Radiology plays starring role in personalized medicine

In the Promised Land of personalized medicine, roulette-style drug selection is a thing of the past. Eschewing delivery by trial and error, physicians prescribe drugs precisely tailored to a patient's genetic code. Imaging plays a heroic role in targeting the best therapy and monitoring response. Disease is foreseen years ahead of time, when perhaps it can be stopped in its tracks.

This vision is futuristic, but important mileposts are visible on the near horizon. Imaging biomarkers are being investigated in several major clinical areas, notably cancer but also including Alzheimer's disease, heart disease, arthritis, and diabetes (see accompanying article).

Those uninitiated in the workings of the promised revolution need not fear. This year's crop of refresher courses at the RSNA meeting includes lectures on the essentials of molecular imaging for clinical radiologists and tips on "practicing in the era of molecular imaging" for three key specialist areas: cardiovascular, neurologic, and oncologic imaging.

This year, the RSNA has brought Dr. Daniel Sullivan, a former top National Cancer Institute official in imaging, onboard as a science advisor. Among other things, Sullivan is helping to guide educational programs for radiologists. His appointment has been encouraging for researchers conducting cutting-edge studies in molecular imaging.

Meeting attendees can expect an increasingly higher profile for imaging biomarkers, corresponding with building demand in society for more objective, or quantitative, approaches to diagnostic imaging, according to Dr. Gary Becker, who has been on the RSNA board since 2001 and became chair in late 2006.

"Quantitative imaging and biomarkers are top priority for the RSNA board," said Becker, a professor of vascular and interventional radiology at the University of Arizona College of Medicine.

The Biomarkers Consortium, a public-private research partnership of the Foundation for the National Institutes of Health defines biomarkers as "molecular, biological, or physical characteristics that indicate a specific underlying physiological state."

In the wider clinical world, biomarkers typically are blood tests, such as the prostate-specific antigen study used in prostate cancer screening. Tremendous interest in such disease markers has, in turn, fueled interest in imaging biomarkers, said Dr. Gregory Sorensen, director of the Center for Biomarkers in Imaging at Massachusetts General Hospital.

The term imaging biomarker may evoke visions of sexy molecular imaging technology or, perhaps, injection of sophisticated nanoparticles. But garden-variety imaging results are already serving informally as biomarkers, notably in cancer treatment for assessing response to therapy within 24 to 48 hours.

Strictly speaking, something as simple as a chest x-ray for pneumonia could be considered an imaging biomarker, though not a very good one, Sorensen said. More commonly, the term is used to describe tests that accurately monitor response to treatment and help clinicians predict the future.

BIG PHARMA, BIG SAVINGS

Drug companies could potentially save hundreds of millions of dollars in research costs by using various modalities to measure response to treatment in clinical trials. But the FDA needs to see greater standardization in imaging study protocols before it will accept imaging results as endpoints. Standardization is the focus of a number of ongoing trials, and outcomes will affect mainstream radiology.

"We are aware that the interest and need for imaging methods to play a role in drug development will carry over to clinical practice as personalized medicine comes into realization," said Sullivan, former director of the Cancer Imaging Program at the NCI. "We want to help radiologists to understand where modern medicine is going and how soon that is going to happen."

Biomarkers are "qualified" for particular purposes. Currently, few imaging studies are qualified by the FDA to serve as a surrogate marker in trials. CT is accepted for measuring the shrinkage of tumor volume following administration of an anticancer agent, using criteria established in the Response Evaluation Criteria in Solid Tumors (RECIST) trial (J Natl Cancer Inst 2000:92;3:205-216).

Although imaging is often used in clinical practice to measure tumor response, standardization is still lacking, said John Boone, Ph.D., vice chair of the radiology department at the University of California, Davis Medical Center.

CT is ubiquitous for measuring tumor size, but the value of comparative studies is sometimes questionable. A study from one institution on an early model CT scanner, for example, may serve as the baseline scan to be compared with follow-up images from a state-of-the-art multislice CT unit.

UC Davis is one of eight Imaging Response Assessment Teams set up by the NCI. The teams aim to unite oncologists, physicists, and radiologists to establish protocols for cancer trials.

"There is a groundswell to make radiology fundamentally more involved in clinical cancer trials and to become involved in more sophisticated ways," said Boone, who is also moderating a session called "Imaging as a Biomarker" at this month's RSNA meeting.

PET/CT could benefit from better standardization as well. Each exam may have 100 different parameters, including the amount of FDG used for PET, CT slice thickness, length of time for patient fasting, timing of imaging after injection, and selection of which imaging study comes first-PET or CT. New protocols will help standardize these steps.

Separately, the Biomarkers Consortium's first projects are testing the use of FDG-PET as a biomarker in non-Hodgkin's lymphoma and non-small cell lung cancer. Investigators assess the role of imaging in monitoring tumor response and patient outcome, establishing standards in the process.

"FDG-PET is used clinically, but it has never been qualified for use in clinical trials," said Dr. Barbara Mittleman, director of the consortium's program on public-private partnerships.

Mittleman notes that the consortium's members include the Centers for Medicare and Medicaid Services and that trial outcomes will inform reimbursement decisions generally.

"Payers are very interested in making sure practice conforms with best possible use," she said.

Another partnership of the Biomarkers Consortium is a major trial in neurodegenerative disease-the Alzheimer's Disease Neuroimaging Initiative. The $60-plus million ADNI trial, which recently completed enrollment of over 400 patients at multiple centers, will develop stan-dards for imaging and seek to opt-imize protocols for modalities tested. Results are expected in 2010.

Memory loss is a striking feature of Alzheimer's disease. Assessment of improvement due to therapy, however, is often based on subjective measures such as psychological testing and observances from family members and friends. In Alzheimer's disease, nerve cells die and the hippocampus shrinks. Imaging could provide more objective measures of the status and progression of disease or of improvement in response to therapy.

Every six months, trial participants will undergo MR and FDG-PET scans. All participants will have 1.5T MRI studies, and one-quarter will also undergo 3T MRI. A subsample will also undergo imaging with the PET tracer carbon-11 Pittsburgh compound B (PIB), which allows visualization of amyloid pathology common in Alzheimer's disease.

"Results from ADNI will help show with more clarity the advantages and disadvantages of PET and MR," said Dr. Michael Weiner, a professor of radiology at the University of California, San Francisco, who heads the research project.

Weiner notes that the ADNI findings will be made available online to scientists across the globe. Japan and Australia have launched projects using ADNI standards, and a European version is in the planning stage.

"We are hoping there will be worldwide adoption of uniform standards for doing clinical trials in Alzheimer's disease," Weiner said.

Meanwhile, advanced devices like PET/MR scanners are starting to be deployed in a handful of research labs, including Sorensen's center. Mass General will be using PET/MR for research in Alzheimer's disease and other conditions such as brain cancer, stroke, and psychiatric illnesses.

Sorensen envisages that imaging biomarkers will create new opportunities in clinical services for radiologists. Imaging might help to determine,

for example, which antidepressant a patient should receive. Today, absent a good imaging biomarker, the selection is done by a sometimes prolonged trial-and-error process.

Imaging could also play a role in showing when to stop and start administration of particular therapeutic agents in cancer patients.

"Today's research is tomorrow's clinical application," Sorensen said.

Emily Hayes is feature editor of Diagnostic Imaging.