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

Abstract

Objectives

These 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.

Methods

These 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.

Results

The 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.

Zusammenfassung

Hintergrund

Diese 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.

Methodik

Die 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.

Ergebnisse

Diese 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.

7 Appendix

7.1 Applicator requirements

7.1.1 Minimum requirements

An applicator for deep hyperthermia has to meet certain requirements with regard to the characteristics of the energy distribution in order to have the basic ability to provide preferential heat to tumours located centrally in the human body. Ideally, the energy deposition in the target volume is higher than the energy deposition in healthy tissue. To obtain this feature, focusing of the energy distribution is essential as well as the ability to steer the focus. Based on phantom results a minimum ratio of energy deposition in the target (SAR_target) and energy deposition in the healthy tissue (SAR_non-target) is defined [5].

A proposal for three conditions for a standardised hyperthermia test phantom for the checking of applicator characteristics in the range 75–140 MHz is as follows:

• phantom of diameter 20 cm and length 60 cm,

• abdomen-equivalent tissue material (2 g/l NaCl in distilled water), i.e. effective conductivity (σ) 0.32 S/m at 20 °C and relative dielectric permittivity (ε_r) 80 and

• definition of a centrally located cylindrical target volume of diameter 5 cm and length 10 cm, with the axial orientation of the target similar to that of the phantom.

Each applicator used in deep hyperthermia must be able to reach an average SAR level inside the target volume that is higher than the average SAR level in the whole phantom. Hence, for any applicator the ratio of SAR_target and SAR_nontarget in the phantom must be minimally above 1.5 in order to be considered as an applicator feasible to induce deep heating in the pelvic and abdominal regions. Whether an applicator fulfils this minimum criterion can be checked by measurements and simulations using the standardised hyperthermia test phantom, appropriate measuring devices and a QA protocol such as defined by the European Society for Hyperthermic Oncology (ESHO). The Rotterdam group calculated the ratio of SAR_target and SAR_nontarget in the phantom for the Sigma 60 and Sigma Eye applicators and found values of 3.0 and 4.3, respectively.

7.1.2 Requirements for clinical hyperthermia treatments

It is not possible to extract guidelines for hot spot levels from phantom measurements. To set a minimum requirement, the authors have therefore chosen a requirement based on current practice with the most frequently used device for deep hyperthermia, i.e. the Sigma 60, with which more than 5,000 patients have been treated with deep hyperthermia in Europe. For this device, the Rotterdam group has analysed their extensive modelling in 10 patients with locally advanced cervical cancer. This analysis provides sufficient data to select a maximum permitted SAR level for hot spots in healthy tissue in order to apply deep hyperthermia at an acceptable level of quality, i.e. to measure therapeutic temperatures in the target region. For these 10 patients Manufacturers of new deep hyperthermia equipment are expected to obtain the patients models through proper procedures and to make sure that these models are representative for the average dimensions of their patient population. these values are SAR_tumor = 74 ± 32 W/kg (mean ± 1 standard deviation) and for hot spots SAR_max= 290 ± 100 W/kg (mean ± 1 standard deviation), with an input power to the Sigma 60 applicator of 700 W. In this analysis hot spots are defined as all hot spots with a total volume of 0.1% of the tissue volume (V_0.1) with the highest SAR. This leads to the conclusion that hot spot SAR levels (in the 0.1th percentile) should generally not exceed the SAR_target by a factor of 4. Applicators that meet both criteria: SAR_target> 1.5 • SAR_non-target and SAR_0.1< 4 • SAR_target are generally able to heat a patient up to therapeutic temperatures.

7.2 Minimum requirements for hyperthermia treatment planning

Treatment positions are required to coincide with the position modelled in planning (maximum deviation 1 cm) in order to reliably simulate optimum treatment parameters using computer supported hyperthermia planning (HTP) [1, 7, 33]. The positioning of the patient is described in more detail in Section 4.2.1. Furthermore, control of the radio frequency emitted from the antenna is essential with an amplitude and phase accuracy better than 5%/5° in order to guarantee reliable modelling of the power distribution with HTP. Preferably, the SAR measurement sensors or the temperature measurement using non-invasive thermometry (NIT) for feedback of the current SAR or the temperature distribution calculated with the planning system can be used.

The image of a 3D dataset for the hyperthermia planning using a CT or MRT scan must be performed, as far as possible, in the treatment position during hyperthermia. This means that the imaging must be completed for example, in the patient position grid. The layer thickness of the planning data must be selected optimally for the E-field calculation method to be used later. For example, 5 mm for finite elements (FE) with tetraedral grids, or higher resolution for FDTD.

Hyperthermia planning is started by segmenting the different tissue types. Two levels of segmentation are distinguished:

• 1. Hounsfield unit (HU) based automatic segmentation. This is based on the Hounsfield values of raw CT data records. The tissue types lung, fat, muscle and bone can be automatically segmented. The bowel volume and the organs are usually segmented as muscle.

• 2. Full organ segmentation. Additionally for the HU based automatic segmentation, the bowel and organs of the pelvis are segmented separately.

If using the FE method on tetrahedron grids, it must be guaranteed that the side length of the tetrahedrons are smaller than 1/10th of the wavelength in the tissue, e.g. 90 MHz, muscle and smaller than 3 cm. The dielectric and temperature relevant tissue properties needed for the calculations can be obtained from well documented literature sources [6, 8, 11, 12, 17, 18, 19, 23, 26, 27, 28, 37, 38] or from individual measurements (http://www.brooks.af.mil/AFRL/HED/hedr/reports/dielectric/home.html; [53, 54, 55]).

In the case of sole SAR modelling, after segmenting and calculating the electromagnetic fields, a patient-specific optimisation routine should be implemented, which maximises the SAR coverage of the target area and minimises the energy deposit in the healthy tissue. Furthermore, it should be possible to define regions in which additional specific limit values can be specified for the optimisation.

An equivalent approach is necessary for temperature modelling, which maximises the temperature in the target area and limits it in the healthy tissue to absolute maximum temperature values [27]. That is, 44 °C in healthy tissue and 42 °C in bone marrow for 30 min. Thermal and perfusion properties can be found in the literature [37, 38, 53, 54, 55]. The impact of blood flow can be incorporated using either the bioheat equation or by modelling discrete vessels [6, 12, 35, 48].

The transfer of the optimum therapy parameter for the power control should preferably occur automatically/online, in order to minimise errors. The treatment position of the patient and the therapy parameters must be adequately documented for the patient documentation (see Section 5.2).

7.3 Documentation of medical history

Example: information about disease, previous history and treatment planning

General information:

• patient identification

• date of birth

• patient identification number

Disease information:

• current disease

  • date of diagnosis: DDMMYYYY

  • examining physician

  • histology

  • medical history of current disease

    • first symptoms

    • date of first symptoms

    • duration of symptoms

    • Karnofsky status at time of diagnosis

    • previous diseases

    • other information

• family medical history (if relevant)

  • diseases suffered by family members (parents and siblings)

• co-existing diseases

  • diabetes mellitus: yes/no

  • heart disease: yes/no

    • if yes, heart failure: yes/no

  • thrombosis < 3 months (embolism risk)

  • Oedema in the therapy region or directly bordering it: yes/no

Personal information:

• occupation(s)

• social history

  • living situation

  • number of children

• alcohol consumption

• nicotine consumption (cigarettes, cigars, pipe smoking)

• height (m)

• weight (kg)

• pregnant: yes/no

• currently claustrophobic: yes/no

Clinical examination results:

• general condition

• external examination

• internal examination

• neurology

Previous therapies:

• pre-treatments

  • radiation therapy

  • chemotherapy

Justification for therapy:

• curative or palliative

• neoadjuvant: yes/no

Contraindications:

• pacemaker/defibrillator/neurostimulator: yes/no

• metal implants: yes/no

• other possible contraindications

  • burning: yes/no

  • abscess: yes/no

  • skin damage: yes/no

  • recent operation scar: yes/no

Consent form:

• written consent provided: yes/no

Objective of the treatment:

• treatment as part of a study or series of case studies: yes/no

  • description of the study or case studies

• information about the treatment volume based on the 3D imaging

  • target volume

  • risk volume

Treatment plan:

• radiation therapy

  • CT supported 3D planning

  • planned reference dose: xx.x Gy

  • fractionation: x times per week

  • fractionation dose: x.x Gy/week

• chemotherapy

  • details

• hyperthermia

  • information about the treatment volume

    • planning target volume (PTV)

    • positioning of the patient in the applicator (longitudinal, vertical)

  • volume at risk

  • verification

    • probe thermometry, MR thermometry