Oncological molecular imaging: nuclear medicine techniques


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Oncological molecular imaging: nuclear medicine techniques

  1. 1. Oncological molecular imaging: nuclear medicine techniques G J R COOK, MSc, MD, FRCP, FRCR Department of Nuclear Medicine & PET, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK With the expanding interest and development in mol- ecular biology, nuclear medicine imaging, essentially a molecular imaging technique studying biological processes at the cellular and molecular level, has much to offer. As other non-isotope techniques develop there has also been an opportunity for nuclear medicine to broaden its horizons in this field. Nuclear medicine’s involvement in molecular imaging has been enhanced by the improvement in single photon emission computed tomography (SPECT), the wider availability of positron emission tomography (PET) and a greater input and new developments in radiochemistry. Nuclear medicine can be regarded as a method by which biological processes may be non-invasively monitored by radiopharmaceuticals delivered in tracer amounts. By measuring radioactive concentrations in tissue samples, either directly or by means of imaging, it is possible to explore and quantify biological processes in health and disease at the molecular or cellular level. The major advantage of nuclear medicine methods is that only picomolar concentrations of radiotracers are required to provide a measurable signal without interfering with the process under investigation. It is often true that biochemical or metabolic changes can therefore be iden- tified before a significant change in structure or anatomy can be determined. In oncology this has the potential advantage of not only being able to detect abnormal function related to malignant tissue at diagnosis but also to identify changes as a result of therapy earlier than is possible with anatomical techniques alone. However, this high sensitivity is often at the expense of inferior spatial resolution. Here PET techniques show advantages over SPECT, as not only is spatial resolution better, but positron emitting radionuclides include isotopes of carbon (11 C), nitrogen (13 N) and oxygen (15 O), allowing radio- labelling of biological compounds of interest. SPECT relies more frequently on the use of radiolabelled analogues. The spatial resolution of PET remains inferior to that of anatomical techniques including CT, MRI and ultrasound but with the advent of combined dual-modality scanners, such as PET/CT, it is possible that some of the disadvantages of the two techniques may be minimized and the advantages maximized. Another potential disadvantage of SPECT and PET techniques is that the measured signal is not chemically specific; for example, it is not possible to differentiate signal between the administered radiopharmaceutical and its metabolites without more complex metabolite analysis in blood. Due to the spatial resolution advantages of PET over SPECT, coupled with an ability to more accurately correct for attenuation of photons, quantitative accuracy is superior with PET. Absolute measurements of radioactive concentrations in tissue over time allow the measurement of dynamic processes in absolute units such as ml min21 ml21 . Realistic goals of nuclear medicine in oncological molecular imaging are to develop high affinity, high specific activity radiopharmaceuticals, allowing quantita- tion of molecular processes in whole tumour in a repro- ducible and repeatable manner. In oncology there are a number of areas where nuclear medicine techniques may give information on molecular and cellular events, many of which are already absorbed into routine clinical practice and others that are at a more developmental stage. These applications include the detection and measurement of a number of events in untreated tumours, including glycolysis, proliferation, membrane synthesis and receptor expression, amongst many others. In treated tumours there are methods to non- specifically measure the downstream effect of cytotoxic therapies but with the development of molecular therapies targeting specific aspects of cancer cell biology there is a greater interest in the development of markers aimed at specifically measuring the molecular consequence of each therapeutic agent. For example, a marker to measure the amount of tumour angiogenesis is likely to be a more sensitive measure of response to an antiangiogenic agent than a non-specific marker of downstream effects such as tumour cell viability. Molecular imaging techniques may also allow us to tailor therapy to individual patients. Visualization of specific molecular targets prior to therapy may identify patients most likely to benefit from a particular molecular therapy. Many novel anticancer therapies are cytostatic rather than cytotoxic and conventional methods of measuring treatment response may be particularly insensi- tive when tumour shrinkage is not anticipated but where functional changes may be marked. It is here that nuclear medicine techniques also have a role to play and it is important that molecular imaging techniques are devel- oped in conjunction with molecular therapeutics for some of the reasons stated above. Additionally, in nuclear medicine there is the opportunity to label specific molecular probes with a or b emitting radionuclides to deliver a therapeutic dose of targeted radiation to abnormal cells that concentrate these radiopharmaceuti- cals whilst minimizing radiation dose to normal tissues. Tumour glycolysis Perhaps one of the most successful molecular imaging techniques to be rapidly incorporated into routine clinical management in oncology is 18 F-fluorodeoxyglucose (18 FDG) PET. It has been known for many years that malignant tissue is associated with an increased utilization The British Journal of Radiology, 76 (2003), S152–S158 E 2003 The British Institute of Radiology DOI: 10.1259/bjr/16098061 S152 The British Journal of Radiology, Special Issue 2003
  2. 2. of glucose [1]. Many cancers are known to overexpress glucose transporters, including Glut-1, that allow entry of glucose and the radiolabelled analogue, 18 FDG [2]. Both glucose and DG are then phosphorylated by hexokinase with glucose entering the tricarboxylic acid cycle but DG remaining effectively trapped due to a high negative charge and no entry into significant further enzymatic reactions. As there is low activity of glucose-6-phosphatase in most malignant and normal tissues there is relatively little dephosphorylation of 18 FDG and therefore accumulation is proportional to glycolytic rate. 18 FDG-PET is therefore a method for measurement of the molecular and cellular events involved in glycolysis. As these processes are enhanced in malignant tissue there is preferential accu- mulation of 18 FDG compared with normal tissue, that with modern PET scanning systems can be detected with high sensitivity and where the signal from active tumours as small as a few millimetres can be identified. There is now incontrovertible evidence that 18 FDG-PET has incremental value over standard imaging techniques, significantly altering patient management in many cancers [3] but especially in the staging of lung cancer, recurrent colorectal cancer and lymphoma. 18 FDG-PET scanning is commonly performed at 1 h after injection as a compromise between patient conve- nience, half-life of 18 F (110 min) and tumour uptake. There are benign processes that may show enhanced uptake of this radiopharmaceutical that may be potentially mistaken for malignancy. However, it has been noted that malignant cells continue to accumulate 18 FDG for a number of hours [4] and either scanning at 4 h or dual time-point scanning, e.g. at 1 h and 2 h, [5] may lead to better discrimination between benign and malignant processes. In the latter method, malignant cells continue to accumulate 18 FDG between 1 h and 2 h whilst benign tissue does not. Although semiquantitative measurements of uptake on static scans at 1 h are convenient and relatively simple for clinical use, a more thorough knowledge of the kinetics of 18 FDG metabolism can be acquired by dynamic scanning and measurement of arterial blood activity over time. Although not practical in the routine clinical setting, this method may allow calculation of various rate constants with a more detailed and possibly, more discriminating measure of malignant cell biology [6]. Most commonly, a non-linear regression method is used to calculate the various rate constants describing 18 FDG kinetics by using dynamic tissue data from the PET scan, dynamic arterial data, either directly from arterial measurement or indirectly from arterial image data, and a three compart- ment model consisting of blood 18 FDG, free 18 FDG in the tissue and phosphorylated 18 FDG (Figure 1). Whilst K1 describes delivery and transport of 18 FDG, k3 describes the phosphorylation rate. The macroparameter, Ki (Equation 1), describes the net transport of 18 FDG into the fixed, phosphorylated state. In the brain an attempt is made to calculate glucose metabolism from the 18 FDG signal by the use of the ‘‘lump’’ constant to account for differences between glucose and DG. This ‘‘constant’’ is too variable and unpredictable in tumours and the metabolic rate of 18 FDG (MRFDG) is quoted instead. Ki~ K1:k3 k2zk3 ð1Þ Although a marker of glycolysis, uptake of 18 FDG has been correlated with a number of processes and states including tissue viability, cellular proliferation, tumour hypoxia and inflammatory cell infiltrate associated with tumours [7–9]. Currently 18 FDG PET is used predominantly as a sensitive clinical staging technique but the promise and interest for the future is to use it as an indirect marker of therapy response giving information on residual tumour cell viability, either early in a course of therapy to assess efficacy of a treatment regimen or at the end of therapy to differentiate tumour from fibrosis in residual masses. In the former there is some evidence that changes in uptake of 18 FDG pre-date changes in tumour size and it may therefore be possible to assess efficacy of chemotherapy after one or two cycles, with the option to change treatment and avoid further potential toxicity in those not responding [10]. In fact, significant changes in 18 FDG uptake have been seen as soon as 1 day after starting therapy in patients with gastrointestinal stromal tumours responding to imantinib mesylate [11]. In the latter, the more accurate prediction of residual viable tumour will help avoid long-term toxicity from radiotherapy in patients who are PET-negative. In the hope that uptake of 18 FDG reflects extent of viable tumour better than conventional anatomical imaging techniques, there is great interest in using 18 FDG PET in radiotherapy planning. Interest has accelerated since the introduction of combined PET/CT systems whereby the accurately co-registered CT scan can provide anatomical reference for the functional map of 18 FDG uptake, allowing a maximization of dose to tumour tissue whilst minimizing toxicity to surrounding non-tumour tissues [12]. Tumour proliferation Whilst it is possible to see changes in tumour uptake of 18 FDG soon after initiating therapy, it is known that some of the signal is due to uptake into activated inflammatory cells after chemotherapy but particularly after radio- therapy, in some situations. As mentioned above, the change in signal may not specifically reflect the mode of action of the anticancer agent being used. For these reasons there has been interest in developing pyrimidine analogues to monitor DNA activity and tumour prolifera- tion more directly. Whilst 3 H and 14 C labelled thymidine have been validated as lab techniques for measurement of proliferation in tissue samples, initial in vivo imaging studies used 11 C labelled thymidine. However, use of this positron-emitting radiopharmaceutical is hampered by the Figure 1. A three compartment model of cellular fluorodeoxy- glucose (FDG) trapping. Oncological molecular imaging S153The British Journal of Radiology, Special Issue 2003
  3. 3. short 20 min half-life of 11 C-carbon and its breakdown to a number of metabolites. 18 F-fluorothymidine (18 FLT) is a more attractive radiopharmaceutical as it resists degrada- tion and has a more convenient half-life [13]. In a similar model to 18 FDG accumulation, 18 FLT is trapped intra- cellularly following phosphorylation by thymidine kinase 1 (TK1). Although this does not reflect the full incorpora- tion of thymidine into DNA, uptake of 18 FLT has been shown to correlate with other markers of cellular proliferation including Ki-67 [14]. In cell cultures there is evidence of a correlation between 18 FLT uptake and TK1 activity as well as the fraction of cells in S phase [15]. It is early days in the evaluation of this tracer and as yet it is unknown whether it will live up to the hopes of tumour specificity and treatment effect sensitivity. It is possible that changes in tumour uptake of 18 FLT will depend on the type of cytotoxic therapy being used. For example, some agents may lead to an initial increase in uptake of 18 FLT that reflects activation of the salvage pathway of DNA synthesis rather than changes in proliferation [16] and so more knowledge of the use of this tracer is specific situations must be acquired before its more routine use. Tumour hypoxia The importance of tumour hypoxia is that its existence may confer resistance to some tumours during radio- therapy and some forms of chemotherapy and may be associated with poorer prognosis [17]. As tumour hypoxia cannot be predicted, either direct or indirect measurements of hypoxia are required to identify patients who may benefit from more aggressive therapy. Examples of such treatments include the administration of hypoxia sensi- tizers [18], hyperbaric oxygen therapy [19] or boosting radiation doses to hypoxic tissue with intensity-modulated radiotherapy (IMRT) [20] techniques. It remains very difficult to predict tumour hypoxia in individual patients as there is both intertumoural and intratumoural variation in oxygen status and no consistent relationship between oxygen status and hypoxic fraction and tumour size [21]. Nuclear medicine offers non-invasive methods for demon- strating tissue hypoxia, the gold standard requiring transdermal electrode measurements that are invasive, prone to sampling errors and not practical for clinical routine. Compounds that are selectively trapped in hypoxic tissue may be labelled with positron-emitting radionuclides or single photon gamma emitters, including technetium- 99m (99 Tcm ). The nitroimidazole-containing compounds have received most attention with a number of compounds containing a 2-nitroimidazole moiety as a bioreductive molecule. The nitro group undergoes one electron reduc- tion in viable cells to produce a radical anion. In hypoxic cells this intermediate is further reduced to species that react with cellular components and remain trapped within the cell. In normoxic cells rapid re-oxidation takes place allowing the compound to diffuse out of the cell. Fluorine-18 labelled fluoromisonidazole (18 F-miso) is probably the most extensively studied hypoxia-selective radiopharmaceutical using PET. A number of malignant tumours including squamous cell carcinomas of the head and neck [22] and non-small cell lung cancer [23] have been studied with this compound. As the majority of tumours studied in these series exhibited some degree of hypoxia and because the degree of hypoxia varied greatly, quanti- fication of fractional hypoxic volume [21] or more complex mathematical modelling [24] may be important to accurately identify those patients who should be offered more aggressive therapy. In the SPECT world there has also been interest in labelling nitroimidazole compounds, initially directly with iodine isotopes or via iodinated sugars [25]. More recently there have been reports of successful imaging with 99 Tcm of nitroimadazoles and some of their core ligands [26, 27]. In spite of a number of promising PET and SPECT radiopharmaceuticals having been described for hypoxia- selective imaging, further work is required to correlate uptake with the degree of tissue hypoxia, or perhaps more importantly, with tumour resistance to therapy. Once these important steps are made it will be possible to design trials where tumour hypoxia identified by non- invasive nuclear medicine techniques can be used to select patients for new therapies designed to overcome hypoxia induced resistance. Tumour angiogenesis In malignant tumours the process of neoangiogenesis results in the formation of a chaotic network of a complex capillary growth stimulated by agonists including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), integrins and others. Without angiogenesis, tumour growth is limited to 1–2 mm and one of the other reasons that tumour angiogenesis has been a therapeutic target is that it is associated with metastatic potential and implantation of tumours. With the intense interest in producing angiogenesis inhibitors as anticancer agents there is a need for markers to directly monitor the effects of these drugs. As many are cytostatic, rather than cyto- toxic, measurement of changes in tumour size may not be the most sensitive means of response evaluation and there is a need for functional methods. In addition, the identification of particular molecular markers of angio- genesis in an individual tumour may allow the selection of patients who are most likely to benefit from a particular antiangiogenic treatment. As angiogenesis is related to factors such as metastatic potential it is possible that angiogenic molecular imaging may also be used as a prognostic marker. A potential advantage of targeting molecular processes related to angiogenesis, rather than those related to the tumour cells themselves, is that the vascular angiogenic targets are potentially more accessible, allowing rapid imaging with high target signal. The other potential advantage of targeting molecular processes involved in tumour angiogenesis is that therapeutic radiopharmaceuticals can be directed at the same targets. This may not only inhibit the angiogenic process, and therefore tumour growth directly, but also impart a therapeutic dose of radiation to tumour cells from the bystander effect. A number of methods have been described to image and quantify the angiogenic process, using direct or indirect measurements with both PET and SPECT radiopharma- ceuticals. The simplest of these is to measure tumour perfusion, commonly with tracers with high or predictable first pass extraction. For example, the uptake of 99 Tcm sestamibi into a mouse breast cancer model has been G J R Cook S154 The British Journal of Radiology, Special Issue 2003
  4. 4. correlated with tumour microvessel density (MVD) [28]. Results in human breast cancers have been variable [29, 30] and further work on the methodology and timing of imaging this compound is required. This compound is lipophilic and its uptake is associated with mitochondrial activity but the mechanisms of uptake with relation to correlations with tumour perfusion and vessel density are not fully understood. Another lipophilic perfusion SPECT agent, 99 Tcm hexamethyl-propylene amine oxime (HMPAO), has been used to determine tumour perfusion in humans, [31] and has also been used to measure changes in perfusion after pharmacological intervention [32]. The superior quantitative accuracy of PET has also led to interest in measuring tumour blood flow with this method. Pharmacologically induced changes in blood flow have been measured in colorectal liver metastases using copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicar- bazone (62 Cu-PTSM) PET and shown to be highly variable in individual patients [33]. This technique may therefore be of use in selecting patients for particular pharmacological interventions. Similarly the pharmacodynamic response of the anti- vascular agent, combretastatin, has been measured with H2 15 O PET in advanced solid tumours. Dose-dependent reduction in tumour perfusion could be identified as soon as 30 min after administration of combrestatin that at lower doses showed recovery at 24 h [34]. This important study revealed the potential for functional imaging methods in not only measuring tumour vascular shutdown but also in assessing the timecourse of antivascular effects. Rather than measuring tumour blood flow directly there has also been interest in imaging specific molecular targets involved in tumour angiogenesis. Tumour derived VEGF and its associated capillary endothelial receptors are examples and there is early work in humans where gastrointestinal tumour VEGF receptors have been imaged with 123 I-iodine labelled VEGF [35]. Therapeutic radiopharmaceuticals including 131 I-labelled anti-VEGF antibodies have also been shown to reduce tumour growth and metastatic potential in a murine spontaneous breast cancer model [36]. Integrins are transmembrane adhesion receptors involved in regulating the proliferation and survival of endothelial cells implicated in tumour angiogenesis and offer themselves as a further target for imaging with radiopharmaceuticals. These compounds, including aVb3 integrin, are preferentially expressed on activated endothelial cells and tumours and recognise the arginine-glycine-aspartic acid (RGD) sequence and hence are targeted by RGD containing peptides. Glycosylated RGD containing peptides have been success- fully labelled with both SPECT and PET radionuclides including iodine isotopes, 99 Tcm and 18 F [37–39]. Early work has demonstrated successful imaging of melanoma metastases with a synthetic peptide containing two RGD sequences and labelled with 99 Tcm [40]. Six of eight metastatic lymph nodes and 75% of other metastatic lesions showed measurable uptake and therefore evidence of integrin binding on tumour cell surfaces. Tumour choline metabolism Elevated levels of choline, phosphocholine and phos- phoethanolamine have been detected in a number of cancers by MR spectroscopic and biochemical techniques, correlating with increased cellular membrane phospholipid synthesis rates. There are some limitations associated with the most commonly used clinical PET tracer, 18 FDG, related to specificity and tumour detection where there is high background activity, including the brain and urinary tract. Choline tracers including 11 C-choline, and more recently 18 F-choline, have been developed with these limitations in mind. It is hoped that uptake of these tracers will correlate with increased membrane synthesis and hence cellular proliferation. There are early clinical data suggesting favourable imaging characteristics in many cancers, including primary brain tumours and prostate cancer that are inadequately imaged with 18 FDG [41, 42]. Tumour apoptosis Programmed cell death or apoptosis is thought to be an inherent part of successful treatment of tumours with chemotherapy or radiotherapy. Once apoptosis is triggered a series of enzymatic cascades are initiated to ensure the orderly destruction of the cell and its constituents. One of the major pathways involved includes activation of caspases. As a result of this phosphatidylserine (PS), usually restricted to the inner cell membrane, is externa- lized. Annexin V, an endogenous human protein with a molecular weight of 36000, binds to PS with very high affinity. Annexin V has been labelled with 124 I-iodine as a PET tracer [43] and 123 I-iodine [44] and 99 Tcm as SPECT tracers [45]. Accumulation of Annexin V appears to correlate with apoptosis as measured by other means [46] but it is likely that binding will also occur non-specifically during necrosis during membrane breakdown when PS is exposed. However, it is hoped that the ability to image apoptosis will allow an accurate evaluation of cytotoxic therapy effect soon after the administration of the therapeutic agent. A preliminary study of 15 patients with lung, lymphoma or breast cancer is promising [45]. No tumour- related uptake was seen at baseline but measurable uptake was identified as soon as 24–48 h after the first course of chemotherapy in seven patients who went on to have a complete (n54) or partial (n53) response by conventional criteria. In contrast, six of eight patients without an increase in uptake showed progressive disease. The sensitivity of the technique for detecting low levels of apoptosis against non-specific background activity or the ability to differentiate apoptotic cell death from other mechanisms remains unknown but progress is being made with a number of refinements to the imaging method [47]. Gene delivery and expression Perhaps one of the most exciting areas of molecular imaging is that related to the expression and function of various tumour related genes and how genes are delivered and expressed during novel gene therapy techniques. The main current methods for demonstrating gene expression require tissue samples and therefore non-invasive methods to identify and quantify gene transfer and protein expres- sion in vivo are in great demand. Gene therapy may be unsuccessful due to inefficient delivery of the gene to the target tissue, but whatever the method of gene transfer, Oncological molecular imaging S155The British Journal of Radiology, Special Issue 2003
  5. 5. e.g. viral vector, typically a reporter gene can be used to confirm successful transfer and expression in target cells. Common approaches have employed both enzyme and receptor-mediated gene imaging. Once validated, a repor- ter gene/probe system can potentially be used to inter- rogate any gene of interest. The most commonly used system in PET imaging employs the herpes simplex virus 1 thymidine kinase (HSV-TK) enzyme. If viral thymidine kinase is successfully expressed in a cell it will phosphorylate nucleoside analogues (e.g. ganciclovir), which then becomes trapped in the cell. Mammalian thymidine kinase will not phos- phorylate these nucleoside analogues. If nucleoside ana- logues can be radioactively labelled, after active transport and subsequent phosphorylation, the accumulation of radioactivity should indicate HSV-TK expression and hence successful transfection. In the absence of HSK- TK, nucleoside analogues that enter the cell will not be phosphorylated and therefore do not accumulate. A number of PET radiopharmaceuticals have been used to test for HSV-TK expression including ganciclovir, 5-iodo-2-deoxyuridine (IUDR), 5-iodo-2-fluoro-2-deoxy-b- D-arabinofuranosyl uracil (FIAU) [48–50] and others. This work is still largely at the animal stage but successful imaging of HSV-TK expression has been accomplished. Receptor mediated gene expression relies on the encoding of cell surface receptors for which radiolabelled substrates are available. An example is the dopamine 2 (D2) receptor that can be delivered by a viral vector to transfect tumour cells that can then be imaged with substrates such as 11 C- raclopride or 18 F-fluoroethylspiperone [51]. Whilst a number of models for the imaging and quantitation of gene expression are being developed in animals, it is anticipated that if successful in man, these non-invasive methods may accelerate and facilitate gene therapy techniques. Tumour multidrug resistance Multidrug resistance (MDR) is a major factor in the failure of chemotherapy in cancer. There are a number of different mechanisms for MDR but one of the most studied involves the MDR-1 gene and its protein, P-glycoprotein (Pgp), as well as the multidrug resistance protein, MRP. These act as ATP-dependent efflux mechanisms for a number of drugs including anthracy- clines, taxol, vinca-alkaloids and others. Identification and measurement of MDR is of potential importance as it may affect choice of drug in an individual patient but also because MDR modulators are being developed that inhibit MDR proteins and enhance tumour accumulation of chemotherapeutic compounds. Sestamibi, a cationic, lipophilic compound developed for myocardial perfusion imaging, is a substrate for Pgp, and when labelled with 99 Tcm , can be used as a marker of Pgp transport activity. Therefore resistant tumour cells will show minimal or absent uptake or enhanced washout of this compound. In human studies, efflux rate of sestamibi from breast tumours has been correlated with Pgp expression [52] and inversely correlated with ther- apeutic response to chemotherapy [53]. In addition, Pgp modulation with PSC 833 has been shown to be associated with increased accumulation of 99 Tcm sestamibi in tumours and the liver in man [54]. Other single photon agents including 99 Tcm -tetrofosmin and PET agents such as copper bis(diphosphine) com- plexes have been investigated as probes for imaging drug resistance [55]. Conclusions Molecular imaging is not based on a single imaging methodology and nuclear medicine techniques are just a small part of the available tools being developed in this field. This review has concentrated on some of the more important oncological aspects of molecular imaging that are relevant to nuclear medicine that have been, or are close to being applicable to man. Many of these techniques have developed through initial animal work and microPET and microSPECT techniques also continue to progress. Of course, there are many other nuclear medicine techniques that are relevant including imaging of the sodium iodide symporter in thyroid and breast cancer, monoclonal antibody targeting of tumour antigens, imaging of other peptide ligands, amongst others. 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