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Intervention

Let’s get small: Interventionalists eye targets at molecular level
Up-and-coming procedures combine popular therapies to tackle tumors, stenosis, venous insufficiency

By Jane Lowers

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 [Fig. 1]. 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 [Fig. 2]. 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.”


Sidebars:
Venous valve aims for huge market
Irradiated beads offer palliative option
IR techniques aid gene delivery
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