Radiofrequency Tumor Ablation
Number: 0492
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Aetna considers radiofrequency ablation (RFA) medically necessary for the following indications:
- Adrenocortical carcinoma not amenable to complete surgical resection;
- Adult with continually growing benign thyroid nodule(s) (greater than 2 cm in diameter, and cytologically benign on fine needle aspiration biopsy) and member is a high-risk surgical candidate;
- Cancer bone pain, management of refractory bone pain in persons with cancer;
- Gastro-intestinal stromal tumors (GIST), treatment of tumors with limited progression;
- Malignant lung masses, in persons who are not candidates for surgical intervention;
- Medullary thyroid carcinoma, treatment of distant metastases;
- Osteoid osteoma, treatment of individuals that remain symptomatic despite treatment with nonsteroidal non-inflammatory drugs (NSAIDs), as a less invasive alternative to surgical resection of the tumor;
- Papillary thyroid microcarcinoma;
- Renal cell carcinoma, up to 4-cm in size, in persons who meet the following criteria:
- High-risk surgical candidates; or
- Persons with renal insufficiency, as defined by a glomerular filtration rate of less than or equal to 60 ml/min/m2; or
- Persons with a solitary kidney;
- Removal of other primary or metastatic malignant neoplasms, when removal of the neoplasm may be curative, and the member is unable to tolerate surgical resection;
- Soft tissue sarcoma of the trunk or extremities, treatment of symptomatic persons with disseminated metastases;
- Tumor debulking, as an alternative to surgical (cold knife) resection for debulking of primary and metastatic malignant neoplasms.
Aetna considers RFA experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for indications other than the ones listed above has not been established:
- Curative treatment of primary or metastatic malignant neoplasms (e.g., adrenal metastases from any primary tumor, breast cancer, cartilaginous tumors in the long bones, chondroblastoma, desmoid tumors, esophageal cancer, gallbladder cancer, kidney cancer including renal angiomyolipoma, lung cancer, pancreatic cancer, spinal metastases, and thymoma; not an all-inclusive list) in persons who are able to tolerate surgical resection;
- Treatment of biliary obstructions / strictures;
- Treatment of Brunner's gland hyperplasia;
- Treatment of large renal angiomyolipomas;
- Treatment of malignant bile duct obstruction;
- Treatment of renal allograft neoplasms;
- Treatment of renal cysts;
- Treatment of sporadic renal angiomyolipomas;
- Unresectable localized recurrent thyroid cancers without distant metastases.
Aetna considers combined RFA with trans-arterial chemoembolization experimental and investigational for the treatment of intermediate-stage hepatocellular carcinoma because the effectiveness of this approach has not been established.
For Aetna's policy on RFA for the treatment of Barrett's esophagus, see CPB 0728 - Barrett's Esophagus.
For Aetna's policy on RFA of hepatic tumors, see CPB 0274 - Ablation of Hepatic Lesions.
For Aetna's policy on RFA of benign prostatic hypertrophy (transurethral needle ablation or TUNA), see CPB 0079 - Benign Prostatic Hyperplasia.
For Aetna's policy on RFA of treatment of uterine fibroids, see CPB 0304 - Fibroid Treatment.
Background
Radiofrequency ablation (RFA) of tumor is a procedure in which a needle electrode is inserted (via image guidance) into a lesion (tumor) and electrical energy generates heat to destroy cancer cells. This can either be performed percutaneously or through an intraoperative approach. The procedure is typically used for those patients whose tumors are inoperable or for those who are ineligible for surgery due to age, presence of comorbidities or overall poor general health.
RF tumor ablation is performed by inserting electrodes directly into the affected area where alternating high frequency current is then emitted. The current moves from the tip of the electrode into the surrounding tissue. The movement of ions results in frictional heating of the tissue and as the temperature becomes elevated beyond 60 degrees Celsius, cells around the electrode begin to die (coagulative necrosis).
Osteoid osteoma is a benign neoplasm most often seen in young males. Most osteoid osteomas are found in the first 3 decades of life, but an occasional lesion in an older patient has been reported. Almost any bone can be involved. The typical patient has pain that is worse at night and relieved by aspirin. When the growth is near a joint, swelling, stiffness, and contracture may occur. When in a vertebra, scoliosis may occur. In children, over-growth and angular deformities may occur. Routine roentgenograms are often diagnostic, but bone scans or computed tomographies commonly are required to accurately localize the lesion. To effect a cure the entire nidus must be removed. The standard method of removal is surgical resection. Recurrence after apparently complete excision has been reported but is rare.
Percutaneous RF thermal ablation has been used as a less invasive alternative to surgical resection of osteoid osteoma. The primary advantage of percutaneous RF thermal ablation is a reduction in the need for post-operative hospitalization and a reduced duration of convalescence.
Several studies have been published reporting successful removal of osteoid osteoma using percutaneous RFA. Rosenthal et al (1998) compared percutaneous RFA with standard resection in 87 patients who were treated with operative excision and 38 patients who were treated with percutaneous RFA. The former group did not require post-operative hospitalization (average of 0.2 days), whereas the latter group required an average of about 5 days of post-operative hospitalization. The rates of recurrence between the 2 treatments were approximately the same. The rate of pain relief, as measured by questionnaire, was also similar between the 2 groups. An assessment conducted for the National Institute for Clinical Excellence (2004) concluded that the evidence supporting percutaneous RFA of osteoid osteoma appears adequate to support its use, provided that the normal arrangements are in place for consent, audit and clinical governance.
Radiofrequency ablation has been advocated as an alternative to resection in persons with lung nodules who can not be treated surgically because of medical problems, multiple tumors, or poor surgical risk. Satisfactory clinical results have been reported using this method for liver tumors, and several reports have been published regarding RFA therapy for human lung neoplasms. There are, however, no adequate prospective clinical studies that demonstrate that RFA of lung metastases is as effective as surgical (cold knife) resection in curative resection of malignant neoplasms. An important concern is that RFA does not allow for examination of surgical margins to ensure that cancer is completely resected. Le and Petrik (2005) considered RFA as a promising technique for the treatment of early states (state I and stage II) non-small cell lung cancer. Stamatis (2005) stated that for the treatment of lung metastases, RFA in particular is currently being investigated. An assessment by the National Institute for Health and Clinical Excellence (NICE, 2006) concluded: "Current evidence on the safety and efficacy of percutaneous radiofrequency ablation for primary and secondary lung cancers shows that there are no major safety concerns with this procedure. There is evidence that the treatment can reduce tumour bulk; however, this evidence is limited and is based on heterogeneous indications for treatment. The procedure should therefore be used only with special arrangements for consent, audit and clinical governance."
Radiofrequency ablation has been used as a treatment of pancreatic cancer for a number of years in Japan. Current evidence of effectiveness of RFA for pancreatic cancer consists of case reports and a phase II (safety) study; the latter concluded that RFA was a relatively safe treatment for pancreatic cancer. However, this evidence is insufficient to draw conclusions about the effectiveness of RFA for this indication.
Girelli et al (2010) examined the feasibility and safety of RFA as a treatment option for locally advanced pancreatic cancer. A total of 50 patients with locally advanced pancreatic cancer were studied prospectively. Ultrasound-guided RFA was performed during laparotomy. The main outcome measures were short-term morbidity and mortality. The tumor was located in the pancreatic head or uncinate process in 34 patients and in the body or tail in 16; median diameter was 40 (inter-quartile range [IQR] of 30 to 50) mm. Radiofrequency ablation was the only treatment in 19 patients; it was combined with biliary and gastric bypass in 19 patients, gastric bypass alone in 8, biliary bypass alone in 3 and pancreatico-jejunostomy in 1. The 30-day mortality rate was 2 %. Abdominal complications occurred in 24 % of patients; in half they were directly associated with RFA and treated conservatively. Three patients with surgery-related complications needed re-operation. Reduction of RFA temperature from 105 degrees C to 90 degrees C resulted in a significant reduction in complications (10 versus 2 of 25 patients; p = 0.028). Median post-operative hospital stay was 10 (range of 7 to 31) days. The authors concluded that RFA of locally advanced pancreatic cancer is feasible and relatively well-tolerated, with a 24 % complication rate. This was a feasibility and safety study; it did not provide any data on the effectiveness of RFA in treating pancreatic cancer.
Several authorities have noted that RFA of renal tumors is a promising investigational alternative to partial or total nephrectomy (Janzen et al, 2002; Russo, 2001; Wood et al, 2002). Studies performed to date have focused on the technical feasibility of RFA of renal tumors. Prospective clinical studies are needed to determine if RFA of renal cell carcinomas improve survival and are as effective as total or partial nephrectomy.
An assessment conducted by the NICE (2004) reached the following conclusions about RFA of renal tumors: "Limited evidence suggests that percutaneous radiofrequency ablation (RFA) of renal cancer brings about reduction of tumor bulk as assessed by computed tomography, and that the procedure is adequately safe. However, the procedure has not been shown to improve symptoms or survival …. Patient selection is important and the procedure should normally be limited to patients who are unsuitable for surgery."
An assessment of the evidence for RFA of kidney cancer prepared by the Canadian Coordinating Office for Health Technology Assessment (Hailey, 2006) reached the following conclusions: "RFA is emerging as a useful alternative to nephrectomy in the management of some types of kidney cancer. It appears to be useful for smaller, non-central tumours, and for cases where surgery is contraindicated. A disadvantage is the possibility of residual cancer that cannot be detected by diagnostic imaging during follow-up. There are no results from randomized trials, and the period of follow-up for patients who have had the procedure is short. Only with longer follow-up evaluations (5 years to 10 years) will relevant comparison with radical and partial nephrectomy be possible."
Furthermore, Hinshaw and Lee (2004) stated that RFA, cryoablation, microwave ablation, and laser ablation have all shown promise for the treatment of renal cell carcinomas (RCC), with high local control and low complication rates for RFA and cryoablation. However, the clinical trial data remain early, and survival data are not yet available for a definitive comparison with conventional surgical techniques for removal of RCC (Hinshaw and Lee, 2004). Mahnken et al (2004) noted that the increasing number of clinical reports on RFA of the kidney show the promising potential of renal RFA for minimally invasive tumor treatment. Due to its technical benefits, RFA seems to be advantageous when compared to cryoablation or laser ablation. However, there are no long-term follow-up or comparative data proving an equal effectiveness to surgery (Mahnken et al, 2004).
In a systematic review on focal therapy for kidney cancer, Kutikov and colleagues (2009) stated that most cryoablations are performed using a laparoscopic approach, whereas RFA of the localized small renal masses (SRM) is more commonly administered percutaneously. Pre-treatment biopsy is performed more often for lesions treated by cryoablation than RFA with a significantly higher rate of indeterminate or unknown pathology for SRMs undergoing RFA versus cryoablation (p < 0.0001). Currently available data suggest that cryoablation results in lower re-treatments (p < 0.0001), less local tumor progressions (p < 0.0001) and may be associated with a decreased risk of metastatic progression compared with RFA. It is unclear if these differences are a function of the technologies or their application. The extent to which focal ablation alters the natural history of SRMs has not yet been established. The authors concluded that currently, data on the ability of interventions for SRMs to affect the natural history of these masses are lacking. They stated that prospective randomized evaluations of available clinical approaches to SRMs are needed. This is in agreement with the observations of Carraway et al (2009) who noted that continued studies on renal RFA are needed, especially in regards to oncological outcomes.
A Cochrane systematic evidence review (Nabi et al, 2010) of surgical management of localized RCC found that the main source of evidence for the current practice of laparoscopic excision of renal cancer is drawn from case series, small retrospective studies and very few small randomized controlled trials. "The results and conclusions of these studies must therefore be interpreted with caution." The authors of the systematic evidence review did not identify any randomized trials meeting the inclusion criteria reporting on the comparison between open radical nephrectomy with laparoscopic approach or new modalities of treatment such as RFA or cryoablation. Three randomized controlled trials compared the different laparoscopic approaches to nephrectomy (transperitoneal versus retroperitoneal) and found no statistical difference in operative or peri-operative outcomes between the 2 treatment groups. There were several non-randomized and retrospective case series reporting various advantages of laparoscopic renal cancer surgery such as less blood loss, early recovery and shorter hospital stay.
Sooriakumaran and co-workers (2010) examined the presentation, management and outcomes of patients with renal angiomyolipoma (AML) over a period of 10 years. These investigators evaluated retrospectively 102 patients (median follow-up of 4 years); 70 had tuberous sclerosis complex (TSC; median tumor size of 3.5 cm) and the other 32 were sporadic (median tumor size of 1.2 cm). Data were gathered from several sources, including radiology and clinical genetics databases. The 77 patients with stable disease were followed-up with surveillance imaging, and 25 received interventions, some more than one. Indications for intervention included spontaneous life-threatening hemorrhage, large AML (10 to 20 cm), pain and visceral compressive symptoms. Selective arterial embolization (SAE) was performed in 19 patients; 10 received operative management and 4 had a RFA. Selective arterial embolization was effective in controlling hemorrhage from AMLs in the acute setting (n = 6) but some patients required further intervention (n = 4) and there was a significant complication rate. The reduction in tumor volume was only modest (28 %). No complications occurred after surgery (median follow-up of 5.5 years) or RFA (median follow-up of 9 months). One patient was entered into a trial and treated with sirolimus (rapamycin). The authors concluded that the management of AML is both complex and challenging, especially in those with TSC, where tumors are usually larger and multiple. Although SAE was effective at controlling hemorrhage in the acute setting it was deemed to be of limited value in the longer term management of these tumors. Thus, novel techniques such as focused ablation and pharmacotherapies including the use of anti-angiogenic molecules and mammalian target of rapamycin inhibitors, which might prove to be safer and equally effective, should be further explored.
Radiofrequency ablation has also been used to treat bone metastases. However, there are no adequate clinical studies reported in the literature on the use of RFA of metastatic lesions to bone.
In a review of the evidence on RFA of tumors, Wood et al (2002) concluded that “[m]ore rigorous scientific review, long-term follow-up, and randomized prospective trials are needed to help define the role of RFA [radiofrequency ablation] in oncology.” Rhim (2004) noted that although RFA represents a paradigm shift in local therapy for many commonly seen tumors, more sophisticated strategies to enhance the therapeutic effectiveness are needed and more randomized, controlled trials to estimate its clinical benefit are warranted. de Baere (2005) stated that RFA, although very efficient in local tumor control, has neither proven to prolong survival or to be equivalent to surgery in randomized trial, even if some retrospective studies have done so. Further studies are needed to evaluate the exact benefit of this promising technique.
Barrett's esophagus (BE) is defined as the presence of specialized intestinal metaplasia within the tubular esophagus, and is the pre-malignant precursor of esophageal adenocarcinoma. Esophageal cancer is one of the most deadly gastro-intestinal cancers with a mortality rate over 90 %. The principal risk factors for esophageal adenocarcinoma are gastro-esophageal reflux disease (GERD) and its sequela, BE. Gastro-esophageal 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 (Feagins and Souza, 2005).
A new method of endoscopic ablation of BE is balloon-based, bipolar RFA (Stellartech Research Coagulation System; BARRx, Inc, Sunnyvale, CA), 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 (Johnson, 2005). 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 RF generator and a pre-selected amount of energy is delivered in less than 1 second at 350 W.
In a review of evidence on ablative techniques for BE, Johnston (2005) 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 are 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.
Hubbard and Velanovich (2007) 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 post-fundoplication 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.
- all biopsy specimen fragments obtained at the last biopsy session were negative for HGD (CR-HGD),
- all biopsy specimens were negative for any dysplasia (CR-D), and
- all biopsy specimens were negative for IM (CR-IM).
Shaheen and colleagues (2009) 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-to-treat 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.
- 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,
- 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,
- 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,
- 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, and
- 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.
- is complete response after ablation maintained over time, thus reducing the risk of progression to high-grade dysplasia or cancer?,
- will ablation improve patients' quality of life and decrease costs, as compared with the surveillance strategy?, and
- can we define a stratification index predicting disease progression or response to therapy?
Furthermore, the American College of Gastroenterology's updated guidelines for the diagnosis, surveillance and therapy of BE (Wang and Sampliner, 2008) 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".
Yeh and Triadafilopoulos (2005) noted that a wide variety of endoscopic mucosal ablative techniques have been developed for early esophageal neoplasia. However, long-term control of neoplasic risk has not been demonstrated. The authors explained that most studies show that specialized intestinal metaplasia may persist underneath neo-squamous mucosa, posing a risk for subsequent neoplastic progression.
Shaheen (2005) noted that the pathogenesis of BE is poorly understood. Given that some patients will have repeated bouts of severe erosive esophagitis and never develop BE, host factors must play an important role. The author stated that the utility of neoadjuvant radiation and chemotherapy in those with adenocarcinoma, although they are widely practiced, is not of clear benefit, and some authorities recommend against it. Ablative therapies, as well as endoscopic mucosal resection, hold promise for those with superficial cancer or high-grade dysplasia. The author noted that most series using these modalities feature relatively short follow-up; longer-term studies are needed to better ascertain the effectiveness of these treatments.
Pedrazzani et al (2005) evaluated the effectiveness of 90 W argon plasma coagulation (APC) for the ablation of BE that is considered to be the main risk factor for the development of esophageal adenocarcinoma. They found that high-power setting APC showed to be safe. The effects persist at a mean follow-up period of 2 years with a comparable cost in term of complications with respect to standard power settings. The authors stated, however, that further studies with greater number of patients are required to confirm these results and to assess if ablation reduces the incidence of malignant progression.
Hage et al (2005) stated that although endoscopic removal of BE by ablative therapies is possible in the majority of patients, histologically complete elimination can not be achieved in all cases. Persistent BE may still harbor molecular aberrations and must therefore be considered still to be at risk of progression to adenocarcinoma.
Guidelines on thyroid cancer from the National Comprehensive Cancer Network (NCCN, 2010) state that distant metastases from recurrent or persistent medullary thyroid carcinoma that are causing symptoms (e.g., those in bone) could be considered for pallative resection, RFA, or other regional treament. The guidelines state that these interventions may also be considered for asymptomatic distant metastases (especially for progressive disease) but observation is acceptable, given the lack of data regarding alteration in outcome.
Monchik and colleagues (2006) evaluated the long-term effectiveness of RFA and percutaneous 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 of 17.0 mm; range of 8 to 40 mm), while 6 had ultrasound-guided EtOH injection treatment (mean size of 11.4 mm; range of 6 to 15 mm). Four patients underwent RFA treatment of focal distant metastases from WTC; 3 of these patients had computed tomography (CT)-guided RFA of bone metastases (mean size of 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 play in the treatment of recurrent WTC.
The Food and Drug Administration (FDA) has issued a Public Health Notification as clarification for healthcare providers that no RFA devices are specifically approved for use in partial or full ablation of lung tumors (2008). This notification was sent in follow-up to an earlier notice in December 2007, which indicated that a number of deaths have been associated with the use of RFA for lung tumors. Radiofrequency ablation devices are minimally invasive tools used for general removal of soft tissue, such as those that contain cancer cells. It is an image-guided technique that heats and destroys cancer cells. Imaging techniques such as ultrasound (US) and CT are used to help guide a needle electrode into a cancerous tumor. High-frequency electrical currents are then passed through the electrode, creating heat that destroys the abnormal cells.
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. Under this general indication, RFA can be used as a tool to ablate tumors, including lung tumors. In addition, some RFA devices have been cleared for additional specific treatment indications, including partial or complete ablation of non-resectable liver lesions, and palliation of pain associated with metastatic lesions involving bone. Clearance for specific treatment indications requires the submission of clinical data to justify the indications by showing that the device, when used on a well-defined target population, consistently achieves the desired treatment effect.
As sufficient clinical data has not been submitted, the FDA emphasizes that it has not cleared any RFA devices for the specific treatment indication of partial or complete ablation of lung tumors. Therefore, FDA regulations prevent manufacturers from marketing or promoting the devices for this treatment, which would also include specific training programs; this does not apply to training available from sources other than the manufacturer. The FDA has received reports of death and serious injuries associated with the use of RFA devices in treatment of lung tumors. The actual rate of these adverse events is unknown because no pre-market clinical data have been obtained. It is unclear if these deaths or injuries occur more frequently with RFA devices than with other forms of treatment for lung tumors. These adverse events could be related to a number of factors, including patient selection and management, technical use of the RFA device, post-procedural treatments, and management of complications.
The FDA urges all clinicians to use MedWatch, the FDA’s voluntary reporting program, to report any adverse events related to this or any other device at: FDA MedWatch.
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, treatment availability.)"
The guidelines (NCCN, 2010) also recommend the use of RFA for the treatment of gastro-intestinal stromal tumors with limited progression. Progression is defined as a new lesion or increase in tumor size. The NCCN guidelines state that, for limited progressive disease that is potentially easily resectable, surgical resection should be considered. Other treatment options include RFA or embolization.
In an open-label, pilot study, Steel et al (2011) examined the safety of endobiliary bipolar RFA in patients with malignant biliary obstruction and reported the 90-day biliary patency of this novel procedure. Main outcome measures were immediate and 30-day complications as well as 90-day stent patency. A total of 22 patients (16 pancreatic, 6 cholangiocarcinoma) were includedin this study. Deployment of an RFA catheter was successful in 21 patients. Self-expandable metal stents (SEMSs) placement was achieved in all cases of successful RFA catheter deployment. One patient failed to demonstrate successful biliary decompression after SEMS placement and died within 90 days. All other patients maintained stent patency at 30 days. One patient had asymptomatic biochemical pancreatitis, 2 patients required percutaneous gallbladder drainage, and 1 patient developed rigors. At 90-day follow-up, 1 additional patient had died with a patent stent, and 3 patients had occluded biliary stents. The authors concluded that endobiliary RFA treatment appears to be safe. They stated that randomized studies with prolonged follow-up are needed.
Lee and colleagues (2008) noted that Brunner's gland hyperplasia is a benign tumor of the duodenum and it is rarely associated with clinical symptoms. These investigators reported on the case of a 64-yr old man with Brunner's gland hyperplasia who had undergone a duodenocephalo-pancreatectomy. The reason was that he presented upper gastro-intestinal obstructive symptoms and the esophago-gastroduodenoscopic finding revealed the lesion to be an infiltrating type mass on the second portion of the duodenum with luminal narrowing. An abdominal computed tomography showed a 2.5 cm-sized mass in the duodenal second portion with a suspicious pancreatic invasion and 7 mm-sized lymph node around the duodenum. Duodenocephalo-pancreatectomy was successfully performed. Histological examination revealed a Brunner's gland hyperplasia. The final diagnosis was the co-existence of Brunner's gland hyperplasia and pancreatic heterotopia with a pancreatic head invasion. These researchers (2008) stated that there is no consensus on the treatment of Brunner's gland hyperplasia because follow-up study is insufficient. The medical treatment is to control gastric hyper-acidity, which is one cause of Brunner's gland hyperplasia. However, the regression of Brunner's gland hyperplasia is rare. Thus, excision appears to be the treatment of choice. Lee and associates (2008) recommended complete removal of the lesion by endoscopic resection or surgical resection when Brunner's gland hyperplasia results in symptoms and complications or when definite diagnosis is necessary. There is a lack of evidence on RFA as a treatment for Brunner's gland hyperplasia.
Stewart et al (2009) stated that Brunner's gland hamartomas (BGHs) are uncommon benign tumors of the duodenum forming mature Brunner's glands. These researchers reported an unusual case of a giant BGH that was not amenable to endoscopic or surgical local resection; thus requiring a pancreatico-duodenectomy for extirpation.
Euanorasetr and Sornmayura (2010) noted that BGHs are uncommon benign tumor of the duodenum. Most lesions are small and asymptomatic. Occasionally, those lesions may be large and manifest as a rare cause of upper gastro-intestinal hemorrhage or duodenal obstruction. The authors reported 2 cases of BGHs presenting with upper gastro-intestinal hemorrhage that were not amenable to endoscopic polypectomy; thus requiring surgical resection.
Kroon et al (2011) summarized the consensus developed by a group of Australasian subspecialists in reproductive endocrinology and infertility (the ACCEPT group) on the evidence concerning the impact and management of fibroids in infertility. The location of a fibroid within the uterus influences its effect on fertility. Subserosal fibroids do not appear to impact on fertility outcomes. Intra-mural (IM) fibroids may be associated with reduced fertility and an increased miscarriage rate (MR); however, there is insufficient evidence to inform whether myomectomy for IM fibroids improves fertility outcomes. Submucosal fibroids are associated with reduced fertility and an increased MR, and myomectomy for submucosal fibroids appears likely to improve fertility outcomes. The relative effect of multiple or different sized fibroids on fertility outcomes is uncertain, as is the relative usefulness of myomectomy in these situations. It is recommended that fibroids with suspected cavity involvement are defined by magnetic resonance imaging, sonohysterography or hysteroscopy because modalities such as trans-vaginal ultrasound and hysterosalpingography lack appropriate sensitivity and specificity. Medical management of fibroids delays efforts to conceive and is not recommended for the management of infertility associated with fibroids. Newer treatments such as uterine artery embolization, RFA, bilateral uterine artery ligation, magnetic resonance-guided focussed ultrasound surgery and fibroid myolysis require further investigation prior to their establishment in the routine management of fibroid-associated infertility.
Fegrachi et al (2014) noted that median survival in patients with unresectable locally advanced pancreatic cancer lies in the range of 9 to 15 months. Radiofrequency ablation may prolong survival, but data on its safety and effectiveness are scarce. These investigators performed a systematic literature search in PubMed, EMBASE and the Cochrane Library with the syntax '(radiofrequency OR RFA) AND (pancreas OR pancreatic)' for studies published until January 1, 2012. In addition, a search of the proceedings of conferences on pancreatic disease that took place during 2009 to 2011 was performed. Studies with fewer than 5 patients were excluded as they were considered to be case-reports. The primary endpoint was survival; secondary endpoints included morbidity and mortality. A total of 5 studies involving a total of 158 patients with pancreatic cancer treated with RFA fulfilled the eligibility criteria. These studies reported median survival after RFA of 3 to 33 months, morbidity related to RFA of 4 to 37 %, mortality of 0 to 19 % and overall morbidity of 10 to 43 %. Pooling of data was not appropriate as the study populations and reported outcomes were heterogeneous. Crucial safety aspects included ensuring a maximum RFA tip temperature of less than 90°C and ensuring minimum distances between the RFA probe and surrounding structures. The authors concluded that RFA seems to be feasible and safe when it is used with the correct temperature and at an appropriate distance from vital structures. It appears to have a positive impact on survival. Moreover, they stated that multi-center randomized trials are needed to determine the true effect size of RFA and to minimize the impacts of selection and publication biases.
In a phase II clinical trial, Takaki et al (2013) evaluated the safety and effectiveness of RFA with a multiple-electrode switching system for the treatment of RCC. From November 2009 to December 2010, a total of 33 patients (mean age of 70.7 years; range of 44 to 86 years) with histologically proved RCCs -- including 24 men (mean age of 69.5 years [range of 44 to 86 years]) and 9 women (mean age of 74.1 years [range of 64 to 83 years]) -- were enrolled in this study. The institutional review board approved the study after patients provided written informed consent. The mean maximum tumor diameter was 2.9 cm ± 1.0 (standard deviation) (range of 1.5 to 5.0 cm). Radiofrequency ablation was conducted with a multiple-electrode switching system. The primary end-point was evaluated with the Common Terminology Criteria for Adverse Events. Secondary end-points were changes in renal function, technique effectiveness, local tumor progression, and survival. Changes in renal function were evaluated by using the Mann-Whitney U test. No severe adverse events occurred, but 3 of 33 patients (9 %) had grade-2 adverse events. Although the mean glomerular filtration rate at 1 year after RFA was similar to the baseline value in 26 patients with bilateral kidneys (p = 0.14), it was decreased significantly in 6 patients with a single kidney (p = 0.03). Tumor enhancement disappeared after a single RFA session in 31 patients and after 2 RFA sessions in the other 2 patients (rates of primary and secondary technique effectiveness, 94 % [31 of 33] and 100 % [33 of 33], respectively). No local tumor progression was found during the mean follow-up of 20.0 months (range of 11.6 to 27.6 months). The respective 1-year overall and RCC-related survival rates were 97 % (95 % confidence intervals [CI]: 91 % to 100 %) and 100 %. The authors concluded that RFA with a multiple-electrode switching system is safe and effective for treatment of RCCs. Moreover, they stated that further study is needed to examine if this technology is superior to other previously described methods.
Gunjur et al (2014) systematically reviewed the literature on the use of surgery, stereotactic ablative body radiotherapy (SABR) and percutaneous catheter ablation (PCA) techniques for the treatment of adrenal metastases to develop evidence-based recommendations. A systematic review of the MEDLINE database was performed using structured search terms following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible publications were those published from 1990 to 2012, written in English, had at least 5 patients treated for adrenal metastasis and reported on patient clinical outcomes (local control, survival and treatment related complications/toxicity). Where possible, these researchers analyzed pooled 2-year local control and overall survival outcomes. Their search strategy produced a total of 45 papers addressing the 3 modalities - 30 adrenalectomy, 9 SABR and 6 PCA (818, 178 and 51 patients, respectively). There was marked heterogeneity in outcome reporting, patient selection and follow-up periods between studies. The weighted 2-year local control and overall survival for adrenalectomy were 84 % and 46 %, respectively, compared with 63 % and 19 %, respectively for the SABR cohort. Only 1 study of PCA with 5 patients analyzed clinical outcomes, reporting an actuarial local control of 80 % at 1 year. Treatment related complications/toxicities were inconsistently reported. The authors concluded that there is insufficient evidence to determine the best local treatment modality for isolated or limited adrenal metastases from any primary tumor. Published data suggested adrenalectomy to be a reasonable treatment approach for isolated adrenal metastasis in suitable patients; SABR is a valid alternative in cases when surgery is not feasible or the operative risk is unacceptable. They stated that PCA (including RFA) cannot be recommended until there are more robust studies that include long-term oncological outcomes.
Paliogiannis et al (2014) described a case of successful RFA of an unresectable stage III-type B3 thymoma, and discussed the role of this novel approach in the management of patients with advanced stage thymoma. The patient, a 59-year old Caucasian male underwent neoadjuvant chemotherapy with only a slight reduction of the mass. Subsequently, an explorative sternotomy and debulking were performed; before closing the thorax, RFA of the residual tumor was carried out and a partial necrosis of the mass was achieved. A further percutaneous RFA was performed subsequently, obtaining complete necrosis of the lesion. Successively, the patient underwent adjuvant radiotherapy. As a result of this multi-disciplinary treatment, complete and stable response was obtained. It is hard to say which of the single treatments had the major impact on cure; nevertheless, the results obtained suggest that RFA must be taken into account for the treatment of advanced stage thymomas, and its effectiveness must be further assessed in future studies.
Dierselhuis et al (2014) stated that atypical cartilaginous tumors are usually treated by curettage. In a proof-of-principle study, these researchers showed that RFA was an effective alternative treatment. They enrolled 20 patients (2 males, 18 females, mean age of 56 years (36 to 72). After inclusion, biopsy and RFA were performed, followed 3 months later by curettage and adjuvant phenolization. The primary end-point was the proportional necrosis in the retrieved material. Secondary end-points were correlation with the findings on gadolinium enhanced magnetic resonance imaging (MRI), functional outcome and complications. The results showed that 95 % to 100 % necrosis was obtained in 14 of the 20 patients; MRI had a 91 % sensitivity and 67 % specificity for detecting residual tumor after curettage. The mean functional outcome (MSTS) score 6 weeks after RFA was 27.1 (23 to 30) compared with 18.1 (12 to 25) after curettage (p < 0.001). No complications occurred after ablation, while 2 patients developed a pathological fracture after curettage. These researchers showed that RFA is capable of completely eradicating cartilaginous tumor cells in selective cases; MRI has a 91 % sensitivity for detecting any residual tumor. The authors concluded that RFA can be performed on an out-patient basis allowing a rapid return to normal activities. If it can be made more effective, it has the potential to provide better local control, while improving functional outcome.
Cobianchi et al (2014) noted that desmoid tumors are benign, myofibroblastic stromal neoplasms common in Gardner's syndrome, which is a subtype of familial adenomatous polyposis characterized by colonic polyps, osteomas, thyroid cancer, epidermoid cysts, fibromas and sebaceous cysts. The primary treatment is surgery, followed by adjuvant radiotherapy, but the local recurrence rate is high, and wide resection can result in debilitating loss of function. These investigators reported the case of a 39-year old man with Gardner's syndrome who had already undergone a total prophylactic colectomy. He developed desmoid tumors localized in the mesenteric root, abdominal wall and dorsal region, which were treated from 2003 through 2013 with several surgical procedures and percutaneous RFA. In 2008 and 2013, RFA was applied under ultrasonographic guidance to 2 desmoid tumors localized in the dorsal thoracic wall. The outcomes were low-grade pain and 1 case of superficial skin necrosis, but so far there has been no recurrence of desmoid tumors in these locations. The authors concluded that surgical resection remains the first-line therapy for patients with desmoid tumors, but wide resection may lead to a poor quality of life. They stated that RFA is less invasive and expensive and is a possible therapeutic option for desmoid tumors in patients with Gardner's syndrome. Well-designed studies are needed to ascertain the effectiveness of RFA in the treatment of desmoid tumors.
Furthermore, an UpToDate review on “Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy” (Ravi et al, 2015) does not mention RFA as a therapeutic option.
The American Society for Gastrointestinal Endoscopy’s guideline on “The role of endoscopy in the assessment and treatment of esophageal cancer” (Evans et al, 2013) stated that “APC [argon plasma coagulation], heater probe, cryotherapy, or radiofrequency ablation as monotherapy with curative intent for mucosal esophageal cancer was considered but not recommended”.
Also, an UpToDate review on “Management of superficial esophageal cancer” (Wright and Saltzman, 2015) states that “Radiofrequency ablation -- A specialized circumferential device for delivering radiofrequency energy to ablate Barrett's esophagus is available and has promising initial results in patients with dysplastic Barrett's epithelium (the Halo system). A potential role for RFA in conjunction with ER for the treatment of early intramucosal esophageal cancer arising in the setting of Barrett’s esophagus has been suggested but experience is limited”.
Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Esophageal and esophagogastric junction cancers” (Version 3.2015) only mentions the use of RFA as an option for the treatment of Barrett’s esophagus with high-grade dysplasia. It does not mention the use of RFA as a therapeutic option for esophageal and esophagogastric junction cancers.
Guidelines on adult cancer pain from the National Comprehensive Cancer Network (NCCN, 2015) state that radiofrequency ablation may be used to reduce bone pain and prevent skeletal related events."Radiofrequency ablation of bone lesions has proven successful in pain management, especialy for those failing to achieve adequate analgesia without intolerable side effects."
Unresectable Localized Recurrence of Thyroid Cancers
- 3 or fewer recurrences or lesions with high probability of recurrence at ultrasonography;
- no tumor other than the target tumors; and
- at least 1 year of follow-up.
Zhao and colleagues (2016) evaluated the effectiveness of ultrasound (US)-guided RFA for localized recurrent thyroid cancers. These investigators performed a systematic review and meta-analysis of the scientific literature by searching the PubMed, Embase, Web of Science, Scopus and the Cochrane Library up to November 26, 2015. They assessed the pooled standard mean difference (SMD) of nodule volume, largest diameter and serum thyroglobulin (Tg) level by comparing pre-RFA with post-RFA using fixed or random-effects model. The Newcastle-Ottawa Scale was used to evaluate the methodological quality of the included studies, risk of bias in the selective populations, comparability of groups and exposure. These researchers identified 9 articles including 189 patients (54 males and 135 females) with 255 tumor lesions, who underwent US-guided RFA beyond the mean 6 months of follow-up. The results showed that tumor volume (SWD: 0.77, 95 % CI: 0.57 to 0.97, I2 = 25.9 %, p = 0.231), largest diameter (SWD: 1.56, 95 % CI: 0.94 to 2.17, I2 = 82.6 %, p < 0.001) and Tg level (SWD: 0.52, 95 % CI: 0.30 to 0.73, I2 = 0 %, p = 0.493) were decreased and no significant publication bias was detectable. The authors concluded that the pooled data indicated that the prognosis improved for patients with localized recurrent thyroid cancers and RFA is a promising treatment for these patients with infeasible surgery.
- EBRT or IMRT;
- vandetanib; or
- cabozantinib”.
Breast Cancer
Agnese and Burak (2005) stated that ablative therapies, including RFA have been shown promise in the treatment of small cancers of the breast. However, more research is needed to ascertain the 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. van der Ploeg et al (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 breast conserving therapies.
Grotenhuis et al (2013) summarized the reported treatment outcomes of ultrasound-guided RFA for early-stage breast cancer and high-lighted practical considerations with regard to this treatment. A search of the English-language literature concerning RFA for breast cancer treatment was performed. Radiofrequency ablation is a technique that can be safely applied in patients with early-stage breast cancer, which is restricted to cT1-T2N0 ductal carcinoma with radiologically defined borders without any signs of multi-focality or multi-centricity. However, before RFA can be adopted as local therapy for early-stage breast cancer, more research is needed to assess the post-treatment pathological complete response and margin status, the long-term oncologic outcome in comparison to current standard breast conserving therapy and the potential cosmetic superiority of percutaneous RFA. The authors concluded that RFA appeared to be a feasible technique for the treatment of early-stage breast cancer, but considerable practical considerations form an obstacle to introduce RFA as a standard of care.
Li and co-workers (2016) evaluated the safety and effectiveness of US-guided percutaneous RFA for multiple breast fibro-adenoma as an alternative to surgical resection. A total of 65 patients with multiple breast fibro-adenoma accepted general anesthesia and US-guided percutaneous RFA in the authors’ hospital from September 2014 to January 2016 were included in this study. Contrast-enhanced US (CEUS) was used immediately after operation to examine if the tumor was ablated completely. The complete ablation rate (CAR) and the change of focal volume were evaluated by CEUS at the 1st month and the 3rd month after operation. All the patients were diagnosed by needle biopsy. Among all the patients, 256 nodules were found; 46 nodules (17.96 %) were located less than 5 mm from epidermis; 26 nodules (10.15 %) were located below areola. Complete ablation was achieved for 251 nodules (98.04 %) after the 1st month of operation. The volume reduce rate was 39.06 % and 75.99 % at the 1st and the 3rd month after operation, respectively, of which 45 nodules were completely absorbed (17.58 %). There was a statistically significant difference of the volume reduction rate (VRR) after operation (p < 0.01) compared with pre-operative breast nodules volume. There were no complications such as skin burn, hemorrhage, and hematoma, nipple discharge in the process during and after RFA. The authors concluded that given advantages of high CAR, mild injury, rapid recovery, and cosmetic outcome desired by the patients, RFA has the potential to become the preferred method in the treatment of breast fibro-adenoma.
Peek and colleagues (2017) performed a systematic review and meta-analysis to evaluate the current evidence for clinical outcomes with minimally invasive ablative techniques in the non-surgical treatment of breast cancer. A systematic search of the literature was performed using PubMed and Medline library databases to identify all studies published between 1994 and May 2016. Studies were considered eligible for inclusion if they evaluated the role of ablative techniques in the treatment of breast cancer and included ten patients or more. Studies that failed to fulfil the inclusion criteria were excluded. These researchers identified 63 studies including 1,608 patients whose breast tumors were treated with RFA, high intensity focused ultrasound (HIFU), cryoablation, laser ablation, or microwave ablation. A total of 50 studies reported on the number of patients with complete ablation as found on histopathology and the highest rate of complete ablation was achieved with RFA (87.1 %, 491/564) and microwave ablation (83.2 %, 89/107). Short-term complications were most often reported with microwave ablation (14.6 %, 21/144). Recurrence was reported in 24 patients (4.2 %, 24/570) and most often with laser ablation (10.7 %, 11/103). The shortest treatment times were observed with RFA (15.6 ± 5.6 mins) and the longest with HIFU (101.5 ± 46.6 mins). The authors concluded that minimally invasive ablative techniques are able to successfully induce coagulative necrosis in breast cancer with a low side effect profile. Moreover, they stated that adequately powered and prospectively conducted cohort trials are needed to confirm complete pathological ablation in all patients.
Fleming and associates (2017) examined the potential techniques for percutaneous ablation of breast cancer, discussed the advantages and disadvantages of each technique, and provided results from recent studies on these technologies. The techniques discussed are cryotherapy, laser irradiation, microwave irradiation, RFA, HIFU ablation, and irreversible electroporation. The authors concluded that although percutaneous ablation techniques have some promising potential for less-invasive treatment of breast cancer, larger multi-center trials are needed to confirm their effectiveness, especially in comparison with the reference standard of lumpectomy. The use of these techniques also led to other remaining unanswered questions, including how to manage the axilla and which patients are the best candidates for these treatments.
In a prospective, randomized, open-label, phase-II clinical trial, García-Tejedor and colleagues (2018) compared the safety and efficacy of US-guided percutaneous RFA as a local treatment for breast cancer with that of lumpectomy. This trial was conducted in a single institution from 2013 to 2017. Women with invasive ductal carcinoma of the breast measuring 2 cm or smaller were randomly assigned to receive RFA or lumpectomy alone (control group). Margin status at surgery, tumor cell viability after RFA (with nicotinamide adenine dinucleotide [NADH] and cytokeratin 18 [CK18] staining), cosmetic results, adverse events (AEs), and local recurrences were evaluated with uni-variable and multi-variable analyses. A total of 40 subjects (20 in the RFA group and 20 in the lumpectomy group) were evaluated. The mean age of subjects was 64 years (range of 46 to 86 years). NADH and CK18 staining demonstrated absence of tumor cell viability following RFA with at least one of the two techniques. The surgical margins were positive in 11 of the 20 subjects in the lumpectomy group (55 %) and 4 of the 20 in the RFA group (20 %) (p = 0.02). Median follow-up was 25 months (range of 1 to 83 months). Local breast inflammation after surgery was higher in the RFA group than in the lumpectomy group (40 % [8 of 20 participants] versus 5 % [1 of 20 participants], respectively; p = 0.01). Local infection occurred in 3 subjects who underwent RFA (2 of whom had undergone partial irradiation of the breast). None of the subjects in the control group developed local infection. No subjects had recurrence or the need for a 2nd surgery during the study period. The authors concluded that the findings of this preliminary study showed that RFA was effective for local tumor control and that tumor-free margins were obtained more often with RFA than with lumpectomy; surgical excision following RFA was infrequently associated with local infection.
In a retrospective study, Ito and co-workers (2018) examined the safety and efficacy of percutaneous RFA of breast carcinomas. This study was conducted by the Breast Cancer Society for Minimally Invasive Therapy following approval from institutional review boards (IRBs), and with the written informed consent of patients. A total of 386 patients with breast cancer treated with RFA at 10 institutions between July 2003 and June 2009 were identified and included in the analysis. Patients underwent a standard RFA procedure with US guidance and were followed-up every 6 to 12 months. In this study, feasibility of RFA procedure and related safety and ipsilateral breast tumor recurrence (IBTR) were examined. Fisher exact or χ2 test evaluated associations between clinicopathological factors and IBTR, and local recurrence-free survival was estimated using the Kaplan-Meier method. RFA-related AEs included local pain in 9 patients, skin burns in 15, and nipple retraction in 7. Patients were followed for a median of 50 months; IBTR was more frequently observed in patients with initial tumor sizes of greater than 2 cm (3 of 30, 10 %) than in those with initial tumors of less than or equal to 2 cm (8 of 355, 2.3 %; p = 0.015). IBTR-free rates 5 years after RFA were 97 %, 94 %, and 87 % in patients with initial tumor sizes of less than or equal to 1.0 cm, 1.1 to 2.0 cm, and greater than 2.0 cm, respectively. The authors concluded that RFA in breast cancer was a safe and promising minimally invasive treatment for tumors of less than or equal to 2 cm in diameter. These researchers stated that further studies are needed to optimize the technique and evaluate its future role as local therapy.
Kinoshita (2019) noted that early-stage breast cancer is increasingly detected by screening mammography, and these researchers aimed to establish RFA as a minimally invasive, cost-efficient, and cosmetically acceptable local treatment. Although there were many studies on resection after RFA, none of them provided sufficient evidence to support RFA as a standard therapy for breast cancer. In a phase-I clinical trial, localized tumors with a maximum diameter of 2 cm, pre-operatively diagnosed by imaging and histopathology, were treated with RFA. A 90 % complete ablation rate was confirmed histopathologically. A phase-II multi-center clinical trial of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. These investigators started a phase-III, multi-center clinical trial to demonstrate the non-inferiority of RFA compared with standard treatment (breast-conserving surgery [BCS]) in terms of IBTR rate, which is the best index of local control. The authors concluded that to standardize RFA for breast cancer, the results of their multi-center clinical trial, “Radiofrequency Ablation Therapy for Early Breast Cancer as Local Therapy (the RAFAELO study)” that commenced in 2013, are eagerly awaited.
In a systematic review and meta-analysis, Xia and colleagues (2021) examined the safety and effectiveness of RFA of breast cancer smaller than 2 cm. These investigators carried out a systematic search in the PubMed and Embase databases to identify published studies examining the safety and effectiveness of RFA for breast cancer smaller than 2 cm. The main outcomes were technical success rate of the ablation, complete ablation rate, complications and local recurrence. Secondary considerations were mode of anesthesia, pain tolerance, mean ablation time and surgical excision after ablation. A total of 17 studies involving 399 patients and 401 lesions met the inclusion criteria. Nearly 99 % (95 % CI: 0.98 to 1.00) of lesions achieved good technical success rate. Notably, 83.88 % of the patients received RFA under general anesthesia (333/397) whereas 15.87 % received RFA under local anesthesia (63/397). Of the 63, 98.41 % tolerated the pain associated with the procedure. Majority of patients (65.74 %, 261/397) underwent surgical excision of the tumor after ablation whereas in a few patients (34.26 %, 136/397), the tumor tissue was retained in the breast after ablation. Complete ablation was achieved in 96 % of patients for a mean time of 15.8 mins (95 % CI: 0.93 to 0.99). Overall, only 2 % (95 % CI: 0.01 to 0.04) of the individuals developed complications. Skin burns (2.02 %, 8/397) were the most common complications. There was no local recurrence after a median follow-up of 27.29 months, whether or not they underwent surgical resection following RFA. The authors concluded that the findings of this review showed that RFA for breast cancer smaller than 2 cm was safe and effective; however, prospective studies are needed to validate this conclusion.
The authors stated that this meta-analysis had several drawbacks. First, publication bias was found in the studies, possibly because these researchers only included published studies. However, the influence of publication bias was small; and the conclusions were reliable as determined by the trim and fill method. Second, the use of minimally invasive treatments was at the foundational stage and the quality of the findings may be weakened by the small sample size (401 cases). Finally, in the analysis of local recurrence rate, RFA alone was performed in 136 cases and the median follow-up time was 29 months. This implied that the conclusion regarding local recurrence rate in early breast cancer following treatment with RFA being 0 should be interpreted with caution.
Large Renal Angiomyolipoma
Stamatiou and colleagues (2016) reported on the case of a 78-year old male patient with multiple angiomyolipomas of a solitary right kidney. The largest of these tumors (maximum diameter: 13.4 cm) caused significant extrinsic compression of the inferior vena cava complicated by thrombosis of this vessel. Treatment of thrombosis with anti-coagulants had been ineffective and the patient had experienced a bleeding episode from the largest right renal angiomyolipoma, which had been treated by trans-arterial embolization in another institution, 4 months prior to the authors’ intervention. Their approach included superselective transarterial embolization (SAE) of the dominant, right kidney angiomyolipoma with hydrogel microspheres, which was combined, 20 days later, with US-guided RFA; both interventions were uneventful. Computed tomography 2 months after ablation showed a 53 % reduction in tumor volume, reduced space-occupying effect on inferior vena cava, and resolution of caval thrombus; 9 months after intervention the patient has had no recurrence of thrombosis or hemorrhage and no tumor regrowth has been observed. The authors concluded that the combination of SAE and RFA may be a safe and effective option for the treatment of large renal angiomyolipomas. They stated that this combination is worth being assessed in the context of a large study with adequate follow-up.
Renal Cysts
Menezes and colleagues (2016) reported their initial experience with RFA of Bosniak IV renal cysts. From 2010 to 2014, a total of 154 renal tumor cases were treated with percutaneous thermal ablation, of which 10 cases (6.4 %) from 9 patients were complex renal cysts and were treated with RFA. All complex cysts were classified as Bosniak IV (4 women and 5 men; mean age of 63.6 years, range of 33 to 83 years); 1 patient had a single kidney. Lesion size ranged from 1.5 to 4.1cm (mean of 2.5 cm) and biopsy was performed on 4 cysts immediately before the procedure, all of which were malignant (2 clear cell and 2 papillary carcinoma). Mean volume reduction of complex cysts was 25 % (range of 10 to 40 %). No patients required re-treatment with RFA and no immediate or late complications were observed. The follow-up of Bosniak IV cysts had a median of 27 months (IQR, 23 to 38) and no recurrence or significant loss of renal function were observed. The authors concluded that mid-term follow-up of the cases in their database suggested that image-guided percutaneous RFA can treat Bosniak IV cysts with very low complication rates and satisfactorily maintain renal function.
- relatively small sample size (10 cases from 9 patients),
- intermediate follow-up time (mean of 27 months), and
- selection biases due to the retrospective series.
Spinal Metastases
Greenwood and associates (2015) noted that radiation therapy (RT) is the current gold standard for palliation of painful vertebral metastases; and combined RT and ablation may be more effective than either therapy alone in palliating painful metastatic disease to the spine. In a retrospective, single-center study, these researchers evaluated the safety and effectiveness of combined ablation, either RFA or cryoablation, and RT in the treatment of spinal metastases. Medical records of all patients who underwent ablation of spine lesions at a single institution between March 2012 and June 2014 were reviewed; patients treated with both RT and either RFA or cryoablation concurrently were identified. Pain scores before and after RFA were measured with the numerical rating scale (NRS) (0 to 10 point scale) and compared. Procedural complications, changes in general activity level, and pain medication usage after ablation were also recorded. When available, follow-up imaging was evaluated for evidence of residual or recurrent disease. A total of 21 patients with 36 spine metastases were treated with RT and percutaneous ablation concurrently; either RFA (21/22) or cryoablation (1/22); 1 patient received 2 separate RFA treatments. Overall, mean worst pain score (8.0, SD = 2.3) significantly decreased at both 1 week (4.3, SD = 3.1; p < 0.02) and 4 weeks (2.9, SD = 3.3; p < 0.0003). Temporary post-procedural radicular pain occurred after 1 RFA treatment (4.5 %; 1/22); 7 patients had radiation resistant tumors (renal cell, melanoma, or sarcoma). Post-procedural imaging (median of 6 months; range of 2 to 27 months) showed stable treated disease in 12/13 treatments at 3 months and 10/10 at 6 months. The authors concluded that percutaneous ablation and concurrent RT is safe and effective in palliating painful spinal metastases and can be effective in those who have radiation resistant tumor histology.
- the therapeutic effect of vertebral augmentation versus percutaneous ablation cannot be separated in this retrospective study, and
- RT protocols were variable and included both stereotactic body and conventional RT which may have different safety and efficacy profiles.
Madaelil and colleagues (2016) examined the safety and effectiveness of RFA to treat sacral metastases for pain palliation and local tumor control (LTC). An institutional tumor ablation registry was retrospectively reviewed for sacral RFA procedures performed between January 2012 and December 2015. Clinical history, pre-procedural imaging, and procedural details were reviewed to document indication for treatment, primary tumor histology, tumor volumes, presence of concurrent cementoplasty after RFA, and the occurrence of peri-procedural complications. Pain scores before and 4 weeks after the procedure were recorded. Post-procedure imaging was reviewed for imaging evidence of tumor progression. Long-term complications and duration of clinical follow-up were recorded. During the study period, a total of 11 RFA procedures were performed to treat 16 sacral metastases. All procedures were for pain palliation; 4 procedures (36 %; 4 out of 11) were also performed with the intention of achieving LTC in patients with oligometastatic disease. Concurrent cementoplasty was performed in 63 % of cases (7 out of 11). The median pain score decreased from 8 (IQR, 6 to 9.25) at baseline to 3 (IQR, 1.75 to 6.3) 1 month following RFA (p = 0.004). In the 4 patients with oligometastatic disease, LTC was achieved in 3 patients (75 %; 3 out of 4) after a median follow-up of 7.6 months (range of 3.6 to 11.9 months). No acute or long-term complications were documented during the overall median clinical follow-up of 4.7 months (range of 0.9 to 28.7 months). The authors concluded that RFA maybe a safe and potentially effective treatment for patients with painful sacral metastases and can achieve LTC in selected patients. These preliminary findings need to be validated by well-designed studies with larger sample size and longer follow-up.
Rosian and colleagues (2018) stated that metastatic spinal lesions are difficult-to-treat entities that are most commonly associated with pain and severely reduced health-related quality of life (HRQoL). Within the last 5 to 10 years, RFA has emerged as an option in the palliative treatment of vertebral metastases. In a systematic review, these researchers evaluated the safety and effectiveness of RFA, mostly in combination with vertebroplasty, in patients with painful vertebral metastases. These investigators conducted a systematic literature search and a manual search of 5 databases in December 2016. The review applied a methodological framework based on the HTA Core Model. Data on each selected outcome category were synthesized according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) scheme. Risk of bias was assessed using the Institute of Health Economics (IHE) Risk of Bias checklist for case series. These researchers identified 299 citations. After applying the inclusion criteria, a total of 9 studies (4 prospective and 5 retrospective studies) were determined to be eligible. These studies included a total of 583 patients with vertebral metastases who were treated with RFA and, in most cases, received an additional vertebroplasty treatment (n = 437). The studies were categorized as having a moderate-to-high risk of bias. The strength of evidence was found to be "very low" for safety outcomes and could not be assessed for efficacy outcomes. Current evidence suggested that RFA led to significant pain reduction. Furthermore, no major complications occurred when using RFA. The authors concluded that In patients with vertebral metastases who were unresponsive or have contraindications for conventional treatments such as radiation or chemotherapy, RFA was a safe therapy that could be effective to palliate pain. However, there is a substantial lack of evidence to evaluate the applicability of RFA. These researchers stated that further studies are need to determine the exact patient group that would benefit most from the intervention and to compare individual operation techniques (e.g., differences in RFA techniques, vertebroplasty following RFA, etc.). These investigators stated that study registries may serve this purpose well; further evaluations of RFA (in combination with vertebroplasty) for longer-term clinical efficacy and complication rates, in particular evaluations comparing RFA with traditional therapies, e.g., radiation, are desirable.
The authors stated that the major drawback of this review was the low number of included patients and heterogeneity of study characteristics in most of the studies. The low number of patients also hampered comparison of the effectiveness of RFA alone to RFA in combination with vertebroplasty.
Pusceddu and associates (2021) examined the effectiveness of a navigational RFA device with concurrent vertebral augmentation (VA) in the treatment of posterior vertebral body metastatic lesions, which are technically difficult to access. Primary outcomes of the study were evaluation of pain palliation and radiologic assessment of LTC. A total of 35 patients with 41 vertebral spinal metastases involving the posterior vertebral body underwent CT-guided percutaneous targeted RFA, with a navigational RFA device, associated with VA; 21 patients (60 %) had 1 or 2 metastatic lesions (Group A) and 14 (40 %) patients had multiple (more than 2) vertebral lesions (Group B). Changes in pain severity were evaluated by visual analog scale (VAS). Metastatic lesions were evaluated in terms of radiological local control. The procedure was technically successful in all the treated vertebrae. Among the symptomatic patients, the mean VAS score dropped from 5.7 (95 % CI: 4.9 to 6.5) before targeted RFA (tRFA) and to 0.9 (95 % CI: 0.4 to 1.3) after tRFA (p < 0.001). The mean decrease in VAS score between baseline and 1 week follow-up was 4.8 (95 % CI: 4.2 to 5.4). VAS decreased over time between 1 week and 1 year following RFA was similar, suggesting that pain relief was immediate and durable. Neither patients with 1 to 2 vertebral metastases, nor those with multiple lesions, showed radiological signs of local progression or recurrence of the tumor in the index vertebrae during a median follow up of 19 months (4 to 46 months) and 10 months (4 to 37 months), respectively. The authors concluded that treatment of spinal metastases with a navigational RFA device and VA could be used to obtain LTC with immediate and durable pain relief, providing effective treatment in the multi-modality management of difficult-to-reach spinal metastases. Moreover, these researchers stated that further studies with larger cohorts are needed to establish the optimal role of tRFA and VA in association with radiotherapy in the multi-disciplinary treatment of vertebral metastases.
The authors stated that this study had several drawbacks, the main one being its retrospective nature and the small sample size (n = 35 subjects). Moreover, the overlapping with radiation therapy in some patients and the use of drugs for pain relief, may have influenced the VAS score. To the best of the authors’ knowledge, this was the 1st single-center report from a European institution on the use of a navigational system for the tRFA of vertebral metastases.
In a systematic review and meta-analysis, Murali and colleagues (2021) examined the effectiveness of RFA, with the scope of using it as front-line management of spinal metastases. Electronic databases were searched (to July 2020) for studies evaluating RFA treatment for spinal metastases in adults. Measured outcomes were pain (primary), disability, HRQoL, complications, tumor control and mortality. Study inclusion, data extraction and risk of bias using the ROBIN-I tool were assessed. Meta-analysis was conducted for pooled results with homogeneity, and narrative synthesis was conducted otherwise. A total of 15 studies were included; RFA reduced pain scores at 3 to 5 weeks [SMD 2.24, 95 % CI: 1.55 to 2.93], 3 to 4 months (SMD 3.00, 95 % CI: 1.11 to 4.90) and 5 to 6 months (SMD 3.54, 95 % CI: 1.96 to 5.11). RFA was effective in reducing disability/improving HRQoL in the short-term; however, longer-term effectiveness remains unclear; 13.2 % cases reported LTC failure (2.5 months to 5 years follow-up) whereas mortality was 23.6 % (follow-up of up to 1 year). The authors concluded that low-quality evidence has proven RFA to be safe and effective in reducing pain and disability, especially in the short-term. These researchers stated that RFA may be routinely implemented in all cases involving refractory pain or radiotherapy-resistant tumors; however, controlled trials are needed to compare the effectiveness of RFA to current frontline treatments.
The authors stated that currently, RFA is not part of NICE guidelines in the management of spinal metastases and is only used infrequently in the UK. This systematic review has found evidence that RFA is a safe procedure which is effective in pain and disability reduction, especially in the short-term. There is also some weak evidence on the benefits of RFA being combined with radiotherapy. Though there was a variety of tumor histology in each study, these investigators believed the collated study population represented typical oncological patients who may present with spinal metastases, since many different primary tumors can metastases to the spine. With these results in mind, RFA could potentially be implemented as a treatment for refractory pain following conventional analgesia and radiotherapy, usually followed by vertebral cement augmentation as this was common practice across all included studies. Moreover, these researchers stated that RCTs are needed to definitively examine the effectiveness of RFA compared to standard treatments such as radiotherapy by providing higher quality evidence on the true effectiveness of RFA on clinical outcomes, especially tumor control and mortality (e.g., survival analyses and including cause of death). This would provide higher quality evidence on how RFA could be used alongside or even ahead of radiotherapy. Such trials could also include subjects with a specific primary tumor only (e.g., targeting spinal metastases in a typically radio-resistant tumor such as renal cell carcinoma). Without such trials, it is difficult to determine the role of RFA treatment ahead of current standard treatments such as radiotherapy.
Benign Thyroid Nodules
Li and co-workers (2016) evaluated the safety and efficacy of US-guided percutaneous bipolar RFA (BRFA) of benign thyroid nodules (BTNs) by comparison with a matched untreated control group. A total of 35 patients who were subjected to a single session of US-guided percutaneous BRFA (Group A) for BTNs were compared with those in 35 untreated patients (Group B) with benign nodules. The benign nature of all the nodules was confirmed by US-guided fine-needle aspiration biopsy (FNAB), and all the patients had normal thyroid functions. BRFA was performed with a bipolar electrode (CelonProSurge 150-T20) with an output power of 20 W. Nodule volume, thyroid function and clinical symptoms of all the patients were compared before treatment and during follow-up. In Group A, the BRFA procedures were completed with a mean time of 10.02 ± 3.30 minutes (range of 5.47 to 16.03) and with a mean total energy deposition of 10,747 ± 3,704 J (range of 5,510 to 17,770 ). The procedures were well-tolerated in all the patients without causing any major complications. At the 6-month follow-up, all of the nodule volume decreased significantly (from 8.81 ± 8.66 to 1.59 ± 1.55 ml, p < 0.001) in Group A, whereas the nodule volume increased from 6.90 ± 3.77 to 7.87 ± 3.95 ml in Group B (p < 0.001). All (100 %) the 35 nodules in Group A had volume reduction ratios (VRRs) of greater than 50 %, among which 3 (8.57 %) had VRRs greater than 90 %. In Group A, the clinical symptoms of the patients who had symptoms before BRFA disappeared, whereas in Group B, the patients had no resolution of clinical symptoms at the 6-month follow-up. The authors concluded that US-guided percutaneous BRFA appeared to be a safe and effective method for the treatment of BTNs; it may gain a wide use in clinical practice. Moreover, they stated that a prospective, multi-center trial with larger sample size and longer follow-up is needed to confirm these findings.
The authors stated that this study had several drawbacks. First, only 35 patients were included in both groups, thus future studies with more patient numbers is needed. Second, no nodule disappeared after BRFA at the 6-month follow-up in this study. The follow-up was relatively short, and long-term results were not available at the current stage. Lastly, the technique of BRFA was not compared directly with laser ablation, microwave ablation or surgery.
In a retrospective, single-center study, Cesareo and associates (2017) evaluated the clinical outcomes and safety of RFA for BTNs over a 1-year follow-up. A total of 48 patients with solid, non-functioning BTNs were treated by RFA using a 17-G internally cooled electrode. These investigators categorized thyroid nodules as small (less than or equal to 12 ml), medium (12 to 30 ml), or large (over 30 ml); BTNs volume reduction, thyroid function, cosmetic and compressive score changes and side effect evaluation at 6 and 12 months were evaluated. BTN volume decreased significantly from baseline to 6 (mean percentage decrease of BTN volume was 66.8 ± 13.6 %, p < 0.001). At 12 months, the mean percentage reduction of BTN volume compared to 6 months was 13.7 ± 17.1 % (p < 0.001). At 6-month, symptom score had improved significantly (p < 0.001) while it did not change significantly between 6 and 12 months. In particular, symptom score improved significantly in the medium (p < 0.001) and large (p < 0.01) subgroups. Cosmetic score improved significantly between baseline and 6 months (p < 0.001) and between 6 and 12 months (p < 0.01). In all the subgroups, cosmetic score improved significantly between baseline and 6 months, while between 6 and 12 months it improved significantly only in the large group (p < 0.05); RFA was well-tolerated; only 1 patient experienced permanent right para-median vocal cord palsy. The authors concluded that the findings of this study showed that a single RFA treatment was effective in reducing BTN volume. Moreover, larger BTNs appeared to be less responsive and perhaps in these cases a further RFA treatment should be used to get all the desired clinical and radiological outcomes. Cosmetic score improved in all treated BTNs, while symptom score got better only in medium and large BTN. They stated that RF ablation can be a valuable and generally safe tool for the non-surgical management of BTNs; other large and prospective studies are needed to confirm these findings. Moreover, these researchers noted that this study had several drawbacks; in particular, this was a retrospective study and the follow-up period was quite short (12 months).
In a systematic review, Wang and colleagues (2017) examined if RFA is a safe treatment modality for BTNs. PubMed, Embase, and the Cochrane Library database were searched for articles that targeted human beings and had a study population with BTNs that were confirmed by FNA cytology and/or core needle biopsy. A total of 32 studies relating to 3,409 patients were included in this systematic review. Based on literatures, no deaths were associated with the procedure, serious complications were rare, and RFA appeared to be a safe and well-tolerated treatment modality. However, a broad spectrum of complications offered insights into some undesirable complications, such as track needle seeding and Horner syndrome. The authors concluded that RFA appeared to be a safe and well-tolerated treatment modality for BTNs; more research is needed to characterize the complications of RFA for thyroid nodules.
The authors stated that this study had several drawbacks. First, the criteria used to define complications and the time sequences were different as the patients came from different centers with their own criteria. Only 1 retrospective study defined these terms according to the standardized terminology for image-guided tumor ablation from the Society of Interventional Radiology. Second, post-RFA thyroid complications were rarely recorded systematically. Even in large thyroid RFA series, complications were either not reported or were mentioned to be limited. Such results could reflect the inconsistent definitions of complications, and teams who performed RFA with undesirable consequences may be unwilling to publish their results. Moreover, case reports or case series of minor or previously reported complications were not typically accepted by journals. Third, the absence of randomized controlled trials (RCTs) and the availability of only 2 retrospective studies designed to record thyroid RFA complications as the primary aim prevented a meta-analysis from being performed. Moreover, a majority of the articles had an observational design, which precluded the ability to comment on the precise risks and causes of complications.
Furthermore, an UpToDate review on “Diagnostic approach to and treatment of thyroid nodules” (Ross, 2018) states that “Ablation techniques -- Benign, autonomous, and cystic thyroid nodules can be treated by ultrasound-guided injection of ethanol or sclerosing agents and by ultrasound-directed physical energy. These approaches have not gained widespread acceptance in the United States, because of potential complications, including occasional reports of prolonged pain after the procedure”.
Muhammad and colleagues (2021) stated that benign thyroid nodules (BTNs) are commonly found in the general population. They are usually asymptomatic; and their incidence has increased as a result of wide-spread use of US. Benign nodules are typically monitored clinically until they increase in size, resulting in compressive symptoms warranting surgery. However, although surgery is generally well-tolerated and of low-risk, it is associated with a small risk for several complications including hypothyroidism, nerve injury, hematoma, injury to other structures and wound infection. Recently, newer image-guided ablation techniques including RFA have been introduced. RFA has a similar safety profile when compared to surgery and has shown promising results in challenging surgical candidates. The authors concluded that although several studies have been published in Asian and European countries on the effectiveness of RFA, limited data are available on the North American population. These investigators reviewed the current literature establishing the clinical outcomes and safety of RFA for the treatment of benign thyroid nodules. These researchers stated that randomized trials with longer follow‐up of at least 5 years are needed in North American population, which will help to formulate a surveillance protocol. Level of Evidence = V.
The authors stated that this review had several drawbacks. First, the majority of the included studies were carried out on Asian and European populations; thus, results could not be generalized for the North American population. Second, most of the studies were retrospective with very few of them having more than 1‐year follow‐up. Third, the exact breakdown of nodules based on US features was not discussed in the majority of the studies.
The Austrian Thyroid Association (OSDG), Austrian Society for Nuclear Medicine and Molecular Imaging (OGNMB), Austrian Society for Endocrinology and Metabolism (ÖGES), and the Surgical Endocrinology Working Group (ACE) of the Austrian Surgical Society (OEGCH)’s Good Clinical Practice Recommendations on “Radiofrequency ablation of thyroid nodules” (Dognig et al, 2020) stated that the principal indications of radiofrequency ablation are:
- Benign nodule with symptoms and/or which is optically disturbing
- Continually growing benign nodule (greater than 2 cm diameter) with attendant symptoms
- Autonomous nodule, when radioiodine treatment or surgery is contraindicated or unwanted
- Differentiated, iodine-refractory thyroid carcinoma with local recurrence, high surgical risk (palliative therapy approach).
Monpeyssen et al (2021) stated that nearly 20 years after the 1st feasibility study, minimally invasive ultrasound (US)-guided therapeutic techniques are now considered as a safe and effective alternative to surgery for symptomatic benign thyroid nodules. Radiofrequency ablation (RFA) is one of the most widely used treatment in specialized thyroid centers; however, due to the relatively recent introduction into clinical practice, there are limited long-term follow-up studies. In a systematic review, these investigators examined the outcomes of RFA on solid non-functioning and on autonomous thyroid nodules (AFTN) on a long-time period for assessing the results in term of effectiveness, complications, and costs and to compare them to the current indications of RFA. They carried out a systematic review using Embase and Medline library data between 2008 and 2021. A total of 17 studies evaluated RFA for the treatment of benign solid (non-functioning or autonomous) thyroid nodules, with an at least 18 months of follow-up. Data extraction and quality assessment were performed by 2 endocrinologists according to PRISMA guidelines. Anthropometric data, safety and effectiveness parameters were collected. The majority of the studies was retrospective study and reported 933 nodules, mostly solid. Baseline volume ranged between 6.1 ± 9.6 and 36.3 ± 59.8 ml. Local analgesia was used; and the time duration of the treatment was between 5 ± 2 and 22.1 ± 10.9 mins. The volume reduction rate at 12 months ranged from 67 % to 75 % for the nodule treated with a single procedure and reached to 93.6 % ± 9.7 % for nodules treated with repeat ablations. The regrowth rate at 12 months ranged from 0 % to 34 %. The authors concluded that all the studies under examination consistently validated the long-term effectiveness and the substantial safety of RFA for the treatment of benign thyroid nodules.
Bernardi et al (2021) noted that US-guided minimally-invasive techniques, such as RFA have emerged as an alternative treatment for benign and malignant thyroid nodules. In a systematic review, these investigators provided an overview on the long-term outcomes of US-guided RFA in patients with benign and malignant thyroid nodules. They systematically searched PubMed/Medline, Embase, and Scopus to identify articles reporting the outcomes of thyroid RFA after a follow-up of at least 3 years. A total of 20 studies met the inclusion criteria and were included in the review. In patients with benign thyroid nodules, RFA significantly reduced nodule volume and this was generally maintained for the following 5 years. However, a small but not negligible proportion of nodules regrew and some of them required further treatments over time. In patients with malignant nodules, RFA has been used not only to treat differentiated thyroid cancer (DTC) neck recurrences, but also to treat papillary thyroid microcarcinoma (PTMC). In most patients with PTMC, RFA led to complete disappearance of the tumor. When it was compared to surgery, RFA was not inferior in terms of oncologic effectiveness but it had a lower complication rate. However, RFA did not allow for final pathology, disease staging and accurate risk stratification. The authors concluded that US-guided RFA significantly reduced benign thyroid nodules and destroyed most PTMC, and this is generally maintained for at least 5 years after the initial treatment. Moreover, these researchers stated that further studies addressing the risk of re-growths in patients with benign thyroid nodules, as well as the risk of recurrence in patients with PTMC are needed.
Kandil et al (2022) stated that RFA has been recently adopted into the practice of thyroidology in the U.S., although its use as an alternative to traditional thyroid surgery in Asia and Europe came near the turn of the 21st century. In the U.S., only a few studies with small sample sizes have been published to-date. In a prospective, multi-center study, these researchers examined outcomes of benign thyroid nodules treated with RFA. This trial was carried out between July 2019 and January 2022. Demographics, sonographic characteristics of thyroid nodules, thyroid function profiles, procedural details, complications, and nodule volume measurements at 1-, 3-, 6-, and 12-month follow-ups were evaluated. Adjusted multi-variate logistic regression analysis was conducted to identify sonographic features associated with treatment failure. A total of 233 nodules were included. The median and inter-quartile range (IQR) of volume reduction rate (VRR) at 1, 3, 6, and 12 months were 54 % (IQR: 36 % to 73 %), 58 % (IQR: 37 % to 80 %), 73 % (IQR: 51 % to 90 %), and 76 % (IQR: 52 % to 90 %), respectively (p < 0.001); 4 patients presented with toxic adenomas. All patients were confirmed euthyroid at 3-month post-procedure follow-up. Two patients developed temporary hoarseness of voice, but no hematoma or nodular rupture occurred post-procedure. Elastography was significantly associated with VRR. Compared to soft nodules, stiff nodules were more likely to have a lower VRR (OR: 11.64, 95 % CI: 3.81 to 35.53, p < 0.05), and mixed elasticity was also more likely to have a lower VRR (OR: 4.9; 95 % CI: 1.62 to 14.85, p < 0.05). The authors concluded that this is the largest multi-institutional North American study examining thyroid nodule treatment response to RFA. These researchers stated that RFA is a safe and effective therapeutic option that allows preservation of thyroid function with minimal risk of procedural complications.
Goldfarb and Dinauer (2022) described recent advances in the diagnosis and management of thyroid nodules in both children and adults, highlighting differences between the 2 groups. Thyroid nodules are less common in children than adults; however, the risk of malignancy is higher. Screening recommendations for patients with certain genetic syndromes or specific risk factors for thyroid nodules and cancer continue to evolve, and US is the most appropriate imaging modality for evaluating thyroid nodules in all patients, but radiographic risk stratification systems validated in adults have not been extensively studied in children. Criteria for proceeding to fine needle aspiration (FNA) biopsy differ some between children and adults, with nodule size being less of a consideration in young patients. Molecular testing continues to improve the diagnostic capabilities of FNA for all age groups, but options for pediatric thyroid nodules are currently limited. In children, only oncogene panels are validated and their exact utility, along with miRNA classifiers, is an evolving area of study. For adults, data support selection of a specific molecular test based on US characteristics and pre-test probability of malignancy. Multiple series have shown that fusion mutations are more common in pediatric thyroid nodules, while point mutations are observed more often in adult thyroid nodules. Molecular data can aid in guiding management recommendations regarding the need for surgery when FNA is indeterminate, but clinical use is still being refined. RFA is a non-operative approach that has gained significant traction for the treatment of symptomatic benign nodules in adults, but data are currently extremely limited in children. The authors concluded that there are differences in the diagnosis and treatment of thyroid nodules in adults and children, the nuances of which are important for clinical management.
Grunwald et al (2022) stated that RFA is an effective tool to treat benign thyroid nodules up to about 100 ml. It is well-tolerated and is -- together with echo-pulse therapy -- currently the most frequently used technique in Germany for the local therapy of benign thyroid nodules. Overall, a volume reduction of about 50 % to 70 % can be expected. Cystic nodules and mixed-pattern lesions respond slightly better than solid nodules. Initial volume, structure and echogenicity are important parameters influencing the therapeutic efficacy. Bi-polar as well as mono-polar methods are used -- the choice of the method depends mainly on the personal experience. For bigger nodules, the bi-polar technique is preferred. Cooled systems should be favored, especially when using larger probes. Serious side effects are rare (less than 1 %) and transient in most cases.
Furthermore, an UpToDate review on “Cystic thyroid nodules” (Ross, 2022) states that “Ultrasound-guided radiofrequency ablation (RFA) has also been used to reduce the volume of benign, cystic thyroid nodules. In one study, 20 patients with predominantly cystic nodules and incomplete resolution of symptoms after ethanol ablation underwent RFA. RFA after a single session of ethanol ablation significantly reduced mean symptom score, cosmetic score, and nodule volume (mean nodule volume decreased from 11.3 to 0.9 mL). Two patients required more than one RFA session. The major side effect of RFA is pain and/or a burning sensation in the neck radiating to the head, shoulders, teeth, and chest. Hematoma and transient voice changes have also been reported. RFA of thyroid nodules was first used in 2002. The procedure was not approved in the United States until 2018, and therefore, RFA has not been commonly used in the United States. Many centers in the United States are establishing RFA programs, and it is likely that RFA will be used increasingly as expertise in the technique is developed … Cytologically benign cysts do not require re-aspiration unless it is to alleviate compressive symptoms. If the nodule recurs after repeated aspirations and there is continued enlargement or pain associated with fluid re-accumulation, we suggest surgical excision (Grade 2C). Percutaneous interventional ultrasound-guided therapy reduces the size and recurrence of benign cystic nodules. In countries where these procedures are performed routinely, they are alternatives to surgery”.
Adrenocortical Carcinoma
Fassnacht and colleagues (2018) noted that adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The objective of these guidelines was to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE system. These investigators pre-defined 4 main clinical questions, which they judged as particularly important for the management of ACC patients and performed systematic literature searches: What is needed to diagnose an ACC by histopathology? Which are the best prognostic markers in ACC? Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected recommendations were:
- Every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging
- Adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease)
- All suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index
- Adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 of greater than 10 %
- For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g., radiation therapy, RFA, chemoembolization) are of particular value. However, the authors suggested against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, they recommended either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered.
- In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, the authors recommended surgery or alternatively other local therapies.
In a systematic review, Nadeem and colleagues (2021) examined the technical success and technique efficacy rates of percutaneous image-guided RFA for adrenal tumors. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the electronic databases Medline, Embase, and PubMed were searched for relevant studies from inception to the 3rd week of January 2020. Only studies reporting effectiveness rates of percutaneous RFA for adrenal tumors were included. Data regarding sample size, tumors, effectiveness rates, outcomes, and complications were extracted in duplicate and recorded. A total of 15 studies evaluating 292 individuals with 305 tumors were included. Patient selection criteria included age greater than or equal to 18 years, contraindication to surgical intervention, and no uncorrected coagulopathy. Cumulative technical success, primary technique efficacy, and secondary technique efficacy rates were 99 %, 95.1 % and 100 %, respectively, indicating optimal immediate control of adrenal tumors. Technical success and technique efficacy rates of primary adrenal tumors were higher than adrenal metastases; however, formal statistical analyses were precluded due to lack of comparative studies. Local tumor progression rates for adrenal metastases were 20.3 % at 3 months, 26.3 % at 6 months, and 29.3 % at 12 months; OS rates for adrenal metastases were 81.8 % at 6 months, 59.6 % at 12 months, and 62.9 % at 18 months. The intra-procedural complication rate was 30.2 %, with the most frequency reported complication being procedural hypertensive crisis. The authors concluded that the findings of this study suggested percutaneous image-guided RFA was a safe and effective procedure. Moreover, these researchers stated that further studies are needed to define patient selection criteria and long-term outcomes.
The authors stated that this systematic review was limited by the level of evidence of the included studies, as the studies were primarily retrospective in design. Heterogeneity was also present among included studies, especially with respect to patient selection criteria and pre-intervention tumor characteristics. Furthermore, this systematic review was limited by the incompleteness of data published in the included studies. As such, this review was unable to address the differences in RFA equipment, technique, overall oncological care, and tumor differences that may have impacted the outcomes and complications reported. In addition, formal statistical analyses and meta-analyses were precluded due to lack of comparative studies between adrenal metastases and primary adrenal tumors. Although the findings of this systematic review suggested that image-guided RFA was a safe and efficacious treatment strategy, the body of evidence examining ablation techniques in the management of adrenal tumors are limited in quantity and quality.
Biliary Obstructions / Strictures
Acu and Kurtulus Ozturk (2018) examined the feasibility and safety of percutaneous trans-hepatic endo-biliary RFA combined with biliary stenting in palliative treatment of malignant biliary obstructions. A total of 21 patients who had undergone percutaneous trans-hepatic endo-biliary RFA as an adjunct to biliary stenting were included. There were 12 men and 9 women with a mean age of 67 ± 13.6 (SD) years (range of 34 to 86 years). Demographic data, procedure details and follow-up data including complications, survival time and stent patency time were documented. The median stent patency time and survival time, as well as the 30-day and 180-day cumulative survival and stent patency rates were estimated using the Kaplan-Meier method. A total of 24 percutaneous trans-hepatic endo-biliary RFA procedures were performed. There were no procedure-related major complications or death; 3 patients who had developed stent re-occlusion underwent a 2nd endo-biliary RFA, without insertion of a new stent. The most common complications were post-procedural pain and cholangitis. Overall survival (OS) and stent patency times ranged between 5 to 542 days and 5 to 251 days, respectively. The median survival time was 76 days (95 % CI: 0 to 233 days) and stent patency time was 133 days (95 % CI: 25 to 240 days). The 30- and 180- day cumulative stent patency rates were 75 % and 34 %, respectively. The authors concluded that percutaneous trans-hepatic endo-biliary RFA was a feasible, safe and cost-effective method in restoration of biliary drainage in patients with malignant biliary obstruction. Moreover, these researchers stated that the efficacy of percutaneous RFA in short- and long-term of survival and stent patency rates remains to be proven in future with randomized, controlled prospective clinical trials, enrolling homogenous, large group of patients and controls.
The authors stated that although this retrospective study was not designed to analyze the clinical efficacy of percutaneous endo-biliary RFA, these findings supported the previous observations that endo-biliary RFA may have more impact on stent patency and quality of life (QOL) but not on survival. The relatively small number of the patients with heterogeneous clinical and tumor characteristics was a limitation of the present study. A short follow-up period with high early mortality rate could have been prevented these investigators from identifying true stent patency rate. Furthermore, the type of the stent that was used may alone have played an important role on patency rate.
In a meta-analysis, Sofi and associates (2018) examined the safety and efficacy of biliary stent placement with RFA compared with stent placement alone in patients with malignant biliary strictures. These researchers performed a comprehensive search of electronic databases for all studies comparing RFA with biliary stent placement versus stent placement only. Measured outcomes included patient survival, stent patency, and procedure-related AEs. An inverse variance method was used to pool data on stent patency into a random-effects model. Cox-regression analysis was used to calculate hazard ratio (HR) for survival analysis. They used the GRADE framework to interpret these findings. A total of 9 studies (including 2 abstracts) with a total of 505 patients were included in the meta-analysis. The pooled weighted mean difference (WMD) in stent patency was 50.6 days (95 % CI: 32.83 to 68.48), favoring patients receiving RFA. Pooled survival analysis of the reconstructed Kaplan-Meier data showed improved survival in patients treated with RFA (HR, 1.395; 95 % CI: 1.145 to 1.7; p < 0.001). However, RFA was associated with a higher risk of post-procedural abdominal pain (31 % versus 20 %, p = 0.003). The findings of this meta-analysis did not show significant difference between the RFA and stent placement-only groups with regard to the risk of cholangitis, acute cholecystitis, pancreatitis, and hemobilia. The authors concluded that in the light of this limited data based on observational studies, RFA was found to be safe and was associated with improved stent patency in patients with malignant biliary strictures. In addition, RFA may be associated with improved survival in these patients.
Papillary Thyroid Microcarcinoma
In a systematic review and meta-analysis, Tong and colleagues (2019) examined the safety and efficacy of RFA, microwave ablation (MWA) and laser ablation (LA) for the treatment of papillary thyroid microcarcinoma (PTMC). PubMed and Embase were searched for studies on the safety and efficacy of RFA, MWA and LA for treating PTMC. The SMD of the tumor volume before and after therapy and the proportion of complete disappearance, local recurrence, distant metastasis and complications were assessed using both fixed or random-effects modeling. Heterogeneity among studies was determined using the Q statistic for the pooled estimates and the inconsistency index I2. A total of 12 eligible studies, including a sample size of 1,187 patients and 1,284 PTMCs, were used. RFA, MWA and LA all showed a significant reduction in tumor volume of PTMCs (p < 0.05). Although MWA demonstrated superior efficacy over the other 2 therapies for volume reduction, the differences were not statistically significant. Furthermore, the pooled proportion of complete disappearance after RFA was the highest (76.2 %), and the pooled proportion of recurrence for RFA was the lowest (0.01 %) among the 3 therapeutic methods, but no significant difference was detected. There was no event of distant metastasis during the follow-up in all of these studies. Few major complications were encountered; the pooled proportion of complications for RFA (1.73 %), MWA (6.0 %) and LA (0.92 %) was low, revealing no significant differences (p > 0.05). The authors concluded that RFA, MWA and LA were acceptable treatments to manage PTMCs in terms of safety and efficacy for non-surgical candidates.
In a systematic review and meta-analysis, Choi and Jung (2020) examined the safety and efficacy of thermal ablation techniques for the treatment of PTMC. Medline and Embase data-bases were searched for studies reporting the safety and efficacy of thermal ablations (RFA, LA, and MWA) until August 10, 2019. A review of 105 potential papers identified 11 eligible papers, including 715 patients. The pooled proportions of complete disappearance and recurrence, and the pooled estimates of mean volume reduction and its rate of the treated PTMC were assessed by using random-effects modeling. The pooled proportions of overall and major complications were calculated. Subgroup analysis was performed according to the treatment modality. Between-study heterogeneity was explored by using χ2 statistic for pooled estimates and inconsistency index I2. Quality of the studies was evaluated by using the Risk of Bias Assessment Tool for Non-randomized Studies. The pooled proportions of complete disappearance and recurrence of PTMC were 57.6 % [95 % CI: 35.4 to 79.8] and 0.4 % [95 % CI: 0 to 1.1], respectively. The pooled estimates of mean volume reduction and its rate were 73.5 mm3 [52.4 to 94.6 mm3] and 98.1 % [95 % CI: 96.7 to 99.5], respectively. The pooled proportions of overall and major complications were 3.2 % [95 % CI: 1.1 to 5.2] and 0.7 % [95 % CI: 0 to 1.5], respectively. Significant between-study heterogeneity was observed for complete disappearance (p < 0.001, I2: 99 %), mean volume reduction (p < 0.001, I2: 93 %), and its rate (p < 0.001, I2: 86 %). Subgroup analysis revealed heterogeneity of the complete disappearance proportion among the treatment modality (I2 range: 95 to 100 %); RFA showed the highest mean volume reduction rate (99.3 %), followed by MWA (95.3 %) and LA (88.6 %) (p < 0.001). The authors concluded that all thermal ablation techniques were safe and effective for the treatment of PTMC; however, each treatment modality had significant heterogeneity with respect to complete disappearance of PTMC. Compared with RFA and MWA, LA was less effective in reducing the volume of PTMC.
Renal Allograft Neoplasms
Favi and colleague (2019) stated that currently there are no guidelines on the treatment of solid neoplasms in the transplanted kidney. Historically, allograft nephrectomy has been considered the only reasonable option. More recently, nephron-sparing surgery (NSS) and ablative therapy (AT) have been proposed as alternative procedures in selected cases. In a systematic review, these researchers examined outcomes of AT for the treatment of renal allograft tumors. They conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 Checklist. PubMed was searched in March 2019 without time restrictions for all papers reporting on RFA, cryoablation (CA), MWA, high-intensity focused ultrasound (HIFU), and irreversible electroporation (IRE) of solid tumors of the kidney allograft. Only original manuscripts describing actual cases and edited in English were considered. All relevant articles were accessed in full text. Additional searches included all pertinent references. Selected studies were also assessed for methodological quality using a tool based on a modification of the Newcastle Ottawa scale. Data on recipient characteristics, transplant characteristics, disease characteristics, treatment protocols, and treatment outcomes were extracted and analyzed. Given the nature and the quality of the studies available (mostly retrospective case reports and small retrospective uncontrolled case series), a descriptive summary was provided. Atotal of 28 relevant studies were selected describing a total of 100 AT procedures in 92 patients. Recipient age at diagnosis ranged from 21 to 71 years whereas time from transplant to diagnosis ranged from 0.1 to 312 months. Most of the neoplasms were asymptomatic and diagnosed incidentally during imaging performed for screening purposes or for other clinical reasons. Preferred diagnostic modality was Doppler US scan followed by CT scan, and MRI. Main tumor types were: papillary RCC and clear cell RCC. Maximal tumor diameter ranged from 5 to 55 mm. The vast majority of neoplasms were T1a N0 M0 with only 2 lesions staged T1b N0 M0. Neoplasms were managed by RFA (n = 78), CA (n = 15), MWA (n = 3), HIFU (n = 3), and IRE (n = 1). Overall, 3 episodes of primary treatment failure were reported. A single case of recurrence was identified. Follow-up ranged from 1 to 81 months. No cancer-related deaths were observed. Complication rate was extremely low (mostly less than 10 %). Graft function remained stable in the majority of recipients. Due to the limited sample size, no clear benefit of a single procedure over the other ones could be demonstrated. The authors concluded that AT for renal allograft neoplasms represented a promising alternative to radical nephrectomy and NSS in carefully selected patients. Moreover, these researchers stated that properly designed, prospective, multi-center, randomized clinical trials are needed to validate this therapeutic approach.
The authors stated that despite the numerous advantages, AT has several drawbacks. First, it was impossible to perform any sort of meta-analysis due to the small case series considered with heterogeneous patients. Second, the lack of long-term follow-up data,. Third, percutaneous procedures do not allow to obtain definitive histological diagnosis and staging of the lesion treated. There is also the possibility that pre-operative imaging and ablation itself may miss very small satellite lesions or multi-focal neoplasms. Fourth, the optimal strategy for the assessment of complete tumor ablation and the detection of local recurrence remains debated. In this review, follow-up modalities were very heterogeneous among transplant centers. In most cases, multiple imaging techniques such as US, CT scan, and MRI were used. Such an observation confirmed the difficulty in discriminating between necrosis, vital parenchyma, and neoplastic tissue and underlined the importance of strict and diligent surveillance strategies following AT. Especially in difficult cases, protocol ablation site biopsy may help rule out the presence of residual tumors or local recurrences and prompt timely and effective treatment.
Sporadic Renal Angiomyolipomas
Fernandez-Pello and colleagues (2020) noted that little is known about the natural history of sporadic angiomyolipomas (AMLs); there is uncertainty regarding the indications of treatment and therapeutic options. These investigators examined the indications, effectiveness, harms, and follow-up of different management modalities for sporadic AML to provide guidance for clinical practice. They carried out a systematic review of the literature, incorporating Medline, Embase, and the Cochrane Library (from January 1,1990 to June 30, 2017), in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. No restriction on study design was imposed. Patients with sporadic AML were included. The main interventions included active surveillance, surgery (nephron-sparing surgery and radical nephrectomy), selective arterial embolization, and percutaneous or laparoscopic thermal ablations. The outcomes included indications for active treatment, AML growth rate, AML recurrence rate, risk of bleeding, post-treatment renal function, AEs of treatments, and modalities of follow-up. Risk of bias assessment was performed using standard Cochrane methods. Among 2,704 articles identified, 43 were eligible for inclusion (0 RCT, 9 non-randomized comparative retrospective studies, and 34 single-arm case series). Most studies were retrospective and uncontrolled, and had a moderate-to-high risk of bias. The authors concluded that in active surveillance series, spontaneous bleeding was reported in 2 % of patients and active treatment was undertaken in 5 %. Active surveillance was the most chosen option in 48 % of the cases, followed by surgery in 31 % and selective arterial embolization in 17 % of the cases. Selective arterial embolization appeared to reduce AML volume but required secondary treatment in 30 % of the cases. Surgery (particularly nephron-sparing surgery) was the most effective treatment in terms of recurrence and need for secondary procedures. Ablative series comprised patients treated by CA, MWA, and RFA. There was no reported recurrence. Resolution of symptoms was complete in the single study that reported it. Secondary treatments were inconsistently reported, and only 1 patient required another thermal ablation for a reason that was not specified. The association between AML size and the risk of bleeding remained unclear; as such the traditional 4-cm cut-off should not per se trigger active treatment. These researchers stated that despite the limitations and uncertainties relating to the evidence base, the findings may be used to guide and inform clinical practice, until more robust data emerge.
An UpToDate review on renal angiolipomas noted that percutaneous radiofrequency ablation has been successful in the treatment of renal AMLs <4 cm in diameter without bleeding complications (Torres and Pei, 2017). However, intervention is primarily performed for renal AMLs >4 cm in diameter. The review stated that the efficacy and safety of percutaneous radiofrequency ablation and cryoablation for larger AMLs are not known.
Pancreatic Cancer
Spadaccini and colleagues (2022) noted that endoscopic US-guided RFA (EUS-RFA) is emerging as a complementary therapeutic approach for pancreatic solid masses; however, results of published data were difficult to interpret because of a retrospective design and small sample size. In a systematic review, these researchers examined data on EUS-RFA for solid lesions and pooled the results of the different experiences to provide more consistent evidence in terms of safety and effectiveness. They carried out a comprehensive systematic literature search on the main databases to identify studies in which patients with pancreatic solid lesions underwent EUS-RFA. The primary outcomes were procedure-related AEs and mortality; and secondary outcomes were the technical success rate and the effects on primary tumor growth. Statistical analyses were performed using Stata version 14.0. A total of 14 studies were included, with 120 patients undergoing 153 ablations of 129 solid pancreatic lesions. The STARmed technology was used in 7 studies, the Habib system in 6 studies, and the HybridTherm probe in 1 study. The pooled technical success rate was 99.0 % (I2: 25.82 %). The pooled overall AE rate was 8.0 % (I2: 11.46 %). Excluding mild AEs, the pooled rates of serious AEs was 1.0 % (I2: 0 %). No mortality related to the procedure was reported. The authors concluded that the present pooled analysis confirmed the safety and feasibility of EUS-RFA. Moreover, these researchers stated that further studies with longer follow-up are needed to examine the effectiveness of EUS-RFA as a stand-alone approach or as a part of multi-modality management of pancreatic neoplasia.
The authors stated that this review had several drawbacks. First, these investigators included different ablation techniques: the STARmed technology in 7 studies, the Habib system in 6 studies and HybridTherm probe in 1 study. Despite having considered different techniques and different devices, the heterogeneity among the studies was mild-to-moderate for all outcomes. Second, all of the included studies were observational studies, which may have inevitably introduced a bias; therefore, the lack of controlled trials showed that the clinical value of local ablation is still insufficiently known. A multi-center RCT entitled “Pancreatic Locally Advanced Irresectable Cancer Ablation (PELICAN)” is currently ongoing and will compare chemotherapy and surgical RFA with chemotherapy alone. The results are expected in 2022 and will probably provide evidence on the additive role of RFA as part of a multi-modality approach to treat patients with locally advanced pancreatic cancer. Finally, none of the studies published to-date has examined the indirect effects of RFA. In fact, previous results have indicated that besides thermal damage (debulking cytoreductive effect), RFA also appeared to have an indirect immune modulatory effect. A peripheral zone with sub-lethal injury is often observed around the area of necrosis created by local injury. In this area, oxidative stress and inflammation have been suggested to lead to an indirect anti-tumoral systemic effect, generally mediating the immune response. Moreover, the local damage causes the release of tumor antigens that can trigger an immune response and stimulate the inflammatory response, acting on distant circulating neoplastic cells. Therefore, the combination of ablation techniques with immunotherapy could potentially increase the effectiveness of these kind of treatments, although currently only limited experimental evidence has been published.
Combined Radiofrequency Ablation with Radiation Therapy for the Treatment of Bone Metastases
Piras and colleagues (2021) stated that approximately 50 % of cancer patients develop bone metastases in their natural disease history. The management of metastatic bone disease requires a multi-disciplinary approach. Both RFA and RT have been employed in the management of painful metastases, even if they rely on totally different action mechanisms. A synergistic combination of RT and RFA appeared to result in a better pain control. These investigators carried out a systematic review to examine the feasibility and effectiveness of the association between RFA and RT in the treatment of metastatic bone pain in oligo-metastatic patients, evaluating its role in alleviating bone pain, reducing the risk of fractures, and consequently ensuring a better QOL. They performed systematic database search according to PRISMA guidelines. This systematic review included studies that reported populations meeting the following inclusion criteria: confirmed bone metastases in adult patients; active bone metastases pain; patients treated with combined RFA and RT; and original studies. A total of 3 studies that examined the combined treatment with doses ranging from moderately hypo-fractionated three-dimensional conformal RT (3D-CRT) and stereotactic body radiation therapy (SBRT) schedules were selected. The authors concluded that RFA-RT combined strategy appeared to be promising in terms of safety and effectiveness with adequate pain control and QOL improvement. Positive effects on time to local failure and OS increase were also observed. Moreover, these researchers stated that further prospective studies are needed to better delineate RFA-RT treatment benefits.
Combined Radiofrequency Ablation with Trans-Arterial Chemoembolization for the Treatment of Intermediate-Stage Hepatocellular Carcinoma
Yang and colleagues (2022) noted that RFA and MWA are widely used in combination with trans-arterial chemo-embolization (TACE) for the treatment of intermediate-stage hepato-cellular carcinoma (HCC) in clinical practice. In a systematic review and meta-analysis, these investigators compared the d safety and effectiveness of TACE combined with RFA or MWA versus TACE alone for intermediate-stage HCC. They searched PubMed, Embase, Web of Science, and the Cochrane Library for relevant studies. The outcomes included LTC rate, OS, progression-free survival (PFS), and major complication. Subgroup analysis for different TACE combination therapies was performed. A total of 10 studies with 1,799 patients with intermediate-stage HCC were included. The pooled HR for OS was in favor of TACE combination therapy (HR, 0.50, 95 % CI: 0.40 to 0.62). Specifically, the TACE combination therapy was associated with higher 1-, 3-, and 5-year OS rates. Regarding tumor progression, the TACE combination therapy showed significantly better PFS (HR, 0.47, 95 % CI: 0.37 to 0.61) and higher 1-, 2- and 3-year PFS rates than TACE alone. The pooled odds ratio (OR) for the LTC was also in favor of TACE combination therapy (OR, 0.36, 95 % CI: 0.24 to 0.53). No significant difference was found between the 2 groups regarding the major complication rate (OR, 1.26, 95 % CI: 0.74 to 2.16). These results were consistent across subgroups of TACE + RFA versus TACE and TACE + MWA versus TACE. The authors concluded that TACE combined with RFA or MWA could provide significantly better OS, PFS and LTC than TACE monotherapy for patients with intermediate-stage HCC, without increasing the risk of major complications. Moreover, these researchers stated that it is time to re-visit the current treatment strategy for intermediate-stage HCC, and further high-quality RCTs are needed for more evidence.
The authors stated that this study has several drawbacks. The evidence for this meta-analysis was drawn from retrospective, observational studies that might have potential selection bias. Several studies used propensity score matching to minimize selection biases, but more high-quality, low-biased RCTs are still needed. In addition, these researchers did not consider differences in clinical characteristics or in treatment methods across studies, such as HBV or HCV infection, the procedure and interval of TACE and RFA/MWA. However, detailed data were unavailable, and whether these factors could affect the effectiveness of TACE combination therapy is still unclear.
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