Let’s get small: Interventionalists eye targets at molecular level

July 1, 2001

Interventional radiology of the future may appear to resemble its present-day practice, relying on foundation techniques honed for decades: image-guided arterial access, device placement, and therapy delivery. The real action, however, may be going on below the surface, as existing therapies team up in new combinations and refinements increasingly involve the molecular level.

Sidebars:

Venous valve aims for huge market

Irradiated beads offer palliative option

IR techniques aid gene delivery

Interventional radiology of the future may appear to resemble its present-day practice, relying on foundation techniques honed for decades: image-guided arterial access, device placement, and therapy delivery. The real action, however, may be going on below the surface, as existing therapies team up in new combinations and refinements increasingly involve the molecular level.

A number of interventionalists, in fact, speak of the future less in terms of techniques than drugs, genes, implants, and other agents, many yet to be developed, that can be delivered to their anatomical destination via image guidance. The new interventional radiology, they suggest, will combine a radiologist's skills with the best that medical research has to offer in multiple fields.

Expect to see a shift in research, as interventionalists in search of better results take techniques known to be safe and efficacious and combine them: stenting and drug therapy, or ablation and chemotherapy.

Consider stents. With as many as one in four devices producing restenosis, it's clear that a simple mechanical solution is not enough to overcome what is essentially a biological problem.

"I think the design phase of stents is over," said Dr. Julio Palmaz, chief of cardiovascular and interventional radiology at the University of Texas, San Antonio. "Efforts to improve generationally are pretty much done. Every time you gain in one area, such as opacity, you lose in another, such as thickness. The next step is addressing restenosis."

Frustrated by shortcomings from irradiated stents and brachytherapy, researchers hope to see drug-coated stents on the market in a few years. Cook Group, for example, launched a study on coronary stents coated with paclitaxel in the spring, citing good two-year data from animal trials. The drug coating appears to stay active four or five weeks after the stent is deployed, inhibiting endothelial cell growth. Other cytotoxic drugs show potential as well.

"Coated stents offer the ability to prevent a problem without additional procedures, and there are lots of logistical and practical reasons to think it will take hold," said John DeFord, Cook CEO. "I see it as a major player in the near term."

Palmaz offered cautious optimism, pointing out that radiation was promising, too, and that it took a while for its dark side to emerge.

More distant options include gene therapy--coating a balloon catheter with DNA designed to limit cell growth and inflating the balloon to treat the stent and surrounding areas.

For stent inventor Palmaz, however, the long-term solution appears to lie with a challenging concept: The surface of a foreign, nonorganic stent must be made as invisible as possible to the body in which it is inserted. In a keynote lecture at the Society of Cardiovascular and Interventional Radiology meeting in March, he suggested that modifying, or at least controlling, the surface of stents at the molecular level may be the solution. Oxidation is a primary culprit. Attaching themselves to the surface of a stent, oxygen molecules eventually come to make up most of its surface, making it thicker. The oxygen in turn binds to airborne acids, water, methane, and other molecules. Once the stent is placed, proteins latched onto the surface may in turn snare fibrinogen, platelets, and other matter, promoting stenosis.

Ubiquitous among these unwelcome materials is polydimethylsiloxane, or PDMS, a silicone grease used in catheter balloons that keeps desirable cells from growing on the stent surface. The grease covers 5% to 100% of the surfaces of 11 FDA-approved stents, according to Palmaz. Its mere presence doesn't prove its complicity in promoting restenosis, he concedes, but rather points to how little control interventionalists have over the molecular makeup of the devices they place.

"The future of stents is in molecular engineering to create smart surfaces," Palmaz said. "Suppressing tissue is good for today, but we want to prevent adhesion of platelets."

RF's Potential Heats Up

If research on stents is all about smallness--thinner surfaces, smaller arteries, molecules at work--researchers looking at tumor ablation are stepping back for a macroscopic view. Radio-frequency technology in particular, having been proven in the liver, is being tested in the kidney, lung, pancreas, bone, even adrenal glands. Nearly any soft tissue, it seems, is fair game. A few more years, and the procedure may become an alternative to surgery for some patients rather than a second-line treatment when surgery is not possible, according to proponents.

Even though recurrences may be easily retreated, the quest for a minimally invasive alternative to surgery requires an equivalent to thorough resection. If tumor ablation reaches that level of efficacy, chances are it won't be working alone. Gene therapy may be a good adjunct, or drugs that can be activated externally once they are guided to the tumor site.

"RF is like red wine--practically anything pairs well with it," said Dr. Douglas Coldwell, an interventionalist at Good Samaritan Hospital in Phoenix. "There's a good synergy between RF and radiation, some chemotherapeutic agents, and chemoembolization. I think the last one will be a good pairing for colon mets in the liver."

The questions to be answered in the next few years are what benefit the patient derives from such procedures, and which procedures, or combinations, produce the best outcomes.

"We're trying to validate the hypothesis that RF can kill tumors, but it's a jump from there to prolonging life," said Dr. Murray Asch, an assistant professor of radiology at the University of Toronto. "A lot of researchers make RF sound great, like it can treat everything, and it's sexy to listen to, but we have to be careful in how we apply it. There has to be a clear improvement--reducing pain, living longer."

Asch's group is designing a study to compare RF ablation of colorectal liver metastases head-to-head with surgery. Within the next few years, the optimal approaches for a variety of tumor types should be well mapped, with safety and survival data.

Another ongoing question involves choosing which imaging modality will be best to guide ablation procedures and track their progress. The answer may depend on anatomy. CT has the edge in lung procedures, and CT fluoroscopy, though not yet used widely, figures into many interventionalists' ideal IR suite of the future. Opinions are mixed on MR, unless it can develop reliable thermal mapping. Though fairly consistent in cryoablation, the application is prone to misreading heated areas, according to Dr. Patrick Sewell, divisional chief of interventional oncology at the University of Mississippi.

The ideal imaging tool allows accurate probe placement, shows the treated area, and identifies any tumor margin left untreated, preferably all while the patient is still on the table. For this combination, a number of interventionalists expect to turn to ultrasound and contrast agents that highlight vascularity. While heating tissue with RF tends to wipe out ultrasound images with released gas, it's possible that the addition of contrast will light up blood vessels in untreated portions of tumor, even through the microbubble fog.

It's unlikely that ablation will be good enough to stand alone, concedes Thomas Lawson, Ph.D., clinical director of RF manufacturer Radiotherapeutics.

"Researchers have this desire to say that if we use a new technology once, it'll work," he said. "Maybe for a few years the headiness around RF supported that, but the reality of cancer is that one modality rarely is sufficient."

Sidebar

Venous valve aims for huge market

Stent-based model enters clinical trials

By Jane Lowers

Chronic venous insufficiency may lack the sudden-death risk of an aortic aneurysm, but efforts to keep blood from pooling in the lower extremities have met with major challenges.

Most patients are treated with little more than leg rest or compression stockings. Success has been limited with valves imported from animals or patients' arms, because they are prone to thrombosis or failure. A stent-based model entering clinical trials this year offers a new approach, encouraging the body to form a native valve.

Based on a thin, square wire stent, the artificial valve developed by Cook Corp. provides a framework of collagen tissue in the form of small intestine submucosa (SIS). Attracted to the collagen matrix, native cells gradually colonize the stent, remodeling and replacing it, according to developer Dr. Dusan Pavcnik of Oregon's Dotter Institute.

"The valve over time is not foreign. Instead, it provides a biological framework for the body," he said. "It appears to undergo remodeling with the recipient's own cells and function without the need for anticoagulants."

In a six-month sheep study, 22 of 25 valves remained functional at six months. One developed thrombosis while two failed to perform. A 90-day human trial outside the U.S. is scheduled for summer, and Cook expects to bring the results to the FDA for a U.S. trial in 2002.

The market for a successful venous valve is huge, according to Pavcnik.

"In Europe and North America, 2% to 3% of the population has venous problems, three times more patients than arterial disease," he said. "Four or five million people could benefit from a simple procedure."

Sidebar

Irradiated beads offer palliative option

Liver cancer responds to microsphere treatment

By Jane Lowers

When surgery, chemoembolization, and radio-frequency ablation fail, patients with hepatic tumors may respond to treatment with radioactive glass beads delivered intra-arterially. Early data from the University of Maryland show that the therapy is well tolerated, although data on improved survival or tumor remission are unclear.

The 25-µm beads are embedded with beta radiation-emitting yttrium-90, which has a half-life of 64 hours. The outpatient treatment follows a screening angiogram to assess the portal vein. Additional imaging determines whether arteries from the liver shunt into the lungs or could allow beads to infiltrate the bowel mucosa. Either could cause serious complications.

The spheres are delivered by catheter to the entire liver. Doses are calculated to give each patient 140 to 160 Gy radiation exposure, affecting only tissue within 2.5 mm of the beads.

Of 30 patients treated since August 2000, seven have been readmitted to the hospital for medical treatment of complications including nausea, vomiting, sepsis, and hemoperitoneum. Five patients have died. Others have converted from positive to negative PET scans, indicating some form of tumor regression. The exact results are unclear, however, according to Dr. Ravi Murthy, lead researcher.

"The results are preliminary but encouraging," said Murthy, director of vascular and interventional radiology at Maryland. "This will never be a first-line treatment competing with surgery, but it may become a second-line treatment used in combination with other therapies."

Like other palliative options, the microsphere treatment can be repeated as needed, Murthy said. Survival data appear to be comparable to or slightly better than chemoembolization, although no direct comparisons of the two treatments have been done in the U.S. Murthy expects to present data at the 2001 RSNA meeting.

"This is new and the data are incomplete, but it seems to be working with very low toxicity," he said.

Sidebar

IR techniques aid gene delivery

Ultrasound bursts contrast microbubbles

By Jane Lowers

In gene therapy, as in stand-up comedy, successful material depends heavily on the delivery. So far, delivery is proving to be one of the field's toughest challenges. Capable of creating increasingly sophisticated strips of genetic code destined for specific targets within the body, gene therapists are finding it difficult to make the vectors stay where they're wanted and insert their payload into the appropriate cells.

"That's the Holy Grail for this field--successful targeting of the vector to the specific tissue and having it leave other things alone," said Dr. Nelson Wivel, deputy director of the University of Pennsylvania's Institute for Human Gene Therapy. "We're not there."

For radiologists, some of the best delivery methods to date are old favorites: via catheter threaded under fluoroscopy into the hepatic artery, for example, or via direct needle injection for metastases in the liver.

Dr. Evan Unger, an Arizona radiologist, is taking another approach, cranking up ultrasound to burst contrast microbubbles with genes bound to their surface. The technique is being tested in animal models for cardiac applications, and Unger, founder of Imarx, is interested in seeing whether the same principle can be used to deliver other cancer-fighting drugs.

"If you look at a needle in a tumor, first of all it's invasive, and you don't get good distribution because the injection doesn't go very far," he said. "Microbubbles can move right up into microvessels, and popping the bubbles releases a shock wave to drive the genes into the cells."

There's some basis for the argument, Wivel said. An in vitro technique, electroporation, uses electrical current to nudge genetic material into cells.

"For cancer in particular, gene therapy is always going to be an adjunct, and that's where radiologists will play a role," he said. "You're never going to get it into every last cell, but if you can combine it with other techniques, you may help amplify immune response as well."