Abstract
The vascular supply of tumours and the tumour microenvironment both play an important role when tumours are treated with hyperthermia. Blood flow is one of the major vehicles by which heat is dissipated thus the vascular supply will influence the ability to heat the tumour. It also influences the type of microenvironment that exists within tumours, and it is now well-established that cells existing in areas of oxygen deficiency, nutrient deprivation and acidic conditions are more sensitive to the effect of hyperthermia. The vascular supply and microenvironment are also affected by hyperthermia. In general, mild heat temperatures transiently improve blood flow and oxygenation, while higher hyperthermia temperatures cause vascular collapse and so increase the adverse microenvironmental conditions. Being able to image these vascular and microenvironmental parameters both before and after heating will help in our ability to predict and assess response. Here we review the various techniques that can be applied to supply this information, especially using non-invasive imaging approaches.
Introduction
The establishment of a functional vascular supply is essential for tumour growth, and hence new vessels are constantly being formed in proliferating tumours Citation[1], Citation[2]. However, tumour angiogenesis is highly unregulated and lags behind the rapid tumour cell proliferation. The resulting vasculature also possesses several marked differences from the vasculature encountered in the corresponding healthy tissue from which it was derived Citation[3]. It is chaotic, displaying extensive branching and shunts Citation[4]. Vessels are leaky and lack many of the control mechanisms encountered in normal vasculature Citation[3], Citation[5]. As a consequence, tumour blood flow is highly heterogeneous often resulting in significant tumour areas with decreased oxygen and nutrition supply and low extracellular pH Citation[4], Citation[6], Citation[7]. The tumour vascular supply and the resulting tumour microenvironment play a significant role in the response of tumours to hyperthermia treatment ().
Figure 1. Schematic representation of the tumour vasculature and microenvironment and their role in the response to hyperthermia. The tumour vascular supply controls heat deposition. It also delivers oxygen and nutrients to the tumour, thus controlling the microenvironment, and cells that exist in areas where these are deficient are more sensitive to heat damage. Both the vasculature and microenvironment are also influenced by heat, but this is dependent on the temperature of the hyperthermia treatment.
Arguably, the predominant factor governing tumour response to hyperthermia is blood flow. By virtue of convection blood flow constitutes the most potent cooling mechanism. Hence, animal studies have demonstrated a clear connection between tumour blood flow and the ability to heat the tumour Citation[8], Citation[9]. In the latter case it was clearly shown that decreased blood flow resulted in a marked increase in the attainable tumour temperature. However, response is also highly dependent on the local tumour microenvironment, especially with regard to oxygenation and nutritional status, and extracellular pH. In vitro studies exploring the importance of these factors showed that cells incubated under these adverse conditions were more susceptible to heat damage Citation[10–12]. These results have been corroborated by in vivo studies in which the tumour vascular supply was compromised. This has been achieved with physiological modification, such as clamping Citation[13], Citation[14] or physiological agents Citation[15–17]. More recent approaches have utilised so-called vascular disrupting agents (VDAs), which selectively disrupt the established tumour vasculature Citation[18–20]. Such studies showed a clear connection between optimal timing of administration of the vascular modifier for the best enhancement of the hyperthermia response and the time at which maximal shutdown of blood flow was achieved. Additional studies have demonstrated that this improvement in heat response is due partially to a better heating but mostly results from an increase in the heat sensitive adverse microenvironmental conditions within the tumour Citation[15], Citation[28–30].
Although tumour vasculature and the resulting microenvironment influence heat response, these parameters themselves are also affected by heat in return (). When performing mild temperature hyperthermia the initial result is often an improvement in tumour oxygenation status resulting from a heat-induced increase in blood flow in general and in oxy-haemoglobin saturation in particular Citation[19], Citation[24]. At higher temperatures the reverse effect comes into play. Although these higher temperatures may initially lead to an increase in blood flow, vascular damage rapidly ensues with a decrease in tumour blood flow as an immediate result Citation[19], Citation[24]. The decreased blood flow will lead to the adverse conditions described above, but if prolonged may ultimately lead to cell death.
During recent years substantial effort has been put into extending diagnostic imaging to visualisation and quantification of molecular processes Citation[25]. These advances include non-invasive, image-based quantification of vascular parameters, oxygen tension, pH as well as nutritional and energetic status. Knowledge of the spatial distribution of these parameters prior to heat treatment would facilitate prediction of the effect of heating. Post-treatment imaging would additionally enable assessment of the actual efficacy. However, it is important to remember that when applying methods which rely on reference tissue this tissue must be unaffected by the heat treatment, if treatment response is to be measured.
The aim of this review is to present those methods that are currently available for imaging and measuring the pathophysiological parameters involved in hyperthermia treatment in oncology. lists the various methods that can, and often have, been used to monitor the various pathophysiological parameters affected by hyperthermia. For each respective parameter the imaging methods are grouped under those based on magnetic resonance (MR), positron emission tomography (PET), or after techniques. The rationale for such separation is because, as shown in the table, MR- and PET-based methods can actually be used to identify all the relevant heat-related parameters. They are also two of the most commonly used non-invasive techniques in clinical imaging. Below and in the table we have chosen, as a rule, to apply a strict definition of imaging methods, such that only modalities that produce the spatial distribution of the parameter in question have been included. For example, methods such as Xe-clearance and Rb-uptake, which measure global tumour blood flow and perfusion respectively, would not be considered imaging methods.
Table I. List of various parameters of importance for heating and the different methods for imaging them. MR, magnetic resonance; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; DSC-MRI, dynamic susceptibility contrast magnetic resonance imaging; BOLD, blood oxygenation level dependent; VSI, vessel size imaging; NIRS, near infrared spectroscopy; EPR, electron paramagnetic resonance; SPECT, single photon emission computed tomography; CAIX, carbonic anhydrase IX.
Tumour vascularisation parameters
Historically, tumour blood flow/perfusion has been measured by a variety of techniques, including microspheres, radioactive and non-radioactive tracer uptake and clearance, laser Doppler flowmetry, and even heat clearance Citation[26], Citation[27]. Unfortunately these procedures are often invasive in nature and do not deliver information on the spatial distribution of the measured parameter. Information about the spatial distribution of, for example, blood vessels, although this method is highly invasive, can be obtained with histological markers. For a non-invasive and spatially sensitive approach there is dynamic contrast-enhanced (DCE-) MRI. This method involves injecting a contrast agent into the host and obtaining signal time curves that show a signal increase related to the concentration of contrast agent and can be converted to concentration time curves Citation[28–30]. These dynamic data can be analysed in each image voxel or the signal can be averaged for regions of interest (ROIs). Both signal time curves and concentration time curves can be analysed semi-quantitatively; the semi-quantitative parameters are typically initial area under the curve (IAUC); maximal (peak) signal enhancement, which reflects perfusion and cell density Citation[31]; initial slope or signal enhancement rate, which relates to perfusion and permeability; and time to peak. IAUC depends on complex and unknown combinations of several physiological parameters including blood volume, perfusion, vessel permeability surface area product, and extravascular extracellular space (EES). However, IAUC can be interpreted as a qualitative measure for the general level of vascularisation Citation[32]. Furthermore, it is easy to calculate, suffers from fewer assumptions than quantitative model parameters, and has shown good reproducibility Citation[33], Citation[34].
Kinetic model analysis further separates the physiological parameters and yield quantitative measures. This approach requires either a priori estimates of the arterial input function or a direct measurement. Tofts et al. Citation[35] standardised quantities and symbols in the general kinetic model based on the model of Kety Citation[36] to a widely used model. The estimated parameters are: Ktrans, the transfer constant from plasma to the EES; kep, the rate constant from here back to plasma; ve, the volume fraction of EES. The general kinetic model assumes that the blood plasma volume fraction, vp, is 0, but vp can be included and assessed in the model Citation[35].
Ktrans depends on both blood flow and the permeability surface area product because these factors limit the extravasation. In the flow limited condition where permeability is high Ktrans reflects mainly blood flow, and in the permeability limited condition, Ktrans reflects mainly the permeability surface area product Citation[35]. More complicated models separate perfusion and permeability, for example, the model proposed by Lawrence and Lee Citation[37].
Another MR approach utilises the variations in magnetic susceptibility between blood and tissue. The susceptibility imaging methods are based on the transverse relaxation rates, R2 and , which are increased by common intravascular contrast agents. The resulting gradient echo and spin echo signals have been explored analytically, by simulations, and experimentally with the aim of understanding and utilising the susceptibility contrast properties. This has been utilised for measurements of blood flow, blood volume and mean transit time by first pass tracer kinetics Citation[38–40].
DCE-MRI provides information on vascular permeability. Ktrans depends on perfusion and permeability surface area (PSA) and can under certain conditions be assumed to reflect either perfusion or PSA alone Citation[35]. Contrast agent size influences the kinetics because of vessels’ permeability for different particle sizes. Using large contrast particles, Ktrans depends mostly on PSA. Many studies are performed with smaller contrast agents such as Gd-DTPA, which extravasates in normal tissue such as muscle, and often to a higher degree in the often highly permeable tumour vessels. Larger contrast agents, which do not extravasate in normal tissue, may extravasate in tumour tissue, but showing slower kinetics such that a longer dynamic scan may be appropriate.
The finding of specific differences in vessel size dependency of R2 and in susceptibility imaging has led to the MRI method vessel size imaging (VSI) Citation[41–43]. Δ
, the
change caused by the contrast agent, is proportional to the blood volume independently of the vessel sizes when these are at capillary size or above, whereas ΔR2 is most sensitive to smaller vessels. By these quantities, VSI quantitatively estimates blood volume and mean vessel size R. VSI can be performed on cerebral dynamic susceptibility contrast MRI data using standard gadolinium chelates Citation[42] or iron oxide contrast agent Citation[44], or in other organs using a contrast agent that remains intravascular sufficiently long to allow R2 and
measurements at steady state Citation[41], Citation[43], Citation[45]. Besides contrast agent administration, the blood content of the paramagnetic deoxyhaemoglobin can provide vascular information through the relaxation rate
in blood oxygenation level-dependent (BOLD) imaging Citation[46–48]. In VSI,
is measured and can be analysed separately or compared with VSI parameters obtained with contrast agents.
Non-invasive blood flow imaging can also be obtained with dynamic PET scans using 15O-labelled water and has been applied in some clinical studies. PET-derived tumour perfusion estimates have shown good reproducibility Citation[49] and the observation that highly perfused voxels do not retain the PET hypoxia marker 18F-EF5 supports its potential role in blood flow measurements Citation[50]. Qualitative PET-based perfusion assessment requires an accurate input function which can be obtained by continuous blood withdrawal using an image-derived input function Citation[50].
Several of these vascular imaging techniques have already been used in connection with hyperthermia. Both DCE-MRI Citation[51] and PET Citation[52] have been utilised to observe the effects of heating tumours in both animals and humans. In the latter O-PET was used to measure perfusion as well as water diffusion. It was demonstrated that hyperthermia applied for at least 1 h would significantly enhance water diffusion, leading the authors to conclude that this would possibly apply for tumour oxygenation as well. Recently, two studies have attempted to use DCE-MRI measurements in canines Citation[53] and humans Citation[54] to predict response to therapy, albeit with heat in combination with radiation or neoadjuvant chemotherapy, respectively. Computed tomography can be used to monitor many of the same kinetic parameters that are estimated using DCE-MRI, for example Ktrans and the EES which has been done to estimate the response of pancreatic tumours to chemotherapy and radiation therapy Citation[55]. Finally, ultrasound can, especially in combination with contrast agents, be used to provide qualitative estimates of tumour perfusion and its response to radiation therapy Citation[56].
Estimates of tumour hypoxia/oxygenation
A large number of studies have been performed in order to elucidate the relationship between tumour oxygenation and response to heat treatment. Historically this has been performed using invasive micro-electrodes Citation[57–62] to measure actual oxygen tension. Recently a number of non-invasive imaging methods have been developed to measure both oxygen transport and tension parameters, based predominantly on MRI, PET and SPECT. The deoxyhaemoglobin level can also be manipulated by breathing different gasses (e.g., oxygen or carbogen) to indicate vessels, which respond to this Citation[45], Citation[46]. This shows the potential for monitoring blood oxygenation changes without the administration of contrast agents.
A fully quantitative MRI-based method for measuring oxygen tension uses 19F as imaging nucleus. The longitudinal relaxation rate of 19F has been shown to depend on the local oxygen tension Citation[63]. Although this relationship is dependent on the specific fluorine-containing molecule, the dependency is generally linear. A comprehensive list of such molecules and the corresponding coefficients can be found in Yu et al. Citation[64]. Hexafluorobenzene (HFB) has been applied extensively in tumour studies Citation[65–68]. The primary weakness of this approach is the low concentration of the imaged nucleus and consequently low signal. In the case of HFB, this has been remedied by intra-tumoural injection Citation[69], however consecutive systemic intravenous injections on several days before imaging has also been demonstrated to result in a significant accumulation of fluorinated molecules within the tumour. Finally, DCE-MRI has been employed in conjunction with an extended Krogh-model to provide qualitative measurements of oxygen tension Citation[70].
Probably the most direct non-invasive method for monitoring tumour hypoxia involves PET. This primarily involves the use of hypoxia-selective nitroimidazole-based agents (e.g. 18F-fluoromisonidazole, 18F-fluoroazomycin arabinoside), which are reduced enzymatically and trapped when cellular pO2 drops below ∼10 mmHg Citation[71], Citation[72]. In addition to its non-invasive nature, a major advantage of PET is that it can measure global tumour hypoxia status as well as provide three-dimensional maps of regional tumour oxygenation at a resolution down to 100 µL. The major weakness of nitroimidazoles is their slow kinetics, and accurate assessment of hypoxia is therefore only possible several hours after tracer administration, when sufficient tracer has been retained in hypoxic cells and contaminating unbound tracer has cleared from the circulation (for a review on pitfalls in PET hypoxia imaging see Busk et al. Citation[73]). Nitroimidazole-based hypoxia PET scans may be particularly useful for identification of patients with hypoxic (and possible acidic) tumours with reduced sensitivity towards radio and/or chemotherapy, for which a therapeutic benefit from complementary high-temperature hyperthermic treatment is most likely. However, the ability of PET hypoxia imaging to actually identify tumours suitable for hyperthermic treatment has never been tested in patients or animal experimental models, but clearly such studies would be highly valuable.
Due to the aforementioned slow tracer distribution, the usefulness of nitroimidazole-based hypoxia PET to assess the magnitude and durability of the increased oxygenation following mild temperature hyperthermia is more questionable since most studies suggest that enhanced oxygenation in heated tumours is short-lived (minutes to a few hours). In contrast, invasive immunohistochemical quantification of cellular retention of unlabelled nitroimidazole hypoxia markers has been used to assess the magnitude and kinetics of mild-temperature hyperthermia-induced reoxygenation in an animal model. By sequential administration of the two comparable but separable to the nitroimidazole-based hypoxia markers pimonidazole and EF5 before and after treatment, respectively, Sun and colleagues Citation[74] were able to show an improvement in oxygenation in a human colon adenocarcinoma xenograft tumour model 1 h after hyperthermic treatment at 41°C, but the effect had disappeared by 6 h.
Copper-diacetyl-bis (N4-methylthiosemicarbazone) (ATSM) complexes belong to another group of PET hypoxia tracers which has been shown to accumulate in hypoxic cells in vitro and in vivo Citation[75], Citation[76], by a poorly understood mechanism. 64Cu-ATSM, the most widely used compound, distributes much more rapidly than the nitroimidazole-based agents, and it was shown in a recent study that 64Cu-ATSM PET scans are able to detect even short-lived changes in tumour hypoxia elicited by local heating to 41.5°C for 45 min Citation[77]. Complementary electrode measurements confirmed that the PET-observable changes were correlated with real changes in tumour oxygenation Citation[77]. However, the hypoxia specificity of 64Cu-ATSM is apparently tumour-type dependent Citation[78], Citation[79], and furthermore, it was shown by Matsomoto and co-workers Citation[80] that 64Cu-ATSM PET was unable to detect changes in tumour oxygenation induced by exposing tumour-bearing mice to hypo- or hyperoxic gas mixtures. Accordingly, the general value of 64Cu-ATSM as a means to detect transient changes in tumour oxygenation needs to be verified in a broad selection of preclinical tumour models using various interventions to modify tumour hypoxia.
Radioactively labelled tracers have been used to measure oxygen tension for a number for years using in general iodoazomycin containing molecules such as iodoazomycin arabinoside (IAZA). IAZA labelled with 123I and 125I has successfully been utilised to measure tumour hypoxia Citation[81–83]. Minimally invasive quantitative measurements of oxygenation can also be performed in blood with near-infrared spectroscopy Citation[84] and tissue electron paramagnetic resonance Citation[85]. However, none of these techniques have been combined with hyperthermia in oncology.
Measuring pH
The importance of tumour pH in determining response to heating Citation[10–12] has resulted in numerous attempts to monitor it. Most of these have involved using invasive electrode-based measurements, which only estimate extracellular pH Citation[4]. Intracellular pH values can be obtained using MR-based techniques Citation[4] utilising either endogenous agents or following the administration of exogenous agents Citation[86–88]. One of the more popular approaches for estimating pH is based on 31P magnetic resonance spectroscopy (MRS) of inorganic phosphate, and indeed this method has been used to monitor pH distributions before and after heat treatment Citation[89], Citation[90]. Although, strictly speaking MRS is not an imaging method, there are sequences facilitating spatially selective measurements. Tumour pH can also be imaged with magnetisation transfer (MT), which exploits the differences in dephasing rates between free water and water bound by hydrogen bonds to macromolecules such as lipids and proteins, and the subsequent effects on the MR-signal when magnetisation is transferred from the bound pool to the liquid/free pool Citation[91]. Alternatively, one can inject probes with either pH-sensitive 19F or 1H resonances. None of these other approaches have yet been combined with hyperthermia. There is also the possibility to utilise PET to non-invasively image pH. Carbonic anhydrase IX (CAIX) is a pH-responsive protein that is often up-regulated in the adverse microenvironment. Antibodies to CAIX have now been developed which are detectable by PET Citation[92] making pH assessment feasible.
Estimating bioenergetic status
Another important parameter involved in the response to hyperthermia is the metabolic or energy status of tumours. Glucose or lactate levels, for example, will influence pH. Heat itself has also been shown to dramatically change metabolic and energy status within tumours Citation[93]. Many of these parameters can be measured with MRS. 1H spectroscopy allows identification of creatine, phosphocreatine, lactate and glucose, while with 31P spectroscopy, information about phosphocreatine, ATP, ADP, and inorganic phosphorous can be assessed. Investigation of tumour glycolysis through glucose and lactate is possible by the use of 13C-labelled glucose Citation[94].
A surrogate marker of glucose metabolism is fluorodeoxyglucose (FDG) and this is the most commonly used PET tracer in oncology with a huge role in diagnosis, prognosis and treatment-efficacy monitoring (for a review see Hoh Citation[95]). FDG takes advantage of tumour cells’ excessive dependency on glycolysis as a means to produce energy (referred to as aerobic glycolysis or the Warburg effect). Since most glucose is converted to lactic acid in tumour cells, FDG-PET may also provide indirect information on the acid-base status of tumours, especially when combined with blood flow measurements.
Functional imaging with FDG-PET may be useful for rapid assessment of tumour response to treatment, long before morphological changes are evident. In particular, many studies have shown that reduced FDG retention shortly after initiation of a treatment course with radio- and/or chemotherapy correlates well with treatment sensitivity, which allows treatment modification in non-responders (reviewed by Citation[96], Citation[97]). A few studies have examined the usefulness of FDG-PET to predict tumour response in patients treated with hyperthermia and radiotherapy. Ishii and co-workers Citation[98] showed that early evaluation by FDG-microPET, especially 24 h after treatment, is useful to predict the effects of combined radiotherapy (10 Gy) and hyperthermia (43°C for 1 h) in tumour-bearing rabbits. Furthermore, in a clinical study it was concluded that FDG-PET performed before and two weeks after initiation of combined chemoradiation and hyperthermia in patients with oesophageal cancer were able to separate responders and non-responders with reasonable accuracy Citation[99].
A more invasive method for assessing bioenergetic status involves using the bioluminescence technique Citation[100]. This involves exposing frozen tissue selections to a cooled mixture of enzymes and co-enzymes which link the substrate of interest to a luciferase reaction that occurs and can be imaged on warming. Although invasive it does give microenvironmental metabolite concentrations and has been used to monitor the effect of hyperthermia Citation[93].
Conclusions
Hyperthermia is an effective cancer therapy when used in combination with other more conventional treatments, especially radiotherapy Citation[101], but it is has not become an established form of therapy. What is now needed are techniques that are reliable, accurate, easy to apply to patients on a routine basis, and preferably non-invasive for monitoring the more important factors that can both influence response to heat and are indicative of the efficacy of the heating. Since the tumour vascular supply and microenvironment play such an important role in determining the response to heat and are themselves influenced by heating, utilising methods that can actually measure these parameters would clearly be the way to proceed. There are a number of ways that this can be done non-invasively and of these, MRI and PET would certainly seem to be the methods of choice, especially since they are already well-established clinical procedures used routinely in hospitals. Both techniques have been used to some limited extent in connection with hyperthermia, but their full potential in this context has not been achieved. Clearly, additional studies with these procedures are required so that we take full advantage of the beneficial use of hyperthermia in a therapeutic setting.
Acknowledgements
This work has been supported by grants from the Danish Cancer Society and the Danish Research Agency.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Related Research Data
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