Clinical FDG-PET use grows as research moves forward

March 4, 2008

Discoveries chart course toward earlier diagnoses and more effective treatments for cancer, cardiovascular disease, and dementia

Molecular imaging has been redefined. By expanding its definition to apply to most diagnostic and therapeutic procedures formerly associated with nuclear medicine, diagnostic imaging’s leaders hope to make molecular imaging relevant and accessible to mainstream radiology.

MI’s journey from bench to bedside is not going to be easy. Researchers need more time to guide promising applications from preclinical animal testing into practice. Yet progress can be seen on several fronts. In particular, the National Oncology PET Registry, implemented in mid-2006, has greatly expanded Medicare coverage for FDG-PET and raised the visibility of PET imaging for cancer staging and the monitoring of cancer therapies.

The joint conference of the Academy of Molecular Imaging and the Society for Molecular Imaging last September set a precedent for cooperation among potentially competing organizations. The two societies share an interest in advancing MI science, but their histories are vastly different. AMI serves as an advocate and clearinghouse of information about PET reimbursement and practice strategies, while SMI is more closely associated with MI’s scientific advancement.

The first joint meeting was successful enough to plan a second joint conference-this time also involving the European Society of Molecular Imaging-that will take place in Nice, France, in September.

Scientific presentations at the joint meeting exemplified MI’s expanding scope. Previous research was mainly concerned with cancer, cardiovascular disease, Alzheimer’s disease, cell tracking, and image-guided therapy. Research presented at the 2007 conference also explored potential MI applications for arthritis, pneumonia, and parasitic disease (malaria).

The National Cancer Institute is a primary source of molecular imaging research funding. The NCI devoted at least one-third of its $180 million cancer imaging budget to MI in 2007, said Dr. James L. Tatum, acting associate director of the NCI cancer imaging program. The number of funded grants rose slightly in 2007, but total funding for MI was unchanged from 2006.

The NCI assists eight In-Vivo Cancer Molecular Imaging Centers as part of a program established in 1999. Supported by NCI P50 grants of up to $2 million annually, the ICMICs have become powerful engines of MI scientific discovery and leadership.

The NCI is also allied with the National Institute of Biomedical Imaging and Bioengineering for the development of medical nanotechnologies, such as targeted, activatable MR probes and image-guided drug delivery systems. And it has filed master investigational new drug applications for F-18 fluorothymidine (FLT), a PET cell proliferation agent, and F-18 fluoromisonidazole (FMISO), a PET probe that measures hypoxia. Both promising agents are considered generic in the sense that commercial pharmaceutical companies cannot patent them, so they need the NCI’s help to move through the FDA review process.

CARDIOVASCULAR DISEASE

The quest for molecular imaging tests to better identify adults at risk for stroke or myocardial infarction has followed two major tracks. One fuses anatomic CT and functional PET or SPECT perfusion images to diagnose coronary artery disease, myocardial ischemia, and wall motion abnormalities in a single volumetric examination. The other uses advanced molecular techniques to systematically identify the distribution and extent of cardiovascular plaque and assess potential  plaque rupture risk.

PET/CT and SPECT/CT technologies capable of sophisticated cardiac fusion imaging were widely disseminated in 2006 and 2007, according to Dr. Marcelo Di Carli, director of nuclear medicine at Brigham and Women’s Hospital, but most cardiologists and radiologists have not been convinced to use them.

Necessary evidence may come from the Study of Myocardial Perfusion and Coronary Anatomy’s Role in Coronary Artery Disease (SPARC). It aims to find definitive answers concerning the diagnostic power of PET and SPECT nuclear perfusion tests and multislice CT performed separately and in combination for evaluating patients at low to intermediate risk of coronary artery disease. The prospective 38-site trial involving 3700 patients will also demonstrate the predictive value of each modality, Di Carli said. Patient recruitment began in November 2007.

Research focusing on biomarkers that are specific to the inflammatory, angiogenic, or apoptotic indications of very early atherosclerosis is moving through preclinical animal trials. Work on perfluorocarbon nanoparticles developed at Washington University illustrates the status of this work. The phospholipid coating of the particles can carry various molecular payloads, such as an avb3 integrin specifically targeted at early angiogenesis, up to 200,000 gadolinium particles for MR visualization, and fumagillin or other anti-angiogenic drugs to treat the disease.

Published small animal studies have demonstrated that the nanoparticles bind to the neovasculature of atherosclerotic plaques or VX2 tumor models for diagnosis with MRI. A 2006 study established that the antibiotic fumagillin delivered by the nanoparticles suppresses angiogenesis in atherosclerotic plaques. Research awaiting publication in 2008 will demonstrate that the drug-carrying nanoparticles slow the growth of VX2 tumors in rodents and rabbits, said Dr. Greg Lanza, an assistant professor of internal medicine at Washington University.

“We can quantify these tumors serially and recognize fast-growing tumors that are going through the angiogenic switch and those that aren’t,” Lanza said. “We can treat tumors that do go through the angiogenic switch, which are the more malignant cancers, and reduce their volume and the amount of angiogenesis.”

DEMENTIA

Molecular imaging provides the first reimbursable, noninvasive way to diagnose Alzheimer’s disease. It is also being used as a tool to help uncover the causes of the disorder and evaluate possible treatments.

FDG-PET is especially good at differentiating between AD and frontotemporal dementia, said Dr. Daniel Silverman, an assistant professor of nuclear medicine at the University of California, Los Angeles. He pointed out that four of the five drugs cleared to treat AD are cholinesterase inhibitors. They compensate for AD patients’ reduced ability to produce acetylcholine, a primary neurotransmitter in the brain.

The neurotransmitter systems of patients with frontotemporal dementia, however, have no need of a cholinesterase inhibitor. In fact, the drugs can worsen symptoms for these patients, Silverman said.

The ability of carbon-11 Pittsburgh Compound B (C-11 PIB) PET to image the signature beta-amyloid plaques that probably cause AD has been scientifically verified. About 2000 people at 30 hospitals worldwide have been examined with the agent since 2003, according to codeveloper Dr. William Klunk, an associate professor of psychiatry at the University of Pittsburgh. A study by Klunk (in press) will describe how postmortem histological findings from an AD patient correlate well with the results of a C-11 PIB study that revealed extensive amyloid deposition in the patient’s brain 10 months before death.

Klunk and colleagues are also assessing subjects drawn from the 20% to 25% of cognitively normal adults older than age 65 who have at least mild amyloid deposition. The pathology literature suggests that plaques begin to accumulate in the brain 10 to 15 years before cognitive symptoms appear, so this apparently normal population may develop AD in their 70s and 80s. This hypothesis agrees with epidemiological evidence showing that roughly 20% of all individuals over age 80 have at least mild AD, he said.

“Circumstantially, the evidence is fitting together. But we still haven’t shown how many people with mild cognitive impairment who also show PIB retention on their PET scans will go on to develop AD. We don’t know if cognitively normal people who have amyloid deposits will go on to develop the disease,” he said.

PIB-PET also factors into the evaluation of beta-amyloid–inhibiting agents that will soon move into clinical trials, said Dr. Christopher Rowe, director of nuclear medicine at Austin Hospital in Melbourne, Australia. Multicenter trial results are expected soon, for example, on the ability of AN-1792, a synthetic form of beta-amyloid peptide, to stimulate an immune response leading to clearance of beta-amyloid plaques from the brain.

Though C-11 PIB is the formulation of choice for clinical research, the radioisotope, which has a 20-minute half-life, cannot be easily applied in most clinical settings. Promising results were reported in 2007, however, for the first human trials of F-18 PIB, Rowe said. GE Healthcare has filed an investigational new drug application to initiate FDA review.

CELL TRACKING

Christopher Long, a biomedical engineering doctoral candidate at Johns Hopkins University, earned a young investigator award at the joint AMI/SMI meeting in September for demonstrating that dendritic cells can be labeled with an iron oxide MR contrast medium in vivo through cell transfer rather than the conventional prelabeling in vitro. His research on mice also established that cellular MRI is well suited to monitor the kinetics of dendritic cell therapy.

“You can see the cells capturing antigens and going to the lymph nodes,” said Jeff W.M. Bulte, Ph.D., director of the cellular imaging section at the Johns Hopkins Institute for Cell Engineering.

The iron oxide labeling and cell tracking strategy may help boost the reliability of investigational cellular cancer vaccines, such as one us-ing granulocyte-macrophage colony-stimulating factor. GM-CSF–secreting cancer cell vaccines have been shown to elicit potent anticancer immune responses. The vaccine has been introduced clinically to boost the patient’s immune response. Cell tracking can assure that the cancer cell vaccines are taken up by target lymph nodes and delivered to cytotoxic T cells.

OPTICAL IMAGING

Optical imaging shows promise for evaluating cancer, atherosclerosis, arthritis, and thrombosis. Its major advantage is its ability to image the behavior of several different probes  simultaneously and in real-time. It can image whole organisms (mice), organs, tissues, or individual cells.

Exogenously administered probes that fluoresce in the near-infrared range show the most clinical promise. Much of the power of NIR optical imaging stems from the behavior of hemoglobin, which readily absorbs visible light with little effect on energy in the NIR band. This allows optical NIR imaging to examine structures several centimeters within tissues.

Nonspecific NIR probes include small molecules that act like iodine- or gadolinium-based contrast media. Blood pool NIR agents can quantify vascular volume fraction within tissue and have been used to illustrate the anti-angiogenic effect of bevacizumab (Avastin) therapy on tumor vasculature.

Dr. Umar Mamhood, director of small animal research at the Center for Molecular Imaging Research at Massachusetts General Hospital, estimates that such fluoro-optical applications will begin to migrate from small animal to human applications within five years.

“These would include some of the activatable probes,” he said. “They have a lot of promise for improved characterization of colon cancer, ovarian cancer, and atherosclerosis.”

MOLECULAR ULTRASOUND

Researchers have learned to appreciate diagnostic ultrasound for its unique ability to track the movement of molecular targets in real-time and to deliver and deploy targeted drug therapies.

Recent events have had a mixed effect on the modality’s status, said Dr. Katherine W. Ferrara, a professor of biomedical engineering at the University of California, Davis.  Troubles with the FDA in 2007 raised concerns about regulatory barriers to the clinical use of microbubble agents. Yet research continues to suggest that molecular ultrasound will ultimately become a useful tool for identifying the biomarkers of early disease and be able to serve as a platform for therapy.

University of Utah bioengineers demonstrated in a 2007 mouse experiment, for example, that an aggregation of drug-loaded polymeric micelles and perfluoropentane microbubbles can simultaneously enhance ultrasound imaging and serve as a delivery mechanism for chemotherapy. High-energy ultrasound directed to the targeted tumors caused drug-filled microbubbles to release their payload, enhancing the drug uptake of neighboring cancer cells (J Natl Cancer Inst 2007;99 (14):1095-1106).

Such findings are encouraging, according to Ferrara, but they may ultimately have little clinical influence in the U.S. if the microbubble agents cannot survive an FDA regulatory review. The agency’s decision in October to require black box warnings on the packaging of the only two microbubble agents approved for use in echocardiography in the U.S. led researchers to wonder whether an inherent safety problem may ultimately slow the adoption of their investigational microbubble-based molecular probes.

As a surrogate marker of cell proliferation, FLT is compelling for the complementary role it could play with FDG, a surrogate marker of cellular glucose metabolism. Its success rate in early human studies has been mixed, however, with FLT producing the most encouraging results in therapy-monitoring trials, said Dr. Anthony F. Shields of the Karmanos Cancer Institute in Detroit.

Results from a single-center trial published in Clinical Cancer Research in 2007 identified early changes in FLT uptake with R-CHOP or CHOP chemotherapy for non-Hodgkin’s lymphoma. In positive responders, mean FLT uptake fell 77%, indicating a slowing of cancer cell division. It had dropped by 85% after 40 days.

But the results of a study from the Radboud University Medical Center in the Netherlands disappointed researchers who had hoped that F-18 FLT could aid radiation treatment planning for patients with head and neck squamous cell carcinomas.

Progress toward clinical applications for FLT will probably continue to be slow until large multicenter trials testing its efficacy are performed, Shields said.

MICRO-ENVIRONMENTS: HYPOXIA

Oncologists have long realized that hypoxia, regions of deoxygenated tissue in and around metastatic tumors, inhibits effective treatment. Chemo- and radiation therapies are not as effective in the presence of hypoxia, in part because no clinically convenient instrument has yet been perfected that can noninvasively map its presence and intensity. PET imaging solutions employing F-18-labeled FMISO, F-18 fluoroazomycin-arabinoside, or copper-64 diacetyl-bis (N4-methylthiosemicarbazone) radiopharmaceutical probes have been proposed.

F-18 FMISO images have typically presented the pattern of the probe statically. Physicists from Philips Research demonstrated at the RSNA meeting that the data may be presented dynamically with the help of fast pharmacokinetic modeling software that quantifies hypoxia. The Voxulus software conducts tracer-specific analyses at a rate of more than 100 voxels per second to complete an analysis of a mouse in less than three minutes, said Jens-Christoph Georgi, Ph.D., a physicist at the Philips research lab in Aachen, Germany.