Radiofrequency ablation in the musculoskeletal system

Radiofrequency Ablation in the Musculoskeletal System Kirkland W. Davis, James J. Choi, and Donna G. Blankenbaker

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VER THE LAST decade, the application of radiofrequency ablation (RFA) to the treatment of neoplasms has increased remarkably. This has been possible because of the level of sophistication of cross-sectional imaging modalities achieved by the early 1990s. Of course, advances in RFA technology have increased the applicability of this technique, and there has been an impetus to treat more patients with less-invasive methods as well as an increased aggressiveness in treating malignancies both for cure and for palliation. Certainly, the development and applications of RFA in the musculoskeletal (MSK) system mirror the overall pattern for RFA: RFA in the MSK system first gained momentum because it allowed the relatively advanced technology of computed tomography (CT) in the early and mid-1990s to precisely guide percutaneous treatment of osteoid osteomas; lately, intrepid investigators have used RFA to relieve considerable pain in patients with bone metastases. This article will review the history and application of RFA technology in general, followed by a review of the clinical characteristics and treatment of osteoid osteomas and osseous metastases, focusing on RFA of these lesions. BACKGROUND OF RADIOFREQUENCY ABLATION

History of RFA Development of the technique of radiofrequency ablation has been attributed to Harvey Cushing in 1920 for use in the central nervous system.1 Focused heat for surgical coagulation and cutting became possible with the well-known device of W. T. Bovie in 1928,2 allowing heat to gain practical use as a treatment modality in the central nervous system in the 1930s.3 Aranow and Cosman built the first practical radiofrequency devices for the central nervous system in the 1950s.4 RFA then found widespread use in the treatment of trigeminal neuralgia via ablation of the Gasserian ganglion, both in the United States and Europe, with a technique that was standardized by Sweet and coworkers beginning in the 1960s.3 A sampling of other neurologic applications of RFA includes destruction of nerves to facet joints (rhizotomy) for treatment of low-back pain and whiplash5,6; treatment of discogenic back pain by

internal ablation of intervertebral discs6,7; palliation of pain from head and neck cancer by ablating the glossopharyngeal nerve8; blocking afferent impulses in the trigeminal nerve to treat pain in patients with trigeminal neuralgia secondary to neoplasms9; and percutaneous thoracic sympathectomy to treat upper extremity vascular disorders, causalgia, palmar hyperhidrosis, and refractory angina and tachyarrhythmias.10 RFA has further shown its potential as a minimally invasive treatment for remote tissue destruction in its application to cardiac dysrhythmias. This philosophy of therapy in the heart first became popular with the ability to advance catheters to culpable areas of myocardium and then deploy an electrode to produce a focal direct current (DC) shock. Although this was an improvement over the previously necessary open procedures, DC shocks can be quite hazardous because of the extremely high temperatures and local explosions they cause, often leading to unwanted side effects.2,11 Huang and colleagues11 then used radiofrequency ablation to create atrioventricular block in dogs, and RFA is now a safe alternative to DC shock in humans. In the right hands, RFA has a greater than 90% success rate at curing accessory atrioventricular pathways (Wolff-Parkinson-White syndrome), atrial fibrillation and other atrial tachycardias (via atrioventricular junction ablation), atrioventricular nodal re-entrant tachycardia, atrial flutter, and some subsets of idiopathic ventricular tachycardia, with minimal complications. Thus, RFA is now the technique of choice for catheter ablation in the heart.2,12 RFA has also been successful for other functional abnormalities, such as transcervical ablation of endometrium for menorrhagia13 and ablation of the cystic duct to eliminate recurrent gallstone attacks, before the availability of laparascopic cholecystectomy.14 With the wide availability of and marked imFrom the Department of Radiology, Musculoskeletal Division, University of Wisconsin Medical School, Madison, WI. Address reprint requests to Kirkland W. Davis, MD, Department of Radiology, Musculoskeletal Division, University of Wisconsin Hospital and Clinics, Clinical Sciences Center–E3/ 311, 600 Highland Avenue, Madison, WI 53792-3252. © 2004 Elsevier Inc. All rights reserved. 0037-198X/04/3901-0012$30.00/0 doi:10.1053/j.ro.2003.10.002

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provements in ultrasound, CT and magnetic resonance imaging (MRI), radiologists and other physicians with access to advanced imaging have been able to apply RFA to a wider array of internal organs and lesions over the last 15 years. This trend has been augmented by an increasing desire to perform procedures with less-invasive methods and to treat neoplasms and their symptoms more aggressively. After some pioneering early work in vitro15 and in vivo pig livers,16-18 showing that RFA can kill tissue in a controlled fashion and be guided and monitored by ultrasound, RFA was successfully applied to human hepatocellular carcinomas19 and hepatic metastases.20 These investigators showed this technique to be a relatively simple and safe alternative to surgical resection in selected patients. Liver neoplasms are now treated by RFA more than any other tumor. Similarly, after initial success with CT-guided ablations in rabbit lungs,21 RFA is now used in human lung lesions, particularly in patients who are not surgical candidates.22 Other tumors with early RFA success include primary and metastatic brain lesions (with MRI guidance)23; breast cancer24; and in tumors of the kidneys,25 adrenals, spleen, lymph nodes, and prostate.26 Thus, the benefits of RFA, which include realtime guidance, ablation in nonsurgical candidates, diminished morbidity, potential outpatient treatment, and the ability to combine RFA with other techniques and to retreat previously ablated areas, have generated an explosion in interest in this technique.16,27 The work of Tillotson et al28 on RFA characteristics for canine bones has contributed to today’s bone ablation techniques. Their important contributions are many, including the limiting aspect of blood flow within bone on the transmission of heat (as in all organs, flowing blood acts as a heat sink) and the equal susceptibility of marrow, trabecular bone, and cortex to the effects of RFA, but there remains much work to be done, especially in light of the recent improvements in ablation devices. The Physics Behind the Technique RFA creates foci of dead tissue, commonly referred to as “lesions,” by induction of coagulation necrosis via application of lethal heat to the tissue.29 To simplify, RFA cooks tissue. Unlike the Bovie device, in which the device tip itself is heated and placed on tissue, RFA consists of passing an alternating current through an electrode

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into tissue. Within the tissue, this alternating current, with a frequency in the range of radio waves (100 kHz-1.5 MHz), causes rapid oscillation of local ions, generating heat. Thus, resistive heating occurs in the tissue itself, as opposed to within the probe as in the case of the Bovie device. In areas of sufficient heat generation, immediate cell death or a terminal spiral results, and the tissue partially resorbs and partially becomes scar over time.2,25,30,31 RFA is performed by placing a long, thin (21gauge to 14-gauge) electrode, of which all but the distal tip is insulated, into the target tissue. As the current passes through the electrode tip and into the target tissue, resistive heating is greatest in the region immediately adjacent to the tip. This resistive heating falls off in proportion to the fourth power of the distance from the tip. Thus, resistive heating is limited to a very narrow rim around the tip. From this rim, heating of more distant tissues occurs by thermal conduction.2,30-32 To be safe, the current must have a defined path. For the typical monopolar electrode, a grounding pad(s), or “indifferent electrode,” elsewhere on the surface of the body determines this. The much greater surface area of the ground pad allows the current to be spread over a large area, reducing heat production at this site.2,25,32 When this is well planned, the lesion is well controlled, an advantage over some other methods of tissue destruction. The heat generated can be “too high” if temperature is sustained over 100°C. At this point, boiling and vaporization occur. Although this at first sounds effective, it causes formation of a coagulum around the tip or charring of tissue immediately adjacent to the probe tip, denoted by a marked rise in measured impedance. This jump in impedance signals an inability to deposit further current into the tissue. When this occurs, effective kill volume is reduced.2,17,30,33,34 Another unwanted effect of too much heating is explosive vaporization, which will form a large, uncontrolled lesion.30 Thus, temperature monitoring has been helpful in creating sizable, controlled lesions.4 RFA lesion size varies with a number of parameters, including duration of current application (time of procedure), because it takes some time to reach equilibrium between heat generated and convection of heat away by nearby blood vessels. Tissue types also affect lesion size. Although the temperature required for uniform cell death in a volume of tissue varies from report to report and from

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tissue to tissue (range 42°-55°C)2,4,7,13,15,17,31-33 it is generally accepted that several minutes (or less) of temperatures over 50°C produces irrevocable cell damage through disruption of the cell membrane and the denaturing of cell proteins.13,36,37 Thus, current attempts to increase lesion size endeavor to increase the volume of tissue in which 50°C is maintained, without breaching 100°C for substantial periods of time.31 This can be a particularly difficult task near sizable blood vessels. Vessels less than 2-3mm in diameter are effectively coagulated by RFA, but larger vessels are not coagulated and act as heat sinks, altering lesion shape and limiting lesion size.36,38 Comparison to Other Techniques The scope of this review does not permit a full examination of related techniques percutaneous of tissue destruction. Nevertheless, a brief examination of these techniques is instructive. Cryotherapy, which is widely used in liver tumors, allows exquisitely accurate monitoring of its lesion size with ultrasound or CT, but it suffers from more complications than RFA, including death. Cryotherapy historically required laparotomy for placement of the large catheters, but very recent advances have made percutaneous application possible. This technological advance may allow a substantial increase in the use of cryotherapy in the musculoskeletal system. Laser ablation provides unequalled control of the lesion created but is more expensive and creates smaller lesions than RFA, limiting its usefulness.36,39-44 Microwave coagulation therapy has been shown to be effective but offers no advantages over RFA, may be limited in lesion size, and has been the subject of limited study to date.36,45,46 Percutaneous ethanol injection therapy is another safe, repeatable method, but it often requires multiple treatment sessions and distribution of the ethanol is typically quite heterogeneous and unpredictable.36,39,42,46,47 High-intensity focused ultrasound is poorly studied to date.36 In short, RFA has enjoyed proven success in the liver and other organs and is popular because it is relatively simple, effective, safe, and repeatable. It allows limited destruction in the liver in patients who are otherwise not surgical candidates. It is relatively inexpensive, allows for short treatment times, and often is minimally invasive, even sometimes being performed on an outpatient basis.1,19,36,48 Most of these advantages have trans-

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ferred to the use of RFA in the MSK system. Lesion size remains somewhat limited, and in most studies tumor recurrence rates are higher with RFA than with cryoablation.36,48 OSTEOID OSTEOMAS: BACKGROUND

Clinical and Imaging Characteristics The “peculiar bone neoplasm” known as osteoid osteoma is a small benign bone tumor, first categorized and described as a distinct entity in 1935 by Jaffe. He published his findings in a series of 5 cases.49 Osteoid osteomas comprise 10% to 12% of all benign bone neoplasms. Although the age of presentation ranges from a few months to 70 years, most cases occur in adolescents and young adults, with the incidence in males outnumbering females 2-4:1. The typical patient complains of pain that is dull and intermittent but more pronounced at night, progressing over the course of months or years to more severe and constant, “boring” pain. Patients commonly report relief of pain from a small dose of aspirin. Depending on the location of the osteoid osteoma and duration of symptoms, pain may be accompanied by a limp, muscle wasting, synovitis or even premature degeneration of a joint, painful scoliosis, and in young children limb overgrowth and limb length discrepancies.50-63 The majority of osteoid osteomas occur in the femur and tibia and 10% occur in the spine (usually the posterior elements), but they have been reported in almost every bone in the body. Cortical lesions predominate, followed by intramedullary, and then the uncommon exophytic subperiosteal lesion, although there is some thought that some subperiosteal lesions become “intra-cortical” as they mature and induce extensive periosteal new bone.50,56-58,62 At pathology, osteoid osteomas consist of a central core or “nidus” surrounded by dense sclerotic bone. The nidus is usually less than 1 cm in length and contains a mixture of osteoid, newly formed bone, and highly vascular connective tissue stroma. As the lesion matures, the nidus may calcify.50,53,55,57,62,64 Although a case has been reported in which an osteoid osteoma recurred after 2 resections as an aggressive or low-grade malignant osteoblastoma,65 this occurrence is probably extremely rare. The pain accompanying this neoplasm is thought to be a result of increased vascular pressure from high levels of prostaglandins, stimulating the rich plexus of nerve fibers typically seen in these lesions.57,66 The imaging features reflect the pathology. Ra-

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Fig 1. Radiographs of osteoid osteomas. (A) Subtle sclerosis (arrow) surrounds the radiolucent nidus in a femoral neck lesion. (B) Nidus in the posterior tibia has elicited extensive periosteal reaction (arrow).

diographs often reveal a sclerotic halo around the lucent nidus, although sclerosis is typically limited in intramedullary and intra-articular cases (Fig 1A). Periosteal reaction often accompanies cortical and subperiosteal lesions (Fig 1B), but intra-articular lesions may manifest only as periarticular osteopenia. CT has replaced conventional tomog-

raphy and angiography as the confirmatory imaging modality and reveals the well-demarcated, low-attenuation nidus with variable degrees of surrounding high-attenuation sclerosis and internal calcification (Fig 2). These neoplasms almost always show marked uptake on bone scans and sometimes reveal the classic double density sign, with

Fig 2. CTs of osteoid osteomas. (A) Same lesion as Figure 1A shows partial calcification of cortical nidus. (B) Same lesion as Figure 1B shows dense central calcification of a classic cortical nidus with surrounding periosteal reaction.

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row edema and adjacent soft-tissue edema that often accompany these lesions are frequently, but not uniformly, extensive (Fig 3).68-71 On all imaging modalities, the differential diagnosis may include stress fracture, Brodie abscess, bone island,57,62 or eosinophilic granuloma, depending on the specific characteristics (Fig 4). Treatment Modalities

Fig 3. MRI of osteoid osteoma. Axial fat-saturated T2WI shows moderately high-signal cortical nidus with abundant edema in the marrow and surrounding soft tissues. Same lesion as Figures 1B and 2B.

greater uptake centrally and less robust rim of tracer deposition peripherally.50,53,57,62,67,68 Intra-articular cases can be difficult to diagnose, especially early in the course of development of the lesion. Pain may precede imaging findings for months or years, leading to frequent misdiagnosis in these instances.54 Although CT is classically more definitive than MRI in diagnosing osteoid osteomas, today MR is often the first imaging study ordered that shows the pathology. There is surprisingly little published on the topic, but our experience and that of others is that the nidus is usually high signal on T2/inversion recovery and variable on T1 but often does not stand out on any sequence. The surrounding mar-

Most authors agree that the typical osteoid osteoma is often a self-limited phenomenon over the course of several years. Given that aspirin and numerous nonsteroidal anti-inflammatory medications, especially naproxen, usually are effective in treating the pain, it is reasonable to attempt to treat many of these patients medically. This is certainly true if there are mitigating factors such as poor access to the lesion or location near sensitive structures.53,63,72 Using this approach, Kneisl and coworkers achieved full resolution of pain in 6 of 9 patients, with an average length of treatment of 33 months.72 Numerous authors report that most patients will not persist with medical treatment long enough for resolution and eventually demand definitive therapy.62,73 Additionally, there are several scenarios that require expedient definitive therapy: the patient with painful scoliosis, in whom early intervention is more likely to lead to full resolution of the curve and the pain,59,61 and those patients described earlier who are at risk for long-term or permanent sequelae, such as small children at risk for limb overgrowth and limblength discrepancy and patients with intra-articular osteoid osteomas, who risk premature degenerative disease.

Fig 4. Proximal femoral osteoid osteoma in a 5-year-old boy. (A) The predominant findings on coronal fat-saturated T2WI are marrow and soft-tissue edema and a hip effusion. The initial clinical and radiologic impressions were osteomyelitis. (B) Coronal CT-reconstructed image (after biopsy revealed no infection) shows central calcification within the low-attenuation nidus in the medial right femoral neck.

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Ever since Jaffe’s description of osteoid osteomas, the preferred treatment has been surgical, whether en bloc excision or curettage. Curettage is sometimes reserved for more tenuous locations, such as the spine posterior elements, in which wide excision would be more risky.59,61 Complete excision or destruction of the lesion is curative,74 but even in 1935 Jaffe recognized that incomplete removal of the nidus would result in recurrent symptoms.49,53,62,64,67,74 Confidence in complete resection often requires a wide excision because the nidus may be obscure on direct inspection of the bone.56,62,64,75 This can lead to lengthy postoperative hospital stays (7 days in 1 report),72 extended non–weight-bearing status and delayed functional recovery, internal fixation and bone grafting, and pathologic fractures (Fig 5).56,72,76,77 To limit the requisite size of the surgical bed and improve successful resection rates, numerous methods have been used over the last 2 decades to refine localization of the nidus for the surgeon. These have included preoperative administration of Technetium-99m methylene diphosphate with intraoperative use of a handheld scintillation probe or a portable gamma camera67,78,79; preoperative tetracycline labeling, which allows examination of the specimen for ultraviolet fluorescence, analogous to a frozen section80; and CT-guided wire localization immediately before surgery, with CT of the resected specimen and wire serving as a “specimen radiograph.”81 All of these methods have met with limited enthusiasm.67,82 The necessary size of excision, with its attendant morbidity, and limited acceptance of more accurate localizing methods led to investigation of imageguided percutaneous therapies. Interstitial laser coagulation and percutaneous ethanol injection have both been successful55,83 but have received limited acceptance. Much wider acceptance came to the various permutations of CT-guided resection with various drills and biopsy devices.64,75-77,82,84,85 This method does offer significant advantages over surgical excision, including percutaneous treatment; real-time CT guidance (and thus accuracy); reduced morbidity, including diminished hospital stay, recovery, and fracture risk; and success rates comparable to surgery. However, to insure curative treatment of the osteoid osteomas, this technique still requires the creation of a large bone defect, sometimes still necessitating bone grafting and internal fixation or leading to fractures. More finely directed percutaneous methods, such as RFA, were

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Fig 5. Lateral view of the leg demonstrates fractures of the tibia and fibula. This occurred several weeks after surgical resection of a midtibial osteoid osteoma (arrow).

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the next logical step in refining treatment of osteoid osteomas. RFA OF OSTEOID OSTEOMAS

History of RFA of Osteoid Osteomas Rosenthal and colleagues were the first to report taking this next step in treatment of osteoid osteomas. In 1992, they documented their use of RFA in 4 patients with osteoid osteoma, achieving cure in 3.86 A sparse smattering of reports on the technique over the next few years was followed by the first report, by Osti et al,87 of RFA of an osteoid osteoma in the spine. The lesion in this case was in an articular process. They put forth that this technique is safe based on Houpt’s work, but advocated vigilance about position of the electrode. Over the last 5 years, RFA of osteoid osteoma has become widespread and is the treatment of choice for most osteoid osteomas in many centers. Results of RFA of Osteoid Osteomas A number of smaller series, with excellent results, of RFA of osteoid osteoma in the extremities and spine56,59 are backed up by some larger series. In 1995, De Berg and coworkers88 reported initial success (that is, pain resolution) in all 18 patients they treated. Their 1 patient with a recurrence was successfully retreated.88 That same year, Rosenthal and colleagues89 achieved complete relief in 16 of 18 patients. In 2001, Lindner et al55 reported a series of 58 patients treated with RFA of osteoid osteomas. Their success rate was remarkable, with initial relief in all 58 patients and successful retreatment in each of the 3 recurrences they experienced.55 Finally, Rosenthal and coworkers90 retrospectively compared surgery with RFA for osteoid osteoma at their institution and found no significant difference in success between the techniques, with a 9% recurrence rate in the surgery group and 12% in the RFA group. As reported by most authors, these investigators had no complications in the RFA group, but 2 complications requiring 5 additional operations in the surgical group. The Procedure RFA of osteoid osteomas typically begins like CT-guided biopsies. Although we prefer general anesthesia, various authors report performing this procedure with general anesthesia, regional anesthesia, and heavy conscious sedation.55,86,88 Con-

Fig 6. CT scan during RFA of a medial femoral osteoid osteoma (same case as Fig 4). To improve access, the lower extremity is externally rotated, presenting the nidus perpendicular to the anterior approach and rotating the neurovascular structures out of the path of the electrode.

scious sedation is probably advisable when ablating a lesion in the spine to maintain the ability to perform neurologic tests during the procedure.87 Unlike RFA of many intra-abdominal lesions, RFA in bones requires that access be created by a biopsy device or drill.89 Of course, one must plan the approach appropriately to allow a perpendicular impact of the access device on the bone and to avoid vital structures (Fig 6). Sometimes this may require a longer and less direct approach (Fig 7). The radiofrequency electrode is passed through the biopsy device into the osteoid osteoma, and the outer needle is then retracted several centimeters to insure that current will not arc back to it and burn a permanent sinus tract to the skin. The choice of electrode deserves some comment. Most reports on this procedure describe using a standard single electrode without internal cooling. If that is used, the probe should have a 5or 10-mm exposed active tip. Knowing that at this length the RFA lesion extends several millimeters beyond the tip,91 one must be sure to keep the tip sufficiently removed from vital structures, including the skin. A 1-cm clearance is a standard requirement.89 One would presume that an expandable-array electrode could also be used in this setting, with extension of the tines limited to the size of the lesion (see comments on RFA of skeletal metastases for further discussion of electrode choices). Given that the maximum lesion diameter with a

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structures, and skin burns. The topic of ground pad placement is addressed in the section on RFA of metastases. The success of RFA in osteoid osteomas and in abdominal neoplasms has led to the next step: RFA of skeletal metastases. MUSCULOSKELETAL METASTASES: BACKGROUND

Clinical Characteristics

Fig 7. To avoid the peroneal nerve, the electrode was passed through the entire tibia to ablate this osteoid osteoma.

single, noncooled electrode is 16mm,34,91 care should be taken to place the electrode in the center of the osteoid osteoma. If the tumor extends more than 5 mm beyond the probe on either side, repositioning and a second treatment should follow the first.55,89 Most authors perform this procedure using temperature control, achieving 90°C at the tip for 4 to 6 minutes.55,56,59,86,88,90 We prefer to extend the treatment to 6 minutes, knowing that this is a minimal time consideration in a procedure that typically requires 45 to 120 minutes to complete.88 Deposition of bupivicaine at the ablation and bone entry site(s) may benefit the patient as anesthesia wears off.55,89 Very few patients require hospitalization after the procedure for postprocedure pain.25,89 Barei’s report of 11 patients included a questionnaire in which the patients described the immediate postprocedure pain as one half as uncomfortable as the nighttime tumor pain.56 It is interesting to note that our only 2 patients who required parenteral pain medication after the procedure were also our only 2 patients undergoing a second RFA after recurrence following an initial RFA. Patients can bear weight immediately, and activities need be limited only in extreme cases (pole vaulting comes to mind).89,90 Patients are typically pain free in a few days to a week25,55 and need no imaging follow-up unless symptoms recur. Complications are rare. The most concerning possibilities include infection, necrosis of adjacent

The majority of skeletal metastases are not painful.92,93 Still, they are so common, especially from breast, lung, and prostate primaries, that metastatic bone pain is an immense problem.25,94 Pain is typically the most feared and incapacitating symptom for cancer patients,93-95 and pain treatment is often inadequate, both because of undermedication due to physician and patient concerns and because of side effects and ineffectiveness of treatments.93,95-98 Palliation of pain may be the only significant goal that can be achieved in patients with terminal malignancies.96 RFA can sometimes play a part in a multi-modal approach to reaching this goal and shorten the weeks to successful pain relief.92 Pathologic fracture and neural compression are 2 additional unwanted effects of skeletal metastases deserving attention.25,92 Treatment Options There are numerous options in treating pain from skeletal metastases. Despite these options and a multimodality approach, many patients suffer with inadequate pain relief. Front-line therapy, of course, is pharmacological. Often, though, opioid analgesics and anti-inflammatory medications are insufficient or poorly tolerated.96 External-beam radiation therapy (XRT) is widely used and often the treatment of choice in patients with metastatic bone pain.96,99 This modality provides complete relief in the majority of patients and at least partial relief in the vast majority (83%).94,100 However, limitations include common recurrences,100 slow onset of relief,94,96 and tumor types that are less responsive to XRT.99 Other therapies that play a role in palliation of metastatic bone pain include systemic radioisotopes, the best studied of which is Strontium89,94,99 hormonal therapy,96 bisphosphonates,99 and novel therapies such as osteoprotegerin,101 as well as pain relief that may accompany effective chemotherapy and occasionally surgical stabiliza-

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tion.25,94,99 Pain relief, when it occurs, often is delayed for 4 to 12 weeks after initiation of any of these therapies.96 Thus, many of these patients would benefit from a modality of treatment that would focus therapy at the site of pain and relieve symptoms quickly, preferably in a minimally invasive fashion and with limited attendant morbidity. This could markedly improve quality of life for a number of patients,25 some of whom have months or years to live and would be highly functioning were it not for their pain.95 RFA OF SKELETAL METASTASES

Early Reports Although efficacy and safety of radiofrequency ablation in the liver are well established and continue to improve,26,102 only in the last few years have investigators attempted RFA of musculoskeletal metastases. Dupuy et al103 made the first report. The abstract of their study cites 10 patients who underwent RFA of bone metastases (1-8 cm) after failing radiation or chemotherapy. Nine of the 10 patients experienced relief, with no complications.103 Callstrom and colleagues104 reported RFA of severely painful lytic bone metastases (1-11 cm) in 12 patients after unsuccessful XRT and/or chemotherapy. All of the patients had a reduction in their daily worst pain, with the group showing statistically significant reductions in daily worst pain (8.033.1), daily average pain (6.531.8), and pain interference with daily activities at 4 weeks postRFA, on a 10-point scale. Pain relief typically came in less than 1 week. The only complication was a second-degree skin burn at a ground pad site.104 Callstrom and a larger, multi-institutional group of investigators presented a poster at the 2002 annual RSNA meeting. Those data are still in publication at the time of this writing but consisted of 62 patients with painful bone metastases unresponsive to other therapies. By using a 10-point pain reporting scale, 95% of their patients had at least a 2-point reduction in pain after RFA of bone metastases, which was durable at 12 and 24 weeks.105 (These data are taken from the poster itself, in which the authors added cases to the original published abstract.) The other early work in the available literature is from Gronemeyer and coworkers.106 They treated 10 patients with unresectable spine metastases, using heavy conscious sedation to monitor patients’ neurologic status. Nine of these patients

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reported a reduction in their pain, on average by 74%, and an average of 27% improvement in disability. Four of these patients underwent prophylactic vertebroplasty for stabilization 3 to 7 days after RFA.106 Within this body of early work and because of the current rapid spread of the technique, there is little standardization of protocols. Comments on Technique With the lack of standardized protocols, we are unable to offer specifics on exactly how to perform RFA of skeletal malignancies. Nevertheless, standardization of RFA in other organ systems and the recent experience in the musculoskeletal system provide some foundation and insight into RFA of osseous metastases. Obviously, many of the same basic points of RFA of osteoid osteomas apply to bone malignancies. Percutaneous placement of the electrode into the metastasis requires real-time cross-sectional guidance. Although CT or CT fluoroscopy is usually the guidance modality, lesions that have destroyed all intervening cortex may be accessible using ultrasound. MRI-compatible devices have been reported and should be widely available commercially in the near future. Placement of the electrode often does not require a guiding biopsy device if the intervening cortex is absent or thin enough. If coaxial technique is used, one must insure that the outer guiding needle is retracted sufficiently before ablation so that current will not arc down the needle and burn a tract to the skin. Choice of anesthesia, ranging from heavy conscious sedation to general endotracheal anesthesia, again depends on operator and patient preference as well as anticipated procedure length, patient positioning and proximity of the lesion to vital neurologic structures that might require intraprocedure neurologic assessment.106 Because bone metastases imply systemic involvement and local treatments (like RFA) are, by definition, palliative,94 ablation planning may be directed toward killing the “symptomatic” portion of the tumor (Fig 8), as opposed to a requirement for complete tumor destruction as is the case for hepatic lesions. Callstrom and coworkers104 first articulated the concept that RFA of large musculoskeletal metastases would likely be most effective if the advancing margins (bone–soft-tissue interface) were all treated,104 and we use this concept when planning RFA of larger lesions.

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Fig 8. RFA of a large iliac metastasis. (A) Image from 1 of 7 ablations spread around the margins of the tumor. Notice the gas elaborated by the procedure. (B) Postprocedure scan shows enhancing residual tumor within the pelvis, separate from bone and likely not causing pain.

Smaller lesions, of course, can be entirely treated with 1 ablation. Several other general principles apply. Patients should expect to stay in the hospital at least 1 night because many will require parenteral pain medication.104 To that end, anti-inflammatory medications immediately postoperatively and for the next few days are likely beneficial, knowing that this procedure must cause significant inflammation around the area of necrosis. Infection is one of the feared complications, and abscess is known to be a complication of hepatic RFA.107 Thus, we pretreat our patients with antibiotics (1 g cefazolin or 400 mg ciprofloxacin intravenously).25 If the lesion is large, we consider treating with an additional 2 doses of antibiotics after the procedure, although there is no rigorous science behind this practice. Another consideration is burning adjacent structures, both at the active electrode and the indifferent electrode (ground pad). The expected zone of necrosis varies with electrode type and procedural technique (see later), but even basic single uncooled electrodes require at least a centimeter108 clearance to avoid damage to adjacent nerves/cord, bowel, bladder, and skin. Planning the procedure thus requires preemptive analysis of adjacent vulnerable structures (Fig 9). Larger blood vessels are not at risk because they act as heat sinks and actually diminish RF lesion size.35,108 Unwanted tissue damage can also occur at the ground pad sites.39 The same amount of current deposited at the active electrode must return through the ground pads. Given the recent advances in RFA lesion size, deposited currents have increased, requiring greater attention to the ground

pads. A large surface area helps to spread out the current. Likewise, orienting the long axis of the rectangular pads perpendicular to the current path minimizes burn risk. The pads should be placed more than 25 cm from the electrode.109 We use 4 standard pads in all our metastasis cases (2 in osteoid osteomas), and they must be equidistant from the active electrode. They should be monitored periodically during ablation. Given that ground pad burns should be completely preventable, we always place cold packs over each pad during the ablation. The choice of electrode type may greatly affect the lesion size achieved, but this choice may be partially dependent on one’s RFA generator and the geometry of and access to the metastasis to be treated. A full treatment of the topic is well beyond

Fig 9. CT of briskly enhancing renal adenocarcinoma metastasis to the piriformis muscle (white arrow). Because of its proximity to the sciatic nerve (black arrow), RFA was not offered to this patient.

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Fig 10. RFA electrodes. (A) Internally cooled cluster electrode. Courtesy of Radionics, Burlington, MA. (B) Expandable array electrode. Courtesy of RITA Medical Systems Mountain View, CA. (C) LeVeen expandable array electrode. Courtesy of Boston Scientific Corporation, Natick, MA.

the scope of this review, but a few salient comments follow. Single probes without any enhancements typically provide a more cylindrical lesion and cannot exceed 1.6 cm in lesion diameter. Cooling the tissue immediately adjacent to the probe tip can significantly increase the amount of current that can be deposited in a lesion before charring and impedance rise terminate the procedure. In fact, RFA is now usually terminated at a preset time, rather than being limited by impedance rises. This cooling can be achieved in 2 ways. First, the electrode can be internally cooled by chilled saline or water, requiring that the electrode be constructed with afferent and efferent internal lumina. Second, saline can be slowly infused into the lesion through ostia in the tip(s) of the electrode, which both cools the region and is thought to increase electrical conductivity, enhancing current transmission. Both of these methods markedly increase lesion size, but the former is probably more successful and creates more uniform lesions.29,110-115 Electrodes are also available with multiple tips. This feature serves to greatly enhance the “effective diameter” of the RF electrode and can markedly increase the achievable lesion size.31,116 One vendor has a cluster of 3 electrodes in a triangle, each 5 mm from the others (Fig 10A). Several other vendors have various configurations of deployable electrode tips that are extended from the central probe once it is within the tumor (Fig 10B and C). They conform to various shapes, from a teepee-like array to a bubble umbrella configuration. Although 1 report supports greater lesion size with the cluster electrode compared with a deployable array,35 electrode and generator technology change rapidly and likely have outstripped available research as to what is most effective.

Another technique to increase lesion size is pulsed current deposition. This technique is best achieved by using automatic impedance control, in which the RF generator will interrupt current flow for 15 seconds when a 10-ohm rise in impedance is detected.27,35 With the various methods of increasing potential current deposition in a lesion, the ideal ablation time (at each position if multiple burns are necessary) is uncertain. It is doubtful that temperature equilibrium30 is reached in a reasonable ablation time with a cooled electrode, but the rate of increase in lesion size diminishes with increasing ablation time; likewise, the risk of complications increases. Further compounding the confusion is the fact that all of the rigorous studies predicting lesion size have been on tissues other than bone metastases, such as ex vivo and in vivo normal animal tissue and human liver tumors. What those studies do prove is that lesion diameter varies markedly with both tissue type21,24 and with degree of vascularity34,117,118 (which itself also varies widely from 1 primary to another and even between 2 tumors of the same histology). Thus, we are not currently able to establish reliable standard protocols or predict individual lesion size in musculoskeletal metastases. There are 2 important guiding principles. First, based on computer-generated geometric models, it has been shown that placing ablations adjacent to each other creates only a small increase in effective complete spherical lesion necrosis size.119 Thus, one should attempt to create fewer, larger lesions when possible. Second, knowing that 60°C is lethal for almost any length of time and even 50° kills all tissue very quickly,120 one can use the thermistor imbedded in the electrode to judge which areas have reached tumor-cidal temperatures with initial

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ablations and adjust plans for further ablations accordingly, as per the technique described by Zagoria et al.31,107 Spine lesions deserve special consideration. In rabbit models, it has been shown that epidural temperatures of 45°C or higher led to sustained neurologic damage.121 Thus, maintaining temperatures at 44°C or below is advisable. If the intervening cortex is intact, this can serve as a significant insulator,120 but one should also probably rely on thermistors monitoring temperature in the canal122 or forego general anesthesia and perform ongoing neurologic evaluation.106 In short, planning these procedures presents a dizzying array of choices, with little data to definitively determine protocol. In general, we prefer internally cooled electrodes for RFA of skeletal metastases. Peculiar geometry, small tumor size, or vulnerable nearby structures will cause us to choose a single electrode. For larger lesions with a wide zone of safety, we use the cluster electrode. As a rule of thumb, we expect a single cooled electrode to provide a lesion in the range of 2 to 3 cm in diameter, with a 4- to 5-cm kill zone for a triple. Many factors affect our ablation time. Unlike hepatic lesions, in which complete destruction is the overwhelming goal, bone metastases do not have to be completely eradicated; the goal is pain relief. Thus, our philosophy will sometimes be to spread multiple shorter (6 minutes) burns around the entire periphery (especially at the edge of native bone) of a large tumor, rather than restricting ourselves to the 12-minute ablations often required in the liver.31,107 Callstrom and coworkers104 stated their goal for ablation time ranged from 5 to 15 minutes. Most patients can expect a reduction, although typically not a complete cessation, in pain within a few days. Risks include infection, thermal damage to adjacent structures and skin burns as detailed earlier, damage from inserting the probe, and fracture if a bone is sufficiently weakened by the metastasis or ablation.25 Prophylactic vertebroplasty in the spine and surgical stabilization in the extremities may prove to be useful adjuncts in selected cases. FUTURE DIRECTIONS

RFA of musculoskeletal lesions remains in its infancy. Although RFA of osteoid osteomas has proven advantages over resection, curettage, or drilling and is becoming the treatment of choice in

most patients in many centers, much work remains to be done to refine and maximize the potential of RFA of skeletal metastases. There are several areas of obvious interest that will shape the way we implement this technique in the future. First, rigorous studies using well-defined protocols to ablate bone metastases will be necessary to fully establish the efficacy and safety of this technique and to establish a framework under which protocols are developed and implemented. Some of these efforts are ongoing, including a large multicenter trial with a well-defined protocol, which is currently enrolling patients and headed by Dr Dupuy, under the auspices of the American College of Radiology Imaging Network.25 Ideally, we would eventually have data on RFA of each specific tumor type, but this may be difficult or impossible to achieve. Work also should be performed to better define the effects of RFA in normal MSK structures, using today’s devices. In vitro and ex vivo studies do not transfer well to live animals, including humans, because of the major impact of flowing blood. The extent and effect of heating on and around bones, muscles, and joints using current technology capable of producing larger lesions would be invaluable information to have when planning ablations in the musculoskeletal system. Also, trials comparing RFA with various other modalities, especially XRT, and comparing single therapies to combinations of RFA with other therapies are necessary31 and will be truly groundbreaking if we find that RFA and other therapies potentiate each other’s effects. Given that RFA treats poorly vascularized tissue better but that other therapies, such as XRT and chemotherapy, attack more vascular and more metabolically active sites better, one could reasonably expect some synergistic effects between these therapies (Lee F, personal communication, January 2003). Goldberg and coworkers123,124 have performed animal studies that have shown that combining RFA with doxorubicin or with percutaneous ethanol injection both increased lesion size over any of these agents alone. Efforts are underway to improve monitoring and guidance of these procedures. In the skeletal system, ultrasound monitoring is often not feasible. Postprocedure CT with contrast has been shown to be more accurate than ultrasound and an accurate method of follow-up when that is necessary.39,48,125,126 Nevertheless, one cannot repeat-

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edly administer contrast for CT monitoring during a procedure. There has been some early success with MR and RFA.38,127 This is enticing, because MRI accurately describes lesion size after the procedure39 so intraprocedure monitoring should be helpful. Although there has been progress in being able to scan patients during electrode placement and during the ablation, as well as determining lesion progress with T2 and inversion recovery sequences and MRI temperature mapping, these techniques and the compatible devices are not widely available yet.31,128 Clearly, the ability to track lesion size/heating during the procedure would be an advantage and a boon to the technique, as well as assuring the safety of nearby vulnerable structures. Finally, we envision a day when RFA is used to help cure patients with skeletal metastases rather than just palliate their pain. Given that bone metastases imply systemic disease, RFA, which is a local therapy, would have to be accompanied by a systemic tumor-cidal therapy. In a sense, one could percutaneously “debulk” painful macrome-

tastases. This would palliate the pain and give the potential for chemotherapy and systemic radiopharmaceuticals to cure the remaining micrometastases. Clearly, this scenario is optimistic and probably a long way off, but it is the rationale behind percutaneous treatment or surgical resection of oligometastatic disease in the liver, lungs, and elsewhere. CONCLUSION

RFA of musculoskeletal lesions has made great strides in the last decade. RFA is safe and effective in osteoid osteomas, now becoming the treatment of choice in most cases that are not managed medically. RFA of musculoskeletal metastases is much less well established. The early available studies have shown that RFA in skeletal metastases is safe and effective at its primary goal of palliating pain. Much work remains to be done in standardizing, optimizing, and monitoring RFA of skeletal metastases and defining its eventual role in the armamentarium of techniques for palliating and curing these patients.

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