A Genomic Urine Assay for Surveillance of Patients with Bladder Cancer Treated with Radiotherapy.

Background: Patients with muscle-invasive bladder cancer (MIBC) who receive radiotherapy with curative intent are followed by imaging, cystoscopy, and urine cytology. However, interpretation of cytology and cystoscopy is hampered by the impact of ionizing radiation on cells. Objective: To assess the diagnostic performance of a genomic urine assay to detect urinary tract recurrences in patients with MIBC treated by (chemo)radiation. Design setting and participants: Patients with nonmetastatic MIBC who underwent (chemo)radiation with curative intent from 2016 to 2020 were prospectively included. Follow-up consisted of cystoscopy and upper tract imaging. Prior to cystoscopy, a urine sample was analyzed to assess mutations in the genes FGFR3, HRAS, and TERT and methylation of OTX1, TWIST1, and ONECUT2. The treating physician was blinded for the assay result. Outcome measurements and statistical analysis: The primary endpoint was a urinary tract recurrence. Cross-sectional sensitivity, specificity, and negative predictive value (NPV) were analyzed using a previously developed logistic regression model for the detection of bladder cancer with this assay. The secondary endpoint was the risk of a future urinary tract recurrence following a positive test and negative cystoscopy/imaging, using a time-dependent Cox proportional hazard analysis. Results and limitations: A total of 143 patients were included, and 503 urine samples were analyzed. The median study duration was 20 mo (interquartile range [IQR] 10-33), and the median time to a recurrence was 16 mo (IQR 12-26). In 27 patients, 32 urinary tract recurrences were diagnosed, including three upper tract tumors. Of 32 recurrences, 18 (56%) had a concomitant urine test available. The diagnostic model had an area under the curve of 0.80 (95% confidence interval [CI] 0.69-0.90) with corresponding sensitivity, specificity, and NPV of 78 (95% CI 52-94), 77% (95% CI 73-81), and 99% (95% CI 97-100). When taking into account the anticipatory effect of the test, 28/32 (88%) recurrences were detected. A Cox regression analysis showed a hazard ratio of 14.8 for the development of a future recurrence (p < 0.001). A major limitation was the lack of a concomitant urine test result in 14/32 (44%) recurrences. Conclusions: A genomic urine assay detected urinary tract recurrences after (chemo)radiation in patients with MIBC, and a positive test was strongly associated with future recurrences. Although validation in a large cohort is warranted, the test has the potential to limit frequent cystoscopies. Patient summary: Radiotherapy is a bladder-sparing treatment in patients with bladder cancer. After treatment, these patients undergo visual inspection of the bladder by cystoscopy to detect possible recurrences. However, interpretation of cystoscopy is difficult due to the effects of radiation on the bladder lining. Hence, we analyzed the diagnostic value of a molecular urine test to detect recurrent disease in bladder cancer patients treated by radiotherapy, and we showed that the urine test has the potential to limit the number of cystoscopies.

Using MRI to measure position and anatomy changes and assess their impact on the accuracy of hyperthermia treatment planning for cervical cancer.

PURPOSE: We studied the differences between planning and treatment position, their impact on the accuracy of hyperthermia treatment planning (HTP) predictions, and the relevance of including true treatment anatomy and position in HTP based on magnetic resonance (MR) images. MATERIALS AND METHODS: All volunteers were scanned with an MR-compatible hyperthermia device, including a filled waterbolus, to replicate the treatment setup. In the planning setup, the volunteers were scanned without the device to reproduce the imaging in the current HTP. First, we used rigid registration to investigate the patient position displacements between the planning and treatment setup. Second, we performed HTP for the planning anatomy at both positions and the treatment mimicking anatomy to study the effects of positioning and anatomy on the quality of the simulated hyperthermia treatment. Treatment quality was evaluated using SAR-based parameters. RESULTS: We found an average displacement of 2 cm between planning and treatment positions. These displacements caused average absolute differences of ∼12% for TC25 and 10.4%-15.9% in THQ. Furthermore, we found that including the accurate treatment position and anatomy in treatment planning led to an improvement of 2% in TC25 and 4.6%-10.6% in THQ. CONCLUSIONS: This study showed that precise patient position and anatomy are relevant since these affect the accuracy of HTP predictions. The major part of improved accuracy is related to implementing the correct position of the patient in the applicator. Hence, our study shows a clear incentive to accurately match the patient position in HTP with the actual treatment.

A patterns of care analysis of hyperthermia in combination with radio(chemo)therapy or chemotherapy in European clinical centers.

PURPOSE: The combination of hyperthermia (HT) with radio(chemo)therapy or chemotherapy (CT) is an established treatment strategy for specific indications. Its application in routine clinical practice in Europe depends on regulatory and local conditions. We conducted a survey among European clinical centers to determine current practice of HT. METHODS: A questionnaire with 22 questions was sent to 24 European HT centers. The questions were divided into two main categories. The first category assessed how many patients are treated with HT in combination with radio(chemo)therapy or CT for specific indications per year. The second category addressed which hyperthermia parameters are recorded. Analysis was performed using descriptive methods. RESULTS: The response rate was 71% (17/24) and 16 centers were included in this evaluation. Annually, these 16 centers treat approximately 637 patients using HT in combination with radio(chemo)therapy or CT. On average, 34% (range: 3-100%) of patients are treated in clinical study protocols. Temperature readings and the time interval between HT and radio(chemo)therapy or CT are recorded in 13 (81%) and 9 (56%) centers, respectively. The thermal dose quality parameter "cumulative equivalent minutes at 43 °C" (CEM43°C) is only evaluated in five (31%) centers for each HT session. With regard to treatment sequence, 8 (50%) centers administer HT before radio(chemo)therapy and the other 8 in the reverse order. CONCLUSION: There is a significant heterogeneity among European HT centers as to the indications treated and the recording of thermometric parameters. More evidence from clinical studies is necessary to achieve standardization of HT practice.

Avoiding Pitfalls in Thermal Dose Effect Relationship Studies: A Review and Guide Forward.

The challenge to explain the diffuse and unconclusive message reported by hyperthermia studies investigating the thermal dose parameter is still to be unravelled. In the present review, we investigated a wide range of technical and clinical parameters characterising hyperthermia treatment to better understand and improve the probability of detecting a thermal dose effect relationship in clinical studies. We performed a systematic literature review to obtain hyperthermia clinical studies investigating the associations of temperature and thermal dose parameters with treatment outcome or acute toxicity. Different hyperthermia characteristics were retrieved, and their influence on temperature and thermal dose parameters was assessed. In the literature, we found forty-eight articles investigating thermal dose effect relationships. These comprised a total of 4107 patients with different tumour pathologies. The association between thermal dose and treatment outcome was the investigated endpoint in 90% of the articles, while the correlation between thermal dose and toxicity was investigated in 50% of the articles. Significant associations between temperature-related parameters and treatment outcome were reported in 63% of the studies, while those between temperature-related parameters and toxicity were reported in 15% of the studies. One clear difficulty for advancement is that studies often omitted fundamental information regarding the clinical treatment, and among the different characteristics investigated, thermometry details were seldom and divergently reported. To overcome this, we propose a clear definition of the terms and characteristics that should be reported in clinical hyperthermia treatments. A consistent report of data will allow their use to further continue the quest for thermal dose effect relationships.

Patient-derived breast model repository, a tool for hyperthermia treatment planning and applicator design.

OBJECTIVE: The addition of hyperthermia in the treatment of intact breast cancer with the aim to improve local response is currently in a research phase. First, optimal hyperthermia devices need to be developed, for which a diverse, anatomically and pathologically accurate set of patient models is necessary. METHODS: To investigate the effects of inter-subject variations on hyperthermia treatment plans, we generated a repository of 22 anatomically and pathologically diverse patient models based on MR images of breast cancer patients. Hyperthermia treatment plans were generated for the 22 models using a generic theoretical phased array hyperthermia applicator. RESULTS: Good temperature coverage was achieved in the vast majority of the models, with median values for T10 = 43.5°C (41.9-43.8°C), T50 = 42.5°C (41.3-43.3°C), and T90 = 41.3°C (39.8-42.6°C) under the condition that the maximum temperature increase in the patient is limited to 44°C. CONCLUSIONS: For future development of hyperthermia devices and treatment methods, a repository with a sufficiently large number of representative patient models, such as the one provided in this study, should be used to ensure applicability to a wide variety of patients. This repository is therefore made publicly available.

Bladder-sparing (chemo)radiotherapy in elderly patients with muscle-invasive bladder cancer: a retrospective cohort study.

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.

POD-Kalman filtering for improving noninvasive 3D temperature monitoring in MR-guided hyperthermia.

BACKGROUND: During 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. PURPOSE: This 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. METHODS: The 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. RESULTS: First, 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. CONCLUSIONS: We 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.

A Multicenter Retrospective Cohort Series of Muscle-invasive Bladder Cancer Patients Treated with Definitive Concurrent Chemoradiotherapy in Daily Practice.

Background: Concurrent chemoradiotherapy (CRT) as a definitive treatment option for patients with nonmetastatic muscle-invasive bladder carcinoma (MIBC) is increasingly being applied in clinical practice. Objective: To assess the oncological and toxicity outcomes in a contemporary cohort of nonmetastatic MIBC patients treated with concurrent CRT in daily practice. Design setting and participants: Patients with nonmetastatic MIBC (cT2-4aN0M0) who had received CRT with curative intent between January 2010 and April 2020 in three centers were retrospectively identified. The CRT consisted of 66 Gy (or biologically equivalent) plus either mitomycin C and fluorouracil/capecitabine or cisplatinum. Outcome measurements and statistical analysis: The primary endpoint was the 2-yr locoregional disease-free survival (LDFS) estimate. Secondary endpoints were complete response, disease-specific survival (DSS), overall survival (OS), bladder intact event-free survival (BI-EFS), and severe adverse events (<90 d of starting CRT). Kaplan-Meier survival and Cox multivariable regression analyses were performed. Results and limitations: We included data of 240 MIBC patients with a median age of 74 yr and a median follow-up of 27 mo (interquartile range 11-44). Complete response on first cystoscopy after CRT was seen in 209 cases (90%). The 2-yr LDFS was 76% (95% confidence interval [CI] 70-82%); the 5-yr OS and DSS were 50% (95% CI 42-59%) and 70% (95% CI 62-79%), respectively. On multivariable analysis, cT2 versus cT3-4 tumor stage was significantly associated with better DSS (hazard ratio 1.02, 95% CI 1-1.05, p = 0.024). The 2-yr BI-EFS was 75% (95% CI 69-82%). Forty-three (17%) patients experienced a severe adverse event (grade ≥3). Limitations include retrospective design and heterogeneous administration of CRT. Conclusions: Concurrent CRT is a safe and effective treatment modality for nonmetastatic MIBC. Patient summary: Chemoradiotherapy for the treatment of muscle-invasive bladder carcinoma is increasingly being applied. In this study, we reviewed the outcomes of this bladder-sparing treatment using a series of patients treated in three hospitals in daily practice. We found that administration of chemoradiotherapy can be safe and effective.

Feasibility, SAR Distribution, and Clinical Outcome upon Reirradiation and Deep Hyperthermia Using the Hypercollar3D in Head and Neck Cancer Patients.

(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.

Treatment of early-stage breast cancer with percutaneous thermal ablation, an open-label randomised phase 2 screening trial: rationale and design of the THERMAC trial.

INTRODUCTION: Breast 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 ANALYSIS: The 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 DISSEMINATION: This 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 NUMBER: NL9205 (www.trialregister.nl); Pre-results.

MR Thermometry Accuracy and Prospective Imaging-Based Patient Selection in MR-Guided Hyperthermia Treatment for Locally Advanced Cervical Cancer.

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.

Accuracy of dwell position detection with a combined electromagnetic tracking brachytherapy system for treatment verification in pelvic brachytherapy.

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 <1 mm in all cases. CONCLUSION: Dwell position detection with the combined system in interstitial catheters is sufficiently accurate to perform EMT-based treatment verification. The effect of EM interference from the surrounding equipment was limited.

Clinical Performance and Future Potential of Magnetic Resonance Thermometry in Hyperthermia.

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.

Impact of Number of Segmented Tissues on SAR Prediction Accuracy in Deep Pelvic Hyperthermia Treatment Planning.

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.

A multi-institution study: comparison of the heating patterns of five different MR-guided deep hyperthermia systems using an anthropomorphic phantom.

INTRODUCTION: Within the hyperthermia community, consensus exists that clinical outcome of the treatment radiotherapy and/or chemotherapy plus hyperthermia (i.e. elevating tumor temperature to 40 - 44 °C) is related to the applied thermal dose; hence, treatment quality is crucial for the success of prospective multi-institution clinical trials. Currently, applicator quality assurance (QA) measurements are implemented independently at each institution using basic cylindrical phantoms. A multi-institution comparison of heating quality using magnetic resonance thermometry (MRT) and anatomical representative anthropomorphic phantoms provides a unique opportunity to obtain novel QA insights to facilitate multi-institution trial evaluation. OBJECTIVE: Perform a systematic QA procedure to compare the performance of MR-compatible hyperthermia systems in five institutions. METHODS AND MATERIALS: Anthropomorphic phantoms, including pelvic and spinal bones, were produced. Clinically relevant power of 600 watts was applied for ∼12 min to allow for 8 sequential MR-scans. The 3D-heating distribution, steering capabilities, and presence of off-target heating were analyzed. RESULTS: The evaluated devices show comparable heating profiles for centric and eccentric targets. The differences observed in the 3D-heating profiles are the result of variations in the exact phantom positioning and applicator characteristics, whereby positioning of the phantom followed current ESHO-QA guidelines. CONCLUSION: Anthropomorphic phantoms were used to perform QA-measurements of MR-guided hyperthermia systems operating in MR-scanners of different brands. Comparable heating profiles are shown for the five evaluated institutions. Subcentimeter differences in position substantially affected the results when evaluating the heating patterns. Integration of advanced phantoms and precise positioning in QA-guidelines should be evaluated to guarantee the best quality patient care.

Standardization of patient modeling in hyperthermia simulation studies: introducing the Erasmus Virtual Patient Repository.

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.

Quantitative, Multi-institutional Evaluation of MR Thermometry Accuracy for Deep-Pelvic MR-Hyperthermia Systems Operating in Multi-vendor MR-systems Using a New Anthropomorphic Phantom.

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-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 ± standard deviation) of 0.97 ± 0.03 and 0.97 ± 0.02, respectively for centric and eccentric heating targets. The RMSE was found to be 0.52 ± 0.31 °C and 0.30 ± 0.20 °C, respectively. The Bland-Altman evaluation showed a mean difference of 0.46 ± 0.20 °C and 0.13 ± 0.08 °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.

Confirmation of thermal dose as a predictor of local control in cervical carcinoma patients treated with state-of-the-art radiation therapy and hyperthermia.

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.

Ex vivo assays to predict enhanced chemosensitization by hyperthermia in urothelial cancer of the bladder.

INTRODUCTION: Bladder 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°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 METHODS: The 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). RESULTS: Hyperthermia 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. CONCLUSION: The 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.