British Journal of Radiology (2005) Supplement_28, 50-54
© 2005 British Institute of Radiology
doi: 10.1259/bjr/83746792
British Journal of Radiology Supplement_28 (2005),50-54 ©2005 The British Institute of Radiology
The potential of PET to increase understanding of the biological basis of tumour and normal tissue response to radiotherapy
C M L West, PhD1 and
N Charnley, FRCR2
1 Academic Department of Radiation Oncology, The University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX and 2 Wolfson Molecular Imaging Centre, The University of Manchester, Christie Hospital, 27 Palatine Road, Manchester M20 3LJ, UK
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Abstract
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Imaging is playing an increasing role in the management of radiotherapy patients in terms of diagnosis and treatment planning, thus providing a stimulus for an expansion in its parallel development as a tool for imaging tumour biology in man. Positron emission tomography can be used to image not only glucose metabolism but also different biological processes involved in radiotherapy resistance such as hypoxia, blood flow and proliferation. It has potential for increasing our understanding of the biological mechanisms underlying the heterogeneity of tumour and normal tissue response to radiotherapy. It also has potential for the future definition of biological target volumes in tumours for dose escalation, and in normal tissues for dose reduction.
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Introduction
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The increased availability and use of positron emission tomography (PET) in cancer diagnosis and management provides a rationale for an expansion in its parallel development as a tool for imaging tumour biology in man. PET is a powerful and versatile tool for the sensitive and repeatable imaging and quantifying of cellular and molecular biology in situ in humans. Methods are being developed for imaging biological processes involved in radiotherapy resistance such as hypoxia, blood flow, proliferation, angiogenesis, apoptosis and DNA repair [1]. It has potential for increasing our understanding of the biological mechanisms underlying patient heterogeneity in response to radiotherapy and for the future definition of biological target volumes (BTVs) for dose escalation in patients undergoing radiotherapy.
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PET measurements of hypoxia
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The importance of hypoxia as a factor limiting the curability of radiotherapy is now well recognised. This fact has spurred research into finding methods for the routine assessment of hypoxia in cancer patients. The use of PET is attractive because it can provide a non-invasive, repeatable whole tumour assessment in situ. A number of PET probes are being developed for measuring hypoxia, of which 18F-fluoromisonidazole (18F-FMISO) is the most widely studied. Although, as for many PET probes, the early delivery of 18F-FMISO into tumours correlates with blood flow, its high lipophilicity enables flow-independent measurements of tissue hypoxia around 90–120 min following injection. In contrast, the lower lipophilicity of sugar nitroimidazole and copper compounds make them prone to blood flow influences. A number of centres worldwide have now used 18F-FMISO and shown intertumour heterogeneity in PET measurements of hypoxia [2, 3]. Tumour uptake is generally quantified relative to plasma or muscle levels. Recently, a study in 16 patients with head and neck squamous cell cancers showed a correlation between 18F-FMISO uptake and hypoxia measured using oxygen electrodes [4]. Although the exploration of etanidazole as a PET probe for hypoxia is attractive, it could be argued that, because of its wider use and availability compared with other probes under development, 18F-FMISO should now be considered the gold standard for PET measurements of hypoxia.
PET measurements of hypoxia have been used to show the presence of hypoxia in human head and neck cancer, soft tissue sarcoma, breast cancer and glioblastoma multiforme [3]. A number of small studies are starting to report associations between PET measurements of hypoxia and radiotherapy outcome [5–7]. To address a potential problem that severely hypoxic/necrotic tissues show low uptake of a PET tracer and are ignored when using standardised uptake values, a recent paper described a kinetic model for analysis of dynamic 18F-FMISO-PET data [8]. The model was used to derive parameters that reflected well oxygenated/perfused tissue, diffusion-limited hypoxia, diffusion-limited and structural hypoxia, and strong hypoxia/necrosis. Progress in this area requires studies with a large number of uniformly treated patients, where optimal data analysis can be established with regard to interpretation of PET data in terms of different types of hypoxia and prognosis.
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PET measurements of blood flow
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Hypoxia is an important factor driving tumorigenesis and is a key stimulator of angiogenesis. Blood vessels in tumour versus normal tissue, however, are associated with structural and functional abnormalities. Tumour vessels have blind endings, irregular branching, increased permeability and lack supporting pericytes. These features lead to erratic and inadequate perfusion. Hypoxia, therefore, stimulates both angiogenesis and blood flow in tumours and occurs as a result of the aberrant tumour vasculature that develops. The net result is that, although tumour blood flow can be higher than in surrounding normal tissue (owing to increased angiogenesis), it is heterogeneous between and within tumours and can be associated with the level of tumour hypoxia. Because of this link with hypoxia, there is interest in the radiotherapy research community in measuring tumour blood flow as an indicator of prognosis and response to therapy. Measurements obtained using cross-sectional imaging methods (CT, MRI) have shown a relationship between poor perfusion — or blood flow-related contrast agent enhancement parameters — and an adverse outcome following radiotherapy [9–11]. There are also clinical data supporting a relationship between poor flow — or enhancement parameters — and hypoxia as measured using oxygen electrodes [12–14]. However, it is important to remember that, in the field of anti-angiogenesis drug development, interest in imaging blood flow lies in its use to reflect angiogenesis and to assess response to treatment [15]. The literature cited by those in this field point generally to a positive relationship between high flow and angiogenesis, which is associated with a poor treatment outcome. These apparently contradictory assumptions are not necessarily mutually exclusive [16] but highlight the need to increase our understanding of the pathophysiology of tumours and the complex inter-relationships between blood flow, hypoxia and angiogenesis. Such information is required so that the various parameters can be optimally measured.
Although a number of PET probes are available for imaging tissue perfusion, 15O-labelled water is a well-validated standard and has been used widely in brain and cardiac PET studies. Its short half-life (minutes) make its use in dual scanning studies attractive. Interestingly, a dual scanning study in brain tumours showed hypoxia (18F-FMISO) in both well and poorly perfused regions of tumours [2]. This observation suggests that at a regional level — the spatial resolution of PET is around 8 mm — the presence of hypoxia is independent of the level of perfusion.
PET has the potential to increase our biological understanding of tumours in this area. For example, PET studies could explore: whether the discordance between perfusion and hypoxia is a widespread phenomenon between and within tumour types; how different patterns of hypoxia and perfusion distribution relate to adaptation of the tumour microenvironment during the development of hypoxia tolerance (i.e. early vs late stage disease); and how the patterns relate to the prognosis of radiotherapy patients, i.e. which co-localisation patterns should be incorporated within BTVs for different types of tumours.
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PET measurements of glucose metabolism
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Several small studies have shown that the commonly used 18F-fluorodeoxyglucose (18F-FDG)-PET tracer can provide data that are prognostic for the outcome of radiotherapy, with high glucose metabolism associated with a shorter survival [17]. FDG uptake reflects glucose transport (Glut-1 activity) [18], which is enhanced in tumours owing to their generally increased anaerobic glycolysis as a result of increased proliferation and hypoxia compared with surrounding normal tissues. A relationship between FDG uptake and Glut-1 expression in tumours is well established [18]. The uptake of FDG increases under hypoxia and a correlation between FDG-PET data and hypoxia has also been shown [3]. This latter observation is consistent with a weak relationship between Glut-1 expression and hypoxia reported in human tumours [19]. It must be stressed, however, that FDG does not measure hypoxia and that its use as a possible surrogate assay for hypoxia is not a good idea. The uptake of FDG into a tumour can also correlate with proliferation measured as a Ki-67 index [18]. Thus, although FDG-PET can provide prognostic information about "bad cancer", more specific probes of different biological processes (e.g. hypoxia, proliferation) should provide more accurate data and indicate specific treatment modifications, i.e. provide predictive rather than prognostic data. The exception to this is the case of drugs that inhibit glycolysis [20], for which FDG imaging of Glut-1 levels might provide predictive data. Where FDG-PET might also be of interest in the assessment of tumour biology is in dual/triple scanning protocols where glucose metabolism provides data on a cell being metabolically active. For instance, hypoxic regions with high FDG uptake might be more resistant to treatment than hypoxic regions with low FDG that might be so chronically hypoxic that they are doomed to die.
Thus, the relationship between glucose metabolism and hypoxia in tumours might be of interest, but is unlikely to be straightforward. Hypoxia affects glucose metabolism, but PET was used to show hypoxic tumours can have low glucose metabolism while some highly metabolic tumours are not hypoxic [3]. Of interest is the possibility that the discordance between 18F-MISO and 18F-FDG uptake may be tumour type specific, with better agreement in head and neck cancers (r=0.62) than in breast (r=0.47), glioblastoma multiforme (r=0.38) and soft tissue sarcoma (r=0.32). This may be significant because we know that hypoxia is particularly important in head and neck cancers.
As stated above, PET has the potential to increase our understanding of tumour biology in this area and could be used to investigate: whether the discordance between glucose metabolism and hypoxia is a widespread phenomenon between and within tumour types; how different co-localisation patterns of glucose metabolism and hypoxia relate to adaptation of the tumour microenvironment during the development of hypoxia tolerance (i.e. early vs late stage disease); and how the patterns relate to the prognosis of radiotherapy patients, i.e. which co-localisation patterns should be incorporated within biological target volumes for different types of tumours.
Similarly, the relationship between blood flow and glucose metabolism will probably be variable. PET blood flow and FDG data were shown to correlate in breast cancer [21–23], but not in head and neck cancer [24] or non-small cell lung cancer (NSCLC) [25]. Thus, the questions itemised above could be investigated for glucose metabolism and flow.
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PET measurements of proliferation
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There are a number of probes under investigation for measuring proliferation using PET, which should prove useful for radiotherapy research. 18F-FLT (3'-deoxy-3'-fluorothymidine), 18F-FMAU (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine) and 2-[11C]-thymidine are probably of most interest [26]. The different probes have their advantages and disadvantages, and it may be that, for the measurement of proliferation using PET, organ-specific probes will be required. 2-[11C]-thymidine could be used in the liver where glucuronidation of 18F-FLT and 18F-FMAU lead to high background radioactivity and limit their use. There is some evidence for a role for 18F-FMAU in imaging bone marrow, and 18F-FLT has shown some use in the brain and thorax. Although FDG uptake can reflect proliferation in tumours (see above), there is likely to be a role for proliferation-specific probes. Changes in proliferation occur more rapidly than in glucose metabolism in response to anticancer therapy.
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Normal tissue toxicity
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Studies are emerging that highlight the potential of imaging approaches for obtaining quantitative analytic data on the response of normal tissues to radiotherapy. Post-irradiation inflammatory responses are generally considered to be a confounding factor in the interpretation of FDG-PET data soon after radiotherapy. However, a study has raised awareness of the potential of measuring FDG-PET metabolic responses in normal tissues. Assessment of inflammatory changes in irradiated normal tissues was carried out in 73 consecutive NSCLC patients [27]. The changes correlated positively with tumour response, with the authors concluding that the results suggest that tumour radioresponsiveness and normal tissue radiosensitivity may be linked. Although the data were not correlated with any normal tissue toxicity scores, they clearly highlight the potential in this area. In another study, single photon emission computed tomography (SPECT) was used to measure the time course of radiation-induced reductions in regional lung perfusion [28]. Reductions in perfusion were shown to be dose dependent.
A key advantage of PET in this area is the potential for the parallel assessment of multiple biological processes. A study using three probes (for blood flow, glucose metabolism and proliferation) showed transitional metabolic post-irradiation changes in the spinal cord [29]. The transitory increase seen several months following radiotherapy (but absent by 44 months) in FDG uptake and perfusion were attributed to mild inflammatory and regenerative processes. No changes were seen in proliferation. The findings were consistent with the expected spinal cord recovery by 3 years.
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PET for definition of biological target volumes (BTVs)
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PET is also being explored for the definition of BTVs to target high-risk tumour areas for increased radiation dose delivery and normal tissue areas for dose reductions [30]. For example, in 20 patients with head and neck cancer, FDG-PET/CT-guided intensity-modulated radiotherapy (IMRT) planning was shown to markedly reduce the radiation dose to critical normal tissues whilst increasing doses to the planning target volumes [31]. Figure 1
is a theoretical image of radiotherapy planning volumes incorporating a PET-defined BTV for dose escalation. Normal tissue at increased risk of radiation damage is also defined by PET. Careful planning enables the delivery of a reduced dose to the high-risk area.
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Figure 1. Theoretical image of radiotherapy planning volumes incorporating a PET-defined biological target volume (BTV) for dose escalation. GTV, gross tumour volume defined using high spatial resolution CT or MRI; CTV, clinical target volume defined by a clinician to account for microscopic tumour spread; PTV, planning target volume defined by a physicist to incorporate margins allowing for tumour motion and set-up errors; NTI, normal tissue; NTII, normal tissue at increased risk of radiation damage defined by molecular imaging. Careful planning of the 40% isodose (ISO) line to exclude NTII enables the delivery of a reduced dose to the high-risk area.
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It is likely that the use of PET in defining BTVs will be improved by incorporating information on hypoxia, blood flow, glucose metabolism and proliferation. Therefore, to define BTVs optimally we need to understand the relationships between hypoxia, glucose metabolism and blood flow in tumours in situ and how they correlate with radiotherapy outcome.
Hypoxic imaging has evoked the greatest interest for definition of BTVs. Figures 2 and 3 illustrate the use of the hypoxic tracer 64Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) (60Cu-ATSM) in patients with oropharyngeal cancer. Figure 2 shows a colour-washed, fused PET/CT image demonstrating regions of heterogeneous 60Cu-ATSM intensity within the gross tumour, which represents the presence of tumour hypoxia. Figure 3 demonstrates gross tumour volume on CT, and BTV on the corresponding 60Cu-ATSM image.
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Figure 2. Fused PET and CT image of a patient with oropharyngeal carcinoma, where 64Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) (60Cu-ATSM) is used as the hypoxia tracer. The image illustrates regions of heterogeneous 60Cu-ATSM intensity within the gross tumour, representing the presence of tumour hypoxia. Reproduced with kind permission from: Chao KS, Bosch WR, Mutic S, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2001;49:1171–82.
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Figure 3. A gross tumour volume on CT scan in a patient with oropharyngeal carcinoma, and biological target volume on the corresponding 64Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) (60Cu-ATSM) image. Reproduced with kind permission from: Chao KS, Bosch WR, Mutic S, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2001;49:1171–82.
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There is also interest in incorporating biological data into models that predict tumour complication probability and normal tissue complication probability (NCTP) following radiotherapy [32]. For example, in comparison with healthy individuals, normal lung tissue in lung cancer patients can be heterogeneous in terms of perfusion. Information on normal tissue perfusion has potential to predict NTCP [32] and to be used in treatment planning such that normal tissue regions with impaired perfusion could receive less dose than regions with good perfusion.
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Conclusions
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Thus, PET has the potential to increase our biological understanding of radiotherapy response and resistance, but there is a need for the development of standard methods for measuring hypoxia, blood flow, proliferation and other biological processes in man. There is also a need for large studies correlating PET data with radiotherapy outcome. We need to establish how PET-determined biological phenotypes relate to the prognosis of radiotherapy patients to explore which co-localisation patterns should be incorporated within tumour and normal tissue BTVs for different types of cancers.
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Acknowledgments
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The authors are supported by the National Translational Cancer Research Network of the UK and Cancer Research UK.
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Abstract
Introduction