Richard Canters

Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermia

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.

Simulation techniques in hyperthermia treatment planning

Abstract Clinical trials have shown that hyperthermia (HT), i.e. an increase of tissue temperature to 39–44 °C, significantly enhance radiotherapy and chemotherapy effectiveness [1]. Driven by the developments in computational techniques and computing power, personalised hyperthermia treatment planning (HTP) has matured and has become a powerful tool for optimising treatment quality. Electromagnetic, ultrasound, and thermal simulations using realistic clinical set-ups are now being performed to achieve patient-specific treatment optimisation. In addition, extensive studies aimed to properly implement novel HT tools and techniques, and to assess the quality of HT, are becoming more common. In this paper, we review the simulation tools and techniques developed for clinical hyperthermia, and evaluate their current status on the path from ‘model’ to ‘clinic’. In addition, we illustrate the major techniques employed for validation and optimisation. HTP has become an essential tool for improvement, control, and assessment of HT treatment quality. As such, it plays a pivotal role in the quest to establish HT as an efficacious addition to multi-modality treatment of cancer.

Radiotherapy and Hyperthermia for Treatment of Primary Locally Advanced Cervix Cancer: Results in 378 Patients

PURPOSE To report response rate, pelvic tumor control, survival, and late toxicity after treatment with combined radiotherapy and hyperthermia (RHT) for patients with locally advanced cervical carcinoma (LACC) and compare the results with other published series. METHODS AND MATERIALS From 1996 to 2005, a total of 378 patients with LACC (International Federation of Gynecology and Obstetrics Stage IB2-IVA) were treated with RHT. External beam radiotherapy (RT) was applied to 46-50.4 Gy and combined with brachytherapy. The hyperthermia (HT) was prescribed once weekly. Primary end points were complete response (CR) and local control. Secondary end points were overall survival, disease-specific survival, and late toxicity. Patient, tumor, and treatment characteristics predictive for the end points were identified in univariate and multivariate analyses. RESULTS Overall, a CR was achieved in 77% of patients. At 5 years, local control, disease-specific survival, and incidence of late toxicity Common Terminology Criteria for Adverse Events Grade 3 or higher were 53%, 47%, and 12%, respectively. In multivariate analysis, number of HT treatments emerged as a predictor of outcome in addition to commonly identified prognostic factors. CONCLUSIONS The CR, local control, and survival rates are similar to previously observed results of RHT in the randomized Dutch Deep Hyperthermia Trial. Reported treatment results for currently applied combined treatment modalities (i.e., RT with chemotherapy and/or HT) do not permit definite conclusions about which combination is superior. The present results confirm previously shown beneficial effects from adding HT to RT and justify the application of RHT as first-line treatment in patients with LACC as an alternative to chemoradiation.

Quality assurance for clinical studies in regional deep hyperthermia

BackgroundA guideline is provided for the implementation of regional deep hyperthermia treatments under strict rules of quality assurance. The objective is to guarantee a comparable and comprehensible method in the treatment and scientific analysis of hyperthermia. The guideline describes regional deep hyperthermia (RHT) and MR-controlled partial body hyperthermia (PBH) of children, young and adult patients. According to this guideline, hyperthermia treatment is always applied in combination with chemotherapy and/or radiotherapy.MethodsThe guideline is based on practical experience from several hyperthermia centers. The procedure allows applying jointly coordinated standards and quality control in hyperthermia for studies.ResultsThe guideline contains recommendations for hyperthermia treatments, including indication, preparation, treatment, and standardized analysis.HintergrundZur Durchführung von qualitätsgesicherten Tiefenhyperthermiebehandlungen wurde eine Leitlinie erstellt. Ziel war, ein vergleichbares und nachvollziehbares Vorgehen bei der Behandlung und der wissenschaftlichen Auswertung von Hyperthermiebehandlungen zu gewährleisten. Die Leitlinie beschreibt die „Regionale Tiefenhyperthermie“ (RHT) und die „MR-kontrollierte Teilkörperhyperthermie“ (PBH) von Kindern, jugendlichen und erwachsenen Patienten. Hyperthermie im Sinne der Leitlinie wird als Kombinationsbehandlung mit einer Chemo- und/oder Strahlentherapie durchgeführt.MethodikDie Leitlinie basiert auf praktischen Erfahrungen mehrerer Hyperthermiezentren. Dieses Vorgehens erlaubt abgestimmte Standards in der Anwendung und der Qualitätskontrolle in der Hyperthermie für Studien.ErgebnisseDiese Leitlinie enthält Empfehlungen für Hyperthermiebehandlungen mit Indikationsstellung, Vorbereitung, Durchführung und standardisierter Auswertung.

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°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°C after RESG and 40°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.

A literature survey on indicators for characterisation and optimisation of SAR distributions in deep hyperthermia, a plea for standardisation

Purpose: To evaluate the predictive value of SAR indicators by assessing the correlation of a SAR indicator with the corresponding predicted temperature. Ultimately, this should lead to a number of verified SAR indicators for characterization and optimization of a predicted SAR distribution. Methods: A literature survey is followed by an evaluation of the SAR indicators on their functionality, using a set of heuristic classification criteria. To obtain an objective assessment of the predictive value for SAR characterisation, all SAR indicators are evaluated by correlating the value of the SAR indicator to the predicted target temperature when heated with the BSD2000 Sigma 60 applicator. Two methods were followed. First, the specificity of the SAR indicator to target temperature was assessed for each of the 36 patient-specific models, using 30 randomly chosen phase and amplitude settings. Secondly, each SAR indicator was used as a goal function to assess its suitability for optimisation purposes. Results: Only a selected number of SAR indicators correlate well with tumour/target-temperature. Hence, for target-related properties, an adequate set of SAR indicators is found in the literature. For hotspots, modifications are desirable. For optimisation purposes, improved objective functions have been defined. Conclusions: From the correlation of the SAR indicators with tumour temperature, a preferred set of SAR indicators is derived: For target heating, ‘average SAR ratio’, ‘Hotspot-target SAR ratio’, and ‘homogeneity coefficient’ provide suitable objective criteria, while for hotspot reduction, ‘Hotspot-target SAR ratio’ is considered the most useful indicator. For optimisation procedures, ‘Hotspot-target SAR ratio’ is currently the most suitable objective function.

Clinical integration of software tool VEDO for adaptive and quantitative application of phased array hyperthermia in the head and neck.

Abstract Background and purpose: In Rotterdam, patient-specific hyperthermia (HT) treatment planning (HTP) is applied for all deep head and neck (H&N) HT treatments. In this paper we introduce VEDO (the Visualisation Tool for Electromagnetic Dosimetry and Optimisation), the software tool required, and demonstrate its value for HTP-guided online complaint-adaptive (CA) steering based on specific absorption rate (SAR) optimisation during a H&N HT treatment. Materials and methods: VEDO integrates CA steering, visualisation of the SAR patterns and mean tumour SAR (SARtarget) optimisation in a single screen. The pre-calculated electromagnetic fields are loaded into VEDO. During treatment, VEDO shows the SAR pattern, overlaid on the patients’ CT-scan, corresponding to the actually applied power settings and it can (re-)optimise the SAR pattern to minimise SAR at regions where the patient senses discomfort while maintaining a high SARtarget. Results: The potential of the quantitative SAR steering approach using VEDO is demonstrated by analysis of the first treatment in which VEDO was used for two patients using the HYPERcollar. These cases show that VEDO allows response to power-related complaints of the patient and to quantify the change in absolute SAR: increasing either SARtarget from 96 to 178 W/kg (case 1); or show that the first SAR distribution was already optimum (case 2). Conclusion: This analysis shows that VEDO facilitates a quantitative treatment strategy allowing standardised application of HT by technicians of different HT centres, which will potentially lead to improved treatment quality and the possibility of tracking the effectiveness of different treatment strategies.

Patient positioning in deep hyperthermia: influences of inaccuracies, signal correction possibilities and optimization potential

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.

Complaint-adaptive power density optimization as a tool for HTP-guided steering in deep hyperthermia treatment of pelvic tumors

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.

Guideline for the clinical application, documentation and analysis of clinical studies for regional deep hyperthermia

ObjectivesThese guidelines contain recommendations for the implementation of quality-assured hyperthermia treatments. The objective is to guarantee an internationally comparable and easily understandable method for hyperthermia treatment and for the subsequent scientific analysis of the treatment results. The guidelines describe “regional deep hyperthermia” (RHT) and MR-controlled “partial body hyperthermia” (PBH) of children, adolescents and adult patients. Hyperthermia in terms of these guidelines is defined as a treatment combining chemotherapy and/or radiation therapy.MethodsThese guidelines are based on practical experience from several hyperthermia centres in Europe. Our collaborative effort has ensured coordinated standards and quality control procedures in regional deep and partial body hyperthermia. The guidelines were developed by the Atzelsberg Research Group of the IAH (http://www.hyperthermie.org) of the German Cancer Society (“Deutsche Krebsgesellschaft”) to specifically ensure that the multi-institutional studies initiated by the Atzelsberg Research Group are executed following a single, uniform level of quality.ResultsThe guidelines contain recommendations for procedural methods for treatment using hyperthermia. They commence with diagnosis, which is followed by preparation and treatment and concludes with standardised analysis for the reporting of results.ZusammenfassungHintergrundDiese Leitlinie enthält Empfehlungen zur Durchführung von qualitätsgesicherten Hyperthermiebehandlungen. Ziel ist, ein vergleichbares und nachvollziehbares Vorgehen bei der Behandlung und der wissenschaftlichen Auswertung der Hyperthermie zu gewährleisten. Die Leitlinie beschreibt die „Regionale Tiefenhyperthermie“ (RHT) und die „MR-kontrollierte Teilkörperhyperthermie“ (PBH) von Kindern, Jugendlichen und erwachsenen Patienten. Die Hyperthermie im Sinne dieser Leitlinie wird als Kombinationsbehandlung mit einer Chemo- und/oder Strahlentherapie durchgeführt.MethodikDie vorgestellte Leitlinie basiert auf praktischen Erfahrungen von mehreren Hyperthermiezentren. Dieses Vorgehens erlaubt gemeinsam abgestimmte Standards in der Anwendung und der Qualitätskontrolle in der Hyperthermie für Studien, die im Rahmen des Atzelsberger Arbeitskreises in der Interdisziplinären Arbeitsgruppe Hyperthermie (http://www.hyperthermie.org) in der Deutschen Krebsgesellschaft und dem Technischen Komitee der „European Society for Hyperthermic Oncology“ (ESHO) entwickelt wurden, um sicher zu stellen, dass multizentrische Studien, die vom Atzelsberger Arbeitskreis entwickelt wurden, nach einem standardisierten, einheitlichen Qualitätsmaßstab durchgeführt werden.ErgebnisseDiese Leitlinie enthält Empfehlungen für das Vorgehen bei Hyperthermiebehandlungen von der Indikationsstellung, der Vorbereitung, der Durchführung bis zur standardisierten Auswertung.Die deutschsprachige Version des Beitrags ist auf SpringerLink unter „Supplemental“ zu finden.