PROCEEDINGS of the23rd International Congress on Acoustics
9 to 13 September 2019 in Aachen, Germany

EURAMET EMPIR 18HLT06 RaCHy Project: Radiotherapy coupledwith Hyperthermia (Induced by HITU)
Giovanni DURANDO1, Piero MILORO2, Volker WILKENS3, Baki KARABOCE4, Jacco DE
POOTER5, Gerard VAN RHOON6, Gail TER HAAR7, Barbara CACCIA8, Antonello SPINELLI9,Antonia DENKOWA10, Roeland DIJKEMA11
1INRIM -Istituto Nazionale di Ricerca Metrologica-, Italy
234NPL -National Physical Laboratory-, United KingdomPTB -Physikalisch-Technische Bundesanstalt-, GermanyTÜBITAK UME -TÜBITAK National Metrology Institute-, Turkey
5

VSL - Dutch National Metrology Institute-, The Netherlands
6Erasmus University Medical Center, The Netherlands
7

ICR -Institute of Cancer Research-, United Kingdom
8ISS -Istituto Superiore di Sanità-, Italy
910OSR -Ospedale San Raffaele-, Italy

TU Delft -Delft University of Technology-, The Netherlands
11

VSPARTICLE B.V. , The Netherlands

ABSTRACTThe main goal of external beam radiotherapy (EBRT) is to damage all cancer cells in a tumour in such away as to stop their proliferation. Unfortunately, normal tissue toxicity can severely limit doses used, andthus it is useful to combine EBRT with other treatments. An interesting approach to improving local
tumour control is to combine EBRT with hyperthermia (HT). The cell sensitisation induced by the heat is
not completely understood, however evidence suggests that it impairs cellular DNA repair, thus renderingradiation damage more lethal. During hyperthermia treatments the temperature distribution generated iscrucial. High Intensity Therapeutic Ultrasound (HITU) provides superior control of energy deposition, andthus can increase the tumour temperature to the target level homogenously. One of the main goals in theRadiotherapy coupled with Hyperthermia (RaCHy) project is therefore to improve the efficacy, safety andrange of applicability of clinical HITU treatments by providing validated methods for ultrasonic fieldcharacterization, HITU system performance testing, quality assurance and patient exposure monitoring.
The RaCHy project will address both the basic calibration and specification of equipment ( and inparticular characterisation of the acoustic pressure and temperature distribution in water and in-vitro andin-vivo experiments).
Keywords: External beam radiotherapy, EBRT, HITU, Ultrasound, Hyperthermia

1. INTRODUCTION
Cancer is responsible for just over 1.3 million deaths in the European Union per year. With theaging population, the incidence of cancer is rising. Furthermore, while cancer accounts for 22% of
all deaths for those over 65, this figure grows to 38% for people younger than 65 and is the leading
cause of premature death in 28 of the 53 regions in the Europe. Even though the current treatments
available for cancer have improved response they have not improved the survival of patients,
particularly of those diagnosed with advanced tumours. There is a need for integrated approaches,
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g.durando@inrim.it

combining different expertise from different fields, to try to find innovative strategies able tosignificantly improve the outcome of cancer treatments, yet limiting the side effects.
Radiotherapy is one of the frontline treatments for cancer with about 50% of people with cancer
having radiotherapy as part of their treatment, as stated by recent survey of ESTRO (EuropeanSociety for Radiotherapy and Oncology) and HERO (Health Economics in Radiation Oncology).
Radiotherapy uses radiation to kill cancer cells by damaging their DNA, either directly or by creating
charged particles (free radicals) within the cells that can in turn damage the DNA.
In order to reduce the side effects, or to escalate the biological effects related to radiotherapy,
multimodality techniques such as combination with hyperthermia have been shown to be effective
through suppressing DNA repair mechanisms. However, clinical uptake has been hampered by lackof precision in treatment delivery and monitoring. The proposed strategy may also be a valuable
alternative to chemoradiotherapy for advanced stage cancer patients for whom chemotherapy iscontraindicated.
The main aims of EURAMET 18HLT06 - RaCHy - project are to demonstrate experimentally how
the use of different sources to generate hyperthermia, combined with radiotherapy, could result in a
successful treatment of the whole tumour. This approach requires detailed knowledge of temporaland spatial distributions of temperature increase and radiation dose during the treatment.

2. EURAMET EMPIR 18HLT06 -RaCHy- PROJECT
2.1 Project overview
Preclinical experiments have shown that the sensitising effects of heat are greatest when radiationdelivery and heating are delivered at the same time, and that efficacy decreases as the time between
the two increases. Recent in-vitro cell survival data (1) have described combination treatments as afunction of radiation dose, heating temperature and duration, whereas other studies focus on
quantification of the influence of treatment order and timing.
Combinations of hyperthermia with radiation are difficult to study in-vitro, although progress has
been made on designing dedicated experimental set-ups. Also, combination treatments of partial
HITU exposure with RT show promising results in-vivo. However, for both studies (in-vitro andin-vivo) quantification of the observed biological effects as a function of exposure conditions is still
limited by the lack of dosimetric measures. An empirical cell survival model describing radiotherapy
in combination with hyperthermia has recently been proposed and tested for two cells lines, with theobjective of better quantifying heat induced radio-sensitization and thermal dose. There are a numberof factors which are thought to contribute to the enhanced efficacy of radiotherapy and hyperthermia:
inhibition of DNA repair mechanisms, immune stimulation, induction of cell death, changes to local
perfusion environment etc. (2). For these reasons timing of radiotherapy and hyperthermia andtemporal spatial distributions of temperature are crucial. Depending on the tissue (normal vs.
tumour) the treatment order may affect the biological response with a further option to widen thetherapeutic window.
2.2 Scientific objectives
The overall objective of the 18HLT06 RaCHy project is to develop the metrological framework andmeasurement techniques that underpin the adoption of combined therapies (radiotherapy andhyperthermia). The scientific objectives of the project are:To determine the suitability of methods of hyperthermia for use with radiotherapy. 2D and 3D
measurement set-ups, and validated modelling tools, will be developed to estimate the spatial-temporal
distribution of energy deposition and temperature increase in in-vitro cellular systems. The target
uncertainty of the in-vitro determination of the temperature increase should be < 10 %.
To extend the assessment of the spatial-temporal distribution of energy, deposited from radiotherapy
and hyperthermia, and of the related temperature increase, to in-vivo systems. In addition, to demonstrate
the repeatable and controllable clinical use of the hyperthermia methods in in-vivo experiments, in order toguarantee treatments with a temperature distribution from 37 °C to 50 °C and a target fractional uncertainty
below 15 %. Radiation dosimetry should also be demonstrated to have clinically fractional uncertainties
less than 5 %. In-silico models will be adopted to estimate the ability of numerical dosimetry to predict
temperature increases in complex anatomical models to within a fractional uncertainty of less than 10 %.
To extend existing and to develop new measurement methods for accurately assessing thespatial-temporal radiation-field characteristics that are relevant for the combined radiotherapy/hyperthermia

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modalities, including radioactive magnetic nanoparticles for simultaneous radiation and heating. Thisshould focus on the translation of pre-clinical results into future clinical practice.
To exploit and quantify the biological effects of coupling hyperthermia techniques with radiotherapy. Inaddition, to quantify the biological effects of dose reduction by performing in-vivo experiments that resultin the same therapeutic outcome with and without dose reduction. The role of control parameters, such asenergy deposition in tissues, radiation dose and duration of the hyperthermia and/or radiation treatment,
should also be quantified.
2.3 Consortium
The consortium brings together 5 European National Metrological Institute, NMIs, 1 university, 1
health institute, 3 hospitals, 1 manufacturer. NMIs ensure that the methods and measurements arecorrectly and adequately characterised, see Figure 1.

Figure 1. RaCHy Consortium
There are three partner categories:
Internal Funded Partner: National Metrological Institute (NMI)
INRIM
Istituto Nazionale di Ricerca Metrologica (Italy)
NPL
National Physical Laboratory (United Kingdom)
PTB
Physikalisch-Technische Bundesanstalt (Germany)
TUBITAKTÜBİTAK UME Turkish National Metrology Institute (Turkey)
VSL
Dutch National Metrology Institute (Netherland)
External Funded Partner
ERASMUS MC Erasmus University Medical Center (Netherland)
ICR
The Institute of Cancer Research (United Kingom)
ISS
Istituto Superiore di Sanità (Italy)
OSR
Ospedale San Raffaele S.R.L. (Italy)
TU Delft
Delft University of Technology (Netherland)
Unfunded Partner
VSPARTICLEVSPARTICLE B.V. (Netherland)
The partners have experience and facilities, for the entire process of definition of scenarios,
identification of critical parameters and required uncertainty, variability of operating conditions,selection of most significant configurations, especially for verification and validation of simulation
models and results. The consortium has excellent links with standardisation bodies and end-users.

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3. RADIOTHERAPY COUPLED WITH HYPERTHERMIA MEDIATED BY HITU
3.1 Radiotherapy coupled with HITU treatment
The direct experience with HITU for treating, for palliative purposes, bone metastases (3), led us
to consider that the best way to do Radiotherapy is in combination with focused ultrasound.
In principle, if a tumor (of limited dimensions) were embedded in a homogeneous, waterequivalent medium, the advantage of HITU would be so obvious (after ablation no malignant cells
could survive) that we would not need the EBRT help. But the human body is a highly
inhomogeneous medium and tumors are not homogeneous water equivalent media, and so HITU
alone is not sufficient for treating, in particular, invasive local metastatic disease. The
inhomogeneous tissues and organs surrounding a tumor mean that HITU has severe limitations due
to:(i)
Absorption and scattering by bone;(ii)
Reflection by air;(iii)
The need to avoid/protect nerves and major vessels in the US beam path.
The treatment of larger volumes by starting with HITU ablation for debulking in the surgicalsense and then EBRT, possibly with a reduced radiation dose, would be a suitable indication for
EBRT plus HITU. That would reduce the ionizing radiation burden for treating large volumes. We
will apply two techniques:(i)
Homogeneous treatment, with radiotherapy coupled with the whole tumor, or(ii)Treatment with the addition of an ablative procedure in hypoxic regions.
This latter treatment is suggested when a significant hypoxic region is suspected. For this kind ofexperiment, HITU provides an ideal method giving the capability of effectively monitoring in nearreal time the distribution of the temperature field, see Figure 2.

Figure 2. Radiotherapy coupled with hyperthermia mediated by HITU
3.2 Fast HITU Hyperthermia, FHHThe Sapareto equation, describes the equivalence between time and temperature for the same
effect of cell killing with heat, without the possible synergistic effects (4). The relationship that links
temperature, T, and time, t, is:𝑇!" 𝑥, 𝑦, 𝑧 =!!"#$%!

𝑅(!"°!!! !,!,!,!
)
!°!
𝑑𝑡

where: 𝑅 =0.25 𝑇 𝑥, 𝑦, 𝑧, 𝑡 ≤ 43 °C
0.50 𝑇 𝑥, 𝑦, 𝑧, 𝑡 > 43 °C

(1)

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This means that, for T > 43 °C an increase of 1 °C of temperature is equivalent to reducing theexposure time by half. It has been verified that many living entities (cells, tissues) are completely“ablated” (protein denaturation, small vessels coagulation, cell inactivation) when they are exposed
to a heat exposure of 240 min at 43 °C. The quantity T 43 is called Thermal Dose (TD), or ,as thedimension of it is time, Thermally Equivalent Time (TET) (5,6).
Clinical Hyperthermia is administered to the patient (after EBRT treatment) by warming theregion of interest to 42-43 ° C for 60-100 min, providing roughly a TD of about 0.25-0.30. We
propose that FHH treatments could provide good results, by administering a thermal dose of 0.375
TD, corresponding to a Surviving Fraction (SF) of about 0.01 in the Sapareto survival curve (4).
3.3 Hyperthermia corrected Biological Equivalent Dose, BED
The Biological Equivalent Dose, BED, concept is very well recognised for radiotherapy and isbased on its ability to carefully represent the expected biological effects of radiation. The growinginterest in multimodality therapies combining hyperthermia and ionizing radiation is expected toextend this concept to include the synergistic effect of heat on the radiation-induced biological effect.
To this aim, it is important to carefully measure the biological effect of EBRT coupled withhyperthermia mediated by HITU and to compare it to the case of ionizing radiation delivery without
heat. This enables the quantification of a dose modifying factor (named K Heat) taking into account thesynergic effect of hyperthermia. The parameter K Heat is expected to be a complex function of anumber of factors including the local temperature, the way heating is generated and delivered withrespect to ionizing radiation, the heating duration, the temperature distribution (homogeneous orheterogeneous) within the tumor or the considered organ, the physical and biological characteristicsof the tissue, the radiation dose, dose rate and fractionation, etc.

4. CONCLUSIONSAs is clear from Figure 2, the proposed protocol, Radiotherapy combined with Hyperthermia,
easily outperforms the traditional ones; it leads to low survival of tumor cells and a long offset timesuch that the patient is effectively cured. In order to maximize the synergistic effects, the twotreatments, HITU and EBRT, should be applied at the same time or within a maximum10 mininterval. For this reason, it could be necessary to develop a new integrated device, including
real-time echography and CT imaging.

ACKNOWLEDGEMENTS
The activities here presented will be developed in the framework of the EURAMET 18HLT06 RaCHy
Project that received funding from the EMPIR program co-financed by the Participating States and from theEuropean Union’s Horizon 2020 research and innovation program.

REFERENCES
1. Brüningk et al. A comprehensive model for heat-induced radiosensitisation, Int J Hyperthermia Vol. 34(4); 2018. p. 392-402.
2. Peeken et al. Integrating hyperthermia into modern radiation oncology: what evidence is necessary
Front. Oncol. Vol. 7 (132); 2017.
3. Alongi F, De Bari B, Campostrini F, et al. Salvage therapy of intraprostatic failure after radical
external-beam radiotherapy for prostate cancer: a review. Crit Rev Oncol Hematol 2013;88:550-63.
4. Sapareto SA, Dewey WC. Thermal Dose Determination in Cancer-Therapy. International Journal ofRadiation Oncology Biology Physics 1984;10:787-800.
5. IEC/TR 62799: Models for evaluation of thermal hazard in medical diagnostic ultrasonic fields, Ed.1
Geneva: International Electrotechnical Commission, 2013.
6. Shaw A, ter Haar G, Haller J, Wilkens V. Towards a dosimetric framework for therapeutic ultrasound,
Int J Hyperthermia Vol. 31 (2); 2015. p.182-192.

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