British Journal of Radiology (2005) 78, S86-S93
© 2005 British Institute of Radiology
doi: 10.1259/bjr/75936537
Pelvic malignancy: integrating form and function
A S K Dzik-Jurasz, PhD, FRCS, FRCR
Epix Pharmaceuticals, 161 First Street, Cambridge, MA 02142, USA
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Abstract
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Despite the essential role morphological imaging plays in the management of patients with malignancy, anatomical techniques are limited in their ability to report on tumour biology and behaviour. It has therefore been necessary to develop imaging techniques that integrate form and function to probe the micro and molecular environments of cancers. The role of clinical functional and molecular magnetic resonance imaging is discussed with an emphasis on pelvic malignancy. It is argued that the radiological sciences need to take a lead in translating molecular and functional imaging techniques into man. Imaging in support of drug development is suggested as a focus for that development.
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Introduction
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Integration implies an outcome that is greater than the sum of its parts. Integrating form and function is expected to improve our understanding of the mechanisms and management of disease. This article explores how form and function can be used cooperatively in the study of malignancy with a focus on pelvic neoplasms. Since molecular mechanisms underlie many aspects of oncology the role of molecular imaging will also be discussed. The areas which are most likely to benefit from such integration include:- Tumour biology
- Clinical management
- Therapeutic drug development
- Inform and guide innovative technologies
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Form and function in imaging
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The development of cross-sectional imaging is one of the undeniable successes of modern medicine [1]. However, for all its power in visualizing disease, anatomical imaging remains limited in informing on tumour biology and function [2]. It is now accepted that the characteristic imaging features (Figure 1
) of cancer significantly lag behind the genetic and molecular processes that define neoplasia [3]. The advent of molecularly targeted anticancer therapies with their emphasis on earlier and focal therapeutic intervention have defined a need to image those molecular events. This need has been the driving force behind the development of molecular imaging [4, 5]. Much of the work in molecular imaging has focused on validating technologies in experimental systems. The next phase in the development of the discipline will be the translation of those methodologies into man. A fundamental challenge will be to achieve the appropriate sensitivity to visualize targets of interest. Yet, in vivo systems are complex and an understanding of the tumour micro and molecular environment will inform on the appropriate application of technology.
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Figure 1. Coronal T2 weighted image of a previously treated anal cancer in an adult female patient. The arrows indicate the extent of perianal fibrosis following chemoradiotherapy. Despite the exquisite sensitivity of MRI to soft-tissue anatomy this image reveals little about the underlying tumour biology.
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Tumour micro and molecular environments
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The tumour microenvironment represents a composite of interactions which include the tumour and host response mediated via processes such as angiogenesis [6, 7] and hypoxia [8, 9]. The inevitable alteration of these processes over time and location in the tumour results in an additional layer of complexity which explains, for example, the phenomenon of treatment resistance [10–12]. The tumour microenvironment is now being studied in the clinic via several modalities including magnetic resonance (MR) [13–15], in an attempt to respond to the Darwinian behaviour of cancer [16]. Behaviour is mediated via receptors that are inappropriately or abnormally expressed, unsurprisingly, therefore these represent the targets of molecularly focused therapies. It is these targets that imaging seeks to visualize either directly or indirectly. All the clinical imaging modalities have a role in probing these environments according to their individual strength and sensitivity. The role of MR in these studies will now be examined more closely.
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MR in the assessment of the tumour microenvironment: focus on pelvic malignancy
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MR studies of malignancy provide a good example of the integration of form and function. The high spatial resolution of MRI, for example, provides for the staging and prognosis of rectal cancers prior to total mesorectal excision [17–20]. However, the sensitivity of MR to the biophysical characteristics of tissues allows additional assessment of tumour physiology and biochemistry. For example, the application of tracer kinetic models to the T1 signal modulating characteristics of gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) [21] provides information on capillary permeability and insight into tumour blood flow. Additionally, a T2* weighted strategy provides data on tumour blood flow [14], a factor known to be of importance in the therapeutic response of cancers [22–24]. Diffusion weighted imaging (DWI) is a technique that has recently attracted much attention. In DWI the MR sequence is made sensitive to the translational motion of the nuclear species of interest (Figure 2). In clinical studies the nuclear species most commonly examined are water protons. Contrast variation results from the degree of restriction water molecules experience in their immediate molecular environment. In the presence of necrosis there is little to impede the motion of molecules whilst a water molecule will experience considerably more restriction in an area of high cellularity. DWI is therefore sensitive to the structural properties of tissues. Exploiting this property, DWI has been shown to predict outcome and inform on early response to treatment to anticancer therapy both clinically [25, 26] and pre-clinically [27, 28]. MR can further provide insight into tumour and anticancer drug metabolism via MR spectroscopy (MRS) [29]. As in MRI, spectroscopy reports on the signal from a MR sensitive nucleus but in contrast to imaging are represented as a signal on a frequency or parts per million (ppm) scale. The strength of the technique lies in the exquisite sensitivity of nuclei to their chemical environment. Small changes in chemical structure are reflected in the configuration of the molecule's electron cloud, which in turn modulates the local magnetic field. The result is that distinct chemical species resonate at different frequencies (Figure 3) and it is therefore possible to resolve and identify them. Spectroscopic cancer studies typically probe inherent tumour metabolism including the tumour metabolism's alteration by therapy [30]. Alternatively, it is possible to examine anticancer drug metabolism in the clinic via studies of nuclei such as 19F [31].
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Figure 2. Cartoon depicting diffusion of water molecules in two alternative environments. (a) In a region of high cellularity the translational motion of individual water molecules is considerably impeded. (b) In an area with substantial cell loss such as occurs with necrosis and/or apoptosis the translational motion of water molecules is relatively unimpeded. The degree of restriction of molecular translational motion is manifest as contrast differences on a diffusion weighted image and can be quantified. Cartoon courtesy of Dr P Murphy, Pfizer, Inc.
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Figure 3. A 1H-MRS (a) short echo time and (b) long echo time spectrum from a locally advanced rectal cancer. The sensitivity of MRS to different local magnetic fields generated in the molecule's electron valency clouds results in chemical species resonating at different frequencies. This is the basis for the different peaks illustrated in this example and allows investigators to probe the metabolism of cancers in vivo. Reprinted from [35].
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Recent advances in the sensitivity and temporal resolution of MR hardware coupled with substantially enhanced computing speeds has allowed the integration of morphological and functional studies (Figures 4 and 5). The expectation from such "integrated multifunctional" studies in the pelvis is that they will bring additional insight into tumour biology. Key areas of likely value include:- Prognostic information
- Early assessment of response
- Patient and dose stratification
- Information on molecular targets
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Figure 4. Composite of images depicting the output of a multifunctional MRI and MRS study in locally advanced rectal cancer. (a) Axial T2 weighted anatomical image (yellow arrows), (b) a Ktrans map which depicts capillary permeability, (c) a relative blood volume map derived by exploiting the first pass T2* effect. Note this tumour has a low blood volume (the high signal intensity anteriorly is the high blood volume within the body of a recently gravid uterus). (d) A diffusion weighted image. This quantitative map permits pixel-by-pixel analysis of tumour ADC (apparent diffusion coefficient). (e) A 1H-MRS spectrum. 1H-MRS can be used to probe tumour metabolism.
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Figure 5. Composite set of images from a multifunctional MRI study of a T2 stage prostate cancer. (a) The T2 anatomic image (yellow arrow). (b) The Ktrans and (c) relative blood volume maps. (d) The diffusion ADC image depicts the cellularity of the prostate whilst (e) the T2* imaging module has been implemented to probe for possible sensitivity of MRI to hypoxia.
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The latter in this list is the focus of the rapidly expanding discipline of molecular imaging whilst the former three are central to the concept of "personalized medicine". The concept of personalized medicine is based on the premise that, amongst others, molecular information on disease can influence patient management. In oncology this would translate into improved survival, quality of life and reduced patient toxicity.
Such an integrated multifunctional approach has been applied in the study of locally advanced rectal cancers treated with combined chemotherapy and radiotherapy. In addition to a clinical staging T2 sequence it was possible to acquire T1 based gadolinium kinetic data (permeability) and T2* data on tumour relative blood volume (rBV). A BURST [32] based diffusion weighted sequence provided structural information whilst 1H-MRS was used to interrogate tumour metabolism. The findings of the study indicated a strong association between final response as measured by reduction in tumour size and the pre-treatment measure of permeability [33], rBV and apparent diffusion coefficient (ADC). The strongest association was found to be between pre-treatment ADC and response to chemotherapy and chemoradiotherapy [26]. Our hypothesis is that the ADC value is a surrogate marker of necrosis. Although the association between necrosis, hypoxia and poor outcome to radiotherapy has been recognized for many years [34], this is arguably the first opportunity for clinicians to use a non-invasive imaging tool that might inform on patient stratification. Clearly larger studies in this and other tumour types need to corroborate this pilot study but these initial findings suggest a clear use for functional imaging in malignancy.
The results of the 1H-MRS [35] are worth reviewing albeit for the technical difficulties encountered during the study. MRS is a powerful tool that is used daily by chemists in the determination of chemical structure. The translation of the technique to human studies is however technically demanding. In our study we recorded spectra in only 29% of individuals. Residual pockets of luminal air were found to be the principle limitation in positioning a sufficiently large voxel. As a result there was a substantial limit on metabolite sensitivity. There remains hope that improved coil technology and increased field strength will provide the increased sensitivity to tumour physiology and metabolism.
In addition, we have also initiated a multifunctional MRI study into early stage prostate cancer (Figure 5
). There is currently considerable controversy over the optimal management of early stage prostate cancers [36]. Management currently directs either early therapeutic intervention or active surveillance. We have hypothesised that multifunctional imaging of the prostate might identify imaging biomarkers that will facilitate decision making in early stage disease. We were guided in our imaging strategy by the strong influence hypoxia is known to have on prostate cancer [37]. Hypoxia has a complex relationship with malignancy and is known to influence and be mediated by several molecular mechanisms [8]. Perhaps the best known of these is the HIF-1 (hypoxia inducible factor) pathway [38]. Clearly vascularity is closely related to the oxygen tension in an environment and it should therefore be unsurprising that tumour angiogenesis is also intimately related to tumour hypoxia [39], as is tumour cellularity. For these reasons the current prostate cancer study incorporates a permeability and perfusion module to assess tumour vascularity. A T2* sequence has also been incorporated because of its known sensitivity to tissue oxygenation. A diffusion sequence is also run in order to assess tumour cellularity. Only preliminary data are available but demonstrate promising repeatability. Repeatability in the data is an important factor in quantitative clinical imaging as considerable physiological variation is known to occur in several of the parameters recorded in this study [40].
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Molecular imaging: investing in the future of radiology
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Rapid advances in our understanding of the molecular mechanisms of disease have led to a need to non-invasively image those events. Principally, the advances have been made in the field of pre-clinical imaging where combining chemistry, biology and technology have allowed the visualization of single molecular events. Many of these advances have been translated in vivo where exposure of animals to physical stresses and drug concentrations can exceed those tolerated in man.
Disease areas ready for translation via molecular imaging into man include:
- Angiogenesis
- Apoptosis
- Hypoxia
- Gene expression
Clinically the most advanced of these areas is angiogenesis imaging (Figure 6). By combining the high spatial resolution of MRI with kinetic tracer modelling [41–43] estimates of tumour vascularity can be determined. The value of kinetic models is ease in comparing data across sites and scanner types. In addition, the data output are increasingly being validated against the underlying biology [33, 44]. The hope is these clinical research tools will translate to wider clinical use. Clinically, angiogenesis imaging has most successfully been applied to the assessment of anti-angiogenic and antivascular therapies in clinical trials [14, 44, 45]. Dynamic contrast MRI (DCMRI) has been used to demonstrate proof of concept and dose effects with antivascular therapies. Initial indications suggest that DCMRI has prognostic potential but it remains to be determined whether DCMRI acts as an independent prognostic indicator.
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Figure 6. Cartoon of the molecular structure of vascular endothelial growth factor (VEGF). VEGF is potent angiogenic peptide that induces endothelial cell growth as well as increasing the permeability of blood vessels. VEGF is typically over-expressed by tumours and is a principal factor in the altered vascularity of tumours. It is also the target of several molecularly targeted anti-angiogenic therapies. The image was obtained from http://www.rcsb.org/pdb/.
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Apoptosis is the process via which cells undergo programmed cell death [46]. Apoptosis is, for example, essential in the development of all multicellular organisms. Since survival in perpetuity is a feature of malignancy it is unsurprising that the normal apoptotic process is typically inhibited. Apoptosis is therefore a recognized therapeutic target [47] as well as being a focus in the search for MRI and MRS markers of prognosis and early response [48].
Since cancer is a genetic disease [16] the therapeutic approach of gene therapy seeks to replace the mutated cancer genes. Although this remains technically challenging a variation of this approach has been applied in targeted pro-drug therapy [49–51]. In this strategy an exogenous gene is inserted into the host genome which converts a therapeutically innocuous compound into an active drug. A variety of technical issues need to be addressed including the assessment of gene transfection. One approach has been to demonstrate the conversion of pro-drug to drug using MRS. Since MRS is sensitive to the chemical structure of compounds the conversion of pro-drug to drug alters the chemical structure of the pro-drug sufficiently to be resolved via MRS. The conversion of pro-drug to drug has been demonstrated in animal systems [52, 53] but should be seen in man given the high doses of pro-drug administered in some regimens. Additional nuclear conspicuity could be gained by detecting a nucleus rarely found in nature such as 19F. The similarity in the magnetogyric ratio of 19F compared with 1H conveys the highest sensitivity of all the naturally occurring X-nuclei (i.e. nuclei other than 1H).
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How should radiology invest in the future of molecular imaging?
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Developing a molecular imaging research program is not a trivial undertaking. The hardware, laboratory and above all human resources are currently in scarce supply particularly in the UK. A first step would be the cooption of academic and clinical groups that historically rarely interacted. Radiologists and radiological scientists must be prepared to learn and speak the language of chemistry, molecular biology and genetics. Reassuringly public and private (particularly the large pharmaceutical companies) funding bodies and organizations have recognized the importance of investing in molecular imaging. At the time of writing of this article drug development is the area investing most heavily in molecular imaging. With the high in vitro screening rates currently available [54] the early stages of drug research are no longer rate limiting. The focus has therefore turned to the assessment of lead compounds in vivo. Critical issues requiring in vivo confirmation include compound targeting and receptor modulation. The non-invasive quantitation, validation and identification of molecular targets are an active area of research. In vivo this issue can best be assessed by positron emission tomography (PET) imaging, explaining the recent investment in this technology by several large pharmaceutical companies. The roles of CT, MRI and ultrasound are focused on the later clinical trial stages where, for example, DCMRI has proved a useful tool in demonstrating a secondary pharmacodynamic end point in a human antivascular phase II trial [55].
Some overlap will exist between the needs of drug developers and clinical researchers where common goals such as prognostic, early response markers and stratification regimens are being explored. It is important to realise that the needs of drug development are different from the needs of clinicians in respect of imaging biomarkers. In drug development needs are led by regulatory and market as well scientific considerations and biomarkers are looked to as facilitators of decision making. Issues of importance to a pharmaceutical project manager include:
- Pharmacokinetic and pharmacodynamic data
- Compound kill
- Proof of concept
- Dose and patient stratification
- Insights into drug toxicity
Compound kill is a big decision in the drug development process as considerable costs would already have been incurred in taking a compound to clinical trials. Therefore there has to be considerable confidence in the interpretation of the imaging data. In vivo PET biodistribution and quantitation studies have previously influenced the decision to kill compounds. To the author's best knowledge no other clinical imaging modality has substantially influenced the decision to kill a compound. Toxicity remains almost unexplored via imaging but is the cause of over half of all compounds not reaching clinical development. Insight into the mechanisms of in vivo toxicity or early markers would be warmly welcomed by the drug development community.
Imaging remains one of many available biomarkers, many of which are considerably cheaper. A pharmaceutical project manager expects a cheap, validated, robust and repeatable tool to aid in decision making. Currently outside of PET applications in neuropsychiatry and oncology there are very few validated imaging biomarkers. DCMRI in angiogenesis imaging is probably the best non-PET example currently available. Nevertheless it is important to remember imaging is an expensive commodity and there are strong arguments in favour of seeking simple and cheap in vitro solutions to the biomarker problem.
There is no doubt imaging will play a substantial role in the evolution of clinical practice and research. The focus will be on the molecular targets of disease with the prospect of earlier detection of disease, targeted therapies and individualized patient treatment. The role of radiology in the molecular future of imaging will depend on the will of radiologists and their representative bodies to embrace and lead in this new discipline.
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Acknowledgments
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Dr Andy Dzik-Jurasz is an honorary senior lecturer at the Institute of Cancer Research and honorary consultant radiologist at the Royal Marsden Hospital NHS Trust, London. No financial conflicts are declared.
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Abstract
Introduction
