Clinical PET: changing the practice of oncology

Until recently positron emission tomography (PET) has been largely confined to academic institutions with the capital and human resources to support this technologically advanced modality. More recently its utility in oncology has fuelled the wider dissemination of this modality into routine clinical practice. Small animal PET scanners allow tracers to be validated prior to use in human subjects. The Peter MacCallum Cancer Institute clinical PET program began operation in 1996 and since that time has grown to be the first Australian centre with 2 PET scanners, including the first combined PET/CT. Although the majority of the almost 10,000 studies performed in our facility have utilised FDG, new tracers are increasingly being used in clinical trials, particularly for therapeutic monitoring of novel chemotherapeutic agents. In establishing our facility we have sought to influence referral patterns to those situations where epidemiological and case control data suggest that conventional diagnostic algorithms currently fail us. This is particularly the case in situation where recognition of this failure leads to routine use of either a morbid procedure or treatment in an entire population of patients, even in the absence of abnormality after conventional staging. For example, CT scanning is recognised to have insufficient accuracy for staging the status of mediastinal lymph node spread of non-small cell lung cancer to determine operability. Accordingly, a large number of patients undergo mediastinoscopy and pathological sampling of lymph nodes. Other patients are subjected to futile open and close thoracotomies due to incorrect staging. FDG PET has convincingly been shown to be more accurate than CT for staging the mediastinum and in a recent randomised control trial was shown to significantly reduce unnecessary thoractomies. By trying to limit the use of PET to situations where a range of different management options are available depending on the true extent of disease, we have been able to demonstrate that PET has a high and appropriate impact on management. Our group have recently published data on the clinical impact of PET in specific diseases including the staging of NSCLC, the restaging of NSCLC, the staging of cervical cancer, the restaging of colorectal cancer, the diagnosis of solitary pulmonary nodules, evaluation of lymphoma and malignant melanoma. The uptake of FDG in inflammatory conditions, leading to false positive results, is regarded as one of the major limitations of this tracer in oncological settings. In an attempt to address this limitation agents that look at biological processes more specific to cancers than is glycolytic metabolism, have been evaluated. These include amino acid analogues that trace protein synthesis, thymidine analogues that evaluate cellular proliferation, and markers of cellular sterol metabolism. An additional feature of cancers is the presence of hypoxia. PET tracers such as F-18 fluoromisonidazole have been shown to be taken up in a high percentage of some tumours that clinical and experimental evidence suggests are likely to be hypoxic and because of this, more resistant to conventional therapies. Additional potential limitation of FDG is the potential for an increase in uptake during the process of apoptosis, an energy requiring process, that may limit the utility of early scanning to determine therapeutic response. The so-called 'metabolic flare' has been described as actually being predictive of therapeutic response in breast cancer patients treated by hormone manipulation. Due to issues related to synthesis times and providing adequate tracer amounts for several studies at least, we have focussed on fluorinated PET tracers rather than shorter-lived tracers using carbon-11. Currently the Peter MacCallum Cancer Institute Centre for Molecular Imaging has active clinical research trials using the cellular proliferative tracer, F-18 fluorothymidine (FLT), and the hypoxia markers F-18 fluoromisonidazole and F-18 fluoroazamycin aribinoside (FAZA). We also have preclinical experience with F-18 fluoroethyltyrosine (FET). Our radiochemistry program is developing the facility to provide F-18 fluorocholine (FCH) and in the longer term has significant interest in I-124 and Cu-67 tracers. The advances in molecular biology and availability of DNA micro-array are increasing our understanding of cancer rapidly and identifying new cancer targets for both imaging and therapy. Nuclear medicine in general and PET in specific, are uniquely placed to capitalise on this knowledge by applying established tracer kinetic approaches to disease evaluation in vivo. As more and more basic oncological research is being performed in animal models, particularly including immunocompromised and transgenic mice, it is logical to apply functional imaging techniques also to this research. We believe that such translational research will be an important adjunct to clinical PET particularly in the area of drug evaluation. Towards this end, the Peter MacCallum Cancer Institute is installing the first small animal PET scanner in Australia, later this year. Molecular imaging is revolutionising the diagnosis, staging, surveillance and therapeutic monitoring of cancer. Increasingly, its ability to characterise the basic biological features of cancer will provide vital in vivo bioassays that will both aid prognostic stratification and guide selection of the most appropriate treatment. Such treatment selection will be made feasible at an individual patient and possibly individual lesion level rather than our current approach of treating all patients on the basis of broad disease groupings