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Quality Assurance for Clinical Studies in Regional Deep Hyperthermia Gregor Bruggmoser1*, Stefan Bauchowitz2*, Richard Canters9*, Hans Crezee3*, Michael Ehmann4*, Johanna Gellermann5*, Ulf Lamprecht6*, Nicoletta Lomax9*, Marc Benjamin Messmer1, Oliver Ott2*, Sultan Abdel-Rahman7*, Rolf Sauer2, Manfred Schmidt2*, Andreas Thomsen1, Rüdiger Wessalowski8, Gerard van Rhoon10*

Background: A 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. Methods: The guideline is based on practical experience from several hyperthermia centers. The procedure allows applying jointly coordinated standards and quality control in hyperthermia for studies. Results: The guideline contains recommendations for hyperthermia treatments, including indication, preparation, treatment, and standardized analysis. Key Words: Hyperthermia · Responsibilities · Thermometry · Radiation · Chemotherapy · Hyperthermia side effects Strahlenther Onkol 2011;187:605–10

DOI 10.1007/s00066-011-1145-x Qualitätssicherung in der regionalen Tiefenhyperthermie Hintergrund: Zur 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 „MRkontrollierte Teilkörperhyperthermie“ (PBH) von Kindern, jugendlichen und erwachsenen Patienten. Hyperthermie im Sinne der Leitlinie wird als Kombinationsbehandlung mit einer Chemo- und/oder Strahlentherapie durchgeführt. Methodik: Die Leitlinie basiert auf praktischen Erfahrungen mehrerer Hyperthermiezentren. Dieses Vorgehens erlaubt abgestimmte Standards in der Anwendung und der Qualitätskontrolle in der Hyperthermie für Studien. Ergebnisse: Diese Leitlinie enthält Empfehlungen für Hyperthermiebehandlungen mit Indikationsstellung, Vorbereitung, Durchführung und standardisierter Auswertung. Schlüsselwörter: Hyperthermie · Verantwortlichkeiten · Thermometrie · Bestrahlung · Chemotherapie · Hyperthermienebenwirkungen

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The authors of this document are also members of the ESHO Technical Committee. Department of Radiation Oncology, University Hospital of Freiburg, Germany, 2 Clinic for Radiotherapy, University Hospital Erlangen, Germany, 3 Department of Radiation Oncology, Academic Medical Center (AMC), Amsterdam, The Netherlands, 4 Department of Radiation Oncology, University Medical Center Mannheim, Germany, 5 Formerly Radiotherapy Charité University Clinic, Germany, 6 Hospital for Radiation Oncology, University Hospital of Tübingen, Germany, 7 Medical Clinic III, University Clinic Munich, Munich, Germany, 8 Clinic of Pediatric Hematology, Oncology and Clinical Immunology, University Hospital of Düsseldorf, Germany, 9 Clinic for Radiation Oncology, Cantonal Hospital Aarau, Switzerland, 10 Department of Radiation Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. 1

Received: June 17, 2011; accepted: July 4, 2011 Published Online: September 19, 2011

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Bruggmoser G, et al. QA in Regional Deep Hyperthermia

Background and Purpose

Members of the ESHO Technical Committee in the Interdisciplinary Working Group Hyperthermia (IAH) in the German Cancer Society defined an extensive guideline for regional hyperthermia as part of an overall quality assurance (QA) program in hyperthermia, which is essential for physicians, physicists, and technical personnel performing and supervising hyperthermia treatments [19]. The objective is to guarantee an acceptable quality level as well as a comparable and traceable method when applying hyperthermia in clinical studies. The premise of this QA guideline program is that the effectiveness of hyperthermia as proven in several clinical studies relies exclusively on its thermal effect on tumors, [15, 16, 17, 28, 30, 31]. For this reason, it is mandatory that hyperthermia treatments are performed by devices that are technically capable of delivering selective and controlled heating to a predefined target volume, while causing minimal heating of normal tissue at the same time. Technically the most indicated method to achieve such preferential heating is by using radiating and focusing electromagnetic waves to the target volume. In addition, recording the temperature in the target volume directly or in the surrounding, tumor indicative, tissue is essential for an adequate evaluation of the treatment quality. In terms of this guideline, any other devices which technically do not fulfill the requirements for hyperthermia systems, e.g., temperatures in the target volume between 40 and 43 °C for at least 60 min or not capable of measuring the temperatures at the described locations, should not be used for hyperthermia treatment. The current publication provides a short version of the quality assurance guideline for the clinical application of regional deep hyperthermia (RHT) and MR-controlled partial body hyperthermia (PBH) in adult patients in a combined treatment using chemo- and/or radiation therapy [6, 22, 23, 24, 25, 27]. This shortened document focuses on the main responsibilities and technological requirements for clinical application of regional deep hyperthermia according to the QA guidelines. The full version of the guideline is available on the webpage of the IAH (www.hyperthermie.org) in German and English (both will be published as a supplementary document in Strahlentherapie und Onkologie [1]). It also provides a partial update of the ESHO quality assurance guidelines for regional hyperthermia of 1998 [19]. Responsibilities for the Indication, Planning, Treatment, and Documentation

The physician is responsible for the indication for hyperthermia treatment, taking into account inclusion and exclusion criteria, based on medical history and patient information. This is defined in the relevant study protocol. Hyperthermia is a multidisciplinary method based on medical and technical aspects. It involves various professional groups, radiooncologists, medical oncologists, medical physi-

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cists, engineers, as well as technical staff, nurses, and personnel required for special applications. Hyperthermia treatments are always performed under the medical responsibility of a qualified physician. A qualified physicist or engineer is responsible for the physical–technical aspects of hyperthermia, including QA and hyperthermia planning (HTP). Two qualified persons must be present during treatment. In principle, the following guidelines must be considered:  Guidelines of WHO (www.who.int),  Guidelines of DEGRO (www.degro.org),  Guidelines of ESHO (www.esho.info),  Declaration of Helsinki (www.wma.net), and  good clinical practice (GCP) (www.emea.eu.int). Quantities and Units

Measuring temperature is of great significance and is at the present time still the most reliable method to record and verify whether the therapeutically required temperatures are obtained in the target volume. At the same time, these measured temperatures provide important information when evaluating whether undesired hot spots in the normal tissue could be avoided. Temperature probes are preferentially placed in the target volume or in the vicinity of the target volume in order to acquire tumor-related temperatures. To preserve healthy tissue and possible risk organs, other probes are placed appropriately, including a record of the systemic temperature [2, 4, 8]. Relevant parameters for determining the quality of the hyperthermia are  TD43(T90) or CEM43 [T90] in min,  TD43(T50) or CEM43 [T50] in min, and  Tmean, Tmin, Tmax, T90, T50, T20, T10 in °C. The parameter relevant for sparing healthy tissue is  Tmax in normal tissue in °C. Treatment

Only devices that are technically capable of achieving controlled heating in a target volume, while simultaneously sparing normal tissue, may be used for hyperthermia treatments. For the Western patient, who has gained weight at the abdominal wall, hips, or buttocks exceeding 2 cm thickness, these above mentioned requirements are technically best achieved when spatial power control is used, guided by active thermometry in the target volume. Hence, the QA document concentrates on the application of regional deep hyperthermia applied by such systems and the examples given in this document refer to those phased array systems currently used by the majority of the active hyperthermia groups within an academic environment.

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During the hyperthermia treatment, temperatures must be measured intraluminally or intratumorally as prescribed in the treatment plan. At the same time, areas at risk must be defined and protected. A procedure must be specified by the physician how to handle the situation in case of complaints, e.g., if hot spots occur during therapy. Three-dimensional (3D) images (MRI, CT, US) or orthogonal x-rays must be taken to prepare for treatment. The patient must be positioned before treatment according to the imaging in a reproducible manner in the applicator [3]. Furthermore, imaging is used to localize metallic implants (hips, stents, clips) inside and outside the treatment volume [20]. In principle, metal implants should be regarded as a contraindication for hyperthermia treatments induced with electromagnetic energy. Experience exists that in specific cases when the metal implant is small ( 38 °C). The patient must be able to communicate during treatment. Because of claustrophobia, some patients cannot tolerate therapy in the ring applicator for 1 hour or longer. This can be tested in advance by positioning the patient in the applicator. Positioning the Patient

A basic requirement for using optimized control parameters (phase, power) is the reproducible position of the patient with respect to the applicator. The patient should preferably be positioned identically from treatment to treatment, with the hyperthermia target point within the active area of the applicator [3, 9]. For treatments, the dorsoventral diameter of the patient should fit into the applicator. Furthermore, the surface–appli-


cator distance should be ≥ 5 cm for all applications. The applicator edges should be marked on the patient. The craniocaudal position of the applicators in relation to the hyperthermia target point is specified by 3D imaging. The dorsoventral positioning depends on the type of the applicator and must be described in detail. Bolus Control

The water in the bolus should be kept at room temperature. Cooling of the surface for instance to 25 °C (a range of 21–28 °C is common) must be guaranteed for adequate removal of the heat load from the patient. When the target volume includes the body surface, care should be taken to keep the whole tumor at therapeutic temperature, i.e., local cooling may not be necessary. Temperature Measurements Invasive Thermometry

Positioning Thermometry Catheters: All measurement catheters (skin, endoluminal probes) are placed by the physician or nursing staff. At least one probe must be positioned either inside or close to the target volume of the tumor. Invasive temperature measurement catheters are placed under imaging control. Using Temperature Probes: The temperature probes used should not interfere with the electromagnetic field. For other sensors, an on/off cycle must be applied to avoid erroneous temperature readings [21, 32]. The thermometry system must be calibrated against a traceable national standard. Usually, measurements are taken at various specific predefined positions applying a mapping method, or multiple sensors are applied. In case of MR thermometry, additional thermometry must be performed with probes in a similar procedure as in hyperthermia without MR thermometry. Thermal Mapping: Temperature measurement using thermal mapping, i.e., moving the temperature probe within the thermometry catheter through the treatment volume, must be performed under specified conditions. As a reference level, a first mapping must always be recorded with power off before starting the treatment. The time interval for thermal mapping during treatment, i.e., with power on condition, is commonly between 5 and 10 min, and the mapping length should be as long as possible, usually up to 16 cm. Non-Invasive MR Thermometry

When applying hyperthermia in a hybrid system with MR thermometry, measurements must be carried out at regular time intervals (e.g., every 10 min) in the volume to be heated [10, 11, 12, 14, 18, 26]. For the pelvis and thigh regions, PRFS measurement by means of uncorrected phase images of a gradient-echo sequence of two echo periods, and subsequent drift compensation is often suitable.

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T1 measurements or a spectroscopic method may be used, if high fat content regions are measured. To minimize the influence of moving organs, suitable triggering is used, for example, during a breath-hold cycle, or the temperature measurement is reduced to a smaller volume area. The T2 fat saturated measurement with high resolution imaging in different slices before and after the therapy is helpful when possible subcutaneous burns should be detected. E-Field Probes

E-field probes may also be used for treatment control, but it is necessary to be particularly precise when positioning both the patient and the probes. For all applicators, it is important to align the E-field probes with the longitudinal axis of the applicator. Temperature Objectives during Treatment

Temperature limitations for hyperthermia are for normal tissue the maximum temperature and for the hyperthermia target volume the minimum temperature and the duration of the treatment. To prevent acute toxicity, the general objective is to avoid that the temperature exceeds 43 °C in normal tissue. In hyperthermia target volumes, the maximum temperature should not be higher than 44 °C for a certain period. A detailed specification of the maximum and minimum temperatures for individual areas and organs is defined in the study protocol. Treatment Time

The treatment time consists of the  heating-up time: max. 30 min or when the target temperature as prescribed in the study protocol is reached, and  therapy time: 60 min. Amplitude and Phase Control (SAR Steering)

With specific settings for frequency, phase, and amplitude, focusing of the electromagnetic fields in the treatment volume is achieved and will result in selective heating without overheating the surrounding normal tissue [4, 5, 29]. Hyperthermia treatment planning (HTP) can be carried out to find the primary settings for power, phase, and amplitude. Without HTP, the applicator settings for a SAR focus at the center of the applicator is used (i.e., offset settings to move the SAR to the center of the applicator). The target point is taken from 3D imaging. A further possibility is the setting guided by using E-field probes. Procedure to Increase the Target Temperature

The goal for an effective hyperthermia treatment is to apply the highest therapeutic temperature which is tolerable for the patient [9, 29]. This requires an appropriate level of power input at the start and during treatment as well as adequate energy steer-

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ing on patient complaints. To achieve this aim, the following is recommended:  1st treatment: start with about 1/3 to 2/3 of the expected power needed to adequately heat a tumor at the specific localization and applied applicator position.  2nd treatment onward, adapt the parameters from the experience of the prior treatments.  Power should be increased in case of a temperature increase of less than 0.6 °C in 5 min. A temperature increase of 1 °C in 5 min is optimal; increases of more than 2 °C in 5 min should be avoided. Instructions for Complaints during Treatment

In case of complaints, the power must be shut off immediately to determine whether the pain is caused by the applied RF power. If an improvement is realized within 30 s, one can assume that the complaint is power related and the control parameters (focus, amplitude, power) should be adapted to reduce energy deposition at the complaint area. If the pain is not reduced 30–60 s after RF power is turned off, it can be assumed that the pain is caused by the tumor or the positioning of the patient in the applicator and, therefore, pain medication may be given. Alternatively, the patient could be repositioned and water bags may be applied for complaints that affect surface regions [29]. Documentation and Analysis

Accurate and reliable documentation is critical for the evaluation and analyses of any clinical hyperthermia study. This requires that all the parameters that characterize the quality of the hyperthermia treatment are recorded and stored according to the instructions mentioned in the main quality assurance guideline and in the study protocol. For tumor response and toxicity follow-up, the evaluation procedure as defined in the study should be followed with regard to the following points:      

radiological response (RECIST), complete tumor response (CR) local tumor progression (LP), time to progression (TTP), overall survival (OS), and acute or late toxicity. Physical–Technical Documentation

All treatment-relevant control parameters of the system (e.g., power and phase) and all temperature measurement values must be documented in a manner that they can be related to the measurement location or catheter. Changes of the control parameters must be stored with chronological and clinical reference. Furthermore, logging is necessary for treatment interruptions or stopping, unplanned temperatures, power or water pressure-dependent pain or pain caused by positioning.



Clinical Documentation

In particular, the clinical documentation describes medication, given cytostatics, clinical parameters of the patient, and side effects caused by the therapy. All changes and events must be documented with a chronological reference to the hyperthermia treatment. Side Effects

Hyperthermia is not a separate therapy but supplements systemic chemotherapy or radiation therapy. Side effects of the combined treatment correspond primarily to the spectrum of side effects of the chemotherapy or radiation therapy in the sense that the side effects of the primary therapy can be intensified by the tissue heating during hyperthermia. Possible skin changes should be documented, if possible during or at the latest after terminating treatment. Classifying the degree of severity should follow the internationally established scores:  CTCAE V4.03 for chemotherapy-associated side effects, and  RTOG V2.0 for radiation-specific side effects. Hyperthermia-Specific Side Effects

Side effects that are specifically caused by the hyperthermia treatment should be recorded. Unwanted higher temperature in the skin or healthy tissue is the main risk, which is significantly increased in patients with disturbed temperature sensitivity, for example, in polyneuropathy. Low-grade high temperatures are accompanied with false sensations or pain and skin irritation and/or local edema. In case of sustained overheating of tissue, depending on the severity, tissue damage and necrosis may result. The temperature threshold for such irreversible damage is 44–46 °C depending on tissue type [13, 33]. Standardized Analysis of Treatment Data

In order to create comparable analyses for all study participants, the relevant data are extracted from the stored values and analyzed using standard software, e.g., RHyThM (Rotterdam Hyperthermia Thermal Modulator) [7]. A significant feature of the software is the allocation of treated organs/tissue and the normal tissue to the determined thermal data. The program calculates and documents all necessary thermal dose parameters (e.g., Tmax, Tmean, T20/50/90, CEM43T90), the applicator control parameter, and the therapy period. If temperature is measured only on the skin’s surface, only Tmin and Tmax must be stated. Conclusion

The guideline contains recommendations for methods in treating tumors with hyperthermia. The whole procedure is described, starting with the indication, preparation, treatment, and documentation, including standardized analysis of the results.


Acknowledgments

The authors thank the members of the Atzelsberg Clinical Circle of the IAH for their constructive comments and their continuous stimulation to prepare the quality assurance document for regional deep hyperthermia. The authors have no financial interest in any company selling hyperthermia equipment. The opinion of the authors is solely based upon the available scientific knowledge and their personal experience in the clinical application of hyperthermia.

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Address for Correspondence Dr. Gregor Bruggmoser Klinik für Strahlenheilkunde Universitätsklinkum Freiburg Robert-Koch-Straße 3 79106 Freiburg Germany Phone: (+49/761) 270-94790, Fax: -95530 e-mail: [email protected]
