By MICHAEL SIMONSEN, PhD
BB&T Contributing Editor
And Larry Haimovitch
BB&T Contributing Writer
SEATTLE — Interventional radiology (IR) is perhaps one of the most diverse fields of medical science, its device-related procedures applicable to a seemingly increasing range of diseases and disorders.
This variety was on display at the 32nd annual meeting of the Society of Interventional Radiology (SIR; Fairfax, Virginia) in early March. Importantly, the conference’s science presentations and exhibits featured a look at new energy sources and therapeutic strategies in the IR sector.
Energy-based technol-ogies now available for minimally invasive ablation of soft tissues — some employed by interventional radiologists for tumor ablation — include radio frequency ablation (RFA), microwave ablation, cryoablation, ultrasound ablation and Coblation.
Worldwide, suppliers estimate the market opportunity for energy-based soft tissue ablation products, including ablation for treatment of benign prostatic hypertrophy (BPH), at $6 billion, including $1.6 billion for tumor ablation and $4.4 billion for BPH.
Coblation and its varieties
Coblation, developed and marketed by Arthrocare (Sunnyvale, California), is a low-energy RFA technology that forms a focused plasma via RF excitation of electrolytes in a conductive medium. Coblation devices are mainly used in applications other than for tumor ablation, in the areas of ear, nose and throaat and spinal therapy, although Arthrocare’s CAVITY coblation device has been used experimentally for ablation of tumors near the spine.
Key suppliers of RFA devices include the Rita Medical (Fremont, California) unit of AngioDynamics (Queensbury, New York), Boston Scientific (Natick, Massachusetts), and ValleyLab (Denver, Colorado), a business of Tyco Healthcare (Mansfield, Massachusetts).
One application of RFA highlighted at the conference is treatment of osteoid osteoma, a relatively rare benign bone tumor that occurs mainly in younger people in their teens to 20’s. Osteoid osteoma can result in growth deformities in the long bones or scoliosis in the spine, its primary symptom being sharp pain. While the pain can be successfully treated with medications, side effects of those medications include stomach ulcers and intestinal bleeding.
Conventional therapy for osteoid osteoma patients who require intervention is surgery, but RFA has been shown to provide equivalent eradication of tumors and elimination of pain, but with less risk of complications and faster recovery. In addition, using the precise targeting ability of RFA, an interventional radiologist can ablate only the tumor tissue while leaving the surrounding bone intact, whereas with surgical treatment the excision of a 1 cm tumor may require the removal of up to 5 cm of bone.
The ValleyLab CoolTip RF system is FDA-cleared for treatment of osteoma, as well as for non-resectable liver cancer. FDA clearance is pending for treatment of non-resectable lung cancer. In addition, ValleyLab is working to develop an indication for treatment of bone metastases using the CoolTip RF system. ValleyLab is also developing a microwave tissue ablation system, VIVAWAVE, which is in clinical trials in five centers.
A new RFA technology has been introduced in Europe by the Celon unit of Olympus Medical Systems (Teltow, Germany) that employs bipolor or multi-polar electrodes, eliminating the need for a separate ground pad and providing a more precise ablation zone compared to other RFA systems. Bipolar electrodes are widely used in endoscopic surgery because of their increased safety (due to elimination of the risk of burns from the ground pad) and increased precision.
For percutaneous ablation, those same features are important, but the smaller size of the ablation zone can prove problematic in a number of applications where a large mass must be removed. Christopher Brace, PhD, of the University of Wisconsin (Madison), described applications in treatment of lung tumors in which multiple insertions must be performed in order to obtain adequate margins.
Approaches to deal with the low thermal conductivity of tissue and thereby expand the ablation zone can include saline infusion to improve ionic conductivity and bronchial occlusion. However, an initial study using saline infusion found that the complication rate more than doubled (from 20% to 55%). Brace is now evaluating cryoablation devices, such as the Percryo percutaneous cryoablation system from Endocare (Irvine, California) as a better solution for lung tumor ablation.
Cryoablation for kidney tumors
As discussed by J. Louis Hinshaw, MD, of the University of Wisconsin at an SIR press conference, cryoablation has recently been evaluated for treatment of kidney tumors with good results. Kidney cancer is a growing problem in the U.S., with about 30,000 new cases annually and a 300%-400% increase over the past 20 years, much of this due, however, to improved detection: about 50% of all renal cell tumors are identified incidentally during an imaging procedure performed for another purpose.
The classical treatment for renal cell cancer is either partial or total nephrectomy, often using laparoscopic techniques. However, Hinshaw reported on a retrospective study using percutaneous cryoablation in which efficacy of treatment was 10.5%, essentially equivalent to the 12.5% efficacy achieved with laparoscopy in a comparable group of patients.
Most importantly, there were no major complications using cryoablation, whereas 6% of patients suffered major complications that were treated with laparoscopic surgery.
Length of hospital stay was significantly shorter for cryoablation at 1.1 vs. 2.3 days, leading to 59% higher hospitalization costs for laparoscopy. At present, cryoablation is mainly applicable to posterior tumors, whereas for anterior tumors near the bowel or ureter the laparoscopic approach is preferred. In addition, cryoablation is primarily indicated for smaller tumors measuring less than 4-5cm in diameter.
Nevertheless, Hinshaw said that cryoablation is applicable to most incidentally identified renal cell tumors, making between 30% and 50% of all kidney cancer patients candidates for such treatment.
In addition to the system from Endocare, a line of cryotherapy systems is available from Galil Medical (Yokneam, Israel) for minimally invasive treatment of kidney, liver, lung and bone tumors. Galil manufactures the Presice and SeedNet Cryotherapy Systems, which have FDA clearance and CE marking for general surgery, thoracic surgery, gynecology, oncology, and urology applications. The Galil systems have the advantage of MRI compatibility, allowing ablation procedures to be performed under MRI guidance. The Presice is the company’s newest offering, launched in late 2006.
Cryoablation of the prostate
Gary Onik, MD, an interventional radiologist from Celebration Health, Hospital Center for Surgical Advancement (Celebration, Florida), provided another important example of the growing use of cryoablation during a session on “Bone, Lung & Prostate Cancer Ablation,” focusing on its use to treat prostate cancer.
About one-half of prostate cancer patients are treated with radiation (brachytherapy seeds or external means), with about 30% undergoing a radical prostatectomy (RP) or surgical removal of the entire prostate gland. And in the past few years, procedures using the less-invasive da Vinci robotic surgical device from Intuitive Surgical (Sunnyvale, California), have been gaining market share from traditional open surgery.
Cryoablation in this application currently accounts for less than 4% of the total prostate cancer procedures, but it has been the fastest growing modality in the past few years. And Endocare, the cryoablation market leader, enjoyed an increase of about 20% in procedures in 2006.
Onik, recognized as one the early adopters in the field of IR, drew a parallel between surgery for women with breast cancer and surgery for prostate cancer. He contended that breast surgeons have shown that a nMIS lumpectomy, which spares breast tissue, can be as effective as a more aggressive procedure. He asserted: “A woman’s quality of life has been successfully upheld with minimally invasive breast cancer therapy.” He noted that men received a parallel benefit in the MIS strategy for prostate cancer.
These patients could be safely treated with a “middle ground” between the two extreme methods of treating prostate cancer — the gold standard of radical prostatectomy and the more controversial and passive approach of “watchful waiting.” Armed with data from several clinical studies, Onik argued that about 80% of all prostate cancer is amenable to a less-invasive approach.
A key requirement of this approach — which Onik called “focal” therapy — is the need to accurately locate, stage and grade the cancer, but that the traditional imaging and biopsy methods that use transrectal ultrasound imaging are simply not sensitive enough.
Focal therapy requires 3-D biopsy mapping in order to precisely locate the site of the cancer. Using cryoablation equipment and disposable probes manufactured by Endocare, Onik’s patients have enjoyed positive results.
He reported on 80 patients treated between mid-1995 and August 2006, with a mean follow-up of 3.6 years. As measured by their PSA scores, 96% of the patients are considered to be cancer-free. More impressively, 60% of this patient cohort was considered to be either a medium- or high-risk patient prior to the minimally-invasive procedure. Of these patients, 7% required re-treatment due to cancer in the untreated gland and this subgroup is also cancer-free.
Other prostate cancer therapies, notably RP, often result in two troubling side effects: impotency and incontinence. Onik’s data, on the other hand, showed that 90% of the men maintained potency and all were continent.
Although his data came from a single operator at one center, Onik noted that these results are remarkably similar to a study of 28 patients treated with focal cryoablation by Duke Bahn, MD, a urologist at Prostate Institute-Community Memorial Hospital (Ventura, California).
Onik said that “cryo-lumpectomy” results to date are very encouraging and actually better than traditional treatments, with lower morbidity and justify larger controlled clinical trials.
Hot topic: TACE
Another promising area in this field is the minimally invasive treatment of cancer, or interventional oncology, this emphasis captured in an article headline — “Interventional Oncology: The Next Wave” — in SIR’s daily newspaper. Employing various image-guided diagnostic modalities and therapeutic tools, interventional radiologists are beginning to treat cancers, heretofore treated solely by oncologists, via an armamentarium of high-powered, very expensive and often-toxic chemo-therapeutic agents.
One of the most promising of these technologies is drug-eluting beads (DEBs), pre-formed, deformable microspheres delivered percutaneously with specialized micro-catheters. DEBs occlude the blood flow to the target tissue and release a controlled and sustained local dose of one of several FDA-approved oncolytic drugs, e.g., doxorubicin, cisplatin or mitomycin. The procedure, dubbed trans-arterial chemo-embolization (TACE), was one of the hottest topics at the meeting.
In a paper titled “Combined RF Ablation and Doxorubicin Eluting Bead Chemo Embolization in Hepatocellular Carcinoma,” Riccardo Lencioni, MD, of the University of Pisa (Pisa, Italy), reported preliminary, but promising data in a small pilot study in Italy.
TACE, combined with radiofrequency ablation (RFA), had a synergistic effect, and his study clearly showed that TACE significantly increased the effectiveness of RFA for the treatment of liver carcinomas.
Christoph Binkert, MD, associate professor of radiology at Brigham and Women’s Hospital (Boston), discussed TACE and provided animal data that indicated a sustained release of the drug into the liver over several days. Binkert concluded that DEBS are “a new form of trans-arterial treatment of liver tumors with promising preliminary data.”
AngioDynamics began marketing DEBs after acquiring RITA Medical (Fremont, California) in late January. RITA obtained the North American marketing rights to DEBs last summer from Biocompatibles (Surrey, UK) and was enjoying robust growth after its market launch last summer.
Combination modalities for treatment of lung cancer were discussed at the conference by Riccardo Lencioni, MD, of the University of Pisa (Pisa, Italy). Lencioni described the existing gap in effective treatment for patients with Stage 1 non-small cell lung cancer.
Survival for pa-tients who can be treated surgically is 60%-70% at five years, but for those who are not surgical candidates and are referred for radiation therapy, five-year survival drops to 10%-20%.
Image-guided percutaneous ablation may offer an improved alternative for non-surgical patients, according to Lencioni.
In the Radiofrequency Ablation of Pulmonary TUmors Response Evaluation (RAPTURE) trial, overall survival data at two years, as reported in mid-2005, was 48% for patients treated with RFA, and cancer-specific survival was 92%.
More recently, a study combining RFA with external beam radiation therapy in the treatment of Stage 1 NSCLC found overall local control of 67% at 44 month follow-up and improved overall survival compared to historical outcomes. Lencioni said that the combination of RFA and radiation therapy provides improved treatment for Stage 1 NSCLC patients who are not surgical candidates, but so far no randomized controlled trials have been performed to validate the treatment.
Another combination modality mates RFA with conformal radiotherapy for treatment of lung cancer. Studies performed using the ValleyLab RFA system in combination with conformal radiation therapy by Damian Dupuy, MD, of Rhode Island Hospital (Providence) have demonstrated improved local control, no increase in complication rates compared to radiotherapy along, and improved survival rates of 50% and 39% at two and five years respectively.
Device-based stroke therapy
Another major application area for IR technologies is stroke treatment, addressing the 700,000 individuals who suffer a stroke annually in the U.S. To date, treatment of acute stroke has not represented a major market opportunity for device manufacturers because most patients do not present for treatment within the three- to six-hour time window in which therapy is effective. Furthermore, treatment with catheter-directed agents to lyse clots in the brain in patients with occlusive stroke is often not performed due to concerns about inducing hemorrhage, a deadly complication of treatment with agents such as tissue plasminogen activator (tPA).
Preventive stroke therapy, however, is an expanding application, now that carotid stents and associated embolic protection devices have been approved by the FDA. Recent changes in reimbursement policy for carotid stenting also are likely to result in market expansion since treatment of asymptomatic patients under age 80 with a stenosis of greater than 80% is now eligible for reimbursement by Medicare.
In addition, a new Diagnosis Related Group (DRG 577) was created for carotid stenting, with a net effect of increasing reimbursement by 15% to 80% from the previous DRG, based on the presence or absence of co-morbidities or complications.
As discussed by Barry Katzen, MD, of Baptist Cardiac and Vascular Institute (Miami, Florida), recent post-market approval studies such as the Carotid Artery Stenting With Emboli Protection Surveillance-Post-Marketing Study (CASES-PMS) trial have demonstrated carotid stenting as safe in the real world as in randomized trials performed to obtain FDA approval, and results in a similar degree of protection against stroke as carotid endarterectomy — the surgical treatment — at one year follow-up.
The most recent studies also indicate that the design of the stent used to treat carotid artery stenosis can have a significant impact on stroke prevention. In particular, stents with a closed-cell design, which include devices such as the XACT stent from Abbott Vascular (Abbott Park, Illinois) and the NexStent from Boston Scientific, are believed to have an advantage in trapping thrombus and ulcerated plaque compared to open cell designs, resulting in a four-fold reduction in the risk of stroke based on data from a 701 patient registry in Belgium.
Open-cell designs, such as the Abbott RX AccuLink and the Cordis PRECISE stents, have greater flexibility, making them a good choice for stenting of tortuous arteries. Another recent entrant in the market, ev3 (Plymouth, Minnesota), is now selling the PROTéGé RX carotid stent along with the SpideRX embolic protection device, priced at $2,250 and $1,300 respectively, and featuring an open-cell design.
In spite of the challenges in gaining market acceptance of devices for treatment of acute stroke, a number of companies have introduced products in the U.S. and more are in development.
Removing the clot
As shown in Table 1, a number of devices are now available or in clinical trials for acute stroke treatment, including devices for flow manipulation, clot lysis, and extraction of clots and embolic material.
Ekos is performing clinical trials with the NeuroWave for clot removal in stroke patients, using the device in combination with intravenous tPA. Initial results show a 69% recanalization rate at two hours. The device may potentially be applicable in up to 30% of ischemic stroke patients, according to the company.
The Penumbra system is being evaluated in a clinical trial for removal of thrombus from the cerebral vessels, and initial results are promising, with flow restoration observed in 100% of treated vessels, according to Philip Meyers, MD, of Columbia University College of Physicians & Surgeons (New York), who discussed new devices for acute stroke intervention at the SIR conference.
While the Penumbra system does not necessarily address embolization of the distal vessels in the brain, it does appear to provide high rates of recanalization without using thrombolytic drugs, which is important in acute stroke patients.
The Merci L5 Retriever is another mechanical device that has been used effectively in acute stroke treatment. FDA clearance for use of the device in neurovascular clot retrieval in stroke patients was received in early February 2007.
The Merci retriever has become one of the more widely employed devices for acute stroke treatment, and is used in at least 250 centers, with that use continuing to expand. In the MULTI MERCI trial, a 68.3% overall rate of revascularization was achieved, and the device is believed to be applicable to 40%-50% of ischemic stroke patients. The L5 Retriever costs between $5,000 and $7,000, with a reimbursement rate of about $23,000 for the clot removal procedure.
Spinal device competition intensifies
The market for devices used to treat spinal disc disorders is another major segment of the interventional radiology products market and one that continues to expand.
Kyphon (Sunnyvale, California), the leader in this sector, has continued to maintain premium pricing for its disposable kyphoplasty instruments, and as of year-end 2006 the Kyphon devices had been used to treat about 285,000 patients worldwide.
As shown in Table 2, the company’s sales, which up until now consisted almost entirely of kyphoplasty devices, increased more than five-fold between 2002 and 2006.
Vertebroplasty is an alternative minimally invasive treatment for spinal disc disorders, with about 150,000 procedures performed annually in the U.S. and 200,000 performed worldwide. Suppliers of vertebroplasty devices include Integra Spinal Specialties (San Antonio, Texas), Spineology (St. Paul, Minnesota), Disc-O-Tech Medical Technologies (Her-zeliya, Israel), Cardinal Health (Dublin, Ohio), Cook (Bloomington, Indiana), and Stryker (Kalamazoo, Michigan).
A new device for vertebroplasty, the AVAmax advanced vertebral augmentation system, was introduced at the meeting by Cardinal. The AVAmax features a co-axial tube for cement delivery that provides enhanced control over cement flow, as well as a curved nitinol needle that provides increased access to regions that are difficult to reach with straight needles.
Other new devices slated for entry into the market include the Arcuate and Arcuate XP cement delivery systems announced in September 2006 by Medtronic (Minneapolis), demonstrating the growing level of competition in the market. The primary application for kyphoplasty and vertebroplasty is treatment of back pain, although both techniques also provide some restoration of height in patients who have suffered a vertebral compression fracture.
Another alternative back pain treatment exhibited at the conference is neuromodulation using implantable devices such as the Precision Plus system from Advanced Bionics (Valencia, California), a unit of Boston Scientific. The Precision Plus system employs dual implantable multi-electrode leads that are connected to a controller implanted in the lower back.
The use of dual multi-electrodes allows stimulation to be directed to a precise region of the spine by adjusting the electrical waveforms driving the electrodes. Patients initially use an external controller after the electrodes are implanted to select the stimulation pattern best able to eradicate pain. That pattern is then programmed into the implantable controller, although it can be subsequently altered using a wireless external programmer.
The implantable controller’s battery can be recharged wirelessly through the skin, avoiding the need for percutaneous connections. Over 8,000 of the $18,000 Advanced Bionics systems have been implanted worldwide, slightly more than half of the 15,000+ neuromodulation systems implanted industry-wide. The other main supplier of neuromodulation for back pain treatment is Advanced Neuromodulation Systems (Plano, Texas).