BB&T Contributing Editor

WASHINGTON — The growing use of image-guided therapy is a key factor driving expansion of multiple segments of the medical device and diagnostics markets worldwide. From guidance of targeted cancer treatments to directed stem cell therapies in cardiology and neurology, image guidance is playing an increasingly important role in enabling improved therapeutic approaches under development, including advanced minimally invasive therapies.

Interventional radiology is a specialty at the core of image-guided therapy, and it embodies many of the technologies employed in image-guided treatment.

However, as discussed by experts here at the 33^rd Annual Scientific Meeting of the Society of Interventional Radiology (SIR, Fairfax, Virginia) last month, the use of image-guided therapy is expanding well beyond the boundaries of a single specialty, driving market expansion but at the same time threatening the viability of interventional radiology as a stand-alone discipline.

For device suppliers, the trend is a positive one since it expands the size of the market, although it also expands the market's diversity, creating challenges in accessing the increasingly wide array of physicians who use image-guided technologies.

The trend also raises issues related to the level of expertise in image interpretation needed in order to perform image-guided procedures safely and effectively, a topic that was widely addressed at the SIR meeting.

While these issues are far from being resolved, they are creating a new sphere of competition for suppliers in developing image guidance technologies that easier to use, more precise, and that address a wider range of applications.

From hybrid to non-invasive

New developments were described at the SIR conference in hybrid imaging, minimally invasive and non-invasive image-guided ablation therapy for cancer, embolization therapies, stroke treatment, minimally invasive treatment of peripheral vascular disease, and spinal therapy. Advances in imaging modalities, particularly in the areas of MRI, 3D ultrasound and contrast-enhanced imaging also were discussed, modalities promising to expand the range of applications of image-guided therapy and improve the precision and safety of procedures.

For example, 3D ultrasound is proving valuable in guidance of the transjugular intrahepatic portosystemic shunt (TIPS) procedure, a complex interventional radiology procedure used to treat patients with liver disease. In procedures such as radiofrequency ablation (RFA) and cryoablation of tumors, 3D ultrasound is enabling more precise placement of probes, and the added perspective provided by 3D has been demonstrated to alter procedures in up to half of all cases.

Combining hybrid imaging technology with real-time instrument guidance is enabling significant improvements in interventional procedures with concrete benefits in terms of procedure time, efficacy, and safety.

As discussed by Bradford Wood, MD, of the National Institutes of Health, a new medical navigation system employing smart needles from Traxtal (Toronto, Ontario) is being used in combination with hybrid imaging technology from Philips Healthcare (Best, The Netherlands) that integrates CT, MRI, PET and ultrasound to perform a variety of procedures including tumor ablation and biopsy.

CT, MR and PET images captured prior to the procedure are fused with real-time ultrasound images to enable visualization of soft tissue features during a procedure, such as the location and extent of a tumor, that are not readily visible using ultrasound only. The Traxtal PercuNav system is also integrated with the imaging system to allow real-time tracking of the position of the tip of a device such as an RFA probe or a biopsy needle, and to project the device track relative to the target lesion.

Tracking for accurate positioning

Tracking is accomplished via an electromagnetic field generator and miniaturized sensors incorporated into the tip of a needle. Positional accuracy of 3 mm to 5 mm in probe position has been achieved in breathing patients.

In addition to the ergonomic benefits of displaying all images on a single monitor, the PercuNav system can reduce costs by minimizing the time spent in the CT, MR or PET imaging suite. The system allows use of the best modality to image a lesion, while still enabling real-time procedure guidance.

Clinical applications for the system that are expanding rapidly include prostate biopsy, lung biopsy (as an alternative to fiber optic bronchoscopy), and minimally invasive tumor ablation. The PercuNav system is priced at about half the cost of a full-featured ultrasound system, and needles with integrated sensors cost twice as much as conventional needles.

Other suppliers of navigation systems for guidance of interventional procedures include Veran Medical Technologies (Nashville, Tennessee) and Ascension Technology (Burlington, Vermont).

Veran's IG4 Plug-n-Play Delivery System provides real-time procedure guidance of biopsy needles and probes using electromagnetic sensors incorporated into the device along with three patient-attached pads that are used to register images from various modalities such as CT, MRI, ultrasound and PET scanners to the Veran system.

The system also can provide thermal maps to allow temperature at the treatment site to be monitored. An electromagnetic field generator is placed near the patient, and signals from the pads and the integrated sensors are used to determine device location and orientation.

The IG4 system does not require ultrasound imaging during a procedure, but it provides information that allows probe/needle movement during respiration or patient movement to be tracked. The Veran system recently received FDA clearance and is to be launched in April 2008.

Another real-time navigation technology for use in interventional procedure guidance has been developed by Ascension, this technology originally developed by the U.S. Air Force for aerospace applications. This system employs a low-intensity magnetic field generator along with a miniaturized sensor that can be placed at the tip of a needle or interventional probe. The magnetic field has about the same strength as the earth's magnetic field, avoiding the safety issues associated with high-strength magnetic fields such as those employed in MRI.

The technology provides more accurate tracking of device positioning compared to systems that use electromagnetic field generators, according to Ascension. Although there is some distortion when magnetic objects are placed in the field, Ascension is developing methods to compensate for such effects.

The company is searching for partners to commercialize the navigation technology for image-guided medical applications and has already established a partnership with Trig Medical (Yokneam, Israel) for use in a labor and delivery monitoring system. In that application, real-time monitoring using the Ascension technology has enabled a reduction in the rate of Caesarian sections.

Imaging and the need for stroke therapies

New technologies for the diagnosis and treatment of stroke were also discussed at the SRI conference, with the device systems under developoment generally dependent on highly precise imaging. Many new device innovations in this sector are needed, when we consider the (nearly, but not complete) absence of other therapies.

At present, the only FDA-approved therapy for stroke is intravenous tPA administration, a treatment not used for many patients because they present more than three hours after symptom onset or it is determined that the treatment for them could be harmful.

As discussed by Colin Derdeyn, MD, of Washington University School of Medicine (St. Louis), improvements in emergency response systems, including use of point-of-care technologies to diagnose stroke quickly and differentiate hemorrhagic from ischemic stroke as well as better methods to determine brain tissue viability are needed.

Derdeyn anticipates that the IMS-3 trial of combined IV-intra-arterial tPA therapy for stroke will show positive results, resulting in more demand for around-the-clock availability of stroke treatment centers as well as expansion in the number of centers offering such therapy.

Improved treatment methods, such as the Neurovascular Embolization Cover device under development by NFocus Neuromedical (Palo Alto, California) and the NeuroFlo perfusion augmentation system being developed by CoAxia (Maple Grove, Minnesota) are also needed to allow more effective treatment of hemorrhagic and ischemic stroke.

For rapid stroke diagnosis, a key step for enabling expedited stroke treatment, new imaging technologies are emerging that may have a significant impact.

For example, Kieran Murphy, MD, of Johns Hopkins University (Baltimore) described use of the new Aquilion ONE 320-slice CT scanner from Toshiba Medical Systems (Tokyo) for neurovascular imaging at the SIR conference. The Aquilion ONE, which was introduced in the U.S. in November 2007, provides 3D views of the cerebral vasculature with a resolution approaching that of angiography, and captures a whole brain image in a single scan requiring less than 20 minutes.

The system also employs dynamic volume CT imaging, allowing the brain's blood flow and function to be evaluated. With conventional CT, imaging results in stroke patients are often inconclusive, requiring additional diagnostic procedures such as MRI to be performed in order to arrive at a firm diagnosis.

Systems such as the Aquilion ONE promise to allow more rapid diagnosis, leading to development and implementation of a treatment strategy in minutes rather than hours. Combined with emerging interventional therapies, the treatment of stroke may, as a result, rise to a new level of effectiveness.

Imaging, embolization and drug-elution

Embolization therapies are becoming more widely utilized in interventional radiology to treat a variety of conditions including uterine fibroids, liver cancer, renal cancer and vascular aneurysms. Embolization is not a new technology — having been used for decades for minimally invasive treatment of aneurysms as well as for control of bleeding but now new technological developments are driving a significant expansion in the range of applications of embolization. As shown in Table 1, (below) a wide variety of embolization products are available and under development that have applications in interventional therapy.

For example, AGA Medical (Plymouth, Minnesota), introduced at the conference its Amplatzer Vascular Plug II, a multi-segmented self-expanding device used to occlude blood vessels for treatment of arteriovenous fistulas and arteriovenous malformations, as well as for occlusion of arteries prior to organ ablation or chemo-embolization procedures.

The newest development, exemplified by products such as the LC and DC Beads, QuadraSpheres, and the Paragon beads from companies including Biocompatibles/Angiodynamics and Biosphere Medical (Rockland, Massachusetts), is drug-eluting embolization agents used in the treatment of cancer a development apparently finding its genesis in drug-eluting stent technology.

As drug-elution in stents becomes more reliable and increasingly sophisticated, the technique is likely to be frequently adapted to applications throughout the body, not just the coronary vasculature. Thus far, the initial application has been in the treatment of liver cancer, diagnosed in 20,000 individuals in the U.S. in 2007, but applications are expanding to include kidney cancer treatment.

As discussed by Jeff Geschwind, MD, of Johns Hopkins University School of Medicine (Baltimore), the use of drug-eluting implants for cancer treatment dates to the mid-1980s development of the Gliadel Wafer by Robert Langer at the Massachusetts Institute of Technology (Boston), an implantable drug-eluting wafer used to prevent recurrence of brain cancers.

Drug-eluting beads or microspheres are the newest implementation of the technology, enabling high-dose chemotherapy to be delivered to a precisely targeted site using minimally invasive devices such as microcatheters.

The DC Beads developed by Biocompatibles (Surrey, UK) are an example, as are the HepaSpheres from Biosphere Medical (Rockland, Massachusetts), and other microsphere-based technologies under development by Geschwind at Johns Hopkins School of Medicine.

The DC Beads employ a hydrogel structure which swells when immersed in liquid, allowing incorporation of an anti-tumor drug within the bead. When the beads are subsequently delivered via a microcatheter to a target tumor, such as a lesion within the liver, they simultaneously occlude the blood vessels feeding the tumor, inhibiting its growth, and elute high concentrations of the drug which remains locally sequestered at the tumor site.

Side effects of chemotherapy, such as neutropenia, alopecia and thrombocytopenia, are significantly reduced compared to systemic drug delivery, and the higher doses of drug delivered to the tumor improve response rates.

TACE and LC Beads

Geschwind quoted studies in which tumor response rates have been increased from 30% to 70% by the use of transarterial chemo-embolization (TACE) therapy in liver cancer.

An even more dramatic response has been reported when using LC Beads as a second-line therapy for cancers that have metastasized from other organs such as the colon or breast to the liver, where a response rate of 80% has been achieved compared to 10% with standard chemotherapy.

TACE is already in widespread use for liver cancer therapy outside the U.S., particularly in certain Asian countries with a high incidence of hepatocellular cancer, as shown in Table 2 below, and is also showing promise as a treatment for kidney cancer (nephroblastoma).

Another particle-based chemotherapeutic drug delivery product, Abraxane (ABI-007) from American Bioscience (Los Angeles), is FDA-approved for breast cancer treatment, with applications in the treatment of head and neck cancer under development.

Abraxane is not an embolization agent, however, since albumin nanoparticles smaller than a red blood cell are employed; but it is delivered in a targeted manner by image-guided catheter techniques, and enables high local concentrations of drug to be achieved at the tumor site while minimizing the adverse effects of systemic chemotherapy.

CeloNova Biosciences (Newman, Georgia) is another supplier of embolization agents, the Embozene microspheres, which are expected to be on the market in the U.S. shortly pending FDA clearance, and which may have applications in TACE.

Embolization is also employed for the treatment of uterine fibroids, a benign condition that causes pain, heavy menstrual bleeding, urinary frequency and other adverse symptoms typically in women over the age of 35.

Focused ultrasound

Although uterine fibroid embolization (UFE) has been shown to be an effective alternative to hysterectomy for treatment of uterine fibroids, it is not widely utilized in part because gynecologists, who are typically the physicians who first diagnose the condition, rarely inform women of the availability of the procedure.

As a result, the number of hysterectomies performed in the U.S. (more than 600,000 per year) has not changed significantly.

A new study of the use of uterine fibroid embolization as a treatment when focused ultrasound, a non-invasive FDA-approved therapy for uterine fibroids, fails was presented at the SIR conference which could stimulate additional utilization of UFE.

As described by Alisa Suzuki, MD, of Brigham and Women's Hospital (Boston), MR-guided focused ultrasound (MRgFUS) was approved in 2001 for treatment of uterine fibroids, and ExAblate MRgFUS systems marketed by InSightec (Carmel, Israel) and manufactured by Misonix (Farmingdale, New York) are now installed in more than 60 sites worldwide. Thirty-one InSightec ExAblate systems have been installed in combination with MRI systems from GE Healthcare (Waukesha, Wisconsin).

The number of procedures performed to treat uterine fibroids with MRgFUS is small, however, due to the low installed base and the continued dominance of hysterectomy in uterine fibroid treatment. The key attraction of focused ultrasound is its completely non-invasive nature, making it attractive for women who want to avoid surgery.

Between 73% and 91% of patients treated with MRgFUS show significant improvement in symptoms, according to Suzuki, complication rates are low, and the recovery period is short, particularly in comparison to hysterectomy.

In addition, fertility is preserved after MRgFUS, unlike hysterectomy.

However, MRgFUS does not cure fibroids, and in women who have a large number of fibroids, some lesions may not be completely ablated by focused ultrasound, leading to a need for a follow-up procedure.

Suzuki has found that embolization is an effective minimally invasive treatment for fibroids that develop following MRgFUS treatment, allowing women to avoid hysterectomy.

While questions remain regarding maintenance of fertility following UFE, it clearly has fewer long-term adverse effects and a shorter recovery period compared to hysterectomy.