Engineers explore the limits of PET/CT imaging
As new technology appears on the horizon, researchers focus on maximizing what's available now
By: Charles Bankhead
As Baseball Hall of Famer Yogi Berra said, it's tough to make predictions, especially about the future. Berra undoubtedly was not talking about PET imaging, but his malapropism nonetheless speaks to the future of the modality's advances. PET users and researchers agree that the technology will continue to improve, but predictions about the pace and direction of that progress vary widely.
"This is an exciting time," said Dr. David Townsend, a PET researcher and originator of the concept of the PET/CT hybrid scanner. "I have no sense that the development we've seen in the last few years is slowing."
Earlier this year, a hybrid scanner with 16-slice CT capability demonstrated the ability to acquire a whole-body image in six to seven minutes, an achievement that would have been considered a far reach for PET/CT just a few years ago. That advance in imaging capability may be just one indication of how far the technology can be pushed in the future.
Predictions about the direction of future developments in PET include larger, higher resolution detectors, more specific radiopharmaceuticals, predominance of PET/CT scanners, and expansion of clinical applications. Much of the work will focus on honing the capabilities of PET and PET/CT technology, said Dr. Gustav von Schulthess, director of nuclear medicine at University Hospital in Zurich, Switzerland.
"From a technological point of view, PET/CT is mature," von Schulthess said. "We have had PET scanners for 10 years and CT scanners even longer. The process of putting the two components together is mature. However, we don't yet understand the synergy to its fullest extent."
Von Schulthess foresees development of more definitive protocols that maximize the efficiency of PET/CT imaging. A number of unresolved questions remain with respect to how much CT is needed to address specific diagnostic issues. Similarly, the need for contrast-enhanced CT still faces many unknowns. As examples, von Schulthess cites imaging of bronchocarcinoma, follow-up of lymphoma, and evaluation of colorectal cancer involving a single liver metastasis.
"Obviously, there are certain answers that can be guessed, but on the protocol side, there are some key questions that will need to be answered," he said. "We are just starting to accumulate data on these questions."
No groundswell of support has arisen for a hybrid machine combining PET and MR, which are often fused by software. The lack of enthusiasm for a PET/MR machine, an aside to the rapid expansion of PET/CT imaging, stems in part from the probable high cost of such a machine and the challenges of overcoming technical mismatches between the two modalities.
"A magnetic field is definitely not liked by standard PET components," von Schulthess said. "You would have to start such a hybrid machine by designing a nonmagnetic PET scanner."
Beyond the challenges of such a venture, the combination of PET and MR does not lead to the same additive benefits seen with PET and CT. When von Schulthess learned of the concept of a hybrid PET/CT scanner, he could visualize combining two technologies that brought synergy to imaging benefits. With PET and MR, he sees a combination that results in "one plus one."
REFINEMENTS
An example of how the technology has been honed can be found in improvements to the underlying scanner electronics for PET machines that employ LSO (lutetium oxyorthosilicate) crystals. The improvements result in a better signal-to-noise ratio and images with better resolution, said Townsend, a professor of medicine and radiology at the University of Tennessee Medical Center in Knoxville. He predicts that detectors with 4-mm-resolution capability will become routine for general PET clinical scanning.
The combination of PET and CT in one machine has underscored the disparity in imaging acquisition time between the two modalities. Considerable R&D effort has focused on improving PET's imaging speed. Integration of faster crystal technology into PET/CT scanners has been a step in the right direction, and future developments in PET technology will include continued efforts to improve crystal technology.
"There is a real push to do things faster," said Dr. Medhat Osman, director of PET imaging at St. Louis University. "Having detectors that can image larger portions of the body will cut down the imaging time. The types of crystals are improving, and I think we are going to see more emphasis on crystal technology that has higher sensitivity and shorter decay time."
Von Schulthess remains skeptical about the potential benefits of new crystal technology and how quickly those benefits might make their way into clinical practice. A PET scanner has a complex design that requires careful integration and interaction among the components. Replacing one key element such as the detector crystal without making major modifications in the rest of the scanning might be impractical, particularly in terms of improving scan time or quality.
"If you use a new detector material, you have to completely redesign the scanner to make optimal use of it," von Schulthess said. "I think that step has yet to be taken. In detector design, we cannot be as simplistic as we would sometimes like to be."
LSO was discovered in 1991 but not integrated into commercially available PET scanners until more than a decade later. Work continues on the development of new detector materials, but even if they offer advantages over currently available materials, realization of those benefits is likely 10 or more years in the future, said William Moses, Ph.D., a senior staff scientist at Lawrence Berkeley Laboratory in Berkeley, CA.
Perhaps the most promising substance under consideration for future crystal development is cerium-doped lutetium iodide. Cerium-doped lanthanum bromide is another possibility. Development of these substances is in early stages, however, and realization of any benefits is probably at least a decade away, according to Moses. Moreover, use of these crystals would involve a trade-off of energy resolution for spatial resolution.
"Spatial resolution would probably get a little worse than in a PET scanner today, but the energy resolution and the ability to reject background noise would get a lot better," he said.
Despite advances in PET technology, considerable room for improvement remains. Moses notes that in a whole-body 3D PET scan, about 25% of events are true, 25% are scatter, and the remaining 50% are random. Most advances are likely to be incremental, on the order of 10%. From a clinical perspective, improvements that are most likely to come to fruition are those that increase the axial field-of-view, improve scanning efficiency, and reduce dead time.
One potential blockbuster advance in PET imaging could come from ongoing investigations related to time-of-flight, an area of particular interest to Moses. Measuring TOF and incorporating that information into PET imaging could reduce the amount of noise in an image by a factor of two (100% improvement). And this improvement could be integrated into PET scanners within five years.
"People will fight hard for a 10% improvement," Moses said. "Right now, I don't see any other technology on the horizon that is poised to make more than a 10% difference in PET imaging. TOF is the only technology that has the potential to make a 100% difference in the SNR."
TOF refers to the transit of photons from their source in the body to the PET scanner's scintillator ring. Simultaneous interaction in two detectors on a scintillator ring indicates the presence of a positron somewhere along the line joining the two detectors.
Since the photons travel at the (finite) speed of light, measuring the slight difference in the arrival times of two photons from the same positron with sufficiently good timing resolution determines where along the line the positron was. With current PET technology, the timing resolution is on the order of 4 nanoseconds, which constrains the positron to a 50-cm region. As this is about the size of the body, it doesn't add any information. The technology exists, however, to improve the accuracy to 0.5 nanosecond, which constrains the positron to an 8-cm region. While this is still too coarse to improve the spatial resolution, it has a major impact on the noise.
"With the reconstruction algorithms for conventional PET, all of the voxels in a field are coupled," Moses said. "The statistical noise from one voxel adds to the noise of every voxel. If you can measure the TOF, you can identify an area of interest and sort of throw away all of the voxels outside that area, so that their noise doesn't enter in. With 0.5-nanosecond timing resolution, the noise would be reduced by a factor of two."
NEW RADIOPHARMACEUTICALS
Radiopharmaceutical development is another area of investigation that could soon have an impact on PET imaging. Numerous research groups are evaluating tracers that might offer advantages over the standard FDG, at least for certain clinical applications.
"I foresee the development of disease-specific tracers," Osman said. "When we talk about using PET for a specific disease, we will have a tracer that is specific for that disease. Within the next few years, these new tracers will increase the sensitivity and specificity of PET for specific diseases."
Townsend heads a new program at the University of Tennessee established specifically for development and evaluation of new radiopharmaceuticals.
"This is a huge field that is attracting a lot of attention," he said. "A considerable number of tracers have been developed and evaluated for some time, but they are still not in the clinical arena. We hope to use the capability for faster whole-body imaging to evaluate some of these tracers and to determine their clinical potential and further their use in clinical imaging."
F-18 fluorocholine for prostate cancer imaging has progressed to the point of clinical evaluation. PET with FDG has produced disappointing results in prostate imaging, and the availability of a good tracer could help PET make inroads into this region. If PET were to become an indispensable component of the workup for a common malignancy, such as prostate cancer or breast cancer, the economic potential of the imaging modality would increase dramatically.
The concept of fluorocholine imaging of the prostate originated from Japanese data showing that carbon-11 choline localized in the prostate, according to Dr. Edward Coleman, director of nuclear medicine at Duke University Medical Center. The 20-minute half-life of C-11 choline posed a considerable difficulty for use in PET imaging, so a search for an alternative led to development of F-18 fluorocholine.
"We have evaluated fluorocholine in 40 to 50 patients with prostate cancer and have compared it with FDG," Coleman said. "In every case, fluorocholine has been significantly better in terms of increased uptake in lesions and identification of lesions not seen with FDG."
On the basis of the clinical data collected to date, Coleman and his colleagues have filed an investigational new drug application with the FDA. If it is granted, the group plans to pursue additional clinical studies to evaluate F-18 fluorocholine for prostate cancer diagnosis and for staging lymph nodes at the time of surgery.
Evaluation of fluorocholine has not been limited to prostate cancer. The investigational tracer has been compared against FDG in a small group of patients with metastatic breast cancer. The results showed that the two tracers have similar overall accuracy. FDG proved superior for imaging some lesions, and fluorocholine was better for others. The preliminary findings suggest that both agents might have a role in breast cancer imaging.
The Duke group also has compared F-18 fluorocholine and FDG in several patients with primary brain tumors. FDG has proved useful for grading brain malignancies, but the tracer is also taken up by normal brain tissue. The fluorocholine tracer does not localize in normal brain tissue, so tumors tend to stand out better than when imaged with FDG.
"We haven't imaged a large number of patients, but I am optimistic that fluorocholine will be a superior agent for imaging brain tumors," Coleman said.
Fluorodeoxythymidine (FLT) has demonstrated potential as a means of assessing cellular proliferation. Because many chemotherapeutic agents have antiproliferative effects, PET imaging with FLT could have considerable value in monitoring response to therapy. In PET studies of tumor DNA synthesis, FLT has shown the ability to predict response to therapy, or lack thereof, sooner than is possible with FDG.
Another area of investigation focuses on use of copper-labeled radiotracers to assess tumor perfusion and hypoxia. Identification of the proportion of cells that are hypoxic, which are more resistant to radiation therapy, could be used to guide such therapy. If cells are identified as hypoxic, the radiation dose could be increased to compensate for the resistance and perhaps improve the outcome of therapy. Investigators at the University of Texas M. D. Anderson Cancer Center and Washington University in St. Louis have already evaluated hypoxia-guided radiation therapy treatment plans developed as a result of PET studies that employed copper-labeled tracers.
NEW APPLICATIONS
Developments in technology will almost certainly fuel another round of new clinical applications and approved indications for PET imaging. As the technology improves, investigators and clinicians will find new uses and begin to build a case for existing unapproved indications. Oncology, already responsible for the majority of approved indications for PET, will likely lead the way toward new applications. Several oncology-related indications are already pending with the Centers for Medicare and Medicaid Services. Emergence of disease-specific radiopharmaceuticals could prove to be a boon for cancer imaging, particularly if tracers demonstrate good sensitivity and specificity for common malignancies.
Promising applications outside oncology can be found in neurology, cardiology, and infectious disease. As PET technology improves and clinical experience in new applications increases, the imaging modality will find a role in any condition for which metabolic data prove useful, according to Dr. Michael Fagien, medical director of three imaging companies in Florida.
PET has already demonstrated potential for evaluation of Alzheimer's disease, but the application will not take off in the absence of approval for reimbursement. That approval is not likely to occur until a therapy with proven efficacy for halting progression or curing the disease is available, said Dr. Ethan Spiegler, director of nuclear medicine at St. Agnes HealthCare and director of Advanced PET Imaging of Maryland in Baltimore. Because an effective Alzheimer's therapy will probably cost tens of thousands of dollars a year per patient, insurers and other payers will want to verify that a patient has Alzheimer's before starting the drug and that a patient taking it is responding.
Von Schulthess predicts that PET, but not PET/CT, will have a role in brain imaging. MR has become the standard for brain imaging, and metabolic data provided by PET can be fused to MR images easily enough with software.
Development of faster scanners with high resolution, typified by hybrid scanners with fast crystal technology and multidetector CT, should boost the applicability of PET imaging to cardiology.
"If we can come up with ways of measuring myocardial perfusion with fast CT and then do a rapid viability study with PET, a hybrid scanner would make a superb cardiac machine," Townsend said. "I definitely think there is a role for PET/CT imaging in cardiology, but that role is still being defined. With continued improvements in the technology, we will eventually define the role of PET in cardiac imaging."
Some observers are less optimistic about PET's role in cardiac imaging. Even an advanced form of PET/CT will have difficulty competing with other imaging modalities, Spiegler said. In particular, the advent of SPECT imaging with attenuation correction has greatly reduced the false-positive rate for myocardial perfusion imaging, posing a major obstacle to PET's ability to demonstrate an advantage. PET may come into play only when a cardiologist and a cardiac surgeon disagree about the best course of action for a patient.
At von Schulthess' institution, PET is used regularly to image various types of infection. The application relies on many of the same principles as PET imaging of tumors.
"We are looking for foci, and we are looking for therapy control, so it is important to have good localization," he said. "We want to know whether infection is inside or outside of bone, for example. Whatever is good for tumor imaging probably will also be very good for infection imaging."
MR. BANKHEAD is a freelance writer in Houston.
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