3.2.1. Cancer

Cancer develops when cells begin to divide out of control. One hallmark of cancer cells is that they consume larger amounts of glucose than normal cells, because of a shift in energy production. This shift is known as “the Warburg effect” (Sidebar 3.1). Fluorine-18-fluorodeoxyglucose (FDG)- PET (Sidebar 2.2) has exploited this feature of cancer cells to detect differences between cancer and normal cells in the consumption of glucose. The accumulation of FDG in cancer cells represents an in vivo correlate of the abnormal mitochondrial function found in many types of cancer cells. Differences in rate of glucose utilization distinguish malignant from benign tumors and identify the presence and spread of tumor metastases as measures of disease severity. This information is important for tumor staging and for designing therapeutic strategies.

SIDEBAR 3.1

The Warburg Effect. Cells generate energy in two main ways: oxidative phosphorylation in mitochondria and glycolysis in the cytoplasm. In oxidative phosphorylation, 38 adenosine triphosphate (ATP) molecules are generated per glucose molecule. In contrast, (more...)

There is increasing evidence that imaging with FDG-PET may have an even greater impact on patient management as a way of monitoring tumor response to therapy (Juweid and Cheson 2006, Weber and Wieder 2006). Changes in glucose consumption can be detected using FDG-PET, where a reduction in tumor uptake of FDG predicts the likely effectiveness of chemotherapy. As Figure 3.1 illustrates, a favorable response can be detected by PET, but not with CT, as early as 2 weeks from initiation of chemotherapy in a patient with esophageal cancer (Wieder et al. 2005). At 2 weeks, the tumor volume as measured with CT had decreased minimally (diameter from 21 mm to 19 mm), while the FDG uptake had declined by about 50 percent. At 3 months, the tumor volume has strikingly decreased and the FDG uptake is only faintly visible. By contrast, in patients where there is a persistent high uptake of FDG, the absence of a therapeutic response is noted. Therefore, early assessment of tumor response to therapy with FDG-PET has the potential to considerably reduce the side effects and costs of ineffective therapies.

FIGURE 3.1

Monitoring the effects of chemotherapy on tumor volume and glucose uptake with serial multislice computed tomography (MSCT) and PET imaging in a patient with cancer of the esophagus. Imaging was performed before the start of treatment (left), 2 weeks (more...)

As noted above, tumor imaging with FDG-PET has been clinically useful in oncology because it captures the increased rate of glucose utilization. Yet, its utility has some limitations due to organ-specific utilization of glucose. For example, its use in diagnosing prostate and liver cancers has been limited due to the low metabolic activities of these cancers. The brain, in contrast, uses glucose for normal function. This characteristic has made it difficult to delineate tumors from normal brain tissue by FDG-PET. Similarly, increased glucose utilization is also observed when the body responds to damage (i.e., inflammation). Therefore, certain inflammatory processes cannot be differentiated from tumor tissue by FDG-PET.

However, depending on the radiotracer used, PET provides diagnostic information based on other types of metabolic activity, such as amino acid¹ metabolism, cell proliferation, and tissue hypoxia.² For example, amino acids and amino acid analogs³ have been labeled with fluorine-18 or carbon-11 and have been reported to be superior to FDG for imaging of brain tumors (Pirotte et al. 2004, Nariai et al. 2005, W. Chen et al. 2006). Another class of PET tracers that has shown promise is radiolabeled thymidine analogs (Shields 2006). The use of these tracers is based on the hypothesis that they mimic the biological behavior of thymidine, and thereby provide a measurement of DNA synthesis and cell proliferation in vivo. By extension, these tracers provide an accurate measure of tumor growth (Shields et al. 1998). Analogues of thymidine such as fluorine-18-fluoro-L-thymidine and fluorine-18-1-(2'-deoxy-2'-fluoro-β-darabinofuranosyl) thymine, also are being investigated as potential agents for monitoring early response to therapy.

Another promising application of PET is the use of probes, such as fluorine-18-fluoromisonidazole, that detect tumor hypoxia, which can affect tumor response to radiation therapy (Rajendran et al. 2006). The phe nomenon that cells are more sensitive to radiation in the presence of oxygen is well-established (Mottram 1936), and resistance to radiation has been observed in some tumors with considerable hypoxic fractions. Radiolabeled peptides, antibody fragments, and, more recently, nanoparticles targeting different cell surface molecules also hold promise for tumor imaging and for targeted radionuclide therapy. Several of these radiolabeled peptides and antibody fragments targeting a variety of cell surface molecules have entered clinical trials (Sharkey and Goldenberg 2005).

These emerging radiotracer approaches hold promise for further individualization of cancer treatment. They will allow for the imaging of biological processes that are characteristic of cancer cells. For example, a variety of new anti-cancer drugs such as inhibitors of epithelial growth factor receptors have been found highly effective for killing cancer cells (Sequist et al. 2007). If additional tumor characteristics can be identified with target-specific molecular probes, it will become possible to select specific treatment strategies for individual patients and improve the probability of treatment success.

In addition, hybrid imaging devices, such as PET/CT, which combines the functional information provided by PET with the anatomic information provided by CT, have transformed staging and restaging of patients with cancer. As noted earlier, PET has the ability to detect differences in metabolic activity. However, without the map of the body that is provided by conventional imaging methods, it is difficult to pinpoint the organ or organ region in which abnormal activity is occurring. The diagnostic accuracy of PET/CT imaging with FDG exceeds that of PET or CT alone (Lardinois et al. 2003). Figure 3.2 depicts images taken with PET/CT in a patient with lung cancer. PET/magnetic resonance imaging (MRI), another hybrid imaging modality that merges anatomical and functional information, is currently under development (Cherry 2006). Although its role in patient care needs to be determined, it holds particular promise for studies of the brain.

FIGURE 3.2

Staging of lung cancer with FDG and PET/CT. The whole-body image (Panel A) shows normal FDG uptake in the brain and the urinary bladder. In addition, several regions of intensely increased FDG uptake are seen in the chest. On the cross-sectional images (more...)

3.2.2. Cardiovascular Disease

In cardiology, nuclear medicine imaging has assumed an important role in the diagnosis as well as the management of patients with coronary artery disease.⁴ Myocardial perfusion imaging (Sidebar 3.2) is the most widely used approach in patients with suspected cardiac disease. Perfusion imaging of the heart is highly accurate for detecting the presence of coronary artery disease. In addition, the test can predict a patient’s risk for further cardiac disease (e.g., non-fatal heart attack) and cardiac death. This allows physicians to provide better care to patients with advanced and disabling cardiac disease by guiding therapeutic decisions; the therapies can range from conservative, drug-based management of disease to more aggressive forms of intervention, such as surgery to restore blood flow. Because of the high prevalence of coronary artery disease, myocardial perfusion imaging studies have become the most widely used nuclear medicine imaging test. More than 7 million myocardial perfusion imaging studies are performed each year in the United States alone (Heinz Schelbert, UCLA, personal communication, March 8, 2007).

SIDEBAR 3.2

Myocardial Perfusion Imaging. Myocardial perfusion imaging is a test that allows doctors to examine blood flow to the heart muscle (i.e., myocardium). The patient is first injected with material labeled with a radionuclide, such as technetium-99m, thallium-201, (more...)

Approaches that primarily employ PET have been useful in delineating patterns of metabolism of both the healthy and the diseased heart. Metabolic activity demonstrated with PET and FDG in myocardial regions with diminished blood flow predicts an improvement in contractile function if blood flow is restored by coronary artery revascularization (Tillisch et al. 1986). Furthermore, radiotracers of fuel substrates of the heart, such as carbon-11-labeled fatty acid, glucose, and acetate, that can be imaged with PET offer a means for identifying changes in the heart’s substrate metabolism that are associated with age, obesity, or diabetes (Davila-Roman et al. 2002, Kates et al. 2003). Better understanding of these metabolic changes provides a framework for developing therapeutic strategies that may delay or avert progressive deterioration of heart muscle function and possible heart failure. Existing imaging techniques also offer a means for assessing the effectiveness of gene- and cell-based approaches for repairing the injured heart muscle tissue or for improving cardiac function. Changes in blood flow in response to angiogenic gene therapy with vascular endothelial growth factor, for example, can be monitored non-invasively (Udelson and Spiegler 2001). Similarly, effects of stem cell transplants on blood flow and metabolism on ischemically injured myocardium (i.e., after an acute myocardial infarction) can be demonstrated (Dobert et al. 2004). Nuclear medicine imaging will likely play an important role in the development and design of new therapies for cardiac disease.

New radiotracer techniques that are currently being investigated hold promise for the early diagnosis of coronary atherosclerosis.⁵ Inflammation of lipid-rich deposits in the wall of the major arteries, called atherosclerotic plaques, can rupture and cause non-fatal heart attacks or cardiac death. Currently, blood biomarkers, such as C-reactive protein, that measure acute inflammation, have been associated with future coronary events; however, they do not indicate where the atherosclerotic plaque is located. The ability to pinpoint the locations of plaques within the coronary arteries may help predict which individuals are predisposed to serious cardiac events. Cardiovascular imaging with tomographic modalities such as CT is expected to help identify patients with vulnerable plaques earlier than with conventional coronary angiography (Schoenhagen et al. 2004). Nuclear medicine imaging studies have also indicated that localization may indeed be possible (Dunphy et al. 2005). For example, in patients at risk for stroke, FDG uptake was found to be considerably increased in diseased carotid arteries, reflecting severe inflammation of atherosclerotic lesions with a high potential of plaque rupture (Tawakol et al. 2006).

In patients with cardiovascular disease, hybrid imaging techniques such as PET/CT, SPECT/CT, and PET/MRI will likely facilitate the assessment of functional consequences of disease-related structural alterations. Conversely, they will also allow molecular and cellular processes to be assessed in absolute units and assigned accurately to structural alterations. These advantages offer opportunities for improving disease detection, characterization, and treatment, as well as treatment monitoring in patients with cardiovascular disease. Their benefits could include more comprehensive assessments of cardiovascular health and disease and improved targeting of coronary vascular interventions, as well as accurate measurement of the severity of atherosclerotic disease, atherosclerotic plaques, and the effectiveness of plaque stabilizing therapies (Tarahan et al. 2006).

3.2.3. Neurological Disorders

A third clinical specialty where nuclear medicine imaging has played an important role in patient care is neurology. Radiotracer approaches aid in brain tumor evaluation and early identification of recurrence, in the planning of surgical treatment of seizure disorders, and, importantly, in assessing neurodegenerative disorders. As in other tumors, FDG is used in the diagnosis and characterization of brain tumors.

However, as noted earlier, the diagnostic accuracy with FDG has remained limited due to the high rate of glucose metabolism, and the high radiotracer uptake in normal brain tissue. This limitation has prompted the development and application of radiotracers such as carbon-11 methyl-methionine, fluorine-18-fluoro-l-phenylalanine, or fluorine-18-fluoro-L-thymidine, which serve as markers of amino acid transport and metabolism and DNA synthesis. These radiotracers target tumor tissue in the brain and contribute to the grading of tumor aggressiveness and, more importantly, to distinguishing tumor recurrence from post-surgical tissue reactions and scar tissue formation (Chen et al. 2005, P. Chen et al. 2006) (Figure 3.3).

FIGURE 3.3

MRI and PET brain images in a patient with a brain tumor (grade II oligodendroglioma). The tumor in the left brain hemisphere as seen on the MRI image (left panel) is associated with diminished FDG uptake and thus reduced glucose utilization (center) (more...)

In seizure disorders, PET imaging with FDG has been found useful for localizing potentially epileptogenic regions of the brain, and their spatial distribution and extent. Accurate identification of such aberrant brain tissue is critical for determining eligibility of patients for surgical treatment approaches designed to abolish seizure disorders that are inadequately controlled by medications. Neurodegenerative disorders, such as Alzheimer’s (Figure 3.4), Pick’s, and Huntington’s diseases (Sidebar 3.3), are typically associated with decreased glucose metabolism in certain parts of the brain. Each of these disorders is associated with diminished metabolism in specific brain regions that are distinguishable by FDG-PET (Silverman et al. 2001). Serial brain imaging studies with FDG-PET also allows monitoring of the rate of disease progression (Alexander et al. 2002).

FIGURE 3.4

FDG-PET brain images in a normal volunteer (left panel) and in a patient with Alzheimer’s disease (right panel). Tomographic slices through the brain at the level of inferior parietal/superior temporal cortex are shown. The color displayed in (more...)

SIDEBAR 3.3

Neurodegenerative Disorders. Alzheimer’s disease is the most common form of dementia among elderly people, affecting an estimated 4.5 million Americans. It is a brain disorder that seriously affects a person’s ability to carry out daily (more...)

Clinically it is difficult to differentiate mild cognitive impairment that is the result of a neurodegenerative disorder from that which derives from non-neurodegenerative causes or normal aging. This has prompted research and development of novel radioligands for targeting β-amyloid in senile plaques and tau in neurofibrillary tangles as noninvasive neuropathologic markers (Figure 3.5). Clinical studies support the promise of these novel radiotracers (e.g., the carbon-11-labeled Pittsburgh compound B (PIB) or the fluorine-18-labeled-2-dialkylamino-6-acylmalononitrile-substituted naphthalenes) for separating early stages of neurodegeneration from other age-related causes of cognitive impairment (Klunk et al. 2004). These radiotracers also appear to be useful for monitoring disease progression and outcomes of drug treatment (Engler et al. 2006).

FIGURE 3.5

PIB PET brain images in a patient with Alzheimer’s disease (AD, left) and in a normal control person. The PET PIB images are compared to anatomic maps of the brain generated with MRI which do not indicate any abnormalities. Note the intense radiotracer (more...)

Another important future goal will be to develop improved diagnostics and protective therapies for neurological disorders, such as Alzheimer’s and Parkinson’s diseases. To reach this goal, a more detailed understanding of the molecular changes that occur in the brain during the early stages of dis ease development will be required. Furthermore, increasing the availability of radiotracers that have been developed to pinpoint specific molecular changes and monitor response to therapy will enable us to reach this goal. For example, many radiotracers, such as fluorine-18-fluoroDOPA, for assessing the integrity of the brain dopamine system have been developed but are not readily available. Making these and other radiotracers more widely available could result in more accurate diagnosis and differential diagnoses of Parkinson’s disease (Piccini and Whone 2004). In addition, other neurotransmitter systems (e.g., cholinergic, noradrenergic, serotonergic) also degenerate in Parkinson’s disease, and the use of imaging to monitor changes in these systems, particularly in relation to disease progression, could represent another important future research direction (Brooks 2007).

Similarly, treating psychiatric disorders, such as depression, schizophrenia, and addiction, is a special challenge. Many of the existing treatments are inadequate, with major side effects or high non-response rates. In the future, the widespread availability of highly specific radiotracers that can be used in basic neuroscience research in humans can be expected to aid in understanding the biological processes of these diseases and, ultimately, the development of better treatments (Koob 2006, Zipursky et al. 2007).

3.2.4. Drug Development

In addition to its role in patient care, nuclear medicine imaging has the potential to accelerate the drug development process and substantially reduce the time and expense of bringing a drug to market. As described in Chapter 2, use of nuclear medicine imaging during the drug development process could identify which drugs should advance from animal to human studies, validate the mechanism of drug localization, evaluate drug distribution to target tissue, establish the drug occupancy of receptor sites, assess the actions of new agents on specific molecular targets or pathways, and determine appropriate dose range and regimen (Eckelman 2003).

Already, the pharmaceutical industry increasingly relies on small animal imaging laboratories for drug development and evaluation. Small animal imaging laboratories equipped with nuclear medicine imaging devices such as microPET or microSPECT but also with microCT, microMRI, and optical (e.g., bioluminescence and fluorescence) imaging systems offer an ideal environment for rapid and cost-efficient screening and development of new molecular probes and drugs. The new image-based assays account therefore for most of the newly developed radiopharmaceuticals in both academia and industry. Using small-animal imaging instruments and radiolabeled versions of drug candidates in which a carbon atom or other atoms of the drug molecule are substituted with a radionuclide of the same element, the binding of drug candidates to target and non-target tissues can be determined with relative ease and tissue pharmacokinetics can be studied. Furthermore, with targeted radiotracers, the efficiency of target occupancy and inhibition can be assessed non-invasively. Based on these animal data, imaging biomarkers can be developed to monitor treatment effects and to determine optimal drug doses on a molecular level in clinical studies. The small imaging devices also offer a means for rapid screening of potential drug candidates. For example, the effects of novel compounds on cell proliferation or cell metabolism can be determined in small-animal tumor models with fluorine-18-FLT and fluorine-18-FDG and thus serve as a “generic pharmacodynamic readout” (Leyton et al. 2005).