**4.7. Radiofrequency ablation of a parathyroid adenoma**

One of the methods of nonsurgical parathyroid ablation is percutaneous thermal ablation, such as laser or radiofrequency ablation. Percutaneous laser and radiofrequency ablation of parathyroid adenomas has been limited to case reports and small-series cases [31–32]. The ultimate utility of thermal ablation has yet to be determined but because it continues to be refined, it does hold promise as a method for treatment of parathyroid disease when surgery is not indicated. RFA can be a therapeutic alternative for patients with contraindications for surgery. Usually after percutaneous ultrasound guided RFTA of the adenoma of the parathyroid gland, the serum parathormone levels and the serum calcium levels dropped back to normal in most of patients (fig 4). Recurrent hyperparathyroidism is rare following transcatheter ablation of mediastinal parathyroid adenomas. When it occurs it is usually early and resistant to further attempts at ablation (33)

**Figure 4.** Radiofrequency ablation of parathyroid adenoma .A, Transverse sonogram of neck shows 15x10-mm right inferior parathyroid adenoma (PTA) .B; Sonogram of the neck after inflation of 5 ml saline (white arrow) to separate the PTA from the right common carotid artery (CCA). C ; Sonogram shows 25-gauge needle (arrows) inserted into parathyroid adenoma . D; Sonogram shows fans (arrows) of the radiofrequency probe within the PTA . E ; Sonogram during RFA of PTA shows reverberation artifacts (arrows) posterior to the needle) . F; Sonogram at the total RFA of the PTA, The ablated gland (arrows) appears echogenic.

#### **4.8. RFA in management of Barrett's esophagus**

154 Hyperthermia

breast conserving therapies (30).

(arrows) appears echogenic.

**4.7. Radiofrequency ablation of a parathyroid adenoma** 

early and resistant to further attempts at ablation (33)

effectiveness of these techniques when they are used as the sole therapy and to determine the long-term local recurrence rates and survival associated with these treatment strategies (29). van der Ploeg et al in 2007 reviewed the literature on the use of RFA for the treatment of small breast carcinoma. The authors concluded that RFA is a promising new tool for minimally invasive ablation of small carcinomas of the breast. They noted that a large randomized control study is needed to ascertain the long-term advantages of RFA compared to the current

One of the methods of nonsurgical parathyroid ablation is percutaneous thermal ablation, such as laser or radiofrequency ablation. Percutaneous laser and radiofrequency ablation of parathyroid adenomas has been limited to case reports and small-series cases [31–32]. The ultimate utility of thermal ablation has yet to be determined but because it continues to be refined, it does hold promise as a method for treatment of parathyroid disease when surgery is not indicated. RFA can be a therapeutic alternative for patients with contraindications for surgery. Usually after percutaneous ultrasound guided RFTA of the adenoma of the parathyroid gland, the serum parathormone levels and the serum calcium levels dropped back to normal in most of patients (fig 4). Recurrent hyperparathyroidism is rare following transcatheter ablation of mediastinal parathyroid adenomas. When it occurs it is usually

**Figure 4.** Radiofrequency ablation of parathyroid adenoma .A, Transverse sonogram of neck shows 15x10-mm right inferior parathyroid adenoma (PTA) .B; Sonogram of the neck after inflation of 5 ml saline (white arrow) to separate the PTA from the right common carotid artery (CCA). C ; Sonogram shows 25-gauge needle (arrows) inserted into parathyroid adenoma . D; Sonogram shows fans (arrows) of the radiofrequency probe within the PTA . E ; Sonogram during RFA of PTA shows reverberation artifacts (arrows) posterior to the needle) . F; Sonogram at the total RFA of the PTA, The ablated gland

Barrett's esophagus (BE) is defined as the presence of specialized intestinal metaplasia within the esophagus, and it is the pre-malignant precursor of esophageal adenocarcinoma. Esophageal cancer is one of the most deadly gastrointestinal cancers with a mortality rate over 90 %. The principal risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and its sequela, BE. Gastroesophageal reflux disease usually leads to esophagitis. However, in a minority of patients, ongoing GERD leads to replacement of esophageal squamous mucosa with metaplastic, intestinal-type Barrett's mucosa. In the setting of continued peptic injury, Barrett's mucosa can give rise to esophageal adenocarcinoma (34). A new method of endoscopic ablation of BE is balloon-based, bipolar RFA (Stellartech Research Coagulation System; BARRx, Inc, Sunnyvale, Calif), also known as Barrett's endoscopy. This technique requires the use of sizing balloons to determine the inner diameter of the targeted portion of the esophagus. This is followed by placement of a balloon-based electrode with a 3-cm long treatment area that incorporates tightly spaced, bipolar electrodes that alternate in polarity. The electrode is then attached to a radiofrequency generator and a preselected amount of energy is delivered in less than 1 second at 350 W. In a review of evidence on ablative techniques for BE, Johnston stated that it is not clear which of the numerous endoscopic ablative techniques available - photodynamic therapy, laser therapy, multi-polar electrocoagulation, argon plasma coagulation, endoscopic mucosal resection, RFA or cryotherapy -- will emerge as superior for treatment of BE. In addition, it has yet to be determined whether the risks associated with ablation therapy is less than the risk of BE progressing to cancer. Whether ablation therapy eliminates or significantly reduces the risk of cancer, eliminates the need for surveillance endoscopy, or is cost-effective, also remains to be seen. Comparative trials that are now underway should help to answer these questions (35). Hubbard and Velanovich stated that endoscopic endoluminal RFA using the Barrx device (Barrx Medical, Sunnyvale, CA) is a new technique to treat BE. This procedure has been used in patients who have not had anti-reflux surgery. This report presented an early experience of the effects of endoluminal ablation on the reflux symptoms and completeness of ablation in postfundoplication patients. A total of 7 patients who have had either a laparoscopic or open Nissen fundoplication and BE underwent endoscopic endoluminal ablation of the Barrett's metaplasia using the Barrx device. Pre-procedure, none of the patients had significant symptoms related to GERD. One to 2 weeks after the ablation, patients were questioned as to the presence of symptoms. Pre-procedure and post-procedure, they completed the GERD-HRQL symptom severity questionnaire (best possible score, 0; worst possible score, 50). Patients had follow-up endoscopy to assess completeness of ablation 3 months after the original treatment. All patients completed the ablation without complications. No patients reported recurrence of their GERD symptoms. The median pre-procedure total GERD-HRQL score was 2, compared to a median post-procedure score of 1. One patient had residual Barrett's metaplasia at 3 months follow-up, requiring re-ablation. The authors concluded that this preliminary report of a small number of patients demonstrated that endoscopic endoluminal ablation of Barrett's metaplasia using the Barrx device is safe and

effective in patients who have already undergone anti-reflux surgery. There appears to be no disruption in the fundoplication or recurrence of GERD-related symptoms. Nevertheless, they stated that studies with longer-term follow-up and with more patients are needed (36).

Hyperthermia and Radiology 157

limitations: (i) these investigators used eradication of intestinal metaplasia and dysplasia, along with neoplastic progression, as surrogate markers for death from cancer, even though long-term data demonstrating an association between eradication of intestinal metaplasia and a decreased risk of cancer are sparse, (ii) the study duration was 1 year. Although other data suggest that reversion to neosquamous epithelium after RFA is durable, it is unclear if the results of the study will persist, (iii) because of stratified randomization according to the degree of dysplasia and the 2:1 ratio for assignment of patients to the ablation group and the control group, the number of patients in some groups was small, (iv) since this study did not compare RFA with other interventions, such as photodynamic therapy and esophagectomy, these researchers can not determine which of these interventions is superior, (v) whether these findings can be generalized to community-practice settings is unknown. Furthermore, the risk of subsquamous intestinal metaplasia following ablative therapy is a concern for all ablative techniques. However, the malignant potential of subsquamous intestinal metaplasia is unknown. In this study, subsquamous intestinal metaplasia was quite common in patients (25.2 %) before enrollment and, similar to previous reports, was low after RF ablation (5.1 %). Although the biopsy regimen in this study was aggressive, it is possible that some patients had undetected subsquamous intestinal metaplasia. Finally, because these investigators sought to define the efficacy of RFA for the spectrum of dysplasia, they enrolled patients with both low-grade dysplasia and high-grade dysplasia. However, the implications of these 2 diagnoses are markedly different. Low-grade dysplasia implies a risk of progression to cancer of less than 1 % per patient-year, whereas the risk associated with high-grade dysplasia may be higher by a factor of 10. In making decisions about the management of pre-cancerous conditions, clinicians, patients, and policy-makers consider possible benefits and risks of competing strategies. Because high-grade dysplasia has a more ominous natural history than low-grade dysplasia (or non-dysplastic intestinal metaplasia), greater risks and costs are tolerable. For less severe disease, the safety profile and associated costs become increasingly important. Detailed consideration of these trade-offs is beyond the scope of this study. Regardless, both of the dysplasia subgroups showed high rates of reversion to squamous epithelium after RFA and reduced rates of disease progression with few serious adverse effects, suggesting that the application of ablative therapy in patients

with low-grade dysplasia is worth further investigation and consideration (38).

In the accompanying editorial, Bergman stated that it is still too early to promote RFA for patients with non-dysplastic BE. Dr. Bergman also asked the following questions: (i) is complete response after ablation maintained over time, thus reducing the risk of progression to high-grade dysplasia or cancer?, (ii) will ablation improve patients' quality of life and decrease costs, as compared with the surveillance strategy?, and (iii) can we define a stratification index predicting disease progression or response to therapy? The author noted that "[w]e run the risk of losing the momentum to enroll patients in a trial that is required at this stage: a randomized comparison of endoscopic surveillance and radiofrequency ablation for non-dysplastic Barrett's esophagus. Such a study might truly revolutionize the management of this condition and answer the question as to whether radiofrequency ablation is great just for some or justified for many" (39). Furthermore, the American College

Ganz et al evaluated the safety and effectiveness of endoscopic circumferential balloonbased ablation by using radiofrequency energy for treating BE that contains high-grade dysplasia (HGD). Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists were included in this study. A prior endoscopic mucosal resection (EMR) was permitted, provided that residual HGD remained in the BE region for ablation. Histologic complete response (CR) end points: (i) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (ii) all biopsy specimens were negative for any dysplasia (CR-D), and (iii) all biopsy specimens were negative for IM (CR-IM). A total of 142 patients (median age of 66 years, IQR 59 to 75 years) who had BE HGD (median length of 6 cm, IQR 3 to 8 cm) underwent circumferential ablation (median of 1 session, IQR 1 to 2 sessions). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninetytwo patients had at least 1 follow-up biopsy session (median follow-up of 12 months, IQR 8 to 15 months). A CR-HGD was achieved in 90.2 % of patients, CR-D in 80.4 %, and CR-IM in 54.3 %. The authors concluded that endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multi-center registry, the intervention safely achieved a CR for HGD in 90.2 % of patients at a median of 12 months of follow-up. Major drawbacks of this study were a non-randomized study design, absence of a control arm, a lack of centralized pathology review, ablation and biopsy technique not standardized, and a relatively short-term follow-up (37) .

Shaheen et al examined if endoscopic RFA could eradicate dysplastic BE and decrease the rate of neoplastic progression. In a multi-center, sham-controlled trial, these researchers randomly assigned 127 patients with dysplastic BE in a 2:1 ratio to receive either RFA (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of BE. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. In the intention-totreat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5 % of those in the ablation group, as compared with 22.7 % of those in the control group (p < 0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0 % of those in the ablation group, as compared with 19.0 % of those in the control group (p < 0.001). Overall, 77.4 % of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3 % of those in the control group (p < 0.001). Patients in the ablation group had less disease progression (3.6 % versus 16.3 %, p = 0.03) and fewer cancers (1.2 % versus 9.3 %, p = 0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, 1 patient had upper gastrointestinal hemorrhage, and 5 patients (6.0 %) had esophageal stricture. The authors concluded that in patients with dysplastic BE, RFA was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression (38). As stated by the authors, this study has several limitations: (i) these investigators used eradication of intestinal metaplasia and dysplasia, along with neoplastic progression, as surrogate markers for death from cancer, even though long-term data demonstrating an association between eradication of intestinal metaplasia and a decreased risk of cancer are sparse, (ii) the study duration was 1 year. Although other data suggest that reversion to neosquamous epithelium after RFA is durable, it is unclear if the results of the study will persist, (iii) because of stratified randomization according to the degree of dysplasia and the 2:1 ratio for assignment of patients to the ablation group and the control group, the number of patients in some groups was small, (iv) since this study did not compare RFA with other interventions, such as photodynamic therapy and esophagectomy, these researchers can not determine which of these interventions is superior, (v) whether these findings can be generalized to community-practice settings is unknown. Furthermore, the risk of subsquamous intestinal metaplasia following ablative therapy is a concern for all ablative techniques. However, the malignant potential of subsquamous intestinal metaplasia is unknown. In this study, subsquamous intestinal metaplasia was quite common in patients (25.2 %) before enrollment and, similar to previous reports, was low after RF ablation (5.1 %). Although the biopsy regimen in this study was aggressive, it is possible that some patients had undetected subsquamous intestinal metaplasia. Finally, because these investigators sought to define the efficacy of RFA for the spectrum of dysplasia, they enrolled patients with both low-grade dysplasia and high-grade dysplasia. However, the implications of these 2 diagnoses are markedly different. Low-grade dysplasia implies a risk of progression to cancer of less than 1 % per patient-year, whereas the risk associated with high-grade dysplasia may be higher by a factor of 10. In making decisions about the management of pre-cancerous conditions, clinicians, patients, and policy-makers consider possible benefits and risks of competing strategies. Because high-grade dysplasia has a more ominous natural history than low-grade dysplasia (or non-dysplastic intestinal metaplasia), greater risks and costs are tolerable. For less severe disease, the safety profile and associated costs become increasingly important. Detailed consideration of these trade-offs is beyond the scope of this study. Regardless, both of the dysplasia subgroups showed high rates of reversion to squamous epithelium after RFA and reduced rates of disease progression with few serious adverse effects, suggesting that the application of ablative therapy in patients with low-grade dysplasia is worth further investigation and consideration (38).

156 Hyperthermia

effective in patients who have already undergone anti-reflux surgery. There appears to be no disruption in the fundoplication or recurrence of GERD-related symptoms. Nevertheless, they stated that studies with longer-term follow-up and with more patients are needed (36). Ganz et al evaluated the safety and effectiveness of endoscopic circumferential balloonbased ablation by using radiofrequency energy for treating BE that contains high-grade dysplasia (HGD). Patients with histologic evidence of intestinal metaplasia (IM) that contained HGD confirmed by at least 2 expert pathologists were included in this study. A prior endoscopic mucosal resection (EMR) was permitted, provided that residual HGD remained in the BE region for ablation. Histologic complete response (CR) end points: (i) all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD), (ii) all biopsy specimens were negative for any dysplasia (CR-D), and (iii) all biopsy specimens were negative for IM (CR-IM). A total of 142 patients (median age of 66 years, IQR 59 to 75 years) who had BE HGD (median length of 6 cm, IQR 3 to 8 cm) underwent circumferential ablation (median of 1 session, IQR 1 to 2 sessions). No serious adverse events were reported. There was 1 asymptomatic stricture and no buried glands. Ninetytwo patients had at least 1 follow-up biopsy session (median follow-up of 12 months, IQR 8 to 15 months). A CR-HGD was achieved in 90.2 % of patients, CR-D in 80.4 %, and CR-IM in 54.3 %. The authors concluded that endoscopic circumferential ablation is a promising modality for the treatment of BE that contains HGD. In this multi-center registry, the intervention safely achieved a CR for HGD in 90.2 % of patients at a median of 12 months of follow-up. Major drawbacks of this study were a non-randomized study design, absence of a control arm, a lack of centralized pathology review, ablation and biopsy technique not

Shaheen et al examined if endoscopic RFA could eradicate dysplastic BE and decrease the rate of neoplastic progression. In a multi-center, sham-controlled trial, these researchers randomly assigned 127 patients with dysplastic BE in a 2:1 ratio to receive either RFA (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of BE. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. In the intention-totreat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5 % of those in the ablation group, as compared with 22.7 % of those in the control group (p < 0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0 % of those in the ablation group, as compared with 19.0 % of those in the control group (p < 0.001). Overall, 77.4 % of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3 % of those in the control group (p < 0.001). Patients in the ablation group had less disease progression (3.6 % versus 16.3 %, p = 0.03) and fewer cancers (1.2 % versus 9.3 %, p = 0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, 1 patient had upper gastrointestinal hemorrhage, and 5 patients (6.0 %) had esophageal stricture. The authors concluded that in patients with dysplastic BE, RFA was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression (38). As stated by the authors, this study has several

standardized, and a relatively short-term follow-up (37) .

In the accompanying editorial, Bergman stated that it is still too early to promote RFA for patients with non-dysplastic BE. Dr. Bergman also asked the following questions: (i) is complete response after ablation maintained over time, thus reducing the risk of progression to high-grade dysplasia or cancer?, (ii) will ablation improve patients' quality of life and decrease costs, as compared with the surveillance strategy?, and (iii) can we define a stratification index predicting disease progression or response to therapy? The author noted that "[w]e run the risk of losing the momentum to enroll patients in a trial that is required at this stage: a randomized comparison of endoscopic surveillance and radiofrequency ablation for non-dysplastic Barrett's esophagus. Such a study might truly revolutionize the management of this condition and answer the question as to whether radiofrequency ablation is great just for some or justified for many" (39). Furthermore, the American College

of Gastroenterology's updated guidelines for the diagnosis, surveillance and therapy of BE , Wang and Sampliner states that "further evaluation of the most recent technology; radiofrequency ablation is awaited. Cryotherapy is beginning clinical trials and older technologies are becoming more refined (e.g., photodynamic therapy with the development of new agents). Documentation of the frequency and duration of the surveillance protocol after endoscopic ablation therapy requires careful study" (40).

Hyperthermia and Radiology 159

ethanol (EtOH) injection treatment of patients with local recurrence or focal distant metastases of well-differentiated thyroid cancer (WTC). A total of 20 patients underwent treatment of biopsy-proven recurrent WTC in the neck. Sixteen of these patients had lesions treated by ultrasound-guided RFA (mean size, 17.0 mm; range of 8 to 40 mm), while 6 had ultrasound-guided EtOH injection treatment (mean size, 11.4 mm; range of 6 to 15 mm). Four patients underwent RFA treatment of focal distant metastases from WTC. Three of these patients had CT-guided RFA of bone metastases (mean size, 40.0 mm; range of 30 to 60 mm), and 1 patient underwent RFA for a solitary lung metastasis (size, 27 mm). Patients were then followed with routine ultrasound, whole body scan, and/or serum thyroglobulin levels for recurrence at the treatment site. No recurrent disease was detected at the treatment site in 14 of the 16 patients treated with RFA and in all 6 patients treated with EtOH injection at a mean follow-up of 40.7 and 18.7 months, respectively. Two of the 3 patients treated for bone metastases were disease-free at the treatment site at 44 and 53 months of follow-up, respectively. The patient who underwent RFA for a solitary lung metastasis was disease-free at the treatment site at 10 months of follow-up. No complications were experienced in the group treated by EtOH injection, while 1 minor skin burn and 1 permanent vocal cord paralysis occurred in the RFA treatment group. The authors concluded that RFA and EtOH ablation show promise as alternatives to surgical treatment of recurrent WTC in patients with difficult reoperations. They stated that further long-term follow-up studies are needed to ascertain the precise role these therapies should

Radiofrequency ablation devices have been cleared by the FDA for the general indication of soft tissue cutting, coagulation, and ablation by thermal coagulation necrosis. This clearance was based only on bench testing or animal testing performance data. Guidelines from the National Comprehensive Cancer Network (NCCN, 2010) include recommendations for RFA of the trunk and extremities in metastatic soft tissue sarcoma. The guidelines include metastasectomy with RFA as an alternative method for control of metastatic lesions in limited metastases. The guidelines also include RFA as options for symptomatic patients with disseminated metastases. "The guidelines are intentionally nonspecific about this group of options, because many different issues are factored into this decision (e.g., patient performance status, patient preferences, specific clinical problems from the metastases,

Pawlik et al at MD Anderson Cancer Center reported a series with 36 non-GIST sarcoma patients and 31 GIST patients who received RFA and/or surgical resection of liver metastases. (47). When surgical resection was possible, that was the first choice (35 patients). RFA was used in combination with surgical resection of the largest lesions in 18 cases. RFA was used alone in 13 cases. Those patients treated with RFA alone, or in combination with

play in the treatment of recurrent WTC (45).

**4.11. RFA of Soft tissue masses** 

treatment availability.)" (46).

**4.12. RFA of gastrointestinal stromal tumors** 
