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Positron Emission Tomography in Medicine
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Positron Emission Tomography in Medicine: An Overview Abass Alavi and Steve S, Huang
Positron Emission T o m o g r a p h y
Introduction
in Oncology Positron emission tomography (PET) is a noninvasive imaging modality for whole-body imaging of cellular and metabolic functions. The concept of PET was first conceived in the early 1970s. Collaboration between researchers at the University of Pennsylvania and the Brookhaven National Laboratory culminated in the first positron emission tomography of the human brain with Fluorene- 18-Fluorodeoxyglucose (FDG) in 1976. Modern PET cameras differ greatly from the gamma camera used in the first PET scan. The modern coincident two-photondetecting PET instruments provide outstanding images with superb spatial resolution and sensitivity compared to other imaging modalities. Paralleling the refinement in PET cameras has been an explosion in the development of PET tracers serving all aspects of modern medicine. With a chemically diverse repertoire of positron-emitting radionuclide (Table 1), PET chemists can devise tracers that target almost every aspect of the human biochemical milieu. This chapter briefly discusses current and upcoming applications of PET tracers in oncology, neurology, cardiology, infectious disease, and inflammatory disorders.
Cancer Imaging: Lung and Breast Carcinomas
FDG is the most widely available and currently the dominant PET tracer in oncology. Cancer imaging with FDGPET takes advantage of increased glucose metabolism in cancer cells first described by Otto Warburg in the 1930s. FDG is taken up by cells with glucose transporters such as GLUT- 1. Once in the cytoplasm, FDG enters the first step of the glycolytic pathway and is converted to FDG-6phosphate. Unlike glucose-6-phosphate, FDG-6-phosphate is not a substrate of phosphoglucose isomerase, the second enzyme in the glycolytic pathway. Hence, the radioactivity accumulates inside cells. Selective imaging of the cancer cells is practical because of persistent glucose uptake in many cancer cells in low-serum insulin state when most cells outside of the central nervous system consume glycogen or fatty acid instead of glucose for energy needs. This produces a high cancer to surrounding tissue contrast in a fasting patient. This "contrast resolution," based on differential cellular metabolism, makes FDG-PET unique compared with other imaging modalities such as modern X-ray computed tomography (CT) and magnetic resonance imaging (MRI.) Severity and extent of metastatic disease are
39
Copyright © 2008 by Elsevier, Inc. All rights of reproduction in any form reserved.
40
Positron Emission Tomography in Oncoloqy
Table 1 Positron-Emitting Nuclide with Potential Medical Applications and Their Corresponding Half-lives Radionuclide
Half-life
Radionuclide
Half-life
18F llC 150
110 min 20.4 min 2.03 min 9.9 min 9.49 hr 1.14 hr 14.7 hr 100 hr 1.25 min
44Sc
3.97 hr 17.5 hr 3.4 hr 9.74 min 12.7 hr 16.2 hr 1.15 hr 52 min
13N 66Ga 68Ga 86y 124I
82Rb
55Co 61Cu 62Cu 64Cu 76Br ll0mIn 94mTc
Source: Lundqvist, H., and Tolmachev, V. 2002. Targeting peptides and positron emission tomography. Biopolymers 66:381-392, and TakalkarA., Mavi A., Alavi A., and Araujo L. 2005, PET in cardiology, Radiol. Clin. N. Am. 43"107-119.
often poignantly illustrated with an FDG-PET scan in a few frames of projection images (Fig. 4). Clinically, FDG-PET is used for (1) localization of suspected malignancies that appear as foci of high-glucose metabolism in low-insulin state, and (2) ascertaining metabolic activities of a known focus of abnormality. Encompassing these two unique roles are the tasks of initial staging of patients newly diagnosed with cancer, restaging cancer patients with suspected recurrence, assessment of recurrence, and cancer treatment monitoring. Accurate tumor staging is essential for choosing the appropriate treatment strategy for patients with cancer. For example, FDG-PET scanning enables assessment of the local extent of thoracic malignancies as well as the presence of nodal or distant metastasis. At the time of diagnosis, PET is useful in initial preoperative staging for non-small cell lung cancer
(a)
(b)
(NSCLC). Accurate tumor staging is essential for choosing the appropriate treatment strategy in patients with lung cancer. In one study, 30% of patients with lung cancer who were possible surgical candidates based on appearance of limited disease with conventional imaging techniques were found to have metastasis with FDG-PET (Mavi et al., 2005). A PET scan is helpful in evaluating mediastinal-spread lung cancer and in distinguishing stage N3 from potentially resectable stage N1 and N2 disease. Positron emission tomography detects unexpected extrathoracic metastases in 10-20% of patients and changes therapeutic management in about 20% of patients with lung cancer. By staging patients more accurately, FDG-PET utilization decreases unwarranted surgery and morbidity associated with aggressive treatment when palliation should be considered. For restaging, FDG-PET has become an invaluable tool in the evaluation of patients with suspected recurrent cancer based on increased serum tumor marker levels such as thyroglobulin, carcinoembryonic antigen, or CA-125. The role of PET for detecting the recurrence of a tumor following the initial response has become the hallmark of this technique in almost every malignancy. Anatomic imaging techniques, such as CT, suffer from the general shortcoming of morphologic criteria for initial staging. In addition, structural changes following surgery and/or radiation/chemotherapy render anatomic imaging techniques inconclusive in such settings. Restaging with FDG-PET was shown to have sensitivity consistently between 80 and 95%, specificity of 75-90%, and accuracy of 80-90% between 1993 and 2000 (Juweid and Cheson, 2006). It is likely that the performance of the most recent generation of PET scanners will be even better. Conventional treatment monitoring using CT relies on changes in the size of the lymph nodes, which is a slow process and may not be conclusive in the early phases of
(c)
Figure 4 Cancer staging with FDG-PET. Representative cross-sectional images of a PET scan of a patient with metastatic esophageal cancer. (a) Transaxial section showing liver metastasis. (b) Sagittal section illustrating bone marrow involvement in the sternum and a vertebral body (arrows). (c) Coronal section demonstrating liver metastasis, para-aortic lymph node metastasis, and metastatic disease in the right humeral head (arrows).
2 Positron Emission Tomography in Medicine: An Overview favorable response. Furthermore, CT is unable to distinguish between active disease and residual scar tissue after therapy. Given that a treatment course typically lasts several months, undergoing an ineffective treatment not only wastes valuable health-care resources but also causes unnecessary morbidity for patients. Being able to determine treatment effectiveness and to redirect management as necessary can save both valuable time for patients and resources for the society at large. For example, Cachin et al. studied treatment monitoring clinical trial by looking at the therapeutic efficacy of high-dose chemotherapy with bone marrow transplant and concluded that response to therapy as measured by FDGPET is the single most powerful independent predictor of survival. Eighty-three percent of the patients who underwent the high-dose chemotherapy treatment with complete response as shown by FDG-PET were alive at 12 months. By comparison, responses by Response Evaluation Criteria in Solid Tumors (RECIST) based on conventional imaging techniques were unable to predict survival (Cachin et al., 2006). For Hodgkin's Lymphoma (HL), a negative FDGPET scan post-therapy is highly indicative of long-term, disease-free survival and is particularly useful in the presence of residual CT mass (Kumar et al., 2004.) Figure 5 illustrates treatment monitoring of a patient with Hodgkin's Lymphoma. For aggressive non-Hodgkin's Lymphoma (NHL), a positive FDG-PET scan is predictive of disease persistence or recurrence. For both NHL and aggressive HL, early assessment of response appears to be predictive of long-term outcome. Optimal time of FDG-PET scan during therapy needs to be determined. For indolent NHL, the high rate of false-negative FDG-PET scans raises questions regarding its clinical role in treatment monitoring.
(a)
(b)
41
The role of FDG-PET continues to expand as more evidence of its utility and cost-effectiveness in various areas of medical practice continues to emerge. Table 2 offers a glimpse of current applications in oncology and representative sensitivity and specificity for each application. The utility of FDG-PET, however, is limited in detecting lesions < 5 mm in diameter, and FDG-PET is not meant to be a substitute for pathologic examination for detecting micrometastasis. In fact, FDG-PET is likely to be part of the imaging work-up for selection of biopsy sites. PET-guided biopsy/resection has been heavily studied and will likely emerge as the standard of care for neoplastic diseases such as insulinoma or mesothelioma in the near future.
Positron Emission Tomography in Lung and Breast Cancer Lung cancer and breast cancer are two major causes of cancer-related mortality in the United States. The number of deaths due to lung cancer annually is greater than that of breast, colon, and prostate cancers combined (Bunyaviroch and Coleman, 2006). Breast cancer is a leading cause of cancer mortality among women, second only to lung cancer. One in nine women is diagnosed with breast cancer in her lifetime. Diagnosis of lung cancer often starts with a solitary pulmonary nodule incidentally noted during a chest X-ray or a chest CT exam. Positron emission tomography is useful as an adjunct modality in evaluation of solitary pulmonary nodules, especially when results from conventional imaging modalities are equivocal. The sensitivity and specificity of FDG-PET for evaluating radiologically indeterminate nodules
(c)
Figure 5 Treatment monitoring with FDG-PET. (a) Patient with Hodgkin's disease involving the neck, mediastinum, and left supraclavicular lymph nodes (arrows). (b) Post-chemotherapy scan conducted 46 days after the initial scan illustrating resolution of the malignant foci. Prominent bone marrow and spleen uptake were observed due to the recovering hematopoietic system post-chemotherapy. (c) Repeat PET scan 91 days after the initial scan showed resolution of bone marrow and splenic FDG uptake.
42
Positron Emission Tomography in Brain Imaging Table 2 Selected Indications for FDG-PET in Oncology and the Representative Sensitivities and Specificities
Clinical Indication
Sensitivity
Specificity
Head and neck tumor, restaging Thyroid cancer restaging Follicular/papillary Medullary Lung cancer Solitary pulmonary nodule Bone marrow metastasis Adrenal metastasis Restaging (non-small cell) Colon cancer Diagnosis Staging Restaging Breast cancer, restaging Esophageal cancer, staging Lymphoma, staging Pancreatic cancer, staging Cervical cancer, staging Ovarian cancer, restaging Renal cell carcinoma, staging
95%
83%
75% 78%
90% 79%
97% 92% 100% 97-100%
78% 99% 80% 62-100%
74% 82% 97% 97% 51% 90% 79% 80% 90% 64%
84% 94% 76% 92% 94% 93% 86% > 95% 86% 100%
Source: Lin, E., and Alavi, A. 2005, PET and PET/CT." A Clinical Guide (New York: Thieme Medical Publishers).
are 92% and 90%, respectively (Mavi et al., 2005). FDGPET may not be the best modality for evaluating solitary pulmonary nodules that are highly suspicious of cancer by conventional radiography; the negative predictive value of FDG-PET is low in this scenario. Clinicians should also be aware that FDG uptakes in bronchoalveolar carcinoma and carcinoid tumors are lower compared to typical non-small cell lung carcinoma. Hilar and mediastinal staging of NSCLC is necessary to differentiate unresectable N3 disease from N1/N2 disease. Positron emission tomography with FDG has a sensitivity of 85-95% and a specificity of 81-100% for mediastinal/hilar staging (Mavi et al., 2005). Some investigators do feel that one cannot completely exclude mediastinal involvement with negative PET finding. Mediastinoscopy may still be necessary. In one study, mediastinoscopy exhibited 3% false-positive rate, while PET had 11.7% false-positive rate. The use of PET/CT and nextgeneration time-of-flight PET, which has higher spatial resolution, may lower the false-negative rate of PET for mediastinal/hilar staging. The sensitivity of detecting primary breast cancer with PET has been reported as being between 76 and 100% (Kumar and Alavi, 2004). Our experience indicates that PET is not sensitive enough as a single modality for early detection of breast cancer. The deficiency is mainly due to spacial resolution; hence, microscopic lesions such as those found in ductal carcinoma in situ cannot be detected with PET. Although PET has demonstrated good sensitivity and specificity in detecting axillary nodal metastasis, the sensitivity is
not optimal when compared with seminal lymph node biopsy. The sensitivities of axillary lymph node metastasis detection ranges from 20-100%, with more recent studies showing lower sensitivity (Kumar and Alavi, 2004). This is largely due to improvement in pathologic diagnosis. Although PET currently has no role in primary breast cancer detection and axillary node staging, it should be used for evaluation of distant metastasis, restaging, and treatment monitoring. The sensitivity of PET in detecting distant metastasis ranges from 86-100% and specificities range from 79-97%. For detecting recurrence, FDG-PET has sensitivity ranges from 79-89%. FDG-PET has been proven useful in monitoring treatment response in breast cancer, especially for patients undergoing chemotherapy. Separating responders from nonresponders in breast cancer treatment is achievable with FDG-PET with sensitivities of 90-100% and specificities of 74-85%.
Positron Emission Tomography in Brain Imaging FDG-PET was originally intended for tomographic imaging of the brain. Ironically, brain tumor imaging with FDGPET has not enjoyed as much popularity as extracranial tumor imaging, owing largely to the high cortical FDG uptake regardless of patient's fasting state. Many of the current generation of cranial tumor imaging agents are labeled amino acids that have more muted uptake in the normal brain
2 Positron Emission Tomography in Medicine: An Overview structure. Examples of such tracers are O-(2-18F-fluoroethyl)L-tyrosine (FET) and [llC]-L-methionine. However, FDGPET does play an important role in patients with suspected recurrent brain tumors and inconclusive, contrast-enhanced MR/or CT examinations. Because radiation-induced necrosis and recurrent tumors appear enhanced on these scans, metabolic imaging with FDG, which reflects disease activity at the cellular level, is invaluable in this setting. The sensitivity for distinguishing necrosis from brain tumor recurrence is ~ 86% and specificity ~ 56% (Newberg and Alavi, 2005). One prominent use of FDG-PET for brain imaging is for early diagnosis of Alzheimer's disease. A pattern curremly used for diagnosing early Alzheimer's disease (AD) is biparietal, bi-temporal hypometabolism. Using such glucose metabolism patterns, one can differentiate early AD from frontal-temporal dementia or Pick's disease. A typical Pick's disease patient exhibits frontal lobe hypometabolism on FDG-PET scan that is not present in early AD. The task of identifying early AD patients is becoming important now that better therapeutics are on the horizon. FDG-PET can also be used for localization of epileptic foci in patients with partial seizures. While a seizure focus may be identified as a region of increased FDG uptake if FDG is injected during seizure, such an "ictal" study is difficult to conduct. The more practical approach is to examine a patient during the "interictal" state. Contrary to the result of an "ictal" study, a seizure focus appears as a region ofhypometabolism ifFDG is injected during the "interictal" period. This type of study can identify seizure foci in 55-80% of epileptic patients with focal EEG abnormalities. Other PET tracers for brain imaging include Fluorene-18 fluorodopa ([18F]-FDOPA) for dopamine uptake and metabolism in the brain. FDOPA is useful for use in patients with movement disorders such as Parkinson's disease. [150]-H20 can be used for general brain perfusion studies. [llC]-raclopride can be used to image the presence of D2 receptors. There are also seretonine receptor and muscarinic receptor tracers currently undergoing clinical trials.
Positron Emission Tomography in Cardiac Imaging Major categories of tracers for cardiac imaging are those for assessment of (1) blood flow, (2) regions of viability, and (3) regions of hypoxia. Cardiac flow tracers for PET include oxygen- 15-labeled water ([150]-H20), [13N]-ammonium, and the generator produced rubidium-82 chloride (Takalkar et al., 2005). Among these tracers, rubidium-82-chloride has been approved by the FDA. 150- and 13N-based tracers require a well-coordinated cyclotron facility and stress lab due to the relatively short half-life of these tracers and the cyclotron requirement for production. 82Rb also has a short half-life, but production and administration can be better coordinated with the strontium-rubidium generator near the bedside. Copper-
43
62-labeled pyruvaldehyde bis (N4-methylthio-semicarbazone) ([62Cu]-PTSM) is also a flow tracer, but lack of a steady supply of 62Cu has prevented its widespread evaluation. [62Cu]-ATSMis a hypoxia tracer that shows great promise in cardiac imaging. Instead of inferring regions of ischemia based on differential cardiac perfusion between rest and stress, hypoxia tracers can directly illuminate regions of hypoxia.
Positron Emission Tomography in Infection and Inflammation In addition to cancer cells, activated granulocytes and monocytes also have elevated glucose metabolisms that can lead to markedly increased FDG uptake. In fact, FDG is an excellent tracer for detecting infection and inflammation (Zhuang et al., 2005.) FDG uptake has been reported in sarcoidosis, esophagitis, sinusitis, fungal and bacterial pneumonia, abscesses in various locations, mastitis, osteomyelitis, prosthetic infection, inflammatory bowel disease, and even in atherosclerotic plaques. Recent studies have suggested that FDG-PET may be useful in the work-up of patients with fever of unknown origin (FUO). FDG is ideal because of its sensitivity in detecting metabolically active regions that may be the source of infection or neoplasm in this clinical setting. FDG-PET may become the study of choice in orthopedic infections. PET is particularly useful in evaluating prosthetic loosening and infection. MRI evaluation is problematic in hip and knee prosthetics due to artifacts from metal implants. The overall sensitivity of detecting lower extremity prosthetic infection with FDG-PET is reported to be greater than 90%, with specificities of 80 to 89%. FDG-PET can also evaluate acute and chronic osteomyelitis, especially in diabetic feet.
Cell Proliferation Agents Positron emission tomography of cell proliferation is currently performed by indirectly measuring DNA synthesis. 3deoxy-3-[18F]-fluorothymidine (FLT) is a promising cell proliferation agent. FLT is a thymidine analog. However, unlike [3H]-thymidine, which is a standard compound for in vitro proliferation study, FLT is not incorporated into DNA (Mankoff et al., 2005). The biochemical fate of FLT is rather analogous to that of FDG in that it is phosphorylated upon cellular uptake and trapped within a cell without further modification. FLT has the potential to be used as a specific agent for assessing disease activity in various stages of different malignancies, particularly for determining response to therapy because cytotoxic chemotherapeutic agents affect cell division earlier and more prominently than glucose metabolism. Therefore, FLT may prove to be superior to FDG for assessing response to treatment. Also, inflammatory
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References
reactions that may confound the use of FDG will not affect the use of FLT in this setting. Ongoing clinical trials are investigating the role of 18F-FLT in imaging proliferation of liver metastasis of colorectal carcinoma, and treatment monitoring of head and neck tumors.
Hypoxia Positron Emission Tomography Imaging Hypoxia in tumor tissue appears to be an important prognostic indicator of response to either chemotherapy or radiation therapy. Therefore, detection of hypoxia in advance of such interventions may help to optimize the use and outcome of different therapeutic modalities. Also, utilizing hypoxic agents for evaluating the efficacies of emerging anti-angiogenic therapies is a promising approach. Several compounds have been synthesized for detecting hypoxia. These compounds form covalent bonds with cellular proteins under low-oxygen conditions; they are retained substantially in higher concentrations in the hypoxic tissues, which can be detected by external imaging techniques. Examples of hypoxia imaging tracers are [18F]-fluoromisonidazole (FMISO), copper-62 diacetylbis (N4-methylthiosemicarbazone) (62Cu-ATSM), 2-(2nitro imi dazo 1-1 [H]-yl)-N-(3 _[18F]fluoropropyl)acetami de ([18F]-EF1), and [2-(2-nitro-l[H]-imidazol-l-yl)-N-(2,2, 3,3,3-pentafluoropropyl)-acetamide] ([18F]-EF5). The [18FIEF compounds have performed well in animal studies and may also prove to be effective for noninvasive imaging of tumor hypoxia (Alavi et al., 2004). There are currently four clinical trials involving the use of EF5. There is one clinical trial with FMISO in conjunction with 18F-FLT for evaluating treatment response of radiation therapy. 62Cu-ATSM appears to have better pharmacodynamic properties than FMISO and could be a better imaging agent for hypoxia.
Peptide and Protein Positron Emission Tomography Tracers Most tracers with positron-emitting nuclides are small molecules < 1000 Daltons. Increasingly, polypeptides and macromolecules such as Annexin V and various antibodies with molecular weight ~ 150,000 Daltons are being evaluated for clinical use. Positron nuclides with short half-life are less practical for macromolecules. Large molecules in general require hours to days for optimal background clearance. Radionuclides with half-life less than 6 hours decay before optimal images may be acquired. 1241 has the advantage of ease of protein labeling and long half-life. This m a k e s 124I a practical imaging radionuclide for proteins and antibodies. 64Cu is also a very attractive radionuclide
for large molecules because of the 12.7 hr half-life. Synthetically, 64Cuis incorporated through a chelate such as DOTA, which can be attached chemically to large proteins days or months prior to use. Other chelate-based positronemitting radionuclides include 94mTcand l llmIn (Lundqvist and Tolmachev, 2002). Being able to image with antibodies can drastically increase diagnostic information, given the almost endless array of antibodies targeting known cellsurface receptors. In conclusion, modern instrumentations of positron emission tomography allow the detection of nanograms to micrograms of tracers with increasing sensitivity and resolution. The ability to image trace amounts of chemicals in a human body with high sensitivity opens the possibility for constructing and visualizing compounds that target selected cell-surface receptors or biochemical pathways. This gives clinicians and scientific investigators multiple tools for greater understanding and assessment of pathophysiology in vivo in cellular context. Positron emission tomography, therefore, is an unprecedented platform that may bridge the gaps between clinical practice and latest understanding of molecular biology of diseases.
References Alavi, A., Lakhani, P., Mavi, A., Kung, J., and Zhuang, H.M. 2004. PET: a revolution in medical imaging. Radiol. Clin. N. Am. 42:983-1001. Bunyaviroch T., and Coleman, R.E. 2006. PET evaluation of lung cancer. J. Nucl. Med. 47:451-469. Cachin, E, Prince, H.M., Hogg, A., Ware, R.E., and Hicks, R.J. 2006. Powerful prognostic stratification by [18F]fluorodeoxyglucose positron emission tomography in patients with metastatic breast cancer treated with high-dose chemotherapy, J. Clin. OncoL 24:3026-3031. Juweid, M.E., and Cheson, B.D. 2006. Positron emission tomography and assessment of cancer therapy. N. Engl. J. Med. 354:496-507. Kumar R., and Alavi, A. 2004. Fluorodeoxyglucose-PET in the management of breast cancer Radiol. Clin. N. Am. 42:1113-1122. Kumar, R., Maillard, I., Schuster, S.J., and Alavi, A. 2004. Utility of Fluorodeoxyglucose-PET imaging in the management of patients with Hodgkin's and non-Hodgkin's lymphomas. Radiol. Clin. N. Am. 42:1083-1100. Lundqvist, H., and Tolmachev, V. 2002. Targeting peptides and positron emission tomography. Biopolymers 66:381-392. Mankoff, D.A., Shields, A.E, and Krohn, K.A. 2005. PET imaging of cellular proliferation. Radiol. Clin. North. Am. 43:153-167. Mavi, A., Lakhani, P., Zhuang, H., Gupta, N.C., and Alavi, A. 2005. Fluorodeoxyglucose-PET in characterizing solitary pulmonary nodules, assessing pleural diseases, and the initial staging, restaging, therapy planning, and monitoring response of lung cancer. Radiol. Clin. North. Am. 43:1-21. Newberg, A.B., and Alavi, A. 2005. The role of PET imaging in the management of patients with central nervous system disorders. Radiol. Clin. N. Am. 43:49-65. Takalkar, A., Mavi, A., Alavi, A., and Araujo, L. 2005. PET in cardiology. Radiol. Clin. N. Am. 43:107-119. Zhuang, H.M., Yu, J.Q., and Alavi, A. 2005. Applications of fluorodeoxyglucose-PET imaging in the detection of infection and inflammation and other benign disorders. Radiol. Clin. N. Am. 43:121-134.
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Positron Emission Tomography in Medicine: An Overview Abass Alavi and Steve S, Huang
Positron Emission T o m o g r a p h y
Introduction
in Oncology Positron emission tomography (PET) is a noninvasive imaging modality for whole-body imaging of cellular and metabolic functions. The concept of PET was first conceived in the early 1970s. Collaboration between researchers at the University of Pennsylvania and the Brookhaven National Laboratory culminated in the first positron emission tomography of the human brain with Fluorene- 18-Fluorodeoxyglucose (FDG) in 1976. Modern PET cameras differ greatly from the gamma camera used in the first PET scan. The modern coincident two-photondetecting PET instruments provide outstanding images with superb spatial resolution and sensitivity compared to other imaging modalities. Paralleling the refinement in PET cameras has been an explosion in the development of PET tracers serving all aspects of modern medicine. With a chemically diverse repertoire of positron-emitting radionuclide (Table 1), PET chemists can devise tracers that target almost every aspect of the human biochemical milieu. This chapter briefly discusses current and upcoming applications of PET tracers in oncology, neurology, cardiology, infectious disease, and inflammatory disorders.
Cancer Imaging: Lung and Breast Carcinomas
FDG is the most widely available and currently the dominant PET tracer in oncology. Cancer imaging with FDGPET takes advantage of increased glucose metabolism in cancer cells first described by Otto Warburg in the 1930s. FDG is taken up by cells with glucose transporters such as GLUT- 1. Once in the cytoplasm, FDG enters the first step of the glycolytic pathway and is converted to FDG-6phosphate. Unlike glucose-6-phosphate, FDG-6-phosphate is not a substrate of phosphoglucose isomerase, the second enzyme in the glycolytic pathway. Hence, the radioactivity accumulates inside cells. Selective imaging of the cancer cells is practical because of persistent glucose uptake in many cancer cells in low-serum insulin state when most cells outside of the central nervous system consume glycogen or fatty acid instead of glucose for energy needs. This produces a high cancer to surrounding tissue contrast in a fasting patient. This "contrast resolution," based on differential cellular metabolism, makes FDG-PET unique compared with other imaging modalities such as modern X-ray computed tomography (CT) and magnetic resonance imaging (MRI.) Severity and extent of metastatic disease are
39
Copyright © 2008 by Elsevier, Inc. All rights of reproduction in any form reserved.
40
Positron Emission Tomography in Oncoloqy
Table 1 Positron-Emitting Nuclide with Potential Medical Applications and Their Corresponding Half-lives Radionuclide
Half-life
Radionuclide
Half-life
18F llC 150
110 min 20.4 min 2.03 min 9.9 min 9.49 hr 1.14 hr 14.7 hr 100 hr 1.25 min
44Sc
3.97 hr 17.5 hr 3.4 hr 9.74 min 12.7 hr 16.2 hr 1.15 hr 52 min
13N 66Ga 68Ga 86y 124I
82Rb
55Co 61Cu 62Cu 64Cu 76Br ll0mIn 94mTc
Source: Lundqvist, H., and Tolmachev, V. 2002. Targeting peptides and positron emission tomography. Biopolymers 66:381-392, and TakalkarA., Mavi A., Alavi A., and Araujo L. 2005, PET in cardiology, Radiol. Clin. N. Am. 43"107-119.
often poignantly illustrated with an FDG-PET scan in a few frames of projection images (Fig. 4). Clinically, FDG-PET is used for (1) localization of suspected malignancies that appear as foci of high-glucose metabolism in low-insulin state, and (2) ascertaining metabolic activities of a known focus of abnormality. Encompassing these two unique roles are the tasks of initial staging of patients newly diagnosed with cancer, restaging cancer patients with suspected recurrence, assessment of recurrence, and cancer treatment monitoring. Accurate tumor staging is essential for choosing the appropriate treatment strategy for patients with cancer. For example, FDG-PET scanning enables assessment of the local extent of thoracic malignancies as well as the presence of nodal or distant metastasis. At the time of diagnosis, PET is useful in initial preoperative staging for non-small cell lung cancer
(a)
(b)
(NSCLC). Accurate tumor staging is essential for choosing the appropriate treatment strategy in patients with lung cancer. In one study, 30% of patients with lung cancer who were possible surgical candidates based on appearance of limited disease with conventional imaging techniques were found to have metastasis with FDG-PET (Mavi et al., 2005). A PET scan is helpful in evaluating mediastinal-spread lung cancer and in distinguishing stage N3 from potentially resectable stage N1 and N2 disease. Positron emission tomography detects unexpected extrathoracic metastases in 10-20% of patients and changes therapeutic management in about 20% of patients with lung cancer. By staging patients more accurately, FDG-PET utilization decreases unwarranted surgery and morbidity associated with aggressive treatment when palliation should be considered. For restaging, FDG-PET has become an invaluable tool in the evaluation of patients with suspected recurrent cancer based on increased serum tumor marker levels such as thyroglobulin, carcinoembryonic antigen, or CA-125. The role of PET for detecting the recurrence of a tumor following the initial response has become the hallmark of this technique in almost every malignancy. Anatomic imaging techniques, such as CT, suffer from the general shortcoming of morphologic criteria for initial staging. In addition, structural changes following surgery and/or radiation/chemotherapy render anatomic imaging techniques inconclusive in such settings. Restaging with FDG-PET was shown to have sensitivity consistently between 80 and 95%, specificity of 75-90%, and accuracy of 80-90% between 1993 and 2000 (Juweid and Cheson, 2006). It is likely that the performance of the most recent generation of PET scanners will be even better. Conventional treatment monitoring using CT relies on changes in the size of the lymph nodes, which is a slow process and may not be conclusive in the early phases of
(c)
Figure 4 Cancer staging with FDG-PET. Representative cross-sectional images of a PET scan of a patient with metastatic esophageal cancer. (a) Transaxial section showing liver metastasis. (b) Sagittal section illustrating bone marrow involvement in the sternum and a vertebral body (arrows). (c) Coronal section demonstrating liver metastasis, para-aortic lymph node metastasis, and metastatic disease in the right humeral head (arrows).
2 Positron Emission Tomography in Medicine: An Overview favorable response. Furthermore, CT is unable to distinguish between active disease and residual scar tissue after therapy. Given that a treatment course typically lasts several months, undergoing an ineffective treatment not only wastes valuable health-care resources but also causes unnecessary morbidity for patients. Being able to determine treatment effectiveness and to redirect management as necessary can save both valuable time for patients and resources for the society at large. For example, Cachin et al. studied treatment monitoring clinical trial by looking at the therapeutic efficacy of high-dose chemotherapy with bone marrow transplant and concluded that response to therapy as measured by FDGPET is the single most powerful independent predictor of survival. Eighty-three percent of the patients who underwent the high-dose chemotherapy treatment with complete response as shown by FDG-PET were alive at 12 months. By comparison, responses by Response Evaluation Criteria in Solid Tumors (RECIST) based on conventional imaging techniques were unable to predict survival (Cachin et al., 2006). For Hodgkin's Lymphoma (HL), a negative FDGPET scan post-therapy is highly indicative of long-term, disease-free survival and is particularly useful in the presence of residual CT mass (Kumar et al., 2004.) Figure 5 illustrates treatment monitoring of a patient with Hodgkin's Lymphoma. For aggressive non-Hodgkin's Lymphoma (NHL), a positive FDG-PET scan is predictive of disease persistence or recurrence. For both NHL and aggressive HL, early assessment of response appears to be predictive of long-term outcome. Optimal time of FDG-PET scan during therapy needs to be determined. For indolent NHL, the high rate of false-negative FDG-PET scans raises questions regarding its clinical role in treatment monitoring.
(a)
(b)
41
The role of FDG-PET continues to expand as more evidence of its utility and cost-effectiveness in various areas of medical practice continues to emerge. Table 2 offers a glimpse of current applications in oncology and representative sensitivity and specificity for each application. The utility of FDG-PET, however, is limited in detecting lesions < 5 mm in diameter, and FDG-PET is not meant to be a substitute for pathologic examination for detecting micrometastasis. In fact, FDG-PET is likely to be part of the imaging work-up for selection of biopsy sites. PET-guided biopsy/resection has been heavily studied and will likely emerge as the standard of care for neoplastic diseases such as insulinoma or mesothelioma in the near future.
Positron Emission Tomography in Lung and Breast Cancer Lung cancer and breast cancer are two major causes of cancer-related mortality in the United States. The number of deaths due to lung cancer annually is greater than that of breast, colon, and prostate cancers combined (Bunyaviroch and Coleman, 2006). Breast cancer is a leading cause of cancer mortality among women, second only to lung cancer. One in nine women is diagnosed with breast cancer in her lifetime. Diagnosis of lung cancer often starts with a solitary pulmonary nodule incidentally noted during a chest X-ray or a chest CT exam. Positron emission tomography is useful as an adjunct modality in evaluation of solitary pulmonary nodules, especially when results from conventional imaging modalities are equivocal. The sensitivity and specificity of FDG-PET for evaluating radiologically indeterminate nodules
(c)
Figure 5 Treatment monitoring with FDG-PET. (a) Patient with Hodgkin's disease involving the neck, mediastinum, and left supraclavicular lymph nodes (arrows). (b) Post-chemotherapy scan conducted 46 days after the initial scan illustrating resolution of the malignant foci. Prominent bone marrow and spleen uptake were observed due to the recovering hematopoietic system post-chemotherapy. (c) Repeat PET scan 91 days after the initial scan showed resolution of bone marrow and splenic FDG uptake.
42
Positron Emission Tomography in Brain Imaging Table 2 Selected Indications for FDG-PET in Oncology and the Representative Sensitivities and Specificities
Clinical Indication
Sensitivity
Specificity
Head and neck tumor, restaging Thyroid cancer restaging Follicular/papillary Medullary Lung cancer Solitary pulmonary nodule Bone marrow metastasis Adrenal metastasis Restaging (non-small cell) Colon cancer Diagnosis Staging Restaging Breast cancer, restaging Esophageal cancer, staging Lymphoma, staging Pancreatic cancer, staging Cervical cancer, staging Ovarian cancer, restaging Renal cell carcinoma, staging
95%
83%
75% 78%
90% 79%
97% 92% 100% 97-100%
78% 99% 80% 62-100%
74% 82% 97% 97% 51% 90% 79% 80% 90% 64%
84% 94% 76% 92% 94% 93% 86% > 95% 86% 100%
Source: Lin, E., and Alavi, A. 2005, PET and PET/CT." A Clinical Guide (New York: Thieme Medical Publishers).
are 92% and 90%, respectively (Mavi et al., 2005). FDGPET may not be the best modality for evaluating solitary pulmonary nodules that are highly suspicious of cancer by conventional radiography; the negative predictive value of FDG-PET is low in this scenario. Clinicians should also be aware that FDG uptakes in bronchoalveolar carcinoma and carcinoid tumors are lower compared to typical non-small cell lung carcinoma. Hilar and mediastinal staging of NSCLC is necessary to differentiate unresectable N3 disease from N1/N2 disease. Positron emission tomography with FDG has a sensitivity of 85-95% and a specificity of 81-100% for mediastinal/hilar staging (Mavi et al., 2005). Some investigators do feel that one cannot completely exclude mediastinal involvement with negative PET finding. Mediastinoscopy may still be necessary. In one study, mediastinoscopy exhibited 3% false-positive rate, while PET had 11.7% false-positive rate. The use of PET/CT and nextgeneration time-of-flight PET, which has higher spatial resolution, may lower the false-negative rate of PET for mediastinal/hilar staging. The sensitivity of detecting primary breast cancer with PET has been reported as being between 76 and 100% (Kumar and Alavi, 2004). Our experience indicates that PET is not sensitive enough as a single modality for early detection of breast cancer. The deficiency is mainly due to spacial resolution; hence, microscopic lesions such as those found in ductal carcinoma in situ cannot be detected with PET. Although PET has demonstrated good sensitivity and specificity in detecting axillary nodal metastasis, the sensitivity is
not optimal when compared with seminal lymph node biopsy. The sensitivities of axillary lymph node metastasis detection ranges from 20-100%, with more recent studies showing lower sensitivity (Kumar and Alavi, 2004). This is largely due to improvement in pathologic diagnosis. Although PET currently has no role in primary breast cancer detection and axillary node staging, it should be used for evaluation of distant metastasis, restaging, and treatment monitoring. The sensitivity of PET in detecting distant metastasis ranges from 86-100% and specificities range from 79-97%. For detecting recurrence, FDG-PET has sensitivity ranges from 79-89%. FDG-PET has been proven useful in monitoring treatment response in breast cancer, especially for patients undergoing chemotherapy. Separating responders from nonresponders in breast cancer treatment is achievable with FDG-PET with sensitivities of 90-100% and specificities of 74-85%.
Positron Emission Tomography in Brain Imaging FDG-PET was originally intended for tomographic imaging of the brain. Ironically, brain tumor imaging with FDGPET has not enjoyed as much popularity as extracranial tumor imaging, owing largely to the high cortical FDG uptake regardless of patient's fasting state. Many of the current generation of cranial tumor imaging agents are labeled amino acids that have more muted uptake in the normal brain
2 Positron Emission Tomography in Medicine: An Overview structure. Examples of such tracers are O-(2-18F-fluoroethyl)L-tyrosine (FET) and [llC]-L-methionine. However, FDGPET does play an important role in patients with suspected recurrent brain tumors and inconclusive, contrast-enhanced MR/or CT examinations. Because radiation-induced necrosis and recurrent tumors appear enhanced on these scans, metabolic imaging with FDG, which reflects disease activity at the cellular level, is invaluable in this setting. The sensitivity for distinguishing necrosis from brain tumor recurrence is ~ 86% and specificity ~ 56% (Newberg and Alavi, 2005). One prominent use of FDG-PET for brain imaging is for early diagnosis of Alzheimer's disease. A pattern curremly used for diagnosing early Alzheimer's disease (AD) is biparietal, bi-temporal hypometabolism. Using such glucose metabolism patterns, one can differentiate early AD from frontal-temporal dementia or Pick's disease. A typical Pick's disease patient exhibits frontal lobe hypometabolism on FDG-PET scan that is not present in early AD. The task of identifying early AD patients is becoming important now that better therapeutics are on the horizon. FDG-PET can also be used for localization of epileptic foci in patients with partial seizures. While a seizure focus may be identified as a region of increased FDG uptake if FDG is injected during seizure, such an "ictal" study is difficult to conduct. The more practical approach is to examine a patient during the "interictal" state. Contrary to the result of an "ictal" study, a seizure focus appears as a region ofhypometabolism ifFDG is injected during the "interictal" period. This type of study can identify seizure foci in 55-80% of epileptic patients with focal EEG abnormalities. Other PET tracers for brain imaging include Fluorene-18 fluorodopa ([18F]-FDOPA) for dopamine uptake and metabolism in the brain. FDOPA is useful for use in patients with movement disorders such as Parkinson's disease. [150]-H20 can be used for general brain perfusion studies. [llC]-raclopride can be used to image the presence of D2 receptors. There are also seretonine receptor and muscarinic receptor tracers currently undergoing clinical trials.
Positron Emission Tomography in Cardiac Imaging Major categories of tracers for cardiac imaging are those for assessment of (1) blood flow, (2) regions of viability, and (3) regions of hypoxia. Cardiac flow tracers for PET include oxygen- 15-labeled water ([150]-H20), [13N]-ammonium, and the generator produced rubidium-82 chloride (Takalkar et al., 2005). Among these tracers, rubidium-82-chloride has been approved by the FDA. 150- and 13N-based tracers require a well-coordinated cyclotron facility and stress lab due to the relatively short half-life of these tracers and the cyclotron requirement for production. 82Rb also has a short half-life, but production and administration can be better coordinated with the strontium-rubidium generator near the bedside. Copper-
43
62-labeled pyruvaldehyde bis (N4-methylthio-semicarbazone) ([62Cu]-PTSM) is also a flow tracer, but lack of a steady supply of 62Cu has prevented its widespread evaluation. [62Cu]-ATSMis a hypoxia tracer that shows great promise in cardiac imaging. Instead of inferring regions of ischemia based on differential cardiac perfusion between rest and stress, hypoxia tracers can directly illuminate regions of hypoxia.
Positron Emission Tomography in Infection and Inflammation In addition to cancer cells, activated granulocytes and monocytes also have elevated glucose metabolisms that can lead to markedly increased FDG uptake. In fact, FDG is an excellent tracer for detecting infection and inflammation (Zhuang et al., 2005.) FDG uptake has been reported in sarcoidosis, esophagitis, sinusitis, fungal and bacterial pneumonia, abscesses in various locations, mastitis, osteomyelitis, prosthetic infection, inflammatory bowel disease, and even in atherosclerotic plaques. Recent studies have suggested that FDG-PET may be useful in the work-up of patients with fever of unknown origin (FUO). FDG is ideal because of its sensitivity in detecting metabolically active regions that may be the source of infection or neoplasm in this clinical setting. FDG-PET may become the study of choice in orthopedic infections. PET is particularly useful in evaluating prosthetic loosening and infection. MRI evaluation is problematic in hip and knee prosthetics due to artifacts from metal implants. The overall sensitivity of detecting lower extremity prosthetic infection with FDG-PET is reported to be greater than 90%, with specificities of 80 to 89%. FDG-PET can also evaluate acute and chronic osteomyelitis, especially in diabetic feet.
Cell Proliferation Agents Positron emission tomography of cell proliferation is currently performed by indirectly measuring DNA synthesis. 3deoxy-3-[18F]-fluorothymidine (FLT) is a promising cell proliferation agent. FLT is a thymidine analog. However, unlike [3H]-thymidine, which is a standard compound for in vitro proliferation study, FLT is not incorporated into DNA (Mankoff et al., 2005). The biochemical fate of FLT is rather analogous to that of FDG in that it is phosphorylated upon cellular uptake and trapped within a cell without further modification. FLT has the potential to be used as a specific agent for assessing disease activity in various stages of different malignancies, particularly for determining response to therapy because cytotoxic chemotherapeutic agents affect cell division earlier and more prominently than glucose metabolism. Therefore, FLT may prove to be superior to FDG for assessing response to treatment. Also, inflammatory
44
References
reactions that may confound the use of FDG will not affect the use of FLT in this setting. Ongoing clinical trials are investigating the role of 18F-FLT in imaging proliferation of liver metastasis of colorectal carcinoma, and treatment monitoring of head and neck tumors.
Hypoxia Positron Emission Tomography Imaging Hypoxia in tumor tissue appears to be an important prognostic indicator of response to either chemotherapy or radiation therapy. Therefore, detection of hypoxia in advance of such interventions may help to optimize the use and outcome of different therapeutic modalities. Also, utilizing hypoxic agents for evaluating the efficacies of emerging anti-angiogenic therapies is a promising approach. Several compounds have been synthesized for detecting hypoxia. These compounds form covalent bonds with cellular proteins under low-oxygen conditions; they are retained substantially in higher concentrations in the hypoxic tissues, which can be detected by external imaging techniques. Examples of hypoxia imaging tracers are [18F]-fluoromisonidazole (FMISO), copper-62 diacetylbis (N4-methylthiosemicarbazone) (62Cu-ATSM), 2-(2nitro imi dazo 1-1 [H]-yl)-N-(3 _[18F]fluoropropyl)acetami de ([18F]-EF1), and [2-(2-nitro-l[H]-imidazol-l-yl)-N-(2,2, 3,3,3-pentafluoropropyl)-acetamide] ([18F]-EF5). The [18FIEF compounds have performed well in animal studies and may also prove to be effective for noninvasive imaging of tumor hypoxia (Alavi et al., 2004). There are currently four clinical trials involving the use of EF5. There is one clinical trial with FMISO in conjunction with 18F-FLT for evaluating treatment response of radiation therapy. 62Cu-ATSM appears to have better pharmacodynamic properties than FMISO and could be a better imaging agent for hypoxia.
Peptide and Protein Positron Emission Tomography Tracers Most tracers with positron-emitting nuclides are small molecules < 1000 Daltons. Increasingly, polypeptides and macromolecules such as Annexin V and various antibodies with molecular weight ~ 150,000 Daltons are being evaluated for clinical use. Positron nuclides with short half-life are less practical for macromolecules. Large molecules in general require hours to days for optimal background clearance. Radionuclides with half-life less than 6 hours decay before optimal images may be acquired. 1241 has the advantage of ease of protein labeling and long half-life. This m a k e s 124I a practical imaging radionuclide for proteins and antibodies. 64Cu is also a very attractive radionuclide
for large molecules because of the 12.7 hr half-life. Synthetically, 64Cuis incorporated through a chelate such as DOTA, which can be attached chemically to large proteins days or months prior to use. Other chelate-based positronemitting radionuclides include 94mTcand l llmIn (Lundqvist and Tolmachev, 2002). Being able to image with antibodies can drastically increase diagnostic information, given the almost endless array of antibodies targeting known cellsurface receptors. In conclusion, modern instrumentations of positron emission tomography allow the detection of nanograms to micrograms of tracers with increasing sensitivity and resolution. The ability to image trace amounts of chemicals in a human body with high sensitivity opens the possibility for constructing and visualizing compounds that target selected cell-surface receptors or biochemical pathways. This gives clinicians and scientific investigators multiple tools for greater understanding and assessment of pathophysiology in vivo in cellular context. Positron emission tomography, therefore, is an unprecedented platform that may bridge the gaps between clinical practice and latest understanding of molecular biology of diseases.
References Alavi, A., Lakhani, P., Mavi, A., Kung, J., and Zhuang, H.M. 2004. PET: a revolution in medical imaging. Radiol. Clin. N. Am. 42:983-1001. Bunyaviroch T., and Coleman, R.E. 2006. PET evaluation of lung cancer. J. Nucl. Med. 47:451-469. Cachin, E, Prince, H.M., Hogg, A., Ware, R.E., and Hicks, R.J. 2006. Powerful prognostic stratification by [18F]fluorodeoxyglucose positron emission tomography in patients with metastatic breast cancer treated with high-dose chemotherapy, J. Clin. OncoL 24:3026-3031. Juweid, M.E., and Cheson, B.D. 2006. Positron emission tomography and assessment of cancer therapy. N. Engl. J. Med. 354:496-507. Kumar R., and Alavi, A. 2004. Fluorodeoxyglucose-PET in the management of breast cancer Radiol. Clin. N. Am. 42:1113-1122. Kumar, R., Maillard, I., Schuster, S.J., and Alavi, A. 2004. Utility of Fluorodeoxyglucose-PET imaging in the management of patients with Hodgkin's and non-Hodgkin's lymphomas. Radiol. Clin. N. Am. 42:1083-1100. Lundqvist, H., and Tolmachev, V. 2002. Targeting peptides and positron emission tomography. Biopolymers 66:381-392. Mankoff, D.A., Shields, A.E, and Krohn, K.A. 2005. PET imaging of cellular proliferation. Radiol. Clin. North. Am. 43:153-167. Mavi, A., Lakhani, P., Zhuang, H., Gupta, N.C., and Alavi, A. 2005. Fluorodeoxyglucose-PET in characterizing solitary pulmonary nodules, assessing pleural diseases, and the initial staging, restaging, therapy planning, and monitoring response of lung cancer. Radiol. Clin. North. Am. 43:1-21. Newberg, A.B., and Alavi, A. 2005. The role of PET imaging in the management of patients with central nervous system disorders. Radiol. Clin. N. Am. 43:49-65. Takalkar, A., Mavi, A., Alavi, A., and Araujo, L. 2005. PET in cardiology. Radiol. Clin. N. Am. 43:107-119. Zhuang, H.M., Yu, J.Q., and Alavi, A. 2005. Applications of fluorodeoxyglucose-PET imaging in the detection of infection and inflammation and other benign disorders. Radiol. Clin. N. Am. 43:121-134.