MRI-Guided Cryotherapy

Transcription

1 JOURNAL OF MAGNETIC RESONANCE IMAGING 27: (2008) Invited Review MRI-Guided Cryotherapy Paul R. Morrison, MS,* Stuart G. Silverman, MD, Kemal Tuncali, MD, and Servet Tatli, MD Over the last decade the focus of published research on MRI-guided cryotherapy has switched from the study of experimental models to the clinical treatment of patients. The latter reports attest to the safety and feasibility of treating lesions in the liver, kidney, and other sites throughout the body. Further, the published images and initial results speak to the utility of MRI for the task of monitoring this specific procedure. This clinical utility is a realization of the promise of the earlier experimental work that showed the clarity with which interstitial ice is seen under MRI under various pulse sequence parameters. Early adopters have taken advantage of access to the patient that is provided by low and mid-field open scanners; the near future will test the suitability of higher field systems. It has been critical that an FDA-approved cryotherapy system and suitably thin probes were customized for the MRI environment a decade ago by which percutaneous cryotherapy could be performed. There is still work to be done to expand the role of percutaneous cryotherapy, to understand various tissue responses, and to optimize visualization of therapeutic isotherms. Also, long-term outcomes need to be assessed. Overall, in a worldwide environment in which the practice of ablation is growing and an appreciation for such therapies is on the rise, the work of these recent years provides sound footing for the advances that lay ahead for clinical MRI-guided cryotherapy. Key Words: thermal ablation; interventional MRI; percutaneous; cryosurgery; cryoablation J. Magn. Reson. Imaging 2008;27: Wiley-Liss, Inc. Department of Radiology, Division of Abdominal Imaging and Intervention, Brigham &; Women s Hospital, Boston, Massachusetts. Contract grant sponsor: National Institutes of Health (NIH); Contract grant number: U41RR *Address reprint requests to: P.R.M., Department of Radiology, Brigham and Women s Hospital, 75 Francis St., Boston, MA pmorrison@partners.org Received July 12, 2007; Accepted October 25, DOI /jmri Published online in Wiley InterScience ( AT THE TIME of the first JMRI Special Issue on Interventional MRI in 1998, experimental inroads had been made into the field of MRI-guided percutaneous cryotherapy. In fact, over the prior decade published research had shown that MRI could provide excellent visualization of frozen tissue, and that images could be acquired in a timeframe suitable for near real-time monitoring of the dynamic formation of the ice. Separately, also at the time of that first Special Issue, MRIguided cryotherapy had just begun to be applied in the clinical arena. The advance from experimentation to patient care was made possible with the development of open MRI scanners that were suitable for intervention and cryotherapy devices that were customized for the MRI environment. Three years later, around the time of the subsequent 2000/2001 JMRI Special Issues, the first clinical results had been published demonstrating the feasibility and safety of percutaneous MRI-guided cryotherapy in patients. Research continued to provide additional data on the tissue effects of cryotherapy and reassurance of its feasibility and safety in various organ systems. Researchers also proposed methods to optimize MR imaging techniques for improved intraprocedural guidance as well as postprocedural assessment. Since then, MRI-guided cryotherapy has made considerable headway; hundreds of patients have been treated and with promising results. Publications of both basic science and clinical research continue to grow in number; these have solidified the role of MRI-guided percutaneous cryotherapy among the many thermal ablation techniques. THERMAL ABLATION CRYOTHERAPY MRI-guided percutaneous cryotherapy (or cryoablation ) is a nonvascular interventional procedure and is one of several included in the category of image-guided thermal tumor ablation (1). Other procedures in this category are radiofrequency ablation (RF or RFA), microwave ablation (MW or MWA), laser ablation (ILT or LITT), and high-intensity focused ultrasound (HIFU or FUS) the latter are all heat-based treatments in which energy is deposited interstitially to coagulate tissue. In cryotherapy the targeted tissue is frozen to well below zero degrees centigrade ( C). With the exception of FUS, these are percutaneous procedures that involve placement of one or more needle-like probes ( applicators ) through the skin into a tumor. Thermal ablation treatments are a minimally invasive alternative to surgery, allowing patients with comorbidities or unresectable disease to be treated. The local freezing of focal tumors has a documented history in the medical field as an accepted clinical tool. Whether applied in open surgery (in which case it is known as cryosurgery ), laparoscopically, or percutaneously, cryotherapy results in direct damage to cells through the freezing and thawing process, as well as 2008 Wiley-Liss, Inc. 410

2 MRI-Guided Cryotherapy 411 secondary damage due to vascular thrombosis. Depending on the cryogen and the size of the applicator, the tip of each applicator can reach temperatures as low as 196 C. Such cold temperatures freeze the tumor adjacent to the probe. During freezing, heat is extracted from the surrounding tissue; heat continues to conduct from warmer regions to colder ones, forming a volume of frozen tissue an iceball spherical or elliptical in shape. The diameter of the iceball that forms around a single probe is 2.5 cm (depending on the applicator chosen); multiprobe freezes can create iceballs that are several centimeters in diameter. Each freeze is followed by a thaw; fast freezing and slow thawing are associated with more complete ablation in which a higher percentage of cells are damaged. It has also been proposed that subjecting the tissue to multiple repetitions of freezethaw cycles enhances the cytotoxic effect. At any given time during the treatment there is a spatial temperature gradient present: the lowest temperatures are found closer to the probe and temperatures near 0 C are found at the edge of the iceball. This edge is slightly colder than 0 C because of the tissue s salinity, resulting in a slightly lower freezing temperature. Temperatures at which cells die vary among tissues but are generally in the range of 20 to 50 C (2). Overall, the concept of dose in cryotherapy is related to the duration of exposure of the tissues to the nadir temperature, the rate of freezing, and the rate of thawing (2). Open cryosurgery has been practiced for many years by surgeons for focal destruction of abdominal tumors; the largest experience has been in the liver (3). The liver is accessed by laparotomy and the cryogen is delivered using both large-diameter interstitial and surface applicators. The iceball within the tissue is observed using intraoperative ultrasound (US) as the ice is highly echogenic (4,5). The visualization provided by US can be supplemented to various extents by direct visual observation of that part of the iceball seen at the liver surface, palpation of the iceball within the liver, or by temperature readings from interstitially placed needle-like thermal sensors. Cryotherapy may also be delivered by a laparoscopic approach in which a combination of direct visualization and US are used to monitor iceball formation. The least invasive approach, percutaneous cryotherapy, has been possible with the availability of probes thin enough to be placed percutaneously. Such probes have been used in clinical practice for US-guided treatment of prostate cancer (6,7) and in the abdomen guided by both US and computed tomography (CT) (8 12). MRI FOR MONITORING THERMAL EFFECTS OF CRYOTHERAPY A percutaneous approach to ablation requires suitable imaging to monitor the thermal tissue interactions and to control the process. The first experimental data on MRI of freezing/ice appeared in the late 1980s and early 1990s (Table 1). These early experiments demonstrated that frozen tissues were readily visualized under MRI in sharp contrast to unfrozen regions; this drew attention to the potential for MRI to guide cryotherapy clinically (13 15). The sharp contrast was evident in images acquired with a gradient echo (GRE) pulse sequence in a 0.1T scanner as well as with T1-weighted (T1w) rapid acquisition relaxation-enhanced (RARE) imaging at 1.5T. Since ice is a solid, it has ultrashort T1 and T2 relaxation times that result in a signal void under nearly all MRI pulse sequences in clinical practice. Frozen tissue, which has a high percentage of water ice, thus exhibits a very low signal during cryotherapy. These early experiments not only showed the high image contrast of frozen to unfrozen tissue, but also proved that MR images could be acquired with scan times that were short enough to monitor the dynamic processes of freezing and thawing. The RARE pulse sequence used by Matsumoto et al (15) provided a single image in 16 seconds that was used to monitor a 2-minute freeze followed by a 30-minute thaw in normal rabbit liver tissue in vivo. Also, although freezing is a reversible process, it can induce irreversible effects. MRI was not only able to visualize the reversible temperature changes in tissue, but also the tissue damage left behind after the ice thawed. In 1993 Matsumoto et al (16) reported experimental data suggesting a good correlation between the appearance of the intraprocedural ice and the resulting cryonecrosis in normal rabbit liver in vivo. This offered the potential for a whatyou-see-is-what-you-get feedback during a procedure in which the iceball in the MR image predicts the permanent lesion. In 2001 this was subsequently reported in normal porcine kidney in vivo (17); using a T1w FSE sequence, the iceball was said to have good correlation with the cryonecrosis at histology. The signal void of frozen tissue presents with a high contrast-to-noise ratio (CNR) related to unfrozen tissue. This results in a sharply marginated iceball that can be viewed in 3D. The entire volume of frozen tissue can be viewed, unlike under US, where the iceball is partially hidden due to acoustic shadowing. Ice can be viewed with CT but the contrast between frozen and unfrozen tissue is not as great as with MRI (5,18). CRYOTHERAPY IN THE MRI ENVIRONMENT In recent years researchers have called attention to the advantages of MRI in guiding cryotherapy (Table 2). MRI can be used to identify a tumor, target it with probes, and monitor and control iceball growth, such that the tumor is treated completely and nearby critical structures are unharmed (1). MR imaging is typically performed throughout the procedure in various combinations of axial, coronal, sagittal, and oblique planes (Fig. 1). In general, the clinical implementation of interventional MRI has always been strongly dependent on technological developments to provide MR-compatible instruments including such simple items as hypodermic needles and scalpels (19,20). Further, physicians needed an interventional suite that houses an MRI scanner and provides an environment at a standard level of care suitable for a patient undergoing a percutaneous procedure. This suite must include anesthesia delivery and patient monitoring systems.

3 412 Morrison et al. Table 1 Chronology of Experimental and Clinical MRI-Guided Cryotherapy in Closed and Open Bore Scanners Year Scanner Field Strength & Configuration Laboratory:Experimental Model Clinical:Target Organ T Closed Bore Isoda; Gel phantom 0.1 T Closed Bore Isoda; In vivo rat tumor T Closed Bore Matsumoto et al; In vitro and in vivo rabbit liver T Closed Bore Matsumoto et al; In vivo rabbit liver T Closed Bore Hong et al; Gel phantom T Closed Bore Pease et al; Gel phantom T Closed Bore Gilbert et al; In vivo rabbit liver T Vertically Open Klotz et al; In vivo porcine liver T Closed Bore Tacke et al; In vivo rabbit liver T Closed Bore Daniel et al; In vitro bovine liver, fat, muscle 1.5 T Closed Bore Tacke et al; In vitro porcine liver 2000 O.5 T Vertically Open Silverman et al; Liver O.5 T Vertically Open Skjeldal et al; Musculoskeletal system T Closed Bore Butts et al; In vitro bovine liver, in vivo canine prostate 0.3 T Horizontally Open Harada et al; Kidney O.5 T Vertically Open Shingleton et al; In vivo porcine kidney O.5 T Vertically Open Mala et al; Liver O.5 T Vertically Open Shingleton et al; Kidney O.5 T Vertically Open Sewell et al; Fibroid O.5 T Vertically Open Roy et al; Musculoskeletal system 2002 O.5 T Vertically Open Cowan et al; Uterus T Horizontally Open Dohi et al; Liver O.5 T Vertically Open Mala et al; Liver O.5 T Vertically Open Traore et al; Liver O.5 T Vertically Open Sewell et al; Kidney T Horizontally Open Dohi et al; Fibroids O.5 T Vertically Open Morin et al; Breast 2005 O.5 T Vertically Open Silverman et al; Kidney 0.3 T Horizontally Open Kodama et al; Kidney 1.5 T Closed Bore Wansapura et al; In vivo canine prostate T Horizontally Open Miki et al; Kidney 0.3 T Horizontally Open Sakuhara et al; Uterus O.5 T Vertically Open Tuncali et al; Kidney 2007 O.5 T Vertically Open Tuncali et al; Musculoskeletal system Unknown Pusztaszeri et al; Breast 0.23 T Horizontally Open Li et al; Liver A critical advance was the availability of high-quality MRI-compatible cryotherapy probes manufactured by industry. For many years previous, probes of various sizes and geometries had been available to surgeons in the operating room suited for use under US guidance. These were not suitable for MRI applications because of the attraction in the magnetic field and image artifact due to their stainless steel construction. In the early proof-of-principle laboratory experiments, the probes consisted of pieces of dry ice or simple handmade conduits for liquid nitrogen. These were used in a surfacecontact fashion and were of no clinical utility (13 16). Custom, one-of-a-kind prototypes made of glass and copper were devised for interstitial experiments in animal tissues (21 23) (Fig. 2). These were adequate at the time for percutaneous animal work and were MRI-compatible in that they were nonferrous and had minimal artifact due to their low magnetic susceptibility. However, they were relatively large, mm in diameter, and their materials were not suitable for human use. For clinical use, the probes needed to be thinner and more needle-like for placement into moving organs like the liver and kidney. In 1999 Daniel et al (24) reported MRI experiments with a 2.9-mm diameter, manufactured cryotherapy probe (Cordis, Netherlands) that used nitrogen gas as a cryogen. The probe had a bluntend, was nonrigid and catheter-like, and could be placed interstitially using a Seldinger technique (Fig. 2). In 2000 and 2001 clinical and experimental reports appeared on the percutaneous use of MRI-compatible, 2.4 and 3.0 mm probes (Galil Medical, Yokneam, Israel) that used argon gas as the cryogen. This device was used in all publications that are cited in Table 1. These rigid, metallic (inconel) probes were sharp enough to pierce tissue and individually capable of creating an iceball of cm diameter. MRIcompatible probes as thin as 1.5 mm (17 gauge) diameter are now available from the same manufacturer

4 MRI-Guided Cryotherapy 413 Table 2 Imaging Modalities for Percutaneous Cryotherapy Contrast 3D Speed Access Radiation Anesthesia & Patient Care MRI contra-indications for certain patients (pacemaker, etc). Limited cardiac monitoring. Limited access to patient No ionizing radiation High field closed bore scanners present limited access to patient; high field widebore provides improved access. Low field open scanners improve access Near real-time imaging possible Multiplanar imaging for three dimensional view of iceball volume MRI Ice presents high contrast relative to tissues; including bone Limited access to patients; no monitoring issues Ionizing radiation Near full access to patient with most CT scanners; wide bore scanner available Near real-time imaging but limited by radiation dosimetry Axial acquisition with multi-planar reformatting available for volume visualization CT Ice presents moderate contrast in soft tissues; nearly no contrast in fat; none in bone Full access; no monitoring issues Full access to patient No ionizing radiation Real-time imaging Imaging in varied planes possible but acoustic shadowing prevents full visualization of iceball volume US Ice has high contrast relative to soft tissues Figure 1. MRI-guided percutaneous cryotherapy of a 3-cm liver metastasis from breast cancer. a: Oblique axial fast multiplanar spoiled gradient recalled echo scan acquired in plane with 17-gauge probes shows hypointense iceball (arrow) after 12 minutes of freezing. The iceball is sharply marginated. b: Oblique sagittal view complements the axial scan and shows proximity of iceball to dome of the liver (arrowheads), diaphragm, and lung. (Fig. 2). The cryotherapy system that controls the flow of cryogens allows for independent simultaneous control of multiple probes (25). While the probes are made for the MRI environment, the delivery system is not MRIcompatible and is located outside the MRI procedure room beyond the 5 Gauss line; cryogen gases are pumped to the probes inside the procedure room. In recent years MRI scanners (both closed and open configurations; various field strengths) have been increasingly incorporated into surgical and interventional Figure 2. Applicators for MRI-guided cryotherapy. a: Experimental glass probe, 3.5 mm diameter, used to deliver liquid nitrogen (reprinted with permission of Wiley-Liss, a subsidiary of John Wiley & Sons, Inc. (23)). b: Experimental 2.9 mm flexible probe used gaseous nitrogen as cryogen (photo courtesy Bruce Daniel, MD, Department of Radiology, Stanford University, Stanford, CA). c: Early clinical 2.4 mm diameter probe; composite image shows probe, tip and sample iceball (reprinted with permission from the Radiological Society of North America (26)). d: Clinical probes (Galil Medical, Yokneam, Israel) that are currently available, top to bottom, are 1.5 (17 G), 2.4, and 3.0 mm diameter.

5 414 Morrison et al. Figure 3. Clinical MRI systems used for MRI-guided cryotherapy. a: 0.23 T Proview (Philips Medical Systems, Best, Netherlands) at Shandong Provincal Medical Imaging Research Institute, Jinan, China (photo courtesy of Chengli Li, MD, PhD, Interventional MR Center, Shandong Provincal Medical Imaging Research Institute, Jinan, China). b: 0.3 T Centauri MPF3000 (XinAoMDT, Hebei, China) at Langfang People s Hospital, Langfang, China (photo courtesy of Lei Zhao, PhD, XinAoMDT, and Lihua Wu, MD, Langfang Hospital). c: 0.3 T AIRIS II (Hitachi, Tokyo, Japan) at Hokkaido University Hospital, Sapporo, Japan (photo courtesy of Yusuke Sakuhara, MD, Department of Radiology, Hokkaido University Hospital, Sapporo, Japan). d: 0.5 T Signa SP (GE Healthcare, Milwaukee WI) at Brigham & Women s Hospital, Boston, MA (photo courtesy of Stuart Silverman, MD, Department of Radiology, Brigham & Women s Hospital). suites. Scanners with an open configuration provide access to the patient and space to place probes. Probes are typically cm long and are tethered by long, thin gas hoses that connect to the cryogen source. During their placement, probes have a segment of the shaft, and handle, that reside outside the body. Open configuration MRI scanners provide space for the external segments. They allow the physician to have direct ongoing access to the patient throughout the procedure, making for efficient adjustments to the locations of probes. Open configuration MRI scanners are manufactured at low to mid-field strengths, T. Therefore, although they are suited for conducting interventional procedures, the inherent signal available for imaging is less than closed systems that typically operate at 1 3T (Fig. 3). CLINICAL APPLICATIONS OF MRI-GUIDED CRYOTHERAPY Liver In 2000 Silverman et al (26) published their initial clinical experience with the treatment of 12 patients with 15 hepatic tumors. The report emphasized two main innovations for the field. One was that MRI-guided percutaneous cryotherapy could be performed safely in the liver. The procedures involved patients treated under general anesthesia in a 0.5T MRI environment, with the use of one to three 2.4-mm diameter probes (Galil Medical, Yokneam, Israel). The patients recovered well, and without significant complications; notably, there were no instances of liver capsule cracking and bleeding as is sometimes observed in open surgical procedures. The second innovation was that MRI was used to guide the entire procedure. As opposed to placing probes or catheters under US or CT, and then monitoring the ablation under MRI, both probe placement and treatment monitoring were performed in the MRI scanner. Specifically, the procedures were performed in a vertically open MRI scanner (Signa SP, GE Healthcare, Milwaukee, WI). Multislice T1w and T2w FSE sequences were used to monitor the 15-minute freeze, 10-minute thaw, and repeat freeze. Images were acquired in multiple planes. The iceball was well seen as a signal void; its growth was monitored every 1 3 minutes with adequate temporal resolution. The postprocedural necrosis correlated well with the intraprocedural appearance of the ice. In 2001 Mala et al (27) reported six patients with liver metastases treated with cryotherapy using a similar open scanner and probes. The same group provided a follow-up report in 2003 on 15 patients (28). Both reports concluded that percutaneous MRI-guided cryotherapy was safe and extolled the benefits of combining cryotherapy and an open MRI scanner for visualization of the treatment and access to the patient. Dohi et al (29) treated liver tumors in four patients using a 0.3T horizontally open scanner (AIRIS II, Hitachi, Tokyo, Japan). In spite of the lower field strength, MRI scans used to monitor the iceball were deemed excellent. The authors concurred with the previous reports as to the relatively low contrast of ice under CT and the acoustic shadowing problem of US. The procedures were performed with the same argon-based cryotherapy system (Galil Medical) as described above. (At the time of this writing, this remains the only MRIcompatible cryotherapy system that is commercially available.) The authors called attention to the system s ability to switch readily from freezing to thawing by delivering helium through the system, suggesting that it made for more complete control over the ablation process. Also, in contrast to the aforementioned clinical reports, these patients were treated not under general anesthesia, but after having received only local anesthesia. In their initial experience in treating liver tumors, Traore et al (30) treated 11 patients, some of whom received a long-lasting contrast agent (mangafodipir trisodium, MnDPDP) intraprocedurally to increase lesion CNR. These procedures were done under local anesthesia alone in the vertically open Signa SP scanner with the Galil system. They concluded that tumor contrast had been improved by the agent. Clear depiction of the tumor, coupled with the good inherent contrast of the iceball, made it easier to decide whether and where to add probes to optimize tumor coverage. In a recent publication Li et al (31) reported on a combination therapy in which MRI-guided cryotherapy and MRI-guided brachytherapy were used in combination to treat 26 tumors in 16 patients. The procedures were performed in a horizontally open configuration 0.23T Proview scanner (Philips Medical Systems, Best, Netherlands). Cryotherapy was performed with 2 3 mm

6 MRI-Guided Cryotherapy 415 Galil cryotherapy probes. The technique was deemed to be feasible and safe. Kidney The first clinical articles on the feasibility of MRI-guided cryotherapy in the kidney appeared in 2001 (32,33). Shingleton and Sewell (32) treated 22 tumors in 20 patients under either general anesthesia or moderate conscious sedation with excellent short-term results (Signa SP 0.5T scanner; Galil cryotherapy system, multiple probes). T1w FSE images were acquired in multiple planes to both guide probe placement and monitor the iceball. For large tumors, multiple overlapping ablations were applied to optimize coverage. Multiplanar imaging and tissue contrast allowed the renal collecting system and bowel to be viewed such that they were not frozen. A follow-up report on two of these patients at nearly 3 years showed no evidence of disease (34). Harada et al (33) treated renal tumors in four patients under local anesthesia in the 0.3T AIRIS II open scanner with the Galil cryotherapy system. With patients in the oblique, prone, or supine positions 2 4 cryoprobes were placed under T1w GRE images; the same imaging was also used to monitor a single freeze-thaw cycle. The duration of the procedures was, on average, 2 hours. There were no serious complications. At 6 weeks, three patients had no evidence of disease; one had residual tumor that was treated in a second session. In 2005 Silverman et al (35) reported on initial experience in treating 26 kidney tumors in 23 patients. Cryotherapy was performed in the Signa SP with mm diameter Galil probes under general anesthesia. The freeze-thaw-freeze protocol ( minutes) was monitored with multislice scans every 1 3 minutes using a variety of pulse sequences (T1w and T2w FSE and GRE). Specifically, the T2w FSE sequence was used to monitor the injection of saline to create distance between the colon and the iceball in one case. Of 26 tumors, 24 (92%) had no evidence of disease at a mean follow-up of 14 months. Also in 2005, Kodama et al (36) reported treating a patient with five bilateral tumors. Two of the five tumors were treated in one session and three in another both sessions under IV conscious sedation. Treatments were done with the Galil cryotherapy system in the 0.3T AIRIS II scanner. Intravenous Gd-DTPA was administered intraprocedurally prior to the ablation to increase lesion conspicuity. Probes were activated long enough to create an iceball that would cover each tumor. However, two tumors were not completely treated; under MRI visualization the freezing was stopped during the treatment of each of those tumors in order to protect the pancreas and an adjacent bowel loop. In 2006 Miki et al (37) published a follow-up to the 2001 Harada study cited above, reporting on 13 tumors that were treated in the AIRIS open scanner. MRI was used to monitor the freezing, prompting the repositioning of probes in certain cases to optimize tumor coverage. At 12 months, 11 of 13 (85%) lesions had no evidence of disease. Notably, nearly all of the studies above reported on peripheral renal lesions. Several noted explicitly that central lesions were excluded to avoid damage to the collecting system (32 34,37). Silverman et al (35) made no restrictions with respect to how central the tumors were, and, in fact, that study included 20 of 27 procedures in which an edge of the tumor was as little as 1 cm from the collecting system. In three of those 20 procedures the tumors were undertreated and warranted retreatment. In their discussion the authors suggested that that undertreatment in those cases had been due to a cautious approach early in the group s experience. Subsequently, with more experience, there was more confidence to freeze nearer to and just into the collecting system, with improved results. In none of the studies did investigators freeze directly and fully into the collecting system. Uterus and Breast In 2001 Sewell et al (38) used MRI-guided percutaneous cryotherapy to treat two patients with symptomatic fibroids. Both patients were treated under general anesthesia in the GE Signa SP with multiple 2 3-mm diameter Galil cryoprobes. Multiplanar T2w FSE imaging was used to guide probes and monitor the ablation. Scanning included oblique planes along the shaft of the probes and perpendicular planes. There was good resolution of symptoms and, over time, reduction in the volume of each fibroid. In 2002 Cowan et al (39) expanded on this experience to include a total of nine patients. The authors noted the precision and control afforded to the procedure due to the clarity with which the iceball could be observed under MRI. Fibroid volume was reduced by 66% on average and all patients reported an improvement in their clinical symptoms. A transvaginal approach in performing MRI-guided cryotherapy in fibroids was reported by Dohi et al. (40). That group used the same configuration MRI and cryotherapy device set-up as Sewell et al and Cowan et al and reported positively on the feasibility of the approach and the results. In 2006 Sakuhara et al (41) used MRI-guided cryotherapy to treat seven fibroids in six patients. Patients received epidural anesthesia and were placed in supine or oblique positions in a 0.3T AIRIS scanner. Treatment was performed with multiple probes using a minute freeze-thaw-freeze protocol. T1w GRE and T2w SE sequences were used to place probes and monitor freezing; pulse sequences were varied so as to focus on anatomy or probe locations. One patient developed an abscess that required a subsequent separate drainage procedure to resolve; no other complications were observed. Fibroid volumes were reduced by an average of 79% at 12 months. All but one patient had improvement in her symptoms. Overall, these reports concluded that percutaneous MRI-guided cryotherapy was a feasible procedure that was well suited for the task and effective at relieving symptoms caused by uterine fibroids. In 2004 Morin et al (42) reported on the treatment of 25 patients with breast carcinoma under a treat-andresect protocol to demonstrate the feasibility of MRIguided cryotherapy in the breast. Treatments were performed under IV moderate sedation in the GE Signa SP scanner with 3- and 6-mm diameter Galil cryoprobes.

7 416 Morrison et al. Figure 4. MRI-guided percutaneous cryotherapy of a 3-cm renal cell carcinoma. a: Axial fast multiplanar spoiled gradient recalled echo at 11 minutes of the first freeze. b: T2-weighted fast spin echo at 6 minutes of the second freeze. c: Spoiled gradient recalled echo at 13 minutes of second freeze. The contrast-to-noise ratio of the signal void from the iceball to both kidney parenchyma and fat remains high in each of the images regardless of the pulse sequence used in the acquisition. Multiplanar T1w FSE imaging was used to monitor the ablation. The procedure was well-tolerated, with no remarkable complications. Surgical excision was performed 4 weeks after cryotherapy. They reported total ablation of 13 of the 25 tumors treated. For MRI-guided cryotherapy in the breast the results were not as promising in the current report of Pusztaszeri et al (43). The latter group published results on 11 patients under a treat-and-resect (at 4 5 weeks) protocol. Little to no specifics were given on the cryotherapy treatment itself, but rather with a focus on histopathology. They report good technical coverage of the tumors (10 of 11 targeted tumors observed to be within the cryozone ), but variable response to the therapy. Two patients (20%) had a complete response and others had various degrees of residual disease seen on histopathology with a suggestion that ductal carcinoma in situ was more resistant to the cryotherapy. In conclusion, they present cryotherapy as appealing technique (or adjuvant) for various reasons, but that for breast cancer more study was needed. Musculoskeletal System In 2000 Skjeldal et al (44) published a case report on the successful ablation of an osteoid osteoma in the ischium. The procedure was performed in a GE Signa SP with a 3-mm Galil cryotherapy probe. Multiple, brief freezes were used to limit the size of the iceball so as not to affect the adjacent sciatic nerve. The treatment was monitored with a gradient echo sequence that showed the treatment was confined to the bony tissues. In 2001 Roy et al (45) used cryotherapy to treat 48 patients with facet joint syndrome. Treatments were performed under local anesthesia in a Signa SP open MRI scanner. MRI was used to place a single 3-mm Galil probe in the facet joint using single-plane, fast GRE pulse sequences. Except for those with surgically fused joints, patients with either pure facet syndrome or other associated disc pathologies significantly improved. Of 17 patients with pure facet syndrome, 88% exhibited marked improvement in symptoms at 11 months. Recently, in 2007 Tuncali et al (46) used MRI-guided percutaneous cryotherapy to treat 27 tumors of the musculoskeletal system and other soft tissues in 22 patients. Tumors were located in bones, soft tissue, or both including vertebrae, long bones, and sacrum or soft tissues. All procedures were performed under general anesthesia in a Signa SP scanner with 1 5, 2.4-mm diameter probes (Galil) using a minute freeze-thaw-freeze protocol. Scans were acquired in multiple planes during each treatment every 1 3 minutes using T1w, T2w FSE and GRE sequences. Access to certain tumors in bone required the introduction of MRI-compatible bone biopsy cannulae prior to probe placement. Clinical goals of local tumor control and pain palliation were achieved, including patients with tumors that encased or were immediately adjacent to critical structures such as bowel, urinary bladder, and blood vessels. CONTROLLING ABLATION UNDER MRI With adequate image guidance, an ablation proceeds in a controlled fashion and two primary goals can be achieved. One is to cover the target with the iceball completely, and the other is to avoid damaging normal structures. MRI is particularly well suited for monitoring tumor coverage during cryotherapy because of the inherent high contrast of ice (ie, signal void) relative to tissue. As noted before, this contrast is generally independent of the pulse sequence applied (Fig. 4). Thus, pulse sequences can be chosen to optimize tumor conspicuity and the iceball can be observed as it eclipses the tumor (Fig. 5). While MR image acquisition is not instantaneous, both the duration of scanning and the frequency with which scans can be acquired are suitable for cryotherapy. Since the iceball grows slowly, scanning approximately every 3 minutes is usually adequate to observe the changes. Such monitoring can Figure 5. MRI-guided percutaneous cryotherapy of a 3.4-cm liver metastasis from breast cancer. a: Sagittal T2 weighted fast spin echo shows two cryoprobes (arrowheads) in the hyperintense tumor (arrow). b: During freezing, ice forms around the end of each probe. c: Imaging shows part of tumor (arrow) yet to be frozen. d: With continued freezing, the entire tumor is eclipsed (reprinted with permission from Elsevier (1)).

8 MRI-Guided Cryotherapy 417 Figure 6. MRI-guided percutaneous cryotherapy of a 4.0-cm adrenal metastasis from lung cancer. A multislice acquisition in the axial plane with a T2-weighted fast spin echo sequence taken at 6 minutes into the second freeze shows the iceball (arrow, part a) in a 3D context. Imaging through the entire volume of interest not only shows tumor coverage, but also monitors the proximity of the iceball to the inferior vena cava (arrowhead, part c) and the extent of freezing in adjacent normal kidney (black arrowheads, part e). then be used to add or reposition probes, or change the duration of the freeze to assure coverage (26,32,35,37). Multislice acquisitions help to keep the tumor, iceball, and the adjacent structures in view (Fig. 6). Scanning more frequently than every 3 minutes may help to avoid damage to normal and/or critical structures if they are in very close proximity to the region being ablated. The image feedback on the relative position of the iceball over time can prompt the user to slow or stop the freeze so as not to include the adjacent tissues in the treated volume. Since the probes are controlled independently the flow of cryogen can be reduced or turned off to one or more probes to modify the iceball. Such techniques can also be used to maintain adequate tumor coverage while avoiding an excessive margin of ablation of normal tissue. There are other procedural techniques that can be used to protect adjacent structures during ablation in the MRI environment. These include saline injection, manual manipulation of bowel, and catheter warming as described below. Kodama et al (36) noted that, because of the feedback afforded to them by MRI, they stopped short of treating two renal tumors completely in order to prevent freezing adjacent pancreas. In retrospect, they suggested that perhaps saline could have been injected into the perinephric space to create distance between the pancreas and iceball. We have used this technique of saline injection to distance bowel from a tumor in more than 20 MRI-guided procedures to good effect; this technique benefits from the use of a T2w sequence, which provides good contrast of the saline related to adjacent tissues (Fig. 7). In an open MRI scanner it is possible to manually compress the abdomen with the interventionalist s hand and, in effect, distance the bowel from the iceball. Tuncali et al (47) reported on the use of manual compression during MRI-guided cryotherapy of 15 renal tumors in 14 patients. Measurements showed that compression increased the distance from tumor to bowel by an average factor of three (Fig. 7). Sakuhara et al (41) also used this technique during MRI-guided percutaneous cryotherapy of fibroids. In cases where the critical structure cannot be moved, cryotherapy effects can be counteracted with Figure 7. Adjunct techniques for MRI-guided cryotherapy. a: Cryotherapy of a 4.0-cm adrenal metastasis from breast cancer. Axial T2-weighted fast spin echo imaging shows hyperintense injected saline (arrows) separating the hypointense iceball (medial to saline) from the nearby pancreas, stomach, and spleen (lateral to saline). b: Cryotherapy of a renal cell carcinoma. Coronal image shows external compression by hand (curved arrow) to distance the bowel loop (arrow) from the iceball (arrowhead) (reprinted with permission from Elsevier (47)). c: Cryotherapy of rectal tumor invading the prostate. Axial T2-weighted fast spin echo image shows the iceball (arrows) covering the tumor with an indentation due to the heat source effect from the warming catheter (curved arrow) used to protect the urethra during freezing (reprinted with permission from the American Journal of Roentgenology (46)).

9 418 Morrison et al. heat. One such technique, derived from US-guided cryotherapy of prostate cancer, involves the use of a transurethral catheter through which warm saline flows. This serves as a heat source to protect the urethra during the freeze. Of the 22 patients treated with MRI-guided cryotherapy by Tuncali et al (46), one had a rectal carcinoma metastasis to the prostate that abutted the urethra. The warming catheter (Endocare, Irvine, CA) maintained the temperature of the flowing saline at 38 C (Fig. 7). LIMITATIONS OF MRI-GUIDED CRYOTHERAPY While the literature presents promising results in a range of organ systems, there is still research needed to more fully understand the impacts of nadir temperature, time, and cycling, especially as functions of tissue type. One example is the recent publication of data showing that the freezing process itself has different temperature profiles in different organs (48). The variable temperatures draw attention to the different heat capacities and conductivities of the different tissue types studied (liver, kidney, lung). This implies a need for the consideration of adjustments to probe placement in order to achieve critical temperatures for cell death in different parts of the body. As with any thermal therapy, where large vessels are present, complete tumor eradication can be difficult. As there is a heat sink effect in heat-based thermal ablations that can spare cells located near vessels, there is a heat source effect in cryotherapy. Large vessels provide heat that maintains the viability of tumor cells. MRI evidence of this effect has been reported experimentally in vivo (22,23) and clinically (37). There are limitations to MRI-guided cryotherapy that are due to the MRI environment itself. Standard diagnostic MRI is usually performed using closed-bore scanners at or above 1.5T. The higher field strengths offer better SNR. However, these scanners limit access to the patient and there is little room for cryoprobes that typically extend out from the body. Further, the closedbore configuration necessitates a repetitive in/scanout/adjust technique for probe placement that is cumbersome. In this review it is clear that open configuration scanners have provided a good working environment. Although lower in field strength, these scanners provide the access needed to place needles and work in a manner that is consistent with standards of interventional practices. Yet even in the open scanners space is limited. For the vertically open Signa SP (GE Healthcare), while the space above the patient is free, the walls of the working shoulder space are only 56 cm apart (49). In the horizontally open AIRIS II (Hitachi) the vertical space is 43 cm. Both configurations pose limits on the size of the patient that can be accommodated; the effect of these limits is compounded further by the need for the tumor to be situated in the magnet s imaging volume. Also, just as there are MRI safety-related contraindications for patients considered for diagnostic exams, the same issues prevent certain patients from being treated in the MRI scanner. A range of devices, implants, and materials are contraindications for being treated under MRI guidance, including cardiac pacemakers. Also, in the MRI environment cardiac monitoring is incomplete: the magnetic field distorts the ST and T wave components of the ECG, and prevent monitoring for silent cardiac ischemia during the procedure (50). While MR imaging is the best imaging modality by which to monitor percutaneous cryotherapy, it does have an inherent limitation. Although the solid iceball is seen well as a signal void under MRI, there is a thermal gradient within the tissue, from a central low temperature of about 130 to 0 C at the edge. Conventional MRI pulse sequences do not image that variation across the iceball. In general, there is no difference in the contrast between tissue at 0 or 100 C. The MRI appearance of the tissue is binary ; the tissue is seen as frozen or not frozen with no mapping of the temperature gradient within the iceball. Therapeutic temperatures are generally taken to be approximately 30 to 50 C. While there is good correlation between the iceball and the ablated lesion, it has been reported that the actual therapeutic isotherm is 5 mm from the outer edge. Gilbert et al (51) showed that the diameter of the ablation was 2 4 mm less than diameter of iceball as seen on MRI and that it corresponded to the 5 C isotherm. Clinically, this is usually accounted for by forming an iceball that is 5 10 mm larger than the tumor. Of the clinical articles included in this review, however, only three specifically noted this disparity between the iceball s outer edge and the setback of the therapeutic edge by some few millimeters (27,36,37). During procedures, these investigators added a margin of iceball coverage beyond the tumor to account for this disparity, concluding that incomplete treatments with residual tumor were due to an inadequate margin and thus a suboptimal thermal dose. Other authors noted the intent to extend the iceball beyond that of the tumor by cm to establish a margin akin to a surgical margin (30,32,34,35). In the latter, there were no failures (32,34), no talk of failures (30), or failures were noted and attributed to caution in the authors early experience due to abutting critical structures (35). MRI techniques sensitive to temperature changes in the therapeutic range are being developed to provide a thermal map of the temperatures within the iceball. In 1999 Daniel et al (24) showed in vitro that MRI pulse sequences with short echo times ( 1 msec) can elicit signal from the outermost edge of the iceball and were able to resolve temperatures as low as 35 C. The technique relies on the fact that frozen tissue retains some small fraction of unfrozen water molecules. The technique was advanced by in vitro and in vivo experiments, the results of which were reported by Butts et al in 2001 (52). That work focused on R 2 * and used echo times on the order of 0.2 msec. In 2005 Wansapura et al (53) furthered the understanding of the technique and its calibration of temperature to signal and to R 2 * in canine prostate. Another way to image the thermal gradient inside the iceball extrapolates temperatures by mathematical calculation (21,51,54). In such a method the location of the probe and the iceball edge are observed in the MR image; the probe temperature is known from the cryo-

10 MRI-Guided Cryotherapy 419 therapy device itself and the ice edge is taken to be 0 C. These locations and temperatures are used as parameters to solve a thermodynamic energy equation. The solution provides calculated isotherms within the iceball that serve as a thermal map. CURRENT STATUS AND FUTURE MRI provides the ability to monitor the freezing process in 3D over a suitable timescale. This provides the opportunity for the interventional radiologist to interact with the process based on this feedback, and adjust parameters or probe placement to modify the dose intraprocedurally to optimize the treatment. The progress of MRI-guided percutaneous cryotherapy is evident in the breadth of the clinical activity reported since The results show that these procedures are technically feasible and can be performed safely with good clinical results in select patients in a range of organ systems. Critical to this clinical implementation has been the availability of MRI-compatible cryotherapy probes and the integration of a cryogen control system into open configuration MRI scanners. In the near future, one could expect that the design of interventional MRI scanners will be revisited. And, certainly, wide bore ( 70 cm) high-field MRI scanners present a new venue for interventional procedures including cryotherapy. While ablation has been in practice for many years now with different combinations of therapeutic agents and imaging modalities, it is still in transition into mainstream practice. Surgical excision remains the definitive standard treatment of focal tumors. However, ablation provides an option for nonsurgical candidates, or those in whom surgery or chemotherapy has failed, or where indications include pain palliation or quality of life issues. 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