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Majesty’s Stationery Office and NPL Management Ltd. DOI: 10.3109/02656736.2014.997311

RESEARCH ARTICLE

Towards a dosimetric framework for therapeutic ultrasound Adam Shaw1, Gail ter Haar2, Julian Haller3, & Volker Wilkens3 National Physical Laboratory, Acoustics and Ionising Radiation Division, Teddington, UK, 2Institute of Cancer Research, Royal Marsden Hospital, Joint Department of Physics, London, UK, and 3Physikalisch-Technische Bundesanstalt, Braunschweig, Germany

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Abstract

Keywords

There is a need for a coherent set of exposure and dose quantities to describe ultrasound fields in media other than water (including tissue and tissue-simulating materials). This paper proposes an outline dosimetry scheme, with quantities for free field exposure, in situ exposure, dose (both instantaneous and cumulative) and effect, to act as a structure for organising a more complete set of definitions. It also presents findings from a survey of the views of the therapeutic ultrasound community which generally supports the principle of using modified free field quantities to describe the in situ field, and the prioritising of dose quantities which are related to heating and thermal mechanisms. Although there is no one-to-one relationship between any known ultrasound dose quantity and a specific biological effect, this can also be said of radiotherapy and other modalities where weighting factors have been developed to calculate the degree of equivalence between different tissues and radiation types. This same separation is recommended for ultrasound, provided that an appropriate set of recognised ‘engineering’ quantities can be established for exposure and dose quantities.

High intensity focused ultrasound, modelling, quality assurance, thermal ablation, ultrasound

Introduction Probably the easiest way to understand the different concepts of exposure and dose for ultrasound is by analogy with light and photography. The exposure is the intensity of light incident on the photographic film, but in order for that film to register an image, the exposure must be held for a time that depends on the light level – that is, a certain ‘dose’ of photon energy is needed. It seems surprising at first sight that a field as mature as that of medical ultrasound has managed to escape the requirement for formal definitions of exposure and dose until now, despite discussions about the safety of diagnostic ultrasound and its many therapeutic applications. With the increasing use of ultrasound as a therapeutic modality (see below) the need to formalise these terms has become more urgent, in order that treatments such as high intensity focused ultrasound (HIFU) can be considered to be as rigorously delivered as, for example, radiotherapy. The perceived lack of adequate dosimetry for therapy ultrasound led to the funding of a European project called Dosimetry for Therapeutic Ultrasound (DUTy) [1] which involves National Metrology Institutes and other laboratories from the UK, Germany, Italy, Turkey and Spain, and some leading academic institutions from the UK, Russia and Germany. The aim of this EU project is to develop the metrological infrastructure to underpin future standards for

Correspondence: Adam Shaw, National Physical Laboratory, Acoustics and Ionising Radiation Division, Hampton Road, Teddington, TW11 0LW, UK. Tel: +44 20 8943 6581. E-mail: [email protected]

History Received 21 October 2014 Revised 2 December 2014 Accepted 7 December 2014 Published online 16 March 2015

exposure and dose for therapeutic ultrasound. Some of the results discussed here have been obtained in the context of this programme. Current practice is often to use the terms ‘exposure’ and ‘dose’ incorrectly and interchangeably. The reporting of exposure conditions in scientific papers is very variable and ter Haar et al. have promoted a more consistent approach [2] with accepted good practice being to quote characteristics of the acoustic field measured under free field conditions in water, and best practice being to report additionally estimated in situ values using knowledge of the acoustic properties of tissue taken from the published literature. Most ultrasound sources can be well characterised using existing pressuresensitive devices (hydrophones) and acoustic power balances, although it is sometimes necessary to reduce the excitation voltage or the duty cycle to avoid damaging the measuring device. Their output is described in terms of values measured under free field conditions in water. For diagnostic and physiotherapy ultrasound devices, the field quantities needed for full characterisation of a field have been agreed and are listed in international standards [3–8]. Similar standards for high intensity therapeutic ultrasound have been published more recently [9,11] but have not yet fully bedded in. Although regulatory approval for therapy through the USA Food and Drug Administration (FDA) or the European Medical Device Directive (MDD) is not, as yet, contingent on complying with these standards, best practice will ensure that this will be necessary in the near future. In the fields of both diagnostic ultrasound safety and therapeutic ultrasound, where the biological effects of the

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interaction of ultrasound with tissue are studied, it is important to be able to relate the exposure (e.g. the energy flux or the acoustic pressure of an ultrasonic wave incident on the region of interest) to the dose (e.g. the amount of energy absorbed, or some measure of the cavitation activity resulting from the exposure). Currently, given knowledge of the acoustic field and the acoustic and thermal properties of the tissue, the heating distribution can be estimated using the bioheat equation [12,13]. Prediction of the non-thermal effects of ultrasound (for instance, those due to cavitation or radiation force) is more challenging; cavitation scatters the incident field when it occurs and is a chaotic phenomenon since it depends also on dissolved gas levels and the presence of material weaknesses or cavitation nuclei; for radiation force, the interaction mechanism and the relevant mechanical properties of tissue are not well understood. Uses and benefits of dose and exposure quantities In an online survey prepared as part of the DUTy project, workers in the field were asked a number of questions about their perceptions of ultrasound dose. There were 93 replies to the dose part of the survey, largely from people working in physics, engineering and bio-effects, rather than from clinicians [14]. Asked ‘Do you think there is a generally understood meaning of the term ‘‘dose’’ when applied to ultrasound?’, opinions were widely spread but the most common view (33%) was that ‘There are several different views, none of which predominates.’ To the question ‘How do you use the word ‘‘dose’’ when applied to ultrasound?’, the most widespread response (37%) was ‘It means something quantifiable about the amount of energy absorbed by the target tissue’, although a further 25% said they rarely used the word dose. Whatever their own understanding of the word, 88% thought it to be very relevant to thermal mechanisms. Only 34% thought it very relevant to cavitation mechanisms, but 51% said it had some relevance. Respondents were given a list of potential benefits (more effective treatment, better advance planning of treatment parameters, more patient-specific treatments, safer treatment, more consistent treatment, easier comparison of equipment performance, greater acceptability for new treatments, easier route to market, and better education of the patient before treatment) and were asked ‘Which aspects are most likely to benefit from a better developed and more widespread common understanding of dose?’ Apart from better patient education, more than 75% thought that all were likely to benefit substantially or slightly. Better treatment planning scored most highly, with 65% expecting substantial benefit, but the others were not far behind. To find out what type of quantity was wanted, participants were asked to contrast pairs of general characteristics. From this a clear set of preferences emerged: the preferred dose quantity should be aimed at improving effective treatment delivery rather than reducing side effects, it should be related to the energy reaching the tissue and be spatially and a temporally varying, it should preferably be a traceable physical quantity (such as energy or temperature), as opposed to describing cellular or structural changes to the tissue.

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Participants were clear that dose quantities for thermal mechanisms were the highest priority (70%), with quantities for cavitation being the second priority for 67%; quantities for other mechanical effects had the lowest priority for more than 80% of respondents. Existing literature on dose for ultrasound Energy deposition Duck [15,16] reviewed various approaches to dose quantities for ultrasound, and recommended a definition based on the concept of energy deposition with the term ‘acoustic dose’ being the energy deposited by absorption of an acoustic wave per unit mass of the medium supporting the wave. The advantages to this proposal are described in more detail in the references mentioned. Firstly, this is a clear and unambiguous definition with units (J/kg) which are the same as those used for the quantity ‘absorbed dose’ in ionising radiation, and with a time derivative (or ‘acoustic dose rate’) which is dimensionally consistent with the specific absorption rate (SAR) commonly used for electromagnetic radiation. Secondly, this SAR is related to both thermal and some non-thermal effects, as it is directly proportional to the initial rate of increase in temperature, as well as to the volumetric force that a travelling ultrasound wave applies to the supporting medium. There are several drawbacks to this definition. Firstly, neither energy deposition nor the SAR are directly or locally measurable, and must be inferred from indirect measurements or computation. However, this is also true in radiotherapy where calorimetry is used to determine the energy deposited in reference materials. Secondly, the deposited energy (or its rate), is not generally considered to be the direct cause of bioeffects. Increase in temperature is the more direct cause of a wide range of effects, but for any given energy deposition the temperature increase depends on the specific heat capacity, on position (for example distance from blood vessels), and on adaptive physiological mechanisms. Recent work has also shown how the production of multiple lesions in tissue with high intensity therapeutic ultrasound (HITU) depends on the scanning pathway, although the delivered energy distribution at each point remains the same [17]. Thermally equivalent time Taking into account the points made above, and initially accepting the idea of separating ‘dose’ into expressions relevant for different mechanisms (for example, thermal mechanisms, cavitation mechanisms and other mechanical mechanisms), it seems sensible to seek a definition of dose that is based on temperature increase as the stimulus for thermal effects. The commonly used candidate here is often called ‘thermal dose’ or ‘cumulative equivalent minutes’ (CEM) in the literature. It is based on the so-called isodose concept, which attempts to compare different thermal treatments. This is derived from the observation that the overwhelming majority of biological systems exhibit the same exponential relationship between time and temperature for a given isoeffect [18]. The isodose concept allows a (measured) time temperature profile T(t) to be used to

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DOI: 10.3109/02656736.2014.997311

calculate the time tREF over which a constant temperature T ¼ 43  C will yield the same biological effect in a given tissue; Z t¼final    43 CT ðtÞ ð1Þ R 1 C dt, t43 ¼

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t¼0

with R ¼ 0.5 for T(t)443  C and R ¼ 0.25 for T(t)  43  C. Since the unit of t43 is that of time, there is a growing preference for the term ‘thermally equivalent time’ (TET) [19]. This terminology will be used here. There are several advantages to this definition. The measurability is good as numerous ways of measuring temperature exist, with some, such as magnetic resonance (MR) thermometry, being non-invasive, and thus suitable for in vivo measurements [20,21]. It is already common to monitor TET during some applications [18], and the biological relevance of this definition is thought to be good, as this definition has been empirically derived from biological data. Numerous studies of TET responses for different permanent or transient effects exist. An extensive review can be found in Yarmolenko et al. [22]. However, there are also several open issues concerning its biological relevance. Firstly, Equation 1 has been derived on the basis of data from thermal treatments between 42  C and 47  C. Its validity for higher or lower temperatures has thus been questioned both for short exposures to higher temperatures [21] and for very long exposures to low temperatures (541  C) due to a lower threshold and the creation of heat-shock proteins [13]. There is ongoing work to explore these regimes further [23]. Secondly, it is well known that different types of tissue show different responses to the same TET (which could be accounted for by using tissue-weighting factors as is done in radiotherapy - see below). For instance, it is reported that the thermal equivalent time required to cause chronic damage in muscle is 240 min, but only 30 min for liver [19]; the tissue weighting factor for thermal dose in liver would therefore be eight times that in muscle to account for this different sensitivity to heat. Furthermore, the same type of tissue can respond differently if it has been thermally pretreated, due to the production of heat shock proteins [19]. Whilst in principle such thermotolerance could be accounted for using a tissueweighting factor (i.e. different factors for untreated and pretreated tissues), the quantification of this effect is challenging. Dose terms related to cavitation In several investigations of the bioeffects of cavitation, effects are correlated with measured quantities which are often referred to as ‘cavitation dose’, but which may be very different between researchers. For example, in Chen et al. [24] ‘cavitation dose’ for inertial cavitation is defined as the cumulative root mean squared broadband noise amplitude of the cavitational acoustic emissions recorded with a hydrophone, and in Huber and Debus [25] as the amount of light scattered from a given volume. Although there has already been significant work concerning both the probability and the quantification of cavitation [26–30] there is as yet no commonly agreed definition that is suitable for a wide range of sonication

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modalities (e.g. for bursts with low duty ratios as well as for continuous wave sonications). Furthermore, an appropriate implementation of the cumulative role of ‘time’ is needed – taking into account both that a longer sonication will increase the statistical probability of cavitation in some cases, and that several cavitation events in the same place will lead to a different biological effect than a single cavitation event.

Therapeutic ultrasound The term ‘therapeutic ultrasound’ covers a wide range of existing and potential clinical applications. While HIFU is perhaps the application receiving most clinical attention at this time, many unfocused high intensity applications are also under consideration. For this reason, the International Electrotechnical Commission (IEC) has termed this group of ultrasound therapies ‘HITU’, where the T stands for therapeutic [9,11]. It should, however, be remembered that a number of low intensity applications are also in clinical use. Table 1 shows some of the therapeutic applications currently being used, or under pre-clinical investigation. This table attempts to summarise the range of applications in terms of the usual target tissue, the physical mechanism which produces the therapeutic change, the type of acoustic exposure, the targeting method employed and the general configuration of the equipment. While not all-inclusive in this rapidly expanding field, it shows the breadth of interest.

Dose in other modalities It is instructive to try and put ultrasound into the wider context of other therapeutic treatment modalities in order to consider how exposure and dose are handled, and to establish whether there are parallels that might inform a dose concept for ultrasound. Radiotherapy For ionising radiation, the attempt to quantify ‘dose’ occurred immediately after the discovery of X-rays in 1895, but it took more than 25 years for the first (more or less) commonly agreed definition for exposure using the roentgen unit [44], Today there exists a complete suite of quantities for ionising radiation dosimetry used for different purposes:  The quantity ‘exposure’ is defined in terms of the amount of ionisation produced in air. The unit for exposure is based on charge per unit mass of air (C/kg).  Kinetic energy released per unit mass (KERMA), which is defined as the sum of the initial kinetic energies of all the charged particles liberated by uncharged ionizing radiation in a sample of matter, divided by the mass of the sample [45]. This is a clear and unambiguous definition but one that is inadequate for predicting bioeffects.  Hence, another value, the ‘Absorbed dose D to. . . (air/ water/tissue/. . ..)’, is defined as ‘the amount of energy from radiation deposited or absorbed by an object per unit mass’ with the main difference from KERMA being that it is not limited to ‘initial kinetic energies’. There is a certain similarity with ultrasound, since for heated tissue it does not matter whether the heat is produced directly

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Table 1. Overview of therapeutic ultrasound applications.

Application

Treatment site

Aim

Acoustic exposure

Guidance

HIFU

Uterine fibroids [31] Prostate cancer [32]

Thermal ablation Thermal ablation

HI HI

US/MR US/MR

Breast cancer [33] Abdominal cancer (liver, kidney, pancreas) [34] Bones [35]

Thermal ablation Thermal ablation

HI HI

US/MR US/MR

Pain palliation, tumour control Thermal ablation

HI

US/MR

E-C E-C T-R E-C E-C I-O E-C

HI

MR

E-C

Clin

HI

US

E-C

Preclin

HI HP

– US

E-C E-C

Clin Clin

HP

US

E-C

Clin

MI/LI

US/MR

E-C

Preclin (early trials)

MI/LI

MR

E-C

Preclin (early trials)

LI MI

– –

E-C E-C

Clin Clin

Lithotripsy

Brain (essential tremor, Parkinson’s dyskinesia, OCD, depression, epilepsy) [36] Uterus (twin-twin syndrome) [35] Eye (glaucoma) [37,38] Kidney, Gall bladder [39]

Histotripsy [40]

Prostate

US mediated drug delivery [41]

Malignant tumours of abdomen

US mediated drug delivery [41]

Brain (cancer, Alzheimer’s disease)

Fracture healing [42] Physiotherapy [43]

Bone Soft tissues

Vascular occlusion by thermal ablation Thermal ablation Stone destruction by mechanical disruption Cavitation-induced tissue disruption Mechanically or thermally enhanced local drug delivery Breaching of BBB using mechanical effects from microbubbles Non-thermal effects Improved function via thermal and non-thermal effects

System type

Status Clin Clin Clin Clin Clin

BBB, blood–brain barrier; Clin, in clinical use; E-C, extra-corporeal; HI, high intensity; MI, medium intensity; LI, low intensity; High pulse pressure amplitude; I-O, intra-operative; preclin, under laboratory investigation; T-R, trans-rectal.

from the absorption of ultrasound, or whether it is dissipated from adjacent tissues (i.e. through a secondary effect).  The equivalent dose H is a computed average measure of the radiation absorbed by a fixed mass of biological tissue that attempts to account for the different biological damage potential of different types of ionising radiation by specifying weighting factors for each radiation type. There is perhaps a parallel between different ultrasonic frequencies and different radiation types in this context.  The effective dose E is the sum of equivalent doses to organs and tissues exposed, each multiplied by the appropriate tissue weighting factor. A parallel here is with the range of damage thresholds (in terms of TET) which have been observed for different tissue types [46] D, E and H are typically used as mass-averaged values over an item of interest but it is also possible to use them as spatially variant quantities (e.g. D(x, y, z)).

quantity (commonly the mass) of the agent that may impact the organism biologically. A weakness of this definition may be seen in the fact that it does not include any measure of how much of the agent actually impacts the organism, and how much, for example, is excreted before it has time to act. In pharmacology there exist several established terminologies some of which might also be useful for an ultrasound dose concept. These include the lethal dose (LDx): the dose at which a percentage x of subjects will die (e.g. LD50); the effective dose (EDy): the dose that produces a therapeutic response or desired effect in some, y%, of the subjects taking it (e.g. ED50); the no observed effect level (NOEL): the highest dose known to show no effect; the optimal biological dose (OBD): the dose that will produce the desired effect with acceptable toxicity; or the maximum tolerated dose (MTD): the highest dose that will produce the desired effect without unacceptable side effects.

A dose structure for ultrasound Other modalities Most other modalities for which the term ‘dose’ is commonly used are thermal therapies (for example, laser and microwave therapies), and often the quantity ‘thermal dose’ (meaning the TET, see above) is used. Furthermore, in many of these applications the term ‘exposure’ is used for the applied intensity (or power per area). One prominent exception is in drug delivery and the related discipline of pharmacology, where dose is usually the

There are two distinct uses for in situ and dose quantities: (1) To permit comparison of the ‘therapeutic power’ of different pieces of equipment, or of different settings under reference conditions (i.e. where all properties are known exactly); (2) To describe or predict effects in a particular sample of a particular medium (e.g. in the liver of an individual patient) where the properties may not be known precisely.

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DOI: 10.3109/02656736.2014.997311

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Table 2. Relationship of free field, in situ, dose and effect quantities. Type of quantity

Description

Free field (water) exposure quantities

These describe the ultrasound field in water and depend only on the source and the acoustic properties of water. Typically they are local pressures, local intensities, beam-shape descriptors, for example. These describe the ultrasound field in a medium other than water. The in situ level depends on the source and on the acoustic properties of the medium. Essentially these quantities are similar to those used for free field quantities (e.g. local pressures, local intensities, beamshape descriptors). These quantify the interaction of the ultrasound field with the medium. The magnitude of the dose depends on the in situ exposure level and on the acoustic and other physical properties of the medium. These quantify the change in the behaviour or properties of the tissue. The size of the effect depends on the dose and the dose-response of the tissue. (e.g. lesion volume rate, cell surviving fraction, the rate of production of a specified bio-marker).

In situ exposure quantities

Dose quantities

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Effect quantities

The first of these can be considered primarily of engineering or metrological use, and the second primarily of clinical use. They are clearly related, and it is important not only that the language used should be common, but that the base definitions should also be suitable for both. However, it is not necessary, or even desirable, to assume that the values of acoustic properties of the medium will be the same for both purposes. We cannot specify or standardise the properties of the acoustic path in a patient (although we may want to be able to determine them before treatment), but it is essential to specify properties for engineering and traceability purposes. A framework of four types of ‘quantity’ is proposed below to describe different aspects of an ultrasound treatment (these are also summarised more concisely in Table 2). In short, for a successful treatment we want to predict the final effect (as measured by an appropriate ‘effect quantity’) but generally we can only measure with confidence the ‘free field exposure quantities’; sometimes even these must be estimated from models or by extrapolation from lower output settings. This paper primarily addresses the intermediate ‘in situ’ and ‘dose’ types. Free field exposure quantities These are mainly the pressure, intensity, power and beamshape descriptors defined in existing IEC Standards [4,6]. We already have the ability to make traceable measurements of these, using hydrophones and radiation force balances, although this ability is limited in practice at very high pressures or intensities, by cavitation in the water or damage to the sensor [47,48]. In situ exposure quantities There are presently no IEC-defined in situ terms, apart from so-called ‘attenuated’ versions of the free field quantities [7,8]. In diagnostic ultrasound, these attenuated quantities are also often called ‘derated’, where a specified attenuating factor (usually 0.3 dBcm1 MHz1) is applied at the acoustic working frequency. However, these are not defined as the field quantity in situ ‘but are, by definition, quantities measured in water with a depth-dependent scaling factor applied, and this simple scaling factor is not appropriate for fields containing multiple harmonics. Many free field definitions could be generalised to encompass the in situ case by including an explicit statement

about the ‘medium’ in the definition. It may be necessary to distinguish formally between standard in situ quantities (in idealised reference media) and actual in situ quantities (for treatment in the individual patient). In the former case, standard properties for the medium must be agreed on. This will become clearer in the example later. Dose quantities Dose quantities characterise the interaction between the ultrasound field and the medium; there are no IEC-defined dose terms for ultrasound. It is not necessary for there to be a single dose quantity which is suitable for all therapeutic ultrasound applications. For instance, a useful dose quantity for lithotripsy may be very different from that for physiotherapy. Dose based on energy deposited per unit mass or volume (as already used for radiotherapy and proposed for ultrasound by Duck [15,16]) is undoubtedly a useful approach for thermally based effects, but it should be recognised that it will not be enough on its own to determine the end effect. Even in ionising radiation, weighting factors are applied for particle energy and for tissue type when predicting the biological effect. For non-thermal mechanisms, ‘dose’ in this sense may be less useful, but metrics such as the number of cavitation events or the energy released by cavitation may be valuable alongside in situ quantities. In many applications of ultrasound, the temperature at certain positions in the propagation path will increase significantly over time, leading to change in the material properties. Non-thermal changes such as the appearance of bubbles due to cavitation may also occur. It therefore becomes important to allow a distinction between ‘instantaneous’ dose quantities and ‘cumulative’ quantities:  Instantaneous dose quantities are analogous to ‘absorbed dose rate’ in radiotherapy; these quantify the interaction with the medium before the properties of the medium change significantly from their starting condition. An example would be the rate of energy absorbed per unit mass.  Cumulative dose quantities are analogous to ‘absorbed dose’ in radiotherapy, these quantify an interaction which accumulates with time and which is allowed to change the properties of the medium. An example would be the total energy absorbed per unit mass.

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Validated measurement methods are, of course, missing for dose quantities, but measurement of rate of temperature rise is an obvious candidate method for determining the dose rate. Thermal phantoms have been developed and validated – again subject to limitations caused by destruction of the medium or sensor at high pressures and intensities [47,48].

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developed to provide traceability, such as ‘standard’ polyacrylamide gel or ‘standard’ polyethylene. There can also be standard tissues such as ‘standard’ muscle or ‘standard’ liver which are simplified approximations of tissues suitable for precise engineering comparison but not for detailed clinical planning. In radiotherapy, water, Perspex and graphite are examples of standard materials.

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Effect quantities The purpose of including effect quantities in this framework is not to suggest definitions for them, but to make clear that they are different from dose, in situ and free field quantities. Few, if any, effects are likely to depend on ‘dose’ alone, but dose can be an important intermediate step in predicting an effect. The aforementioned weighting factors, along with other in situ quantities, will probably also be important. The relationship between in situ exposure and effect, or between dose and effect, is also dependent on the interaction mechanism (e.g. thermal, cavitation or radiation force). Examples of effect quantities might be the ablated lesion volume, the surviving cell fraction, or perhaps effects more remote from the targeted site such as the change in pain perception (e.g. caused by destruction of nerves in the periosteum). Within a formal metrological infrastructure it is essential not to allow these valuable clinical effect metrics to be confused with more basic physical quantities. An example Taking temporal average intensity (Ita) as an example of a field quantity, related quantities can be considered using the proposed framework. Base definition Temporal average intensity: time average of the instantaneous intensity at a particular point in an acoustic field. This is a general definition which can be applied to a field in any medium. Measurements for therapeutic ultrasound are typically made in water, but the use of water is (correctly) not a requirement within the definition. Free field exposure quantity Free field temporal average intensity: time average of the instantaneous intensity at a particular point in an acoustic field in water. This clearly distinguishes the special free field case of the base definition. In radiotherapy, the free field medium is air. In situ exposure quantity In situ temporal average intensity: time average of the instantaneous intensity at a particular point in an acoustic field in a specified medium. Likewise, this distinguishes the general case from the base definition and from the special case of water. The specified medium in this context could be very complex, including, for clinical use, any exposed part of a patient. However, for engineering and metrological use there must be some recognised standard media for which the properties of the media are specified. For example, there will be some materials which are specific to the measurement methods

Instantaneous dose quantity Absorbed ultrasound dose rate: the rate per unit mass at which energy is deposited by absorption of the acoustic wave in a specified medium. This example definition follows Duck [15,16] but other quantities are possible. Local energy deposition will of course be strongly dependent on the in situ intensity, but is not dependent solely upon it. Hence, this is defined in terms of energy deposited and not in terms of in situ intensity, nor of the square of the in situ pressure. It is a quantity which may vary with time at any location, but a case of special interest is the value immediately after the start of insonation when, in the absence of other significant energy storage mechanisms, it is proportional to the rate of change of temperature at that point. Cumulative dose quantity Absorbed ultrasound dose: the energy per unit mass which is deposited within a specified time by absorption of the acoustic wave in a specified medium. Note that this is also defined in terms of energy deposited and not in terms of in situ intensity or of the square of the in situ pressure. It is a quantity which increases with time at each location, hence the need to specify the time. Effect quantity True measures of effect are only relevant in tissue, and often only in living tissue. However, some engineering metrics could be defined; for example, the volume in which the temperature exceeds a specified threshold value, or where the TET exceeds a specified threshold, or where the acoustic dose exceeds a threshold, or where the peak negative in situ pressure exceeds a threshold. In attempting to calculate a particular effect accurately it is important to account for thermally induced changes in the acoustic properties of the medium (especially speed of sound and absorption coefficient) which in some situations will have a significant influence on the magnitude and spatial distribution of the effect.

Candidate in situ and dose quantities In May 2012 at the start of the DUTy project a 2-day workshop was held at which 38 invited experts from 26 institutions in nine countries discussed aspects concerning in situ exposure and dose concepts for therapeutic ultrasound. The participants covered a wide range of this topic’s stakeholders, including researchers, metrologists, regulators, clinicians and manufacturers. Participants also presented their own position papers and ideas for scrutiny and discussion. The ideas were summarised and considered by the project

Dosimetric framework

DOI: 10.3109/02656736.2014.997311

Table 3. What characteristics of the ultrasound exposure do you think are important for effective therapy in your application? Exposure characteristics

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General Frequency and/or spectrum Transducer dimensions Beam shape Exposure time Acoustic field Acoustic power Pulse parameters (e.g. burst length, pulse repetition rate) Acoustic pressure parameters Acoustic intensity parameters Heating related Maximum temperature rise Variation of temperature rise with time Cavitation related Amount of stable cavitation Amount of collapse cavitation

Agree (%) 77.6 45.9 69.4 80.0 80.0 69.4 56.5 54.1 56.5 47.1 40.0 48.2

team and eventually reduced to a manageable group of quantities which were also used to formulate a survey. In situ exposure quantities

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conditions. Hill et al. proposed this as being relevant especially for predicting lesion size during thermal ablation [49].  Thermally equivalent time: For a given time-temperature profile T(t) at any point in heated tissue, t43 is the time over which a constant temperature T ¼ 43  C is expected to yield the same biological effect in the same tissue.  Local Cavitation Index: At any point in an ultrasound field LCI is the ratio of the temporal peak value of the rarefactional pressure, at this point to the square root of the acoustic working frequency of the ultrasound field at the same point, multiplied with a constant to make the LCI dimensionless. The two quantities which are most used by the participants were thermally equivalent time and total applied energy (Figure 1A). These are also, not surprisingly, the quantities that were seen as being of most direct relevance to the individuals’ own work (Figure 1B) and also of most general relevance (Figure 1C). They were also therefore the quantities likely to be most acceptable to the wider community (Figure 1D). Absorbed energy per unit mass is generally the next highest scoring but it should be noted that this quantity (coupled to the thermal properties of the tissue) is what governs the temperature rise and therefore the thermally equivalent time. So, although not directly important in itself, knowledge of this distribution is a critical step in planning a treatment.

In the DUTy survey we asked ‘What characteristics of the ultrasound exposure do you think are important for effective therapy in your application? Please tick all that apply.’ The responses are given in Table 3; whilst all quantities offered had significant support, frequency, beam shape, acoustic power, exposure time, and pulse parameters (e.g. burst length, pulse repetition rate) all scored close to 70% or more. So it appears that simple in situ versions of the existing free field quantities will be useful.

Discussion

Dose quantities

Engineering and metrological roles

In the survey, respondents were asked to score selected quantities according to five criteria. These criteria were: familiarity with the concept, perceived relevance to their own applications of ultrasound, perceived relevance to other applications, and likely acceptability to the ultrasound community. The quantities and their definitions were:  Absorbed energy per unit mass: The energy converted to heat per unit mass at any point in an ultrasound field is the energy deposited by absorption of the acoustic wave per unit mass of the medium supporting the wave, which is converted to heat.  Applied total acoustic energy: The total acoustic energy which is emitted from an ultrasound transducer during an application.  Intensity-time-integral: The time integral of the instantaneous acoustic intensity at any point in an ultrasound field over the total duration of the exposure. (The calculation may be frequency-weighted to account for the presence of harmonics and the variation in the absorption coefficient of the medium with frequency.)  Intensity spatially averaged under linear conditions (ISAL): The temporal average intensity spatially averaged over the area enclosed by the half-pressure-maximum contour determined in the focal plane under linear

For any exposure or dose quantity to be useful for comparing equipment or settings, it is essential that a reference method is established for determining the quantity under specified conditions with known uncertainty. Existing free field exposure quantities are measured in water with calibrated hydrophones; for a routine calibration at the UK National Physical Laboratory (NPL), the best uncertainties are of the order of 6% in the low megahertz range [50] giving an uncertainty of at least 6% for pressure parameters and 12% for intensity parameters. Factors such as spatial averaging and directional response will increase the uncertainty achievable in practice. Haller et al. [48] found differences of up to 15% in measuring the magnitude of the fundamental frequency component for single-element HITU sources using different hydrophone systems. For measurements of HITU devices especially, it may not be possible to characterise the field at clinical settings due to the occurrence of cavitation or the risk of damaging the hydrophone. In these situations the uncertainty in estimating the true clinical field will be greater still. In general a more direct measurement of a physical quantity is preferable as it requires fewer assumptions and is likely to give the lowest uncertainty. However, it is often necessary to use less direct means; for example, the in situ temporal average intensity in a ‘standard’ material such as polythene

In the proposed framework, clinical use builds on more fundamental engineering and metrology considerations and so it is sensible to discuss these first.

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Figure 1. Different approaches to describing dose (vertical axis) rated according to specified criteria: (A) familiarity with the concept, (B) perceived relevance to their own applications of ultrasound, (C) perceived relevance to other applications, (D) likely acceptability to the ultrasound community). In each case, the possible responses are listed below each chart. Results are expressed as a percentage from 93 reponses to these questions.

might not be measured directly, but instead calculated from a measurement of temperature rise. It should also be possible to establish ways of disseminating a dose standard to end users. A gold standard method of measuring dose in well-equipped laboratories might not be workable in everyday clinical practice. Nevertheless, regular checks of the dose delivered by therapeutic devices and comparisons against transfer standards would be essential. It should be possible to put in place a chain of traceability so that end users can make measurements with an appropriate level of confidence. For instance, routine Quality Assurance (QA) tests might be carried out on the clinical system using a polyacrylamide gel with a small embedded wire thermocouple visible under ultrasound or MR guidance; whereas a laboratory standard method might require use of a thin-film thermocouple (which is easily damaged by cavitation), a closely temperature-controlled environment and a separate scanning system and water tank. Definitions must be compatible with existing terminology and standards. This requires care and attention to detail in finalising the definitions, and it can sometimes lead to wording which appears unnecessarily complex for clinical use. However, from the view of metrology and standardisation this requirement is important and must be kept in mind during development. Finally, it is of great importance for the successful establishment of a uniform dosimetry framework

that it is acceptable to the wider community. It should ideally be reasonably intuitive and accessible to different parts of the community, preferably following an established model such as that used in radiotherapy. Clinical role It is likely to be impossible to measure the dose or in situ field in an individual patient during treatment, so planning will require that the treatment can be modelled to an appropriate level of detail. In radiotherapy this is done using powerful Monte Carlo simulations, with standard codes available as benchmarks. While the existence of suitable computing capabilities and an understanding of how to solve the underlying equations for any situation should become achievable, the reliability of modelling is strongly dependent on the uncertainties of other inputs such as the source boundary conditions, and the medium properties. Numerical calculations typically need at least four properties of the medium for the acoustic calculations (sound velocity, density, absorption coefficient and non-linearity parameter) and at least two additional properties for the thermal calculations (thermal conductivity and specific heat capacity) [29]. Of the given examples, all six properties are temperature-dependent, with the absorption coefficient and to a lesser extent sound velocity also being frequency-dependent.

Dosimetric framework

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DOI: 10.3109/02656736.2014.997311

Due to the high diversity of bioeffects caused by ultrasound, and due to the different sensitivity of different types of tissue to stimuli, no single value exists that universally and unambiguously predicts all bioeffects for all tissues. However, looking to radiotherapy as a model, there is a potential solution to this dilemma: besides as the basic definition of absorbed dose energy deposited by ionising radiation per unit mass of the medium), the terms ‘equivalent dose’, which accounts for the different impact of different radiation types using radiation weighting factors, and ‘effective dose’, which accounts for the relative sensitivities of different types of tissue using tissue weighting factors, are also defined [30]. Tissue weighting factors range from 0.01 for brain to 0.12 for breast tissue, and radiation weighting factors range from 1.0 for gamma rays to approximately 22.0 for neutrons. Determining appropriate weighting factors for ultrasound will require substantial research, but first requires that measures for determining in situ exposure levels and dose are in place; measuring the response of a system without being able to measure the stimulus does not allow prediction of response. Future standards To put in place an internationally accepted metrological infrastructure which supports both engineering and clinical purposes will of course take time. It will require the following aspects to be addressed.  Establishment of definitions for exposure and dose The definitions for many quantities can be written now and submitted through the IEC standardisation process, with the expectation of achieving international consensus.  Development of validated measurement methods Development of methods to determine some quantities is already proceeding. These will need to be finalised, tested more widely and refined before they can be written into standards.  Development of validated modelling methods The most complete approach developed so far is the 3D Westervelt model. This is a computationally demanding approach which permits the calculation of non-linear field distributions from asymmetric sources in isotropic media. Domain sizes are now sufficiently large to be useful in many situations, but the solutions so far developed are forward-wave only (reflections are not calculated) and rapid spatial variations in the medium properties (for instance to model bone or gas) are not possible. For tissues, relevant physical properties are difficult to measure, and reference methods are missing. All of these issues need to be addressed to enable the development of more accurate models for exposure planning.  Determination of weighting factors relating specific biological effects to precise exposure conditions With the establishment of validated methods to specify and measure exposure levels and delivered dose precisely, it becomes possible in principle to determine the relationship between a particular effect in tissue and the combination of exposure and/or dose conditions that cause it. In doing so, it will also be important to specify the nature of the effect being sought precisely and to account for the high degree of spatial

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variation in exposure conditions that can occur on a submillimetre scale in most ultrasound fields. Of course, the effort to put all of these in place is substantial and will involve National Measurement Institutes, regulatory bodies, academic researchers, manufacturers and clinicians, with results feeding into the International Electrotechnical Commission standards and also into more easily accessible professional and technical good practice guidelines.

Summary and conclusions The need for a coherent set of exposure and dose quantities to describe ultrasound fields in media (including tissue and tissue-simulating materials) which are not water has been discussed. A framework comprising free field quantities, in situ exposure quantities, dose quantities (instantaneous and cumulative) and effect quantities which could act as a structure for organising a more complete set of definitions has been proposed. Findings from a survey of the views of the therapeutic ultrasound community on exposure and dose quantities have been reported. These findings generally support the principles of using modified free field quantities to describe the in situ field, and of prioritising dose quantities which are related to heating and thermal mechanisms. Although there is no one-to-one relationship between any known dose quantity and biological effect, other modalities such as radiotherapy showed the same limitation and this led to the development of a range of weighting factors to calculate the degree of equivalence between different tissues and different radiation types. This same approach can work for ultrasound provided that an appropriate set of recognised ‘engineering’ quantities can be established for exposure and dose quantities. To help encourage innovation, and to advance the use of therapeutic ultrasound further, scientific and medical experts should therefore work with the IEC to establish internationally agreed standards. The areas requiring immediate attention are the definitions, measurement methods and calculation techniques for exposure and dose quantities which can be used for engineering and metrological purposes; a second area, requiring a longer timescale, and much greater clinical research and input, is to determine the weighting factors which will allow the biological effect of exposure to be predicted, in a clinically useful way, from a knowledge of the dose and exposure distributions within the patient.

Acknowledgements The authors would like to thank all partners in the DUTy project and the participants of the workshop held in Heidelberg, Germany on 14–15 June 2012 for fruitful discussions and contributions that have influenced this work, as well as all survey respondents for their input.

Declaration of interest Much of this work was carried out under the European Metrology Research Programme (project HLT-03, Dosimetry for Ultrasound Therapy) with funding by the European Union.

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The EMRP is jointly funded by the EMRP participating countries within EURAMET and the European Union. Adam Shaw was also funded by the Acoustics and Ionizing Radiation Programme of the National Measurement Office of the UK Department for Business, Innovation and Skills. Gail ter Haar is in receipt of funding from the Focused Ultrasound Foundation for the study of QA and dosimetry for therapeutic ultrasound. The authors alone are responsible for the content and writing of the paper.

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