD-2000 Sigma-60 with the Sigma-Eye applicator, taking into account effects of uncertainties in tissue and water bolus parameters. For 20 patients, specific absorption rate (SAR) and temperature distributions were calculated and optimized, based on computed tomography (CT) scans in treatment position. The impact of uncertainties on predicted distributions was studied using a Monte Carlo uncertainty assessment. Replacing the Sigma-60 by the Sigma-Eye applicator resulted in a higher SAR in the tumor [on average a decrease of the hotspot tumor quotient (HTQ) by 24%; p

This manuscript provides an overview in the field of hyperthermia treatment planning (HTP) in cervical cancer. Treatment planning techniques: The workflow of an HTP assisted treatment generally consists of patient imaging, tissue segmentation, model generation, electromagnetic (EM) and thermal calculations, optimisation, and clinical implementation. A main role in HTP is played by numerical simulations, for which currently a number of software packages are available in hyperthermia. To implement these simulations, accurate applicator models and accurate knowledge of dielectric and thermal parameters is mandatory. Model validation is necessary to check if this is implemented well. In the translation from HTP models to the clinic, the main aspect is accurate representation of the actual treatment situation in the HTP models. Accurate patient positioning and organ-specific segmentation can be helpful in minimising the differences between model and clinic.In the clinic, different approaches are possible: simple, i.e. target centre point (TCP) steering, often called 'target steering', or only pretreatment planning versus advanced, i.e. active HTP guided steering or image guided hyperthermia by non-invasive thermometry (NIT). The Rotterdam experience: To illustrate the implementation of HTP guided steering, the Rotterdam approach of complaint adaptive steering is elaborated, in which optimisation is adapted with increased constraints on tissues with heat-induced discomfort.Many publications on HTP show that HTP can be considered a feasible method to optimise and control a hyperthermia treatment, with the objective to enhance treatment quality and documentation. Ultimately, after overcoming the various uncertainties, this may lead to dose prescription.

This review focuses on combined radiotherapy and hyperthermia for the primary treatment of cervical cancer compared to the current international standard of chemoradiation. Practical considerations, biological effects and clinical results are discussed.

During deep hyperthermia treatment, patient pain complaints due to heating are common when maximizing power. Hence, there exists a good rationale to investigate whether the locations of predicted SAR peaks by hyperthermia treatment planning (HTP) are correlated with the locations of patient pain during treatment. A retrospective analysis was performed, using the treatment reports of 35 patients treated with deep hyperthermia controlled by extensive treatment planning. For various SAR indicators, the average distance from a SAR peak to a patient discomfort location was calculated, for each complaint. The investigated V(0.1 closest) (i.e. the part of the 0.1th SAR percentile closest to the patient complaint) performed the best, and leads to an average distance between the SAR peak and the complaint location of 3.9 cm. Other SAR indicators produced average distances that were all above 10 cm. Further, the predicted SAR peak location with V(0.1) provides a 77% match with the region of complaint. The current study demonstrates that HTP is able to provide a global indication of the regions where hotspots during treatment will most likely occur. Further development of this technology is necessary in order to use HTP as a valuable toll for objective and advanced SAR steering. The latter is especially valid for applications that enable 3D SAR steering.

Purpose of review We reviewed all literature on the clinical use of combined radiation and hyperthermia for gynecologic malignancies. Recent findings Combined radiation and hyperthermia should be considered an alternative to chemoradiation for patients with locally advanced cervix cancer and be the first treatment of choice for these patients when radiation cannot be combined with chemotherapy. Several randomized trials have shown an improvement by adding hyperthermia to radiation that is comparable to the improvement found with the addition of chemotherapy to radiation. Hyperthermia does not seem to add to treatment-induced toxicity and the results of hyperthermia are consistent even at 12 years follow-up and could be reproduced in a large, unselected group of cervix cancer patients. A novel indication for combined radiotherapy and hyperthermia is vaginal cancer. Recently, a cohort study showed that the addition of hyperthermia to radiation seems to improve overall survival for patients with vaginal cancer International Federation of Gynecology and Obstetrics stage III. Summary Combined radiation and hyperthermia should be considered for patients with locally advanced cervix cancer (International Federation of Gynecology and Obstetrics stage IIb and upwards) as an alternative to chemoradiation for patients with a contraindication for chemotherapy. For other patients, the optimal treatment combination is the subject of randomized trials. For vaginal cancer, a prospective registration study is currently ongoing.

Purpose: To assess the current feasibility of online hyperthermia treatment planning guided steering (HGS) and its current contribution to treatment quality in deep hyperthermia for locally advanced cervical cancer. Materials and methods: 36 patients were randomized to receive either their second and fourth (arm A) or their third and fifth (arm B) hyperthermia treatment of the series with the aid of HGS. The other treatments were conducted according to the Rotterdam Empirical Steering Guidelines (RESG). Results: During period I (second and third treatment of the series) similar results were found for HGS and RESG with a slight, non-significant difference found in favour of HGS. The average temperature T50 was 40.3 degrees C for both (p = 0.409) and the dose parameter CEM43T90 was 0.64 for RESG and 0.63 for HGS (p = 0.154). However, during period II (fourth and fifth treatment of the series) HGS performed less well, with significant lower thermal dose parameters, minimum, mean and maximum intraluminal temperatures, tolerance measures and net integrated power. T50 was 40.4 degrees C after RESG and 40 degrees C after HGS (p = 0.001) and CEM43T90 0.57 and 0.38 (p = 0.01) respectively. Conclusion: We found that the procedure of online treatment planning guided steering is feasible. For maximal exploitation of its possibilities, however, better control and understanding of several patient, tumour and technical parameters is required. This study has been very helpful in identifying some of the challenges and flaws that warrant further investigation in the near future, such as patient positioning and the prevention of hotspot-related complaints.

Adding hyperthermia to standard radiotherapy (RT + HT) improves treatment outcome for patients with locally advanced cervical cancer (LACC). We investigated the effect of hyperthermia dose on treatment outcome for patients with LACC treated with RT + HT. We collected treatment and outcome data of 420 patients with LACC treated with hyperthermia at our institute from 1990 to 2005. Univariate and multivariate analyses were performed on response rate, local control, disease-specific survival and toxicity for these patients to search for a thermal dose response relationship. Besides commonly identified prognostic factors in LACC like tumour stage, performance status, radiotherapy dose and tumour size, thermal parameters involving both temperature and duration of heating emerged as significant predictors of the various end-points. The more commonly used CEM43T90 (cumulative equivalent minutes of T90 above 43 degrees C) was less influential than TRISE (based on the average T50 increase and the duration of heating, normalised to the scheduled duration of treatment). CEM43T90 and TRISE measured intraluminally correlate significantly and independently with tumour control and survival. These findings stimulate further technological development and improvement of deep hyperthermia, as they strongly suggest that it might be worthwhile to increase the thermal dose for LACC, either by treatment optimisation or by prolonging the treatment time. These results also confirm the beneficial effects from hyperthermia as demonstrated in our earlier randomised trial, and justify applying radiotherapy and hyperthermia as treatment of choice for patients with advanced cervical cancer. (c) 2009 Elsevier Ltd. All rights reserved.

In this deep hyperthermia study, the robustness of SAR (specific absorption rate) patterns to patient-position variations is assessed, as well as the possibilities to correct for improper positioning and the benefits of non-standard positions. With a finite element model, the SAR distributions were predicted for ten patients at 33 positions. Position sensitivity is assessed for both SAR-focus steering, i.e. settings based on a calculated focus in a cylindrical patient representation, and HTP (hyperthermia treatment planning)-guided steering, i.e. model-based optimization of the SAR distribution. Position inaccuracies of less than 1 cm do not significantly affect SAR patterns. For SAR-focus steering, the SAR maximum is not always at the desired focus location, especially in the Y (anterior/posterior)- and Z (axial)-directions. For a maximum shift of 5 cm in all directions, both SAR-focus steering and HTP-guided steering are suitable to correct for improper positioning up to the level that none of the investigated positions appears preferable. Current positioning precision is sufficient in the X (right-left)-direction, but precision measurements are needed to reach the desired accuracy in the Y-direction. In the Z-direction, a cranial shift of the applicator is predicted to be beneficial. If the position is known accurately, correction of the treatment setting is possible without loss of heating efficiency. Additionally, no preferable positions exist.

For an efficient clinical use of HTP (hyperthermia treatment planning), optimization methods are needed. In this study, a complaint-adaptive PD (power density) optimization as a tool for HTP-guided steering in deep hyperthermia of pelvic tumors is developed and tested. PD distribution in patients is predicted using FE-models. Two goal functions, Opt1 and Opt2, are applied to optimize PD distributions. Optimization consists of three steps: initial optimization, adaptive optimization after a first complaint and increasing the weight of a region after recurring complaints. Opt1 initially considers only target PD whereas Opt2 also takes into account hot spots. After patient complaints though, both limit PD in a region. Opt1 and Opt2 are evaluated in a phantom test, using patient models and during hyperthermia treatment. The phantom test and a sensitivity study in ten patient models, show that HTP-guided steering is most effective in peripheral complaint regions. Clinical evaluation in two groups of five patients shows that time between complaints is longer using Opt2 (p = 0.007). However, this does not lead to significantly different temperatures (T50s of 40.3 (Opt1) versus 40.1 degrees C (Opt2) (p = 0.898)). HTP-guided steering is feasible in terms of PD reduction in complaint regions and in time consumption. Opt2 is preferable in future use, because of better complaint reduction and control.

Patients with recurrent cervical carcinoma within a previously irradiated area respond poorly to chemotherapy. We have treated these patients with simultaneous cisplatin and hyperthermia (CDDP + HT) and investigated response, toxicity, palliative effect and survival.Between 1992 and 2005 47 patients received CDDP + HT. Response was evaluated by gynaecologic examination and CT-scan. The Common Toxicity Criteria (CTC) were used for evaluation of toxicity and palliative effect. The Kaplan-Meier method was used to estimate survival, and Cox regression analysis to evaluate the influence of prognostic factors.The objective response rate was 55%, palliation was achieved in 74% and operability in 19% of patients. Two patients are currently disease free at 9 years and 18 + months following treatment and 2 remained disease free until death by other causes. The median survival was 8 months and was influenced by duration of disease free interval and tumour diameter. Grade 3-4 haematological toxicity was observed in 36% of patients and renal toxicity was maximum grade 2.CDDP + HT results in a high response rate and acceptable toxicity in patients with recurrent cervical cancer.

Extensive biologic research has shown that adjuvant thermal therapy, i.e. heating tumors to 40–43°C, is a promising approach to increase the efficacy of existing radio- and chemotherapy protocols. The fact that in clinical trials, hyperthermia has shown not to increase toxicity is a major drive to invest in developing innovative devices and applicators to deliver thermal therapies. Moreover, the recent demonstrated ability of hyperthermia to decrease the repair of DNA double strand breaks provides a gateway to new treatments strategies involving hyperthermia and in combination with temperature sensitive drug carriers hyperthermia can be used for triggered local drug delivery.