PET/MR: In Search of the Killer App
The final diagnostic form that the evolving hybrid PET/MR tree will take is uncertain, but it has already begun to blossom. Low-hanging clinical fruit has lured a number of major medical centers to early adoption.
The attraction in acquiring PET and MRI images in one exam, whether simultaneously or sequentially, opens up richer diagnostic opportunities. Simultaneously acquired PET and MRI data, for instance, allows temporal registration and visualization of diseased tissue as they proliferate over time at the molecular level. PET contributes sensitivity to metabolic activity of disease, while MR adds functional and physiological information paired with high spatial resolution and soft-tissue contrast.
This technology is expected to help identify disease sooner by offering higher soft-tissue contrast, simultaneous acquisition and minimum radiation exposure to the patient. It could lead to a paradigm shift in healthcare and possibly revolutionize clinical practice in diagnosing brain disorders, such as Alzheimer's and dementia, and cancers, such as prostate, breast, liver and head and neck, and even heart disease—as well as monitor treatment.
Despite potential clinical indications, the high cost of PET/MR units, as well as the larger size of the scanners, could prohibit many facilities from embracing the technology. While the ultimate cost of a PET/MR system is currently unknown, Frost & Sullivan estimated the cost of a system to be between $2.5 million to $3 million, slightly higher than the $1.9 million to $2.4 million for a PET/CT scanner. Some predict the cost will likely be closer to $4 million. While a few installations are starting to expand out of academic and research sites to public and private imaging facilities, there is significant need to prove clinical and economic value to urge on deployment.
Among the design evolutions, novel detectors that include photodiodes were found to prevent image distortion and installing higher-performing gradients freed up enough space to accommodate a PET inside the MR gantry—and at the same time widen the bore. A wider bore tends to diminish anxiety for claustrophobic patients.
The first PET/MR scanner earned CE mark in Europe in January, while the FDA clearance in June opened the door for use in the U.S.
The fusion of PET and MRI into one system offering simultaneous acquisition will capitalize the strengths of each, providing a hybrid technology that is superior to the sum of its parts, says Habib Zaidi, PhD, head of the PET Instrumentation and Neuroimaging Laboratory at Geneva University Hospital in Switzerland.
With PET/MR, the MR images provide anatomy and tissue characterization combined with metabolic imaging obtained from PET.
"More importantly, using simultaneous rather than sequential scanning will enable the resolution of many of the impediments to precise coregistration of anatomo-molecular information," Zaidi says. But attention correction with PET/MR is more difficult than with PET/CT.
The immediate impact of PET/MR will likely be most significant in oncology, where combining PET and MR in one imaging device could offer advantages over conventional imaging modalities. Oncologic applications of PET/MR allow imaging of the four main processes in cancer formation: apoptosis resistance, angiogenesis, proliferation and metastasis (Technol Cancer Res Treat 2010;9(1):5-20).
"PET/MR will take functional characterization of tissue to another level, and allow one to marry the beautiful soft-tissue contrast of MRI with the tissue characterization of PET," says Vikas Gulani, MD, PhD, director of MRI at Case Western Reserve University in Cleveland.
Moreover, Gulani says, PET imaging probes will not necessarily be limited to FDG. The goal now is to produce imaging probes that characterize specific molecular alterations of disease. "While molecular imaging with MR alone is of major interest worldwide, particularly because of the high tissue contrast of MR, it is made difficult by the inherent low sensitivity of MR," Gulani says.
PET and MRI offer complementary functionality and sensitivity. In the long run, a range of molecular imaging possibilities could open up, which may not be imaginable right now, Gulani says.
"The limited role of PET/CT in some clinical indications including central nervous system disorders, orthopedic infections, inflammatory disorders and in the evaluation and follow-up of metastatic disease is well established," Zaidi says. "The better soft-tissue contrast observed on MRI emphasizes the ineffectiveness of PET/CT for this, as well as the potential role of PET/MR." Clinical research, however, has not yet shown the superiority of either technology.
In one design, the PET and MR machines are operated separately, but positioned in the same room (Ingenuity TF PET/MR, Philips Healthcare), about three meters apart at opposite ends of a patient turntable. The patient, fitted with MR coils, is first scanned by the 3T MR scanner, then rotated 180 degrees, and slid into the PET bore, allowing for sequential acquisition and later fusion of data.
"The advantage here is the patient will be in the same reference frame when imaged by PET and MRI, so you don't need to perform image registration per se," says Osama Mawlawi, PhD, of the department of imaging physics at MD Anderson Cancer Center in Houston. Combining PET and MRI in one single superimposed image improves on current methods of acquiring images at different times and then attempting the difficulty of combining them, he notes.
Mawlawi says the disadvantage with this configuration is both instruments are occupied to scan one patient sequentially, potentially inhibiting throughput because one machine is standing idle.
Another design is a tri-modality configuration (Discovery PET/CT+MR, GE Healthcare) where the PET/CT 690 system is in one room and the MR750 in an adjoining room. The transport table is key, as the patient is positioned only once between exams. With this model too, software registers and fuses the datasets from the two exams.
While configurations one and two do not offer true simultaneous PET/MR acquisition, they provide researchers and clinicians reasonable PET/MR viability at a reduced cost.
The third design is currently the only simultaneous PET/MR (Biograph mMR, Siemens Healthcare). In this case, a PET ring detector fitted inside a 3T magnet combine to acquire MR anatomical data and PET functional data simultaneously.
"Simultaneous imaging is what is interesting about PET/MR and might open a new area of research whereby you can see function and structure at the same time or validate function using two different modalities," Mawlawi says. Still, he says the promise of PET/MR has yet to be realized, and questions what unmet need it will address.
"Most of us are trying to figure out what PET/MR can provide that justifies its development," Mawlawi says. "From a clinical perspective, we do not yet have a killer application for PET/MR."
One possible PET/MR application, he says, would be assessing prostate cancer because of the difficulty in pinpointing malignancies in this area. With PET using FDG, it is difficult to see uptake in the prostate region because most of the FDG ends up in the bladder.
Cardiology is one area. PET is currently the gold standard for noninvasive assessment of myocardial viability and allows accurate detection of coronary artery disease by assessment of myocardial perfusion. MRI provides high-resolution anatomical images that allow accurate evaluation of ventricular structure and function together with detection of myocardial infarction.
PET/MR may facilitate the characterization of atherosclerotic plaques and aid in the evaluation of angiogenetic or stem cell therapies (Eur J Nucl Med Mol Imaging. 2009;36 Suppl 1:S121-30).
Oncologic applications also are being explored (Int J Radiat Oncol Biol Phys 2011;81(1):277-283). The potential of nanoparticle-based dual-modality PET/MR contrast agents is another area being investigated (Biomaterials 2011;32(17):4151-4160; Bioconjug Chem 2010;21(4):715-722).
Heinz-Peter Schlemmer, MD, of the German Cancer Research Center and chair of radiology at the University of Heidelberg, says the bottleneck of diagnostic progress will likely be the development of new radiotracers. "PET alone does not produce images, it only displays what has been injected," he says.
Indications will depend on particular clinical questions. "While PET/CT is faster and cheaper, MR provides better soft-tissue contrast, plus multiple functional information and, what works without radiation exposure to the patient," Schlemmer says.
Thus, PET/MR is indicated where there is concern about radiation risk, such as pediatrics. Another use for PET/MR would be areas of the body—pelvis, head, neck—where CT provides suboptimal tissue contrast (Eur Radiol 2011;21(7):1439-1446).
"The ability to use CT as an anatomical reference is compromised by its relatively poor soft-tissue contrast," says Bruce Rosen, MD, director of the Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston. "Here, MR-based, soft-tissue contrast is superior to CT, so it's actually a better anatomical reference than associated CT studies."
Rosen says another area ripe for PET/MR use is lesion characterization where the contrast properties of MR are again superior to that of CT, including breast imaging. The liver is another area where MR can better characterize lesions compared with CT, he says.
"In many cases, patients who are imaged with PET/CT also are being sent for MR because of MR's ability to assess additional tissue characterization," Rosen says. For example, in patients with rectal carcinomas, Rosen says it may be possible to do M, N and T staging all in a single PET/MR exam.
"We'll be able to look for nodal involvement and see sufficient detail of local tissue spread in a single exam, which we can't do with a single exam with PET/CT," Rosen says. "We often end up having to refer those patients for additional studies with MRI."
Rosen also anticipates more advanced physiological applications for PET/MR, which would evaluate anti-angiogenic effects, where the ability to perform metabolic imaging with PET and physiological imaging with MR are naturally complimentary to understanding what the long-term treatment response to novel therapeutic regimes might be.
Other applications where metabolic information from PET combined with the physiologic information of MR will be complimentary are areas of neuroplasticity and stroke recovery, as well as cases of epilepsy and traumatic brain injury, circumstances where physiological and biophysical properties of MRI, when combined with direct quantitative metabolic imaging of PET could be helpful.
Additional areas where PET/MR could be benefical are cases of epilepsy and traumatic brain injury.
"These aren't studies that are routinely being done today with PET, at least not at all centers, but the combination of the two technologies are extremely synergistic and could be quite valuable," Rosen says.
PET/MR could combine new amyloid imaging agents with quantitative brain morphometry, and maybe functional resting-state studies, as a way to perform one comprehensive exam in patients at the earliest stages of Alzheimer's.
"Here, there's an opportunity for radiologists to be able to define for clinicians the biochemical disease prior to the loss of working brain," Rosen says. "This will be an extremely important opening and PET/MR is ideally situated to make a contribution here."
PET/MR may be able to pinpoint abnormalities in brain networks, then provide a map to target a pharmacological treatment, or intervene with deep brain electrical stimulation of certain key nodes.
"Performing receptor-based, targeted imaging with PET, combined with functional connectivity mapping with either resting-state MR or diffusion tractography or some combination of those really becomes a potential paradigm change in the way we think about diagnosing and treating mental illnesses, Rosen says."
The fundamental capabilities of PET/MR are present in the technology. "Emerging neuroscience suggests that this may be an important future direction for this technology," he says.
The attraction in acquiring PET and MRI images in one exam, whether simultaneously or sequentially, opens up richer diagnostic opportunities. Simultaneously acquired PET and MRI data, for instance, allows temporal registration and visualization of diseased tissue as they proliferate over time at the molecular level. PET contributes sensitivity to metabolic activity of disease, while MR adds functional and physiological information paired with high spatial resolution and soft-tissue contrast.
This technology is expected to help identify disease sooner by offering higher soft-tissue contrast, simultaneous acquisition and minimum radiation exposure to the patient. It could lead to a paradigm shift in healthcare and possibly revolutionize clinical practice in diagnosing brain disorders, such as Alzheimer's and dementia, and cancers, such as prostate, breast, liver and head and neck, and even heart disease—as well as monitor treatment.
Despite potential clinical indications, the high cost of PET/MR units, as well as the larger size of the scanners, could prohibit many facilities from embracing the technology. While the ultimate cost of a PET/MR system is currently unknown, Frost & Sullivan estimated the cost of a system to be between $2.5 million to $3 million, slightly higher than the $1.9 million to $2.4 million for a PET/CT scanner. Some predict the cost will likely be closer to $4 million. While a few installations are starting to expand out of academic and research sites to public and private imaging facilities, there is significant need to prove clinical and economic value to urge on deployment.
Best of both worlds
PET/MR emerged nearly a decade after PET/CT was first commercialized. The first PET/MR design was published in 1997, and changes to the scanners were necessary to overcome various obstacles. For instance, there wasn't space enough inside an MRI system to house a PET system.Among the design evolutions, novel detectors that include photodiodes were found to prevent image distortion and installing higher-performing gradients freed up enough space to accommodate a PET inside the MR gantry—and at the same time widen the bore. A wider bore tends to diminish anxiety for claustrophobic patients.
The first PET/MR scanner earned CE mark in Europe in January, while the FDA clearance in June opened the door for use in the U.S.
The fusion of PET and MRI into one system offering simultaneous acquisition will capitalize the strengths of each, providing a hybrid technology that is superior to the sum of its parts, says Habib Zaidi, PhD, head of the PET Instrumentation and Neuroimaging Laboratory at Geneva University Hospital in Switzerland.
 |
| (A) MRI, (B) PET, (C) PET/MRI. Source: Habib Zaidi, PhD, head of the PET Instrumentation and Neuroimaging Laboratory, Geneva University Hospital. |
"More importantly, using simultaneous rather than sequential scanning will enable the resolution of many of the impediments to precise coregistration of anatomo-molecular information," Zaidi says. But attention correction with PET/MR is more difficult than with PET/CT.
The immediate impact of PET/MR will likely be most significant in oncology, where combining PET and MR in one imaging device could offer advantages over conventional imaging modalities. Oncologic applications of PET/MR allow imaging of the four main processes in cancer formation: apoptosis resistance, angiogenesis, proliferation and metastasis (Technol Cancer Res Treat 2010;9(1):5-20).
"PET/MR will take functional characterization of tissue to another level, and allow one to marry the beautiful soft-tissue contrast of MRI with the tissue characterization of PET," says Vikas Gulani, MD, PhD, director of MRI at Case Western Reserve University in Cleveland.
Moreover, Gulani says, PET imaging probes will not necessarily be limited to FDG. The goal now is to produce imaging probes that characterize specific molecular alterations of disease. "While molecular imaging with MR alone is of major interest worldwide, particularly because of the high tissue contrast of MR, it is made difficult by the inherent low sensitivity of MR," Gulani says.
PET and MRI offer complementary functionality and sensitivity. In the long run, a range of molecular imaging possibilities could open up, which may not be imaginable right now, Gulani says.
"The limited role of PET/CT in some clinical indications including central nervous system disorders, orthopedic infections, inflammatory disorders and in the evaluation and follow-up of metastatic disease is well established," Zaidi says. "The better soft-tissue contrast observed on MRI emphasizes the ineffectiveness of PET/CT for this, as well as the potential role of PET/MR." Clinical research, however, has not yet shown the superiority of either technology.
Three designs, one technology
PET/MR has been rolled out in three different design configurations.In one design, the PET and MR machines are operated separately, but positioned in the same room (Ingenuity TF PET/MR, Philips Healthcare), about three meters apart at opposite ends of a patient turntable. The patient, fitted with MR coils, is first scanned by the 3T MR scanner, then rotated 180 degrees, and slid into the PET bore, allowing for sequential acquisition and later fusion of data.
 |
| Metabolic uptake of glucose in an area of the brain indicating a large tumor, which is probably very old since the center is necrotic or dead tissue. Source: GE Healthcare |
Mawlawi says the disadvantage with this configuration is both instruments are occupied to scan one patient sequentially, potentially inhibiting throughput because one machine is standing idle.
Another design is a tri-modality configuration (Discovery PET/CT+MR, GE Healthcare) where the PET/CT 690 system is in one room and the MR750 in an adjoining room. The transport table is key, as the patient is positioned only once between exams. With this model too, software registers and fuses the datasets from the two exams.
While configurations one and two do not offer true simultaneous PET/MR acquisition, they provide researchers and clinicians reasonable PET/MR viability at a reduced cost.
The third design is currently the only simultaneous PET/MR (Biograph mMR, Siemens Healthcare). In this case, a PET ring detector fitted inside a 3T magnet combine to acquire MR anatomical data and PET functional data simultaneously.
"Simultaneous imaging is what is interesting about PET/MR and might open a new area of research whereby you can see function and structure at the same time or validate function using two different modalities," Mawlawi says. Still, he says the promise of PET/MR has yet to be realized, and questions what unmet need it will address.
"Most of us are trying to figure out what PET/MR can provide that justifies its development," Mawlawi says. "From a clinical perspective, we do not yet have a killer application for PET/MR."
One possible PET/MR application, he says, would be assessing prostate cancer because of the difficulty in pinpointing malignancies in this area. With PET using FDG, it is difficult to see uptake in the prostate region because most of the FDG ends up in the bladder.
Potential applications
While PET/MR technology may still be in an embryonic stage, advances are imminent on multiple fronts. Numerous potential applications for hybrid PET/MR imaging are being discussed.Cardiology is one area. PET is currently the gold standard for noninvasive assessment of myocardial viability and allows accurate detection of coronary artery disease by assessment of myocardial perfusion. MRI provides high-resolution anatomical images that allow accurate evaluation of ventricular structure and function together with detection of myocardial infarction.
PET/MR may facilitate the characterization of atherosclerotic plaques and aid in the evaluation of angiogenetic or stem cell therapies (Eur J Nucl Med Mol Imaging. 2009;36 Suppl 1:S121-30).
Oncologic applications also are being explored (Int J Radiat Oncol Biol Phys 2011;81(1):277-283). The potential of nanoparticle-based dual-modality PET/MR contrast agents is another area being investigated (Biomaterials 2011;32(17):4151-4160; Bioconjug Chem 2010;21(4):715-722).
Heinz-Peter Schlemmer, MD, of the German Cancer Research Center and chair of radiology at the University of Heidelberg, says the bottleneck of diagnostic progress will likely be the development of new radiotracers. "PET alone does not produce images, it only displays what has been injected," he says.
Indications will depend on particular clinical questions. "While PET/CT is faster and cheaper, MR provides better soft-tissue contrast, plus multiple functional information and, what works without radiation exposure to the patient," Schlemmer says.
Thus, PET/MR is indicated where there is concern about radiation risk, such as pediatrics. Another use for PET/MR would be areas of the body—pelvis, head, neck—where CT provides suboptimal tissue contrast (Eur Radiol 2011;21(7):1439-1446).
"The ability to use CT as an anatomical reference is compromised by its relatively poor soft-tissue contrast," says Bruce Rosen, MD, director of the Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston. "Here, MR-based, soft-tissue contrast is superior to CT, so it's actually a better anatomical reference than associated CT studies."
Rosen says another area ripe for PET/MR use is lesion characterization where the contrast properties of MR are again superior to that of CT, including breast imaging. The liver is another area where MR can better characterize lesions compared with CT, he says.
"In many cases, patients who are imaged with PET/CT also are being sent for MR because of MR's ability to assess additional tissue characterization," Rosen says. For example, in patients with rectal carcinomas, Rosen says it may be possible to do M, N and T staging all in a single PET/MR exam.
"We'll be able to look for nodal involvement and see sufficient detail of local tissue spread in a single exam, which we can't do with a single exam with PET/CT," Rosen says. "We often end up having to refer those patients for additional studies with MRI."
Rosen also anticipates more advanced physiological applications for PET/MR, which would evaluate anti-angiogenic effects, where the ability to perform metabolic imaging with PET and physiological imaging with MR are naturally complimentary to understanding what the long-term treatment response to novel therapeutic regimes might be.
Other applications where metabolic information from PET combined with the physiologic information of MR will be complimentary are areas of neuroplasticity and stroke recovery, as well as cases of epilepsy and traumatic brain injury, circumstances where physiological and biophysical properties of MRI, when combined with direct quantitative metabolic imaging of PET could be helpful.
Additional areas where PET/MR could be benefical are cases of epilepsy and traumatic brain injury.
"These aren't studies that are routinely being done today with PET, at least not at all centers, but the combination of the two technologies are extremely synergistic and could be quite valuable," Rosen says.
Zen radiology
The biggest advances for PET/MR may come in neuroscience, neurobiology and neurological disease, specifically Alzheimer's. PET/MR has arrived just as a National Institutes of Health study group has changed the definition of Alzheimer's from a clinical syndrome to a biological phenomenon and new clinical guidelines have emerged.PET/MR could combine new amyloid imaging agents with quantitative brain morphometry, and maybe functional resting-state studies, as a way to perform one comprehensive exam in patients at the earliest stages of Alzheimer's.
"Here, there's an opportunity for radiologists to be able to define for clinicians the biochemical disease prior to the loss of working brain," Rosen says. "This will be an extremely important opening and PET/MR is ideally situated to make a contribution here."
PET/MR may be able to pinpoint abnormalities in brain networks, then provide a map to target a pharmacological treatment, or intervene with deep brain electrical stimulation of certain key nodes.
"Performing receptor-based, targeted imaging with PET, combined with functional connectivity mapping with either resting-state MR or diffusion tractography or some combination of those really becomes a potential paradigm change in the way we think about diagnosing and treating mental illnesses, Rosen says."
The fundamental capabilities of PET/MR are present in the technology. "Emerging neuroscience suggests that this may be an important future direction for this technology," he says.
| PET/MR Sends Resident Training Back to School | ||
PET/MR will require rigorous training in study protocols for nuke medicine residents, who will need to learn more about MR—both for basic physics and image interpretation. "Making these curriculum changes mandatory could take two to three years, due to the relatively slow pace of changing official program requirements," says Michael M. Graham, MD, PhD, director of nuclear medicine at the University of Iowa and past president of SNM. Because there is uncertainty about how PET/MR will be used clinically, there is companion uncertainty about specifically what to add to the curriculum. "This uncertainty will further delay implementation of changes in program requirements," Graham says. Currently, it is unclear what PET/MR offers that will justify the expense. Thus, adoption is likely PET/MR adoption also will be slow. "This is compounded by shifting economic constraints, the high cost of the instruments, and the lack of study reimbursement," Graham says. Knowledge of PET and subspecialty radiological imaging using MR, such as neurologic, body and musculoskeletal imaging, will likely be optimum, says Milton J. Guiberteau, MD, of the radiology department at St. Joseph Medical Center in Houston. "In contrast to hybrid imaging employing CT, the use of MR with its anatomic and functional components, as well as its molecular imaging potential, including spectroscopy and emerging contrast agents, may render mastery more challenging," says Guiberteau. It is axiomatic in this setting, he says, that Nuclear Regulatory Commission-mandated training in the use of radioactive material will be required before physicians obtain appropriate authorized user status. Most of the current discussion about nuclear medicine training is focused on developing a combined radiology/NM training program, according to Graham. "This would be ideal for ensuring incorporation of adequate MR into resident training," he says. |
