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British Journal of Radiology (2005) Supplement_28, 6-16
© 2005 British Institute of Radiology
doi: 10.1259/bjr/44857153
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British Journal of Radiology Supplement_28 (2005),6-16 ©2005 The British Institute of Radiology

Full Paper

Potential of PET in oncology and radiotherapy

A Saleem, PhD, FRCR

Clatterbridge Centre for Oncology, Wirral, UK


   Introduction
Top
 Introduction
Radiotherapy applications
 Evaluation of pathophysiology
 Anticancer drug development
 Response assessment
 Prognostic evaluation
 Conclusion
 References
 
Positron emission tomography (PET) is a non-invasive imaging technique based on coincidence detection of two simultaneously emitted photons that occurs when a positron annihilates after combination with an electron. Positrons are emitted from proton-rich unstable isotopes. Such short-lived radioactive isotopes are made in a cyclotron and then chemically linked to a probe molecule (e.g. a drug, water or a metabolite) to form a labelled PET tracer that is injected intravenously into a patient. Single emitted positrons combine with an electron to form a positronium, the lifetime of which is very short, resulting in annihilation of the positron and electron (all the mass is converted into electromagnetic radiation). To conserve energy and linear momentum, the electromagnetic radiation appears in the form of two photons of equal energy (511 keV; equal to the rest mass energy of the electron and positron), which are emitted at 180° to each other. The emitted photons are detected by a technique known as coincidence detection. A PET scanner comprises a large number of scintillation detectors; when two scintillation detectors that are separated by 180° are both stimulated simultaneously, they will transmit a coincident signal. This enables localisation of a source without the need for physical (lead) collimation. This fundamental physics forms the basis of dynamic detection and three-dimensional localisation of the positron emitter and confers advantages of greater efficiency and resolution for PET over other nuclear imaging methods. Since a number of commonly occurring elements such as carbon, oxygen, nitrogen and fluorine have positron-emitting radionuclides, the stable nuclides of these elements can potentially be replaced by their positron-emitting counterparts in a number of compounds and evaluated using PET (Table 1Go). Emission of positrons from the compound follows the presence of such compounds when used as tracers of tissue function within the body; hence, PET can provide unique functional imaging data not available with other modalities. Moreover, the ability to correct for attenuation of radiation by body tissue as well as the highly sensitive nature of PET technology makes it possible for accurate quantification of the radiolabelled compound to picogram amounts. These properties of PET can be utilised to provide functional in vivo imaging data and as a result, the utility of PET has increased considerably over the last few years.


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  		Table 1. Decay characteristics of positron-emitting radionuclides. Kindly reproduced with permission from: Aboagye E, Saleem A, Price P. Tumor imaging applications in the testing of new drugs. In: Baguley B, Kerr D, editors. Anticancer drug development. London, UK: Academic Press, 2002

 
The wide usage and worldwide acceptability of the radioligand fluorine-18-radiolabelled fluorodeoxyglucose (18F-FDG) as a diagnostic PET imaging tool has made FDG-PET synonymous with PET. FDG follows the same route as glucose into cells, where it is phosphorylated by hexokinase to FDG-6-phosphate. Unlike glucose, little further metabolism occurs and FDG-6-phosphate remains essentially trapped within cells, with the rate of accumulation proportional to the rate of glucose utilisation. FDG-6-phosphate has low membrane permeability and although dephosphorylation does occur, it is very slow in brain, heart and tumour, which have very low levels of glucose-6-phosphatase. FDG uptake in tumours probably reflects a combination of factors, including phosphorylating activity of mitochondria, degree of hypoxia and levels of glucose transporters [1–3].

The role of FDG-PET for imaging and staging of malignant tumours is well established in oncology and is used in a routine clinical environment in many countries for diagnostic purposes. In addition to its diagnostic utility, other salient features of PET, notably its capability to image functional changes, make it a potential tool for further research in oncology. Therefore, a number of other PET probes in addition to FDG have been imaged and are being developed. The potential role of PET as a research tool in oncology can be broadly divided into five main areas:

  1. radiotherapy research;
  2. evaluation of pathophysiology;
  3. anticancer drug development;
  4. therapy response; and
  5. prognostic evaluation.


   Radiotherapy applications
Top
 Introduction
 Radiotherapy applications
Evaluation of pathophysiology
 Anticancer drug development
 Response assessment
 Prognostic evaluation
 Conclusion
 References
 
The potential role of PET in radiotherapy can be broadly divided into four main areas. First, in radiotherapy treatment planning (RTP) where diagnostic information obtained with PET can be utilised in target delineation. Second, in the modulation of radiotherapy dose to target volume based on information obtained with functional PET imaging (image-guided functional radiotherapy). Third, radiobiological processes can be assessed during and after radiotherapy, which I shall refer to as "radiodynamics". Finally, PET can be utilised for in vivo predictive testing and in the assessment of response to radiation therapy.

Radiotherapy treatment planning (RTP)
Advancements in technology in the last few decades have had a great impact on RTP. With the increasing integration of structural imaging techniques such as CT and MRI in the planning of radiotherapy treatment, it is now possible to define treatment targets with greater precision and confidence. Additional functional information obtained via PET is likely to aid in better target delineation. For example, unlike structural imaging techniques, FDG-PET can differentiate tumour from atelectasis [4] or necrosis [5]. Diagnostic PET can also provide information about disease not visualised by structural imaging methods, so that geographical misses are avoided. Additionally, PET information regarding the tumour phenotype [5–7] can aid target volume modification by accounting for subclinical disease extent. Finally, functional information on pathological processes such as hypoxia and proliferation obtained with validated PET markers can be used in the definition of a biological target volume (BTV) and integrated into the RTP process.

Diagnostic information obtained with FDG-PET has already been integrated in the RTP process for a number of tumour types such as oesophageal cancer [8], lung cancer [9, 10] and lymphomas [11], and it is reviewed by other authors in this issue. Prior to its integration in RTP, it is essential to recognise opportunities and limitations of PET, so that specific caveats are understood and addressed. For example, with FDG-PET, knowledge of its sensitivity and specificity in various tumour types is vital when diagnostic FDG-PET information is utilised for purposes of target delineation. In tumour types where FDG-PET has high sensitivity, i.e. the false-negative rate is low, the chances of a geographical miss are low if the target volume is tailored to the PET image. However, some areas with false-positive uptake of FDG will be included in the target volume. In contrast, if the sensitivity of PET is low, then delineation of the target volume based entirely on PET alone is likely to result in a high degree of geographical miss or non-inclusion of the tumour in the target volume. In these circumstances, both structural and functional imaging information should be considered in the definition of target volume. Specificity issues are important in the exclusion of normal tissue from the target volume. With high specificity, the rate of false positivity is low and exclusion of areas that are not positive on the PET scan will eliminate irradiation of normal tissue. The value of FDG-PET in the pre-operative diagnosis in non-small cell lung cancer (NSCLC) has been underlined by level one evidence that shows a reduction in the need for unnecessary thoracotomies in one out of five patients who had a pre-operative FDG-PET scan [12]. As a corollary of the above conclusion, disease staging with PET prior to RTP is also likely to result in exclusion of patients unlikely to benefit from radical radiotherapy or chemoradiotherapy.

Image-guided functional radiotherapy
The existence of a dose–response relationship with radiotherapy implies that a higher dose is likely to eradicate a greater number of clonogens and thus attain maximal benefit. However, in clinical situations this has to be balanced against the normal tissue morbidity associated with such high doses, which has previously limited dose escalation. Recent developments in radiotherapy techniques, such as conformal and intensity-modulated radiotherapy, have made it possible to increase the dose while limiting normal tissue dose so that maximal therapeutic benefit is achieved [13]. Such conformal techniques escalate the dose to the entire tumour within the target volume and limit the normal tissue dose. However, since tumours are composed of a heterogeneous mix of cells, it may be more appropriate to deliver variable doses to different regions of the tumour, depending on the characteristics of the tumour. PET and PET/CT, which is associated with better spatial resolution, are likely to be helpful in discerning the heterogeneous population within the tumour. For example, FDG uptake, which is a surrogate marker for tumour cell density [14], and [18F]3'-deoxy-3'fluorothymidine (FLT), a surrogate proliferative marker, can both be used for clonogen-directed radiotherapy. Dose escalation can also be used in tumour sites such as the prostate, where instead of increasing the dose to the whole prostate, which is normally considered as gross tumour volume, even in the presence of a unilobar nodule, functional imaging of the prostate would allow for intraprostatic dose escalation directed to the site of the disease [13, 14]. [11C]Choline is a promising marker for prostatic imaging, as the value of FDG-PET imaging in prostatic neoplasms is limited, partly due to the urinary excretion of FDG. [11C]Choline uptake is related to the synthesis of cellular membrane components [15] and its high uptake is seen both in primary prostatic cancer and in lymph node and distant metastases [15, 16]. Such intraprostatic clonogen-directed dose escalation may be possible if high-resolution images are obtained with [11C]choline-PET.

The spatial variability in the distribution of hypoxic cells, perfusion and drug pharmacology can also be used to modulate radiotherapy doses to the tumour. 18F-fluoromisonidazole (18F-FMISO), which binds selectively to hypoxic cells, has been used to map hypoxic areas in tumours [17] and can be used for hypoxia-directed radiation. Functional imaging can be used for chemotherapy-directed radiotherapy, i.e. modulation of radiotherapy dose based on tumour pharmacology of a radiolabelled drug. It is known that despite the benefit of chemoradiation over radiation alone, a number of failures of a local nature can occur [18–20]. It is possible that local failures may be due to an attenuation of radiosensitisation partly owing to variation in drug kinetics within the tumour. Tumour drug kinetics of radiolabelled drugs such as [18F]5-fluorouracil (18F-5-FU) [21] and [11C]temozolomide [22] can be assessed by PET and used as a basis to modulate the tumour dose according to the variations in tumour drug pharmacology within various sites of the tumour.

Radiodynamics
The biological factors that influence the response of normal and neoplastic tissues to fractionated radiotherapy can be summarised as the five Rs. These are repair, reassortment, repopulation, reoxygenation and radiosensitivity [23]. Two of these processes, repair and repopulation, tend to make the tissue more resistant to a second dose of radiation, whilst reassortment and reoxygenation tend to make cells more sensitive to radiotherapy. Repair refers to the process by which function of the macromolecules is restored during the few hours after radiotherapy, and the reproliferation of cells during a course of radiotherapy is known as repopulation. The redistribution of cells to a sensitive phase of the cell cycle and the process by which hypoxic cells become less hypoxic are known as reassortment and reoxygenation, respectively. Radiosensitivity denotes the intrinsic sensitivity of the tumour cells and dictates the radioresponsiveness of different tumours.

Our knowledge of the various radiobiological processes obtained from in vitro and ex vivo studies has been the basis of previous radiobiological understanding, and there is now in vivo information of the dynamics of these processes during and after a fractionated course of radiotherapy. PET, by providing further in vivo data, is in a unique position as an ideal tool for additional translational research into the various radiobiological processes. PET studies can be designed so that the in vivo biological processes can be evaluated both during and after a fractionated course of radiotherapy and with various fractionation schedules. Hypoxic markers such as 18F-FMISO can be used to understand the dynamic changes in the hypoxic status of tumours both during and after a course of radiotherapy. At the same time, changes in perfusion during radiotherapy can be assessed with [15O]H2O-PET. Similarly, proliferative markers such as 18F-FLT can be used to evaluate the effects of cancer cell repopulation and to assess the process of accelerated repopulation that has a hazardous effect on radiotherapy outcome [24]. PET markers for fibrosis such as cis-4-[18F]fluoro-L-proline, once validated, can be used to evaluate and assess the effects of radiotherapy [25]. Such knowledge can in turn be used to manipulate the delivery of radiotherapy so that maximal therapeutic gain can be obtained.


   Evaluation of pathophysiology
Top
 Introduction
 Radiotherapy applications
 Evaluation of pathophysiology
Anticancer drug development
 Response assessment
 Prognostic evaluation
 Conclusion
 References
 
The relative lack of knowledge of the underlying pathophysiological processes that drive a cell into neoplastic activity and the limited understanding of the specific differences between normal and cancer cells inhibit rational therapy development. PET, being a functional imaging modality, can play an important role in the elucidation of pathophysiological processes. Such an understanding of underlying disease processes would enable rational drug discovery and aid in the development of cancer therapy. A number of pathophysiological PET markers such as radiolabelled water (tissue perfusion), FDG (glucose metabolism) [26] and FMISO (hypoxia) [17] have already been adopted for clinical use.

An increased understanding of the apoptotic process would help to devise strategies to increase or restore the capacity of cancer cells to undergo apoptosis, thus improving cancer therapy. Current methods for monitoring apoptosis are based on excision of tumours followed by immunohistochemical or flow cytometric analysis. PET methodology for measuring apoptosis holds promise for detecting apoptosis within patient tumours over time. An early sign after initiation of the apoptotic signalling pathway is the externalisation of phosphatidylserine from the inner leaflet to the outer leaflet of the cell membrane, followed by membrane "blebbing" and DNA degradation. Annexin V, a human protein known to have a high affinity for cells with externalised phosphatidylserine groups, allows cells undergoing apoptosis to be detected. Radiolabelling of Annexin V has already been achieved and animal PET studies are underway [27, 28].

It is envisaged that for newer drugs there will be a shift in drug development study design for animal studies and phase I trials. Rather than aiming to ensure that drug plasma concentrations associated with antitumour activity in rodents are achieved in humans, it is likely that drug activity will be monitored by the degree of modulation of PET probes in animal models of cancer, prior to similar studies in humans. The availability of new cameras designed for animal PET studies (e.g. Micropet, Concorde Microsystems, Knoxville, TN, USA; and HIDAC, Oxford Positron Systems, Oxford, UK) with high sensitivity and resolutions of less than 1 mm has allowed the evaluation of such PET probes in animal models prior to clinical use. For this, the imaging paradigm would need to be set up and refined in animals and the image data would need to be related to ex vivo assays prior to clinical studies. Once a PET probe has been validated, it can also be used as a marker of therapy assessment.


   Anticancer drug development
Top
 Introduction
 Radiotherapy applications
 Evaluation of pathophysiology
 Anticancer drug development
Response assessment
 Prognostic evaluation
 Conclusion
 References
 
It takes many years and millions of dollars before a novel anticancer drug is accepted for clinical use. Our increased understanding of the processes that induce and drive malignant transformation has led to a change in paradigm from the development of predominantly cytotoxic agents to compounds that target the specific alterations that drive malignant transformation. The number of potential drug targets has dramatically increased in the post-genomic era: new targets include pathways involved in the cell cycle, signal transduction, cell death, drug resistance, invasion and metastasis, angiogenesis, and specific cancer genes and antigens. Owing to the increase in potential anticancer targets, and the use of new technologies such as combinatorial chemistry and high-throughput screening, the need to revise the way we test new drugs has become apparent.

PET has a key role to play in supporting drug development. It can provide information on in vivo normal tissue and tumour pharmacology, which so far has relied on surrogate information obtained from body fluids. Such an understanding both of the drug's behaviour within the body (pharmacokinetics) and of its effects (pharmacodynamics) could also aid in rational modifications to the drug development processes and hence save time. Moreover, hypothesis-testing clinical trial designs can be used, allowing early proof-of-principle studies showing mechanism of action, which could be obtained during early drug development.

A number of PET pathophysiological markers have been adopted as PET pharmacodynamic markers and used in the evaluation of antineoplastic agents. For example, [15O]H2O has been used as a pharmacodynamic marker to assess blood flow [29], and the value of 18F-FDG, in the diagnosis, staging, grading of tumours and as a prognostic indicator is well recognised [30].

In addition to pharmacokinetic studies with cytotoxic agents, a significant role for PET in the development of biological agents is anticipated. Pre-clinical studies of new target-directed agents have indicated that these agents may not necessarily lead to tumour shrinkage (the conventional measure of drug efficacy) and that higher doses may not inevitably be better (there may be an optimal therapeutic dose). Since the tissue and tumour levels of the investigative agent can be easily quantified in vivo using PET, it would be possible to incorporate the inclusion of PET pharmacology studies early into phase I and II clinical evaluation and thus establish the optimal therapeutic dose. Pharmacokinetic studies would allow quantification of the agent in the tumour, which can be correlated with changes in functional PET pharmacodynamic markers, such as tumour metabolism (FDG) or proliferation (thymidine), which are likely to be seen earlier than anatomical tumour shrinkage.

Pharmacokinetic evaluation
A number of cytotoxic agents [26] have been radiolabelled, and tissue and tumour pharmacokinetics of these agents have been assessed using PET. For example, PET has been used to evaluate the early development of the anticancer agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA; XR5000; Xenova, Slough, UK), a topoisomerase I and II inhibitor, prior to conventional phase I study (pre-phase I) setting in humans [31] and in conjunction with phase I and II studies [31, 32]. These clinical PET studies have shed important light on normal tissue toxicity and tumour pharmacokinetics not available by other means during the course of early drug development. The pre-phase I studies were performed at 1/1000th levels of the phase I DACA starting dose, and the phase I studies were performed midway during a 3-h infusion and during a 120-h infusion at the maximum tolerated dose (MTD) when 11C radiolabelled DACA was infused and pharmacokinetics analysed. PET images of 11C-DACA and its time course of 11C-radiolabelled radiotracer are illustrated in Figures 1 and 2GoGo, respectively. These studies predicted potential myocardial toxicity as evidenced by saturation at phase I doses compared with pre-phase I doses (Figure 3Go) [31], although pre-clinical studies demonstrated a dose-limiting neurotoxicity [33]. PET studies also predicted that with the 120-h infusion, although the MTD in plasma was reached, DACA did not demonstrate saturable uptake in tumours at that dose (Figure 4Go). This was likely to predict lack of efficacy of the agent [32]. It was therefore possible to predict drug efficacy and toxicity early during drug development that was not possible by other means.



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  		Figure 1. Typical transabdominal CT (a) and corresponding 11C-DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) PET images demonstrating radiotracer uptake in kidneys, spleen and renal tumour (b). Uptake of radiotracer is also seen in the heart, myocardium and mesothelioma (c) and gliomas (d). Kindly reproduced with permission from: Saleem A, Harte R, Matthews J, Osman S, Brady F, Luthra S et al. Pharmacokinetic evaluation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in patients by positron emission tomography. J Clin Oncol 2001;19:1421–9.

 


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  		Figure 2. 11C-DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) time–activity curves for various tissues and tumour in the pre-phase I study group. The time–activity curves were corrected for decay and normalised for the injected activity per body surface area. Kindly reproduced with permission from: Saleem A, Harte R, Matthews J, Osman S, Brady F, Luthra S, et al. Pharmacokinetic evaluation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in patients by positron emission tomography. J Clin Oncol 2001;19:1421–9.

 


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  		Figure 3. A significant decrease (p<0.05) in myocardial 11C-radiotracer exposure (area under the time–activity curve (AUC)) with phase I compared with pre-phase I doses of DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) demonstrated myocardial saturation. However, a significant increase in tumour exposure was seen, signifying a lack of tumour saturation with the 3-h infusion of DACA.

 


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  		Figure 4. Area under the time–activity curve (AUC) of 11C-DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) PET scan prior to and after 120-h infusion of DACA at the maximum tolerated dose (MTD). The lack of substantial change implies that there is no evidence of a saturable process either systemically or within the tumour, despite reaching the MTD.

 
Pharmacokinetic evaluation of temozolomide, an alkylating agent of the imidazo[5,1-d]-1,2,3,5-tetrazine series and structurally related to dacarbazine, has also provided valuable information. Temozolomide is a pro-drug that is stable in an acidic environment, undergoing ring opening of its structure and activity in an alkaline pH [34]. This pH-dependent activity allows for oral administration of temozolomide and it is postulated that temozolomide targets tumours where it undergoes ring opening and becomes active. Using a strategy of labelling temozolomide in two different positions with 11C, and performing paired studies in patients with gliomas, the pharmacokinetics of temozolomide were evaluated [22]. Studies demonstrated that tumour exposure (area under the time–activity curve) to temozolomide was higher than in the normal brain (Figure 5Go). However, there was no difference in ring opening in tumours compared with normal tissue, implying that ring opening did not preferentially occur in tumours compared with normal tissue (Figure 6Go). Currently, temozolomide is the fastest growing drug in the treatment of brain tumours.



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  		Figure 5. 11C-temozolomide-PET studies demonstrating that a higher area under the time–activity curve (AUC) was reached in tumours compared with normal brain.

 


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  		Figure 6. Temozolomide was tissue specific but did not demonstrate tumour-specific activity; there was no difference between the percentage of ring opening that occurred in tumours compared with normal tissue.

 
Pharmacodynamic evaluation
In addition to pharmacokinetic studies, PET can be used to evaluate a number of pharmacodynamic endpoints. If it is not possible to image the true endpoint, validated surrogate endpoints can be imaged. In a phase I study of combretastatin, a tubulin-binding antivascular agent, tumour and normal tissue perfusion were assessed with [15O]H2O-PET at 30 min and 24 h after drug administration [29]. Tissue and tumour perfusion decreased with increasing doses, with tumour perfusion decreasing above a threshold dose of 52 mg m–2 (Figure 7Go). In contrast to normal tissue perfusion, which was reversed at 24 h, tumour perfusion continued to be suppressed (Figure 8Go). Such data indicate how PET imaging can provide insights for timing of drug administration.



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  		Figure 7. Percentage changes in tumour perfusion with combretastatin (CA4P) at (A) 30 min and (B) 24 h after infusion. A threshold response is clearly seen. Kindly reproduced with permission from: Anderson H, Yap J, Miller M, Robbins A, Jones T, Price P. Assessment of pharmacodynamic vascular response in a Phase I trial of combretastatin A4 phosphate. J Clin Oncol 2003;21:2823–30.

 


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  		Figure 8. Changes in perfusion at 24 h after intravenous combretastatin were reversed in normal tissue, whilst tumour perfusion was non-reversible at 24 h.

 
Proof-of-principle studies
In the development of anticancer agents, hypothesis-confirming proof-of-principle studies are sought at an early stage. As an example, the utility of PET in such proof-of-principle studies is illustrated for eniluracil, which is an inactivator of dihydropyrimidine dehydrogenase (DPD), the primary degradative enzyme of 5-FU. Inactivation of DPD would prevent the catabolism of 5-FU and channel 5-FU to its active anabolites. PET studies were based on the hypothesis that inactivation of DPD by eniluracil would result in a substantial decrease in uptake of the 18F-radiolabelled tracer consisting of 5-FU and metabolites by the liver, which is the primary site of 5-FU catabolism by DPD. 5-FU pharmacokinetics evaluated prior to and after administration of eniluracil demonstrated a significant decrease in hepatic uptake and exposure to the radiotracer (Figure 9Go). In addition, a decrease in renal exposure with an absence of primary catabolite, fluoro-beta-alanine (FBAL), in urine confirmed the mechanism of action of 5-FU [21]. Non-visualisation of radiotracer in the gall bladder after eniluracil demonstrated the absence of FBAL conjugates after DPD inactivation (Figure 10Go).



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  		Figure 9. Typical transabdominal CT scan (a), and corresponding PET blood flow (b), and [18F]5-fluorouracil images without eniluracil (c) and with eniluracil (d), showing liver, spleen and multiple liver metastases.

 


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  		Figure 10. Temporal representation of 18F-radiotracer localisation in a selected transabdominal plane passing through the liver after the injection of [18F]5-fluorouracil without eniluracil (A) and after eniluracil (B). Kindly reproduced with permission from: Saleem A, Yap J, Osman S, Brady F, Suttle B, Lucas SV, et al. Modulation of fluorouracil tissue pharmacokinetics by eniluracil: in-vivo imaging of drug action. Lancet 2000;355:2125–31.

 

   Response assessment
Top
 Introduction
 Radiotherapy applications
 Evaluation of pathophysiology
 Anticancer drug development
 Response assessment
Prognostic evaluation
 Conclusion
 References
 
Structural tumour changes are used as a prospective endpoint to assess drug activity in phase II studies. Tumour response is also a surrogate endpoint for other measures of clinical benefit such as disease-free survival and overall survival in the more definitive phase III clinical trials. Tumour response also serves as an important guide for the clinician and patient in decisions regarding continuation of therapy both in clinical trials and in routine practice. This is primarily assessed by imaging, with CT scanning and MRI being the most reproducible and widely used modalities currently available.

A number of criteria have been proposed to assess tumour response, with Response Evaluation Criteria in Solid Tumours (RECIST) being the most recent criteria formulated by representatives of several research groups [35]. These criteria, based on single dimensional measures divide responses into four groups as in the original World Health Organization criteria, i.e. complete response, partial response, stable disease and disease progression. Concerns that a subject could be mistakenly noted to have progressive disease owing to measurement error (and therefore leading to rejection of a drug in early clinical trials) have been addressed by the requirement of an increase by 73% in volume in order to be deemed as having progressive disease [35].

The development of cytostatic agents has introduced new challenges in the assessment of tumour response. The usual clinical paradigm of anticancer drug development involving phase I, II and III clinical trials is based on the assumption that the agent will shrink tumours, and that more of the agent will shrink tumours better (if toxicity is acceptable). It is also thought that tumour shrinkage will lead to potential benefit in terms of increased survival and/or quality of life. In contrast, studies of newer target-directed agents suggest that these agents may not lead to tumour shrinkage and that higher doses may not necessarily be better: an optimal therapeutic dose may exist. Since these agents may slow the growth of tumours and prevent the occurrence of metastases, without an anatomical shrinkage of tumours, such a strategy may result in the erroneous rejection of certain agents.

Since changes in tissue function predate volume changes, it is possible to assess response to a drug using functional imaging techniques. Changes in glucose metabolism in responding tumours are seen as early as a few days after treatment and can be used for evaluation of response and as a guide for further treatment. As shown in Figure 11Go, changes in FDG uptake are seen at 7 days after temozolomide therapy and confirmed by CT changes at 2 months. FDG-PET has been used for therapy monitoring in a variety of tumours such as colorectal cancer, oesophageal cancer, gliomas and lung cancer. As discussed above, functional assessment of response is likely to be especially important where structural changes may not occur or may be slow to manifest. With gastrointestinal stromal tumours (GISTs), changes in FDG uptake are seen early after treatment with imatinib. The value of FDG-PET in response assessment in GISTs has been recognised and expressed in the consensus document on GIST [36]. Tumour response assessment with functional imaging is not included in the RECIST criteria. The European Organization for Research and Treatment of cancer (EORTC) PET group has defined response assessment guidelines with PET, which are widely but not universally followed [37].



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  		Figure 11. Fluorodeoxyglucose (FDG)-PET response seen in a brain tumour after 7 days, and corresponding CT changes at 2 months. Kindly reproduced with permission from: Aboagye E, Saleem A, Price P. Tumor imaging applications in the testing of new drugs. In: Baguley B, Kerr D, editors. Anticancer drug development. London, UK: Academic Press, 2002.

 
The low or variable glycolytic activity of some tumour types has limited the utility of FDG-PET in certain tumour entities such as hepatocellular carcinoma [38], carcinoid [39] and differentiated teratomas [40]. Furthermore, physiological uptake in the brain, accumulation in inflammatory diseases, confounding effects of tissue inflammation on FDG uptake soon after radiotherapy, non-specific bowel uptake and urinary excretion of FDG may limit tumour detection and/or cause false-positive findings. Therefore, other PET markers, especially those targeting proliferation, such as thymidine and its analogues – 11C-thymidine [41] (Figure 12Go), [18F]3'-deoxy-3'fluorothymidine (FLT) [42] and [18F]1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU) [43], can be used as therapy response markers in man. FLT, a promising PET marker for proliferation, is taken up by proliferating cancer cells by thymidine kinase (TK-1) and trapped intracellularly [44]. FLT uptake reflects proliferation, but incorporation of FLT into DNA is negligible [45] and is therefore an indirect tracer of proliferation. A closer correlation has been demonstrated between FLT uptake and the Ki-67 labelling index with lung tumours compared with FDG [46]. Initial clinical studies have also demonstrated that 18F-FLT was more sensitive than 18F-FDG in imaging recurrent high-grade brain tumours, correlated better with Ki-67 values, and was a more powerful predictor of tumour progression and survival [6].



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  		Figure 12. Response in a patient with Ewing's sarcoma assessed with 11C-thymidine PET. Kindly reproduced with permission from: Gupta N, Price P, Aboagye E. PET for in vivo pharmacokinetic and pharmacodynamic measurements. Eur J Cancer 2002;38:2094–107.

 

   Prognostic evaluation
Top
 Introduction
 Radiotherapy applications
 Evaluation of pathophysiology
 Anticancer drug development
 Response assessment
 Prognostic evaluation
Conclusion
 References
 
In addition to its value in response evaluation, the role of PET as a prognostic indicator is increasingly recognised. FDG-PET has been used to evaluate post-treatment tumour response and to assess the value of response on parameters such as overall survival and progression-free survival. Responses can be observed as early as a few days after treatment with PET and used to plan further therapy. This will allow management decisions to be made early during the course of treatment and will additionally save time and money by avoiding unnecessary treatment. For example, in aggressive lymphomas, early PET responses at 4 months were independently prognostic for overall survival, with PET responders and non-responders being associated with 2-year overall survival of 90% and 61%, respectively [47]. Early functional responses have also been prognostically correlated in a variety of tumours such as nasopharyngeal carcinoma [48], Hodgkin's lymphoma [49], oesophageal cancer [50] and NSCLS [51]. It is clear that just as pathological response is an important predictor of overall survival after therapy [52], PET or functional responses may soon become important predictors of the efficacy of therapy.


   Conclusion
Top
 Introduction
 Radiotherapy applications
 Evaluation of pathophysiology
 Anticancer drug development
 Response assessment
 Prognostic evaluation
 Conclusion
References
 
With advances both in technology and in our understanding of the radiobiological processes, the role of PET in radiotherapy is likely to increase in the future. As with anticancer drug development, PET methodology can be used in the evaluation of radiobiological and pathophysiological processes such as hypoxia. In addition, the role of PET in RTP is currently being evaluated and PET is likely to be increasingly integrated into the planning process. PET also has the potential to incorporate clonogen-, hypoxia- or chemotherapy-directed functional image-guided techniques to maximise therapeutic gain. It is also likely that a greater interest will be shown in the evaluation of PET markers for tissue repair and fibrosis, as insight into the basis of tissue repair will enable the attenuation of radiotherapy-induced late tissue damage seen in long-term survivors after radiotherapy.

A number of challenges need to be tackled before these modalities are widely adopted. These include methodological developments, which are still required across the board and need funding and time. In addition, there is a need for oncologists, clinical trialists and industry to be aware of PET, its capabilities and limitations. It is also essential for the fraternity involved in clinical trials to be convinced that the information provided will be unique, complementary and unlikely to be gained by other means. This will allow more time and money to be invested and the integration of functional imaging into therapeutic clinical trials, which is likely to benefit the overall development of the compound. The capabilities and limitations of the technology need to be carefully considered before the start of any research, and methodological support that has been validated should be in place in order to process the study and gain meaningful results.

In summary, in addition to its use and value in RTP and research, functional imaging with PET can be utilised in a variety of applications for the research and therapy of cancer. Its value in the elucidation of pathophysiological processes, development of anticancer drugs and as a response and prognostic indicator is likely to increase by the day. PET imaging and data interpretation is truly multidisciplinary, requiring co-operation between animal biologists, pharmacologists, physicists, PET technicians, data modellers, radiochemists and clinicians. Finally, the importance of development and validation of methodology and the need for carefully planned studies prior to the universal adoption of novel radioligands, methodology and machines cannot be over emphasised. Functional PET imaging has tremendous potential and we need to harness it in order to use it successfully.


   References
Top
 Introduction
 Radiotherapy applications
 Evaluation of pathophysiology
 Anticancer drug development
 Response assessment
 Prognostic evaluation
 Conclusion
 References
 

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