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.

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.

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 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.

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.

Systematic quality assurance of the BSD2000-3D MR-compatible hyperthermia applicator performance using MR temperature imaging.

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.

Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies.

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.

The effect of thermal dose on hyperthermia-mediated inhibition of DNA repair through homologous recombination.

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.

Hyperthermia by electromagnetic fields to enhanced clinical results in oncology.

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.

Phase I study of cisplatin, hyperthermia, and lapatinib in patients with recurrent carcinoma of the uterine cervix in a previously irradiated area.

BACKGROUND: Patients with recurrent cervical cancer in a previously irradiated area might benefit from cisplatin combined with hyperthermia. Lapatinib inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and HER2. Overexpression of EGFR and HER2 is frequently seen in patients with cervical cancer and is potentially involved in chemotherapy resistance. In addition, preclinical data suggest a synergistic effect of combining cisplatin and lapatinib. Consequently, this phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of lapatinib added to fixed doses of cisplatin and hyperthermia. METHODS: Eight patients with previously irradiated recurrent cervical carcinoma were enrolled and scheduled for 6 weekly administrations of 70 mg/m(2) cisplatin combined with locoregional hyperthermia. Hyperthermia consisted of the achievement of intraluminal temperatures of 40-43°C as homogeneously as possible over 60 minutes. Daily lapatinib was added on days 1-56, starting with a dose level of 1,000 mg. The MTD was defined as the highest dose at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT). DLT was defined as grade 4 neutropenia lasting >7 days, febrile neutropenia grade ≥3, grade 4 thrombocytopenia, grade ≥2 renal toxicity, postponement of cisplatin and hyperthermia for ≥2 weeks, or grade ≥3 nonhematologic adverse events except for nausea or vomiting, diarrhea, or skin toxicity, for which the following DLT definitions were applied: grade ≥3 persistent nausea or vomiting or diarrhea despite optimal medical treatment or grade 4 skin toxicity. Safety, pharmacodynamics, and response were assessed. RESULTS: The first two patients of both the 1,000- and 750-mg dose level experienced DLTs. Of the four patients treated at dose level -2 (500 mg), only one patient was able to complete the treatment as planned, two patients experienced a DLT, and one patient was not evaluable because of early progressive disease. In the evaluable patients, one patient with progressive disease, four patients with stable disease, and two patients with partial response were observed. One patient with a partial response had a resection of the local recurrence. Pathological analysis showed a complete pathological response. Enumeration of circulating endothelial cells measured at baseline and during therapy did not show consistent results. The same applied for the pharmacodynamic effects on Ki-67, p27Kip1, and EGFR in pretreatment and on-therapy skin biopsies. CONCLUSION: It is not feasible to combine lapatinib with fixed doses of cisplatin and hyperthermia in patients with recurrent cervical carcinoma in a previously irradiated area mainly because of increased cisplatin-related toxicity. The observed complete pathological response is intriguing and warrants further investigation of combinations consisting of HER2 blockade and cisplatin plus hyperthermia.

Results of concurrent chemotherapy and hyperthermia in patients with recurrent cervical cancer after previous chemoradiation.

BACKGROUND: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation. OBJECTIVE: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin. METHODS: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant. RESULTS: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27-74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3-4 haematological complications did not exceed 10%. CONCLUSION: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical cancer.

Review of radiotherapy and hyperthermia in primary cervical cancer.

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.

Neoadjuvant chemotherapy followed by radiotherapy and concurrent hyperthermia in patients with advanced-stage cervical cancer: a retrospective study.

OBJECTIVE: To evaluate the efficacy of neoadjuvant chemotherapy, followed by radiotherapy and concurrent hyperthermia (triple therapy) in patients with advanced-stage cervical cancer. METHODS: We selected 43 patients from our hyperthermia database, who were treated from 1996 to 2010 with triple therapy for large primary tumours (>6 cm) or para-aortic lymph node metastases. All patients received platinum-based chemotherapy followed by full-dose radiotherapy, brachytherapy and five hyperthermia treatments. The response was evaluated by gynaecological examination and a CT-scan. Time-to-event variables were estimated using the Kaplan Meier method and the Cox regression method. RESULTS: The mean age of the patients was 50.4 years (range 29-80). The median tumour size was 5.6 cm at diagnosis (range 2.6-8.2), positive lymph nodes were present in 90.7%. A total of 67% of the patients completed all six planned courses of chemotherapy. After completion of neoadjuvant chemotherapy, 83.7% of patients achieved a complete or partial response. At the end of treatment, the complete response rate was 81.4% (95%CI 69.2-93.5). Grade 2, 3 and 4 acute vascular toxicity occurred in 17 patients. The incidence of grade 3-4 haematological toxicity did not exceed 10% and no neutropenic fever occurred. For grade 1-2 renal toxicity, a switch to carboplatin was made (n = 6). No acute grade 3-4 renal toxicity was observed. No treatment-related deaths were recorded. The median follow-up time was 29.8 months (range 4.1-124.8). Overall survival rate at 12 months was 79% (95%CI 57.4-92.3). CONCLUSION: The triple therapy seems feasible and effective in the treatment of advanced-stage, high-risk cervical cancer. However, chemotherapy-induced vascular toxicity occurred frequently, which may warrant the use of prophylactic anticoagulants. We recommend a phase II trial for prospective confirmation for comparison with standard chemoradiation and the use of anticoagulants.

Implementation of treatment planning in the routine clinical procedure of regional hyperthermia treatment of cervical cancer: an overview and the Rotterdam experience.

PURPOSE: 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. STEERING STRATEGIES: 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. CONCLUSIONS: 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.

Clinical implementation of hyperthermia treatment planning guided steering: A cross over trial to assess its current contribution to treatment quality.

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.

Use of combined radiation and hyperthermia for gynecological cancer.

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.