British Journal of Radiology (2005) Supplement_28, 2-4
© 2005 British Institute of Radiology
doi: 10.1259/bjr/98023510
British Journal of Radiology Supplement_28 (2005),2-4 ©2005 The British Institute of Radiology
The role of PET scanning in radiotherapy
P M Price, MD, FRCP, FRCR
and
T Jones, DSC, FMedSci
The University of Manchester Wolfson Molecular Imaging Centre, 27 Palatine Road, Withington, Manchester M20 3LJ, UK
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Introduction
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Positron emission tomography (PET) is a powerful and versatile imaging tool that offers the unique opportunity to visualise and measure pathophysiology and key biological parameters that influence disease diagnosis, development and outcome. The field of PET has previously been dominated by studies in neuroscience research, but over the last 10 years with the development of whole-body scanners, fluourine-18-labelled fluorodeoxyglucose (18F-FDG) PET for staging of tumours has dominated in the clinical oncology area. More recently, the role of PET in the radiotherapy management of patients has been investigated. To measure biological parameters in vivo, PET utilises biological molecules such as water, amino acids, metabolic precursors and hormones labelled with positron-emitting radionucleotides such as 18F, 11C, 13N and 15O. Therapeutic drug compounds can also be radioactively labelled. High-resolution images produced by PET allow the presence of such compounds to be accurately monitored in the patients' body, and highly sensitive and specific biological measurements can be made [1]. Consequently, PET is positioned as the ideal tool to provide clinically relevant information. Further research and development of PET methods will contribute to an increased understanding of tumour biology and the complex biological processes that contribute to chemotherapy and radiotherapy resistance. PET is therefore predicted to have a significant impact on our ability to investigate disease processes and to improve and individualise anticancer therapies.
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The role of PET in radiotherapy planning (RTP)
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Radiotherapy aims to deliver the necessary therapeutic dose of ionising radiation to tumour tissue whilst minimising irradiation of normal tissue: precise tumour volume delineation (TVD) is essential to this process. Currently, TVD relies on the anatomical boundaries and diagnostic criteria defined by CT and/or MRI. Further refinements to delineate the boundaries and properties of malignant tissue would enable optimised delivery of radiotherapy.
PET offers additional advantages over CT for TVD, as it can provide both anatomical and biological tumour information. For example, by detailing and quantifying tumour metabolism, hypoxia and perfusion, gross tumour volume (GTV) delineation may be improved and additional biological boundaries, known as biological target volumes (BTVs), can be identified. Considerable research activity is focused on investigating whether additional tumour biological information provided by PET can improve TVD for radiotherapy and subsequent disease outcome. In particular, PET has been explored to assess its ability in accurately defining the boundaries of complex tumours, e.g. in lung cancer with nodal disease [2]. The ability of PET to provide detailed imaging information on relevant BTVs, such as hypoxic subregions of a tumour that would benefit from radiotherapy dose escalation, is also an area of research interest. The combination of PET with other techniques, such as intensity-modulated radiation therapy, offers the opportunity to deliver higher doses of radiation to well-defined tumour volumes accurately and safely, with a low risk of normal tissue irradiation [3]. Recent evidence suggests that improving GTV delineation and delivering higher doses of radiation to targeted subregions of the tumour can improve local control and radiotherapy outcome. Further clinical trials involving long-term patient follow-up are clearly necessary to evaluate the use of PET to improve radiotherapy delivery and subsequent outcome.
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FDG-PET
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Numerous radiotracers have been developed for PET-guided imaging in oncology, of which FDG is the most widely used. FDG is a glucose analogue that is transported into cells, but unlike glucose it is retained intracellularly. When radioactively labelled it provides a useful means to detect tumour cells with raised metabolic activity and increased uptake of FDG.
FDG-PET has high sensitivity and specificity in a number of tumour types and is associated with improvements in GTV delineation. The substantial refinements in tumour detection and localisation provided by FDG-PET have led to improved disease diagnosis and staging, and often a subsequent change in patient management and/or treatment; for example, in patients with lung cancer or head and neck cancer, FDG-PET has successfully identified additional nodal involvement; and in head and neck cancer, FDG-PET was used to detect primary tumours that were previously unidentifiable with CT alone. Accurate disease staging can help to avoid unnecessary treatments, enable individualised patient treatment, and ultimately improve patient management and disease outcome [4].
Whilst it is acknowledged that the addition of FDG-PET to existing clinical investigations and treatment strategies can have a positive impact on patient management, the widespread utilisation of this technology is restricted. This is due to the limitations of FDG uptake as an accurate representation of tumour metabolic activity; for example, some tumour types are not highly metabolic and may be masked by normal FDG uptake in complex anatomical sites, and hypoxic tumours are known to have increased glucose metabolism, as have macrophages that invade neoplastic tissues. To overcome these limitations, additional PET probes capable of accurately measuring a combination of different biological parameters are required.
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New PET probes
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PET probes for biological parameters such as hypoxia, angiogenesis, proliferation and apoptosis, which are associated with resistance to anticancer therapies, can help to identify tumour mass that can be specifically targeted more aggressively with radiotherapy. Such probes must be accurately quantifiable and well validated with histopathology. The potential of PET in this setting can be optimised by combining the biological information obtained using PET with the anatomical information provided by CT/MRI.
Substrates for protein synthesis, such as 11C-labelled methionine and tyrosine, are attractive candidates for new PET probes. In patients with brain gliomas, 123I-alpha-methyl-tyrosine (IMT), 11C-methionine (MET) and 18F-ethyl-tyrosine (FET) have been used successfully for accurate TVD. For example, MET-PET has been used to identify post-operative residual tumour, currently a challenge with CT, leading to improved disease staging and enabling high-dose radiotherapy. In patients with meningioma, TVD is often very difficult to define, but MET-PET has repeatedly been shown to define tumour margins with high precision, sparing normal tissue from high-dose radiotherapy [3].
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Understanding tumour biology to improve radiotherapy outcome
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PET has the potential to increase our understanding of tumour radiobiology, as multiple biological parameters relevant to radiotherapy response/resistance can be measured and investigated. Hypoxia, increased tumour metabolism and poor tumour perfusion are examples of independent negative predictive factors associated with poor disease/radiotherapy outcome. PET enables such biological factors to be examined in situ as well as the identification of key BTVs that could be incorporated into the RTP process.
To optimise BTV delineation, biological factors need to be clearly defined, and the relationships between different biological parameters must also be established. To achieve this, further research using suitable PET probes will be essential. For example, FDG uptake, in addition to changes in tumour metabolism, is influenced by other factors such as tumour burden, blood flow, hypoxia and inflammation. Given the heterogeneous nature of tumours, it will be important to identify, evaluate and understand the impact of different biological factors on specific tumour types and to identify the biological profile of individual tumours.
The assessment of hypoxia is a particularly important consideration in the RTP process. A number of studies have clearly demonstrated a correlation between hypoxia measurements and radiotherapy outcome in patients with head and neck cancer and cervical cancer. Hypoxia-specific PET probes, such as fluoromisonidazole (FMISO), a highly lipophilic PET probe, allow hypoxia measurements to be made independently of blood flow and can provide valuable information on the hypoxic status of tumours in vivo.
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The potential of combined PET/CT imaging
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Highly specific and sensitive biological information with relatively high-resolution anatomical information is obtained with PET. However, in comparison with CT, the spatial resolution achieved with PET is poor. By aligning the biological information obtained with PET with the anatomical information provided by CT, combining PET/CT can overcome the limitations associated with PET alone. This has the advantage of avoiding possible false-positive and false-negative results associated with FDG-PET. As previously described, FDG-PET in combination with CT has demonstrated its use for TVD of complex tumour types, identifying unknown primary tumours and distinguishing malignant, necrotic or fibrotic tissue. In head and neck cancer, studies have indicated that PET/CT has the ability to identify unknown primary tumours more accurately than CT, improving disease staging. In patients with lung cancer, PET/CT has distinguished necrosis and tumour recurrence following surgery and/or radiotherapy, which is often difficult with CT alone. Biological information defined by PET has the potential to become an important component of the RTP process, and in combination with CT may provide more accurate TVD than that outlined with either modality alone [5].
Whilst PET imaging has great potential to monitor tumour response to radiotherapy, refining anatomical margins for GTV delineation is not the strength of this technique. The biology and phenotype information from FDG-PET may, however, help to define gross spread of disease (redefining stage) or enable likelihood prediction of metastatic spread to inform clinical judgement for clinical target volume definition.
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Key considerations for PET/CT imaging
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The combination of PET and CT is still a relatively new imaging concept. As such, patient immobilisation and positioning, and data acquisition and analysis are key areas of development required for its successful use.
To obtain accurate and reproducible imaging data for RTP using combined PET/CT, patient fixation is pivotal. Research is ongoing to develop effective patient immobilisation devices to use during both PET and CT scanning and subsequent radiotherapy delivery.
One of the most significant considerations of sequential PET and CT imaging is fusion of the two data sets. To achieve this, PET data must be spatially co-registered to the CT data set; this requires complex data analysis software. An alternative to separate PET and CT imaging is the use of combined PET/CT scanners, which allow co-registered PET and CT data to be acquired simultaneously in a single imaging session. The availability of combined PET/CT scanners overcomes many of the limitations currently associated with separate PET and CT imaging [5].
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The role of PET in assessing response to chemotherapy and/or radiotherapy
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Early determination of a response to chemotherapy is important for optimal patient management, and ultimately impacts on disease outcome and survival. It is important to identify patients who are not responding to specific anticancer therapies early so that alternative treatment options can be considered [4, 6]. Currently, response to anticancer treatments is determined by a decrease in anatomical tumour size, although this tends to occur late in the treatment course. PET can be used to assess whether biological responses occur earlier in the treatment course. For example, reduced tumour cell metabolism could be measured to determine early treatment efficacy. FDG-PET has been shown to predict an early response to anticancer treatment and in combination with CT, can enable changes in tumour size to be correlated with changes in biological parameters. The potential use for FDG-PET to assess response to radiotherapy (with the inherent problems of post-radiotherapy inflammation contaminating the FDG signal) is currently being explored by many groups [6]. PET studies to investigate radiotherapy response/resistance are also expected to help identify specific biological patterns that are associated with poor disease outcome, allowing integration of defined BTV into the RTP process.
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Summary
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PET has number of important roles in the radiotherapy management/treatment of patients with cancer. In combination with anatomical imaging technology such as CT, PET can provide additional biological information to improve disease staging and TVD. PET studies may allow specific biological subvolumes of tumour tissue to be identified, enabling targeted dose-modulated radiotherapy techniques. Investigations of radiotherapy response/resistance by PET will help to define BTVs and to optimise patient management.
To realise the full potential of PET for radiotherapy, a better understanding of tumour biology as well as new PET probes are required. Ongoing research to develop and refine new PET probes and combined PET/CT scanners and to optimise patient positioning for subsequent radiotherapy will contribute to improved radiotherapy techniques. To fully evaluate the identified potential of PET in radiotherapy and to ensure successful integration of PET into the pre-clinical and clinical setting, well designed and conducted clinical trials, with a critical multidisciplinary approach, form the next crucial stage of research focus.
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Acknowledgments
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The authors of this supplement would like to acknowledge the assistance of Melanie Green for help with manuscript preparation and for enabling the production of this supplement. Thanks also to James Cullen for help with figure preparation and permission requests.
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References
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- Brock CS, Young H, O'Reilly SM, Mathews J, Osman S, Evans H, et al. Early evaluation of tumour metabolic response using [18F]fluorodeoxyglucose and positron emission tomography: a pilot study following a phase II chemotherapy schedule for temozolomide in recurrent high-grade glioma. Br J Cancer 2000;82:608–15.[Medline]
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Introduction
The role of PET...
