CAM 70195

Radiofrequency Ablation of Miscellaneous Solid Tumors Excluding Liver Tumors

Category:Surgery   Last Reviewed:July 2021
Department(s):Medical Affairs   Next Review:July 2022
Original Date:July 2013    

Description
In radiofrequency ablation (RFA), a probe is inserted into the center of a tumor; then, prong-shaped, noninsulated electrodes are projected into the tumor. Next, heat is generated locally by an alternating, high-frequency current that travels through the electrodes. The localized heat treats the tissue adjacent to the probe, resulting in a 3- to 5.5-cm sphere of dead tissue. The cells killed by RFA are not removed but are gradually replaced by fibrosis and scar tissue. If there is local recurrence, it occurs at the edge and can sometimes be retreated. RFA may be performed percutaneously, laparoscopically, or as an open procedure.

Bone Tumors
For individuals who have painful osteolytic bone metastases who have failed or are poor candidates for standard treatments who receive RFA, the evidence includes case series. Relevant outcomes are symptoms, change in disease status, quality of life, medication use, and treatment-related morbidity. Case series have shown clinically significant pain relief and reduction in opioid use following treatment of painful osteolytic metastases. The population is comprised of patients with few or no treatment options, for whom short-term pain relief is an appropriate clinical outcome. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have painful osteoid osteomas who receive RFA, the evidence includes numerous observational studies and a systematic review of these studies. Relevant outcomes are symptoms, change in disease status, quality of life, medication use, and treatment-related morbidity. In a systematic review of thermal ablation techniques, clinical success (pain-free) was achieved in 94% to 98% of patients. Most patients (89%-96%) remained pain-free when assessed during longer term follow-up. Although no randomized trials of RFA for osteoid osteomas have been performed, the uncontrolled studies have demonstrated RFA can provide adequate symptom relief with minimal complications, for a population for whom short-term symptom relief and avoidance of invasive procedures are appropriate clinical outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Localized Renal Cell Carcinoma
For individuals who have localized renal cell carcinoma that is no more than 4 cm in size who receive RFA, the evidence includes a randomized controlled trial (RCT), a large number of observational studies, and systematic reviews of these studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. A recent meta-analysis that included only an RCT and cohort studies found that RFA was as effective as nephrectomy for small renal tumors, with a reduction in complications. Another recent meta-analysis, which included case series of stage I (≤7 cm across) renal tumors, found that the rate of local progression was greater with RFA than with nephrectomy. The differing meta-analytic results may be due to differences in tumor size in selected studies as well as potential selection bias when evaluating case series. Although inconsistent, the evidence does suggest that, for small renal tumors, RFA may result in a similar rate of disease progression with a lower complication rate than nephrectomy. However, comparative trials are needed to determine with greater certainty the effects of these treatments in the same patient population. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input has supported use of RFA for localized renal cell carcinoma that is no more than 4 cm in size when preservation of kidney function is necessary, and a standard surgical approach is likely to worsen kidney function substantially or when the patient is not considered a surgical candidate. Thus, absent other treatment options, RFA for small renal cell tumors may be considered medically necessary

Inoperable Primary Pulmonary and Nonpulmonary Tumors
For individuals who have inoperable primary pulmonary tumors or nonpulmonary tumors metastatic to the lung who receive RFA, the evidence includes observational studies and systematic reviews of these studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. A multicenter study found that, for tumors less than 3.5 cm in size, RFA can lead to a complete response in as many as 88% of patients for at least 1 year. Two-year survival rates have been reported to range from 41% to 75% in case series, with 5-year survival rates of 20% to 27%. In general, the evidence suggests that RFA results in adequate survival and tumor control in patients who are not surgical candidates, with low morbidity rates. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Breast Tumors
For individuals who have breast tumors who receive RFA, the evidence includes observational studies and systematic reviews of these studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. Evidence has reported varied and incomplete ablation rates with concerns about postablation tumor cell viability. Long-term improvements in health outcomes have not been demonstrated. Additionally, available studies do not permit comparisons with conventional breast-conserving procedures. Further studies, with long-term follow-up, should focus on whether RFA of the breast for small tumors can provide local control and survival rates comparable with conventional breast-conserving treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

Benign Thyroid Tumors
For individuals who have benign thyroid tumors who receive RFA, the evidence includes RCTs, case series, and systematic reviews of these studies. Relevant outcomes are symptoms, change in disease status, quality of life, medication use, and treatment-related morbidity. A systematic review that included 4 RCTs and 5 observational studies found significant reductions in nodule size and withdrawal from methimazole following treatment with RFA when compared to a variety of local treatment. Reports of complications have varied. The most frequent major complication in a large multicenter series of specialty centers was voice change. The evidence is insufficient to determine the effects of the technology on health outcomes.

Miscellaneous Solid Tumors
For individuals who have miscellaneous tumors (e.g., head and neck, thyroid cancer, pancreas) who receive RFA, the evidence includes a few case series and retrospective comparative studies. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related morbidity. There is a limited evidence base for each tumor type. Reporting on outcomes or comparisons with other treatments is limited. These studies do not permit conclusions on the health benefits of RFA. The evidence is insufficient to determine the impact of the technology on health outcomes.

Background  
Radiofrequency Ablation
RFA was initially developed to treat inoperable tumors of the liver (see evidence review 70191). Recently, studies have reported on the use of RFA to treat other tumors. For some of these, RFA is being investigated as an alternative to surgery for operable tumors. Well-established local or systemic treatment alternatives are available for each of these malignancies. The hypothesized advantages of RFA for these cancers include improved local control and those common to any minimally invasive procedure (e.g., preserving normal organ tissue, decreasing morbidity, decreasing length of hospitalization).

Goals of RFA may include (1) controlling local tumor growth and preventing recurrence; (2) palliating symptoms; and (3) extending survival duration for patients with certain tumors. The effective volume of RFA depends on the frequency and duration of applied current, local tissue characteristics, and probe configuration (eg, single vs multiple tips). RFA can be performed as an open surgical procedure, laparoscopically or percutaneously, with ultrasound or computed tomography guidance.

Potential complications associated with RFA include those caused by heat damage to normal tissue adjacent to the tumor (e.g., intestinal damage during RFA of kidney), structural damage along the probe track (e.g., pneumothorax as a consequence of procedures on the lung), and secondary tumors (if cells seed during probe removal).

Regulatory Status
The U.S. Food and Drug Administration (FDA) issued a statement in September 2008, concerning the regulatory status of RFA. FDA has cleared RFA devices for the general indication of soft tissue cutting, coagulation, and ablation by thermal coagulation necrosis. Under this general indication, RFA can be used to ablate tumors, including lung tumors. Some RFA devices have been cleared for additional specific treatment indications, including partial or complete ablation of nonresectable liver lesions and palliation of pain associated with metastatic lesions involving bone. FDA has not cleared any RFA devices for the specific treatment indication of partial or complete ablation of lung tumors, citing lack of sufficient clinical data to establish safety and effectiveness for this purpose. FDA has received reports of death and serious injuries associated with the use of RFA devices in the treatment of lung tumors. 

Related Policies
60110 Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy
70191 Radiofrequency Ablation of Primary or Metastatic Liver Tumors
70192 Cryosurgical Ablation of Miscellaneous Solid Tumors Other Than Liver, Prostate or Dermatologic Tumors

Policy:
Radiofrequency ablation may be considered MEDICALLY NECESSARY to palliate pain in patients with osteolytic bone metastases who have failed or are poor candidates for standard treatments such as radiation or opioids.

Radiofrequency ablation may be considered MEDICALLY NECESSARY to treat osteoid osteomas that cannot be managed successfully with medical treatment.

Radiofrequency ablation may be considered MEDICALLY NECESSARY to treat localized renal cell carcinoma that is no more than 4 cm in size when either of the following criteria are met:

  • To preserve kidney function in patients with significantly impaired renal function (i.e., the patient has one kidney or renal insufficiency defined by a glomerular filtration rate [GFR] of less than 60 mL/min per m2)
  • when the standard surgical approach (i.e., resection of renal tissue) is likely to substantially worsen existing kidney function.
  • The patient is not considered a surgical candidate.

Radiofrequency ablation may be considered MEDICALLY NECESSARY to treat an isolated peripheral non-small cell lung cancer lesion that is no more than three cm in size when the following criteria are met:

  • Surgical resection or radiation treatment with curative intent is considered appropriate based on stage of disease. However, medical co-morbidity renders the individual unfit for those interventions.
  • Tumor is located at least 1 cm from the trachea, main bronchi, esophagus, aorta, aortic arch branches, pulmonary artery and the heart.

Radiofrequency ablation may be considered MEDICALLY NECESSARY to treat malignant non-pulmonary tumor(s) metastatic to the lung that are no more than 3 cm in size when the following criteria are met:

  • In order to preserve lung function when surgical resection or radiation treatment is likely to substantially worsen pulmonary status OR
  • the patient is not considered a surgical candidate.
  • There is no evidence of extrapulmonary metastases AND the tumor is located at least 1 cm from the trachea, main bronchi, esophagus, aorta, aortic arch branches, pulmonary artery and the heart.

(See the Policy Guidelines for additional criteria)

Radiofrequency ablation is investigational and /or unproven and therefore considered NOT MEDICALLY NECESSARY as a technique for ablation of:

  • Breast tumors
  • Lung cancer not meeting the criteria above
  • Renal cell cancer not meeting the criteria above
  • Osteoid osteomas that can be managed with medical treatment
  • Painful bony metastases as initial treatment
  • All other tumors outside the liver, including, but not limited to, the head and neck, thyroid, adrenal gland, ovary and pelvic/abdominal metastases of unspecified origin

Policy Guidelines
The following are additional criteria developed by clinical judgment or consensus and existing guidelines for the use of radiofrequency ablation to treat metastatic tumors to the lung: 

  • No more than 3 tumors per lung should be ablated;

  • Tumors should be amenable to complete ablation; AND

  • Twelve months should elapse before a repeat ablation is considered.

Coding 
See the Codes table for details

Benefit Application
BlueCard®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational, and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Osteolytic Bone Metastases
Clinical Context and Therapy Purpose
After lung and liver, bone is the third most common metastatic site and is relatively frequent among patients with primary malignancies of the breast, prostate, and lung. Bone metastases often cause osteolysis (bone breakdown), resulting in pain, fractures, decreased mobility and reduced QOL.

External-beam radiotherapy often is the initial palliative therapy for osteolytic bone metastases. However, pain from bone metastases is refractory to radiotherapy in 20% to 30% of patients, while recurrent pain at previously irradiated sites may be ineligible for additional radiation due to risks of normal tissue damage. Other alternatives include hormonal therapy, radiopharmaceuticals (e.g., strontium 89), and bisphosphonates. Less often, surgery or chemotherapy may be used for palliation, and intractable pain may require opioid medications. Radiofrequency ablation (RFA) has been investigated as an alternative for palliation of bone metastases.

The purpose of RFA in patients who have painful osteolytic bone metastases who have failed or are poor candidates for standard treatments is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in individuals with painful osteolytic bone metastases who have failed or are poor candidates for standard treatments?

The following PICO was used to select literature to inform this review.

Patients
The relevant populations of interest are individuals with painful osteolytic bone metastases who have failed or are poor candidates for standard treatments.

Interventions
The therapy being considered is RFA, which is administered in an outpatient setting by oncologists and radiologists.

Comparators
The following therapies and practices are options to manage painful osteolytic bone metastases: medical management (e.g., chemotherapy) and radiotherapy, which are administered in an outpatient setting by oncologists and radiologists.

Outcomes
The general outcomes of interest are overall survival (OS), reduction in pain and medication use, fractures, functional outcomes, and QOL.

Patients would be followed for several years given the impact of bone metastases on bone remodeling.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Case Series
Goetz et al. (2004) reported on an international study conducted at 9 centers in which 43 patients with painful osteolytic bone metastases were treated palliatively with RFA.1 The study's primary outcome measure was the Brief Pain Inventory-Short Form, a validated scale from 0 (no pain) to 10 (worst pain imaginable). Patient eligibility required baseline values of 4 or more from 2 or fewer painful sites. Thirty-nine (91%) of the patients had previously received opioids to control pain from the lesion(s) treated with RFA, and 32 (74%) had prior radiotherapy to the same lesion. The mean pain score at baseline was 7.9 (range, 4 to 10). At 4, 12, and 24 weeks after RFA, average pain scores decreased to 4.5, 3.0, and 1.4, respectively (all p<0.001). Forty-one (95%) patients achieved clinically significant reductions in pain scores, prospectively defined as a decrease of 2 units from baseline. Investigators also reported statistically significant (p=0.01) decreases in opioid use at weeks 8 (by 59%) and 12 (by 54%).

An earlier case series by Gronemeyer et al. (2002) showed that palliative RFA provided significant pain relief in 9 (90%) of 10 patients with unresectable, osteolytic spine metastases who had no other treatment options.2 Pain was reduced by an average of 74%; back pain-related disability was reduced by an average of 27%. Neurologic function was preserved in 9 patients and improved in the other. In another small case series, Kojima et al. (2006) assessed 24 patients with painful metastatic bone tumors who experienced pain-alleviating effects with RFA is consistent with other evidence.3

Section Summary: Osteolytic Bone Metastases
Case series have shown clinically significant reductions in pain relief and reductions in opioid use following treatment with RFA of osteolytic pain metastases in patients with no or limited treatment options.

Osteoid Osteomas
Clinical Context and Therapy Purpose
Osteomas are the most common benign bone tumor, comprising 10% to 20% of benign and 2% to 3% of all bone tumors. They are typically seen in children and young adults, with most diagnosed in patients between 5 and 20 years of age. Osteomas are most common in the lower extremity (usually the long bones, mainly the femur) and less common in the spine. These tumors typically have a characteristic clinical presentation and radiologic appearance, with pain that is usually continuous and worse at night and commonly relieved by aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). The natural history of the osteoid osteoma varies based on location, and although they rarely exceed 1.5 cm in diameter, may produce bone widening and deformation, limb length inequality, or angular deviations when near a growth plate. When located in the spine, these lesions may lead to painful scoliosis or torticollis. Sometimes they heal spontaneously after 3 to 7 years.

Treatment options include medical management with NSAIDs, surgical excision (wide/en bloc excision or curetting), or the use of computed tomography (CT)- or magnetic resonance imaging-guided minimally invasive procedures including core drill excision, laser photocoagulation, or RFA. For many years, complete surgical excision was the classic treatment of osteomas, usually performed in patients with pain despite medical management. However, a substantial incision may be necessary, with the removal of a considerable amount of bone (especially in the neck of the femur). This increases the need for bone grafting plus internal fixation (which often necessitates a second procedure to remove the metalwork). Other possible risks include avascular necrosis of the femoral head and postoperative pathologic fracture. In addition, surgical excision leads to a lengthier convalescence and postoperative immobilization. Anatomically inaccessible tumors may not be completely resectable and may recur. RFA of osteoid osteoma is done with a needle puncture, so no incision or sutures are needed; further, patients may immediately walk on the treated extremity and return to daily activities when the anesthetic effect wears off. The risk of recurrence with RFA of an osteoma is 5% to 10%, and recurrent tumors can be retreated with RFA. In general, RFA is not performed in many spinal osteomas because of possible thermal-related nerve damage.

The purpose of RFA in patients who have painful osteoid osteomas is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in individuals with painful osteoid osteomas?

The following PICO was used to select literature to inform this review.

Patients
The relevant populations of interest are individuals with painful osteoid osteomas.

Interventions
The therapy being considered is RFA, which is administered in an outpatient setting by oncologists and radiologists.

Comparators
The following therapies and practices are options to treat osteoid osteomas: medical management, surgical excision, core drill excision, and laser photocoagulation.

Outcomes
The general outcomes of interest are reductions in pain and medication use, normal bone development, and postsurgical adverse events.

Patients would be followed through adolescents to ensure normal skeletal development.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Tordjman et al. (2020) conducted a systematic review on CT-guided RFA for osteoid osteomas.4 The review included 69 studies (43 retrospective and 12 prospective studies; rest of study designs were not identifiable) comprising 3023 patients. The weighted overall failure rate was 8.3% for the entire cohort. When studies were analyzed by time period conducted the failure rate was significantly lower in studies conducted between 2011 and 2019 compared to those conducted between 2002 and 2010 (7% vs 14%, p=0.004). The complication rate for the entire cohort was 3%, with skin burns (0.7%) and infections (0.5%) as the most commonly reported.

Lanza et al. (2014) reported on a systematic review of various ablative techniques for osteoid osteomas.5 Included in the review were 23 articles on RFA, 3 on interstitial laser ablation, and 1 with a combination of ablation techniques, totaling 27 articles (N=1,772 patients). The mean technical success was 100% and clinical success, defined as being pain-free, ranged from 94% to 98%, depending on the length of follow-up. Complications occurred in 2% of patients and included skin or muscle burn in 9 patients, 4 infections, nerve lesions or tool breakage in 3 patients each, delayed skin healing, hematoma, and failure to reach target temperature in 2 patients each, and fracture, pulmonary aspiration, thrombophlebitis, and cardiac arrest in 1 patient each. Eighty-six patients had tumor recurrence.

Retrospective Studies
In their retrospective study of the efficacy and complications of CT-guided RFA of spinal osteoid osteoma, Albisinni et al. (2017) concluded that CT-guided RFA is effective as first-line therapy for the disease.6 After RFA, clinical symptoms were evaluated at 3, 6, and 12 months, with a final evaluation at the end of the study. Results showed that the complete regression of osteoid osteoma symptoms in 57 (93.4%) of 61 (p=0.001) for patients observed between 2002 and 2012. Study limitations included the retrospective design and focus on a single treatment.

Lassalle et al. (2017) conducted a single-center retrospective analysis of long-term outcomes for CT-guided RFA in 126 patients with suspected osteoid osteoma.7 The study was conducted from 2008 to 2015. Phone evaluations were performed. The overall success rate was 94.3% among the 88 patients who participated in the follow-up calls. The study was limited by its retrospective design, imprecision of patients' memory over follow-up, the lack of clinical and imaging follow-up, and an inability to perform multivariate statistical analysis of factors associated with treatment failure.

Rimondi et al. (2012) reported on a retrospective study of 557 patients treated with CT-guided RFA as primary treatment for nonspinal osteoid osteomas.8 All patients were followed for a mean of 3.5 years (range, 0.5 to 9 years). Pain relief occurred in all 557 patients within the first week after RFA and continued in 533 (96%) patients who remained asymptomatic through their last follow-up. Pain recurrence occurred in 24 (4%) patients. Complications occurred in 5 patients and included thrombophlebitis, skin burn, broken electrode, and 2 procedures in which the RFA generator failed to reach maximum temperature.

Sahin et al. (2019) conducted a single-center retrospective study that evaluated clinical pain symptoms to demonstrate the rapid relief of pain symptoms after CT-guided RFA for osteoid osteomas.9 A total of 116 patients were included and the efficacy success rate in the study was 98%. All patients reported immediate pain relief following the procedure, with scores of 0 or 1 on a 10-point visual analog pain scale within 24 hours. Mean duration of follow-up was 23 months and pain relapse was reported in 2 of 108 patients available for follow-up. Seven minor complications were reported after the procedure with superficial skin burns as the most common complication (n=4).

Case Series
An observational study by Knudsen et al. (2015) evaluated long-term clinical outcomes after CT-guided RFA in patients diagnosed with osteoid osteoma located in the upper and lower extremities.10 The study population included 52 patients with a typical clinical history and radiologically confirmed osteoid osteoma who received CT-guided RFA treatment from 1998 to 2014 at a Danish university hospital. The clinical outcome was evaluated based on patient-reported outcome measures and medical record review. The response rate was 52 (87%) of 60. After 1 RFA treatment, 46 (88%) of 52 patients experienced pain relief, and 51 (98%) of 52 patients had pain relief after repeat RFA. One patient underwent open resection after RFA. No major complications were reported; 4 patients reported minor complications including small skin burn, minor skin infection, and hypoesthesia at the needle entry point. In all, 50 (96%) of 52 patients were reported to be "very satisfied" with the RFA treatment.

Rosenthal et al. (2003) reported their experience over an 11-year period with 271 RFA procedures for osteoid osteomas in 263 patients.11 The short-term outcome was evaluated to detect procedure-related problems; by this definition, all procedures were considered technically successful. Long-term clinical success data (defined as being free of pain without additional procedures) were available in 126 patients, with a complete clinical success observed in 89%. For procedures performed as the initial treatment, the success rate was 91%.

Section Summary: Osteoid Osteomas
Numerous retrospective studies and case series, and systematic reviews of observational data have evaluated RFA for the treatment of painful osteoid osteomas. In a systematic review of thermal ablation techniques, clinical success (pain-free) was achieved in 94% to 98% of patients. Results have indicated that most patients (89% to 96%) remained pain-free at longer-term follow-up. Another systematic review reported similar success rates noting an average 8.3% failure rate among patients receiving CT-guided RFA.

Localized Renal Cell Carcinoma
Clinical Context and Therapy Purpose
Radical nephrectomy remains the principal treatment of renal cell carcinoma (RCC); however, partial nephrectomy (PN) or nephron-sparing surgery has been shown to be as effective as radical nephrectomy, with comparable long-term recurrence-free survival rates, in a select group of patients. Alternative therapy such as RFA is of interest in patients with small renal tumors when preservation of renal function is necessary (e.g., in patients with marginal renal function, a solitary kidney, bilateral tumors) and in patients with comorbidities that would render them unfit for surgery. Another consideration would be in patients at high-risk of developing additional renal cancers (e.g., von Hippel-Lindau disease).

The purpose of RFA in patients who have localized RCC no more than 4 cm in size is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in individuals with localized RCC no more than 4 cm in size?

The following PICO was used to select literature to inform this review.

Patients
The relevant population of interest is individuals with localized RCC no more than 4 cm in size. Small renal masses (SRM), defined as 4cm or less, are common findings on diagnostic imaging of the abdomen pelvis. Some of these masses are assessed to be suspicious for malignancy or have been identified by biopsy as a localized RCC. Tumors can be further categorized according to international TNM staging where cT1a is a clinically diagnosed tumor ≤ 4cm that is confined to the kidney without any nodal involvement.

Interventions
The therapy being considered is RFA, which is administered in an outpatient setting by oncologists and interventional radiologists.

Comparators
The following practice is currently being used to treat localized RCC: surgical excision; either total nephrectomy or partial nephrectomy (PN) which are performed in a hospital setting.

Outcomes
The general outcomes of interest are recurrence rates and reduction in rates of renal failure.

Patients should be followed for at least 10 years to monitor for tumor recurrence.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
In their systematic review and meta-analysis, Uhlig et al. (2019) compared oncologic, perioperative, and functional outcomes for PN with outcomes for various ablative techniques, including RFA and others, for small renal masses (mean diameter=2.53 to 2.84 cm).12 They identified 47 moderate-quality studies, mostly retrospective, published from 2005-2017, with a total of 24,077 patients. Of these patients, 15,238 received PN and 1,877 received RFA. The network meta-analysis used PN as the reference point. The overall results indicated that PN had better OS and local control over ablative techniques but it was not significantly better for cancer-related mortality. In addition, ablation had fewer complications and better renal function outcomes. Across the studies included, patients treated by PN tended to be younger with less comorbidity compared with patients receiving thermal ablation—a consideration when assessing the outcomes for survival and local control.

In a systematic review and meta-analysis, Katsanos et al. (2014) reviewed 1 RCT and 5 cohort studies (N=587 patients) assessing thermal ablation (RFA or microwave) or nephrectomy for small renal tumors (size, 2.5 cm).13 The local recurrence rate was 3.6% in both groups (relative risk, 0.92; 95% confidence interval [CI], 0.4 to 2.14; p=0.79). Disease-free survival was also similar in both groups up to 5 years (hazard ratio, 1.04; 95% CI, 0.48 to 2.24; p=0.92). However, the overall complication rate was significantly lower in the patients undergoing ablation (7.4%) vs nephrectomy (11.1%; pooled relative risk, 0.55; 95% CI, 0.31 to 0.97; p=0.04).

El Dib et al. (2012) conducted a meta-analysis evaluating RFA and cryoablation for small renal masses.14 Selected were 11 RFA case series (426 patients) and 20 cryoablation case series (457 patients) published through January 2011. The mean tumor size was 2.7 cm (range, 2 to 4.3 cm) in the RFA group and 2.5 cm (range, 2 to 4.2 cm) in the cryoablation group. Mean follow-up times for the RFA and cryoablation groups were 18.1 and 17.9 months, respectively. Clinical efficacy, defined as cancer-specific survival rate, radiographic success, no evidence of local tumor progression, or distant metastases, did not differ significantly between groups. The pooled proportion of clinical efficacy for RFA was 90% (95% CI, 86% to 93%) and 89% (95% CI, 83% to 94%) for cryoablation.

Table 1 summarizes the characteristics of the systematic reviews by Uhlig et al. (2019), Katsanos et al. (2014), and El Dib et al. (2012). Table 2 contains the results of the largest and most recent of the 3 reviews (Uhlig et al. [2019]). 

Table 1. Characteristics of Meta-Analyses Assessing Radiofrequency Ablation for Renal Masses 

Study Dates Trials Participants N (Range) Design Duration
Uhlig (2018)12 2006-2017 47 Patients who had received PN, RFA, CRA, or MWA for small renal masses. 24,077
(18-1803)
Prospective, retrospective, 1 RCT 3-82 mo
Katsanos (2014)13 2007-2012 6 Patients with small renal tumors receiving RFA or nephrectomy. 587
(69-150)
1 RCT,
5 cohort
Up to 6 y
El Dib (2012)14 2000-2008 31 Patients who had received RFA or CRA for renal tumors, regardless of size. 957
(n/a)
Case series 7-45.7 mo

CRA: cryoablation; RCT: randomized controlled trial; RFA: radiofrequency ablation; n/a: data not available; mo: month(s); MWA: microwave ablation; PN: partial nephrectomy; y: year(s).

The results table below does not include Katsanos et al. (2014) because of complete study overlap with Uhlig et al. (2018). El Dib et al. (2012) is not included because the comparator in the studies selected was cryoablation, not surgery.

Table 2. Results of Select Meta-Analyses Assessing Radiofrequency Ablation for Renal Masses  

Study Cancer-Specific Mortality, IRR Local Recurrence, IRR Complications, OR Renal Function Decline, MD
  RFA PN RFA PN RFA PN RFA PN
Uhlig (2018)12 2.03 1.00 1.79 1.00 0.89 1.00 6.49 0.00
95% CI 0.81 to 5.08 1.16 to 2.76 0.59 to 1.33 2.87 to 10.10

CI: confidence interval; IRR: incidence rate ratio; MD: mean difference in glomerular filtration rate; OR: odds ratio;
RFA: radiofrequency ablation; PN: partial nephrectomy.

Randomized Controlled Trials
In an RCT, Liu et al. (2016) analyzed the safety and efficacy of the operative effects of percutaneous RFA in early-state RCC vs retroperitoneoscopic radical operation of RCC.15 The observation group was treated with percutaneous RFA and the control group with a radical retroperitoneoscopy. A total of 76 clinically confirmed diagnosed cases, from January 2011 to January 2013, with RCC, were randomized to the observation (n=41) or the control (n=35) groups. Operation time, blood loss during operation, length of stay, and incidence complications were lower in the control group (p<0.05). For both groups, postsurgical day at 1, 2, and 3 serum C-reactive protein, interleukin 6, and T lymphocyte counts were elevated, however, the increase in the control group was significantly greater (p<0.05). Total efficacy, tumor-free survival times, and survival rates did not differ statistically between groups (p>0.05); however, percutaneous RFA reduced postoperative recovery time and fewer complications. Trial limitations included small sample size and the brief duration of follow-up.

Retrospective Studies
Marshall et al. (2020) conducted a single-center retrospective evaluation in 100 patients with 125 RCCs who received percutaneous RFA between 2004 and 2015.16 Median follow-up in the study was 62.8 months. Five-year overall, cancer-specific, and local progression-free survival were 75%, 92%, and 92%, respectively. Ten-year overall, cancer-specific, and local progression-free survival were 32%, 86%, and 92%, respectively. The rate of local tumor progression was higher in patients with tumors >4 cm compared to those with tumors ≤4 cm, but the difference was not statistically significant (6% vs 13%, p=0.466). The study also noted no significant changes in estimated glomerular filtration rate from baseline to 2-3 years post-procedure (65.2 vs 62.1 mL/min/1.73 m2; p=0.443. The overall complication rate in the study was 9%. Limitations of the study include its retrospective design, lack of a control group, and selection bias where patients selected for RFA over surgical resection likely had worse baseline comorbidity status, which may have negatively impacted OS rates.

Andrews et al. (2019) retrospectively evaluated 1,798 patients with primary cT1 renal masses who underwent PN, percutaneous RFA, or percutaneous cryoablation between 2000 and 2011 at a single center.17 For cT1a tumors, 1,422 patients were treated, receiving PN (n=1,055), RFA (n=180), or cryoablation (n=187). Five-year local recurrence-free survival rates for PN, RFA, and cryoablation were 97.7%, 95.9%, and 95.9%, respectively. Five-year cancer-specific survival rates for PN, RFA, and cryoablation were 99.3%, 95.6%, and 100%, respectively. Propensity score-adjusted OS risk was significantly higher for RFA (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.35 to 2.44) and cryoablation (HR, 2.03; 95% CI, 1.51 to 2.74) compared to PN. For cT1b tumors, 376 patients were treated, but none received RFA. Limitations of the study include its retrospective design and selection bias arising from whom was treated with PN versus ablation.

A retrospective study by Park et al. (2018) compared the mid-term oncologic and functional outcomes of robotic PN with RFA for treating T1a RCC.18 Using propensity score matching, the study analyzed 63 similar patient cases from each treatment group for changes in tumor location, estimated glomerular filtration rates preservation, and 2-year recurrence-free survival rate. Preservation of estimated glomerular filtration rate in the robotic PN group was 91.7% and 86.8% of the RFA group (p=0.088), and exophytic and endophytic RCC occurred in 73% (46/63) and 27% (17/63) of the robotic PN group and 52.4% (33/63) and 47.6% (30/63) of the RFA group, respectively. Two-year recurrence-free survival rate was 100% in the robotic PN group and 95.2% in the RFA group (p=0.029). The mismatching of RCC locations between the robotic PN and RFA groups is a study limitation. Other limitations included the retrospective design, the relatively small sample and the lack of long-term outcomes assessing and kidney function measures.

Dai et al. (2017) conducted a retrospective evaluation of 30 patients with 31 central renal tumors who underwent percutaneous RFA between 2005 and 2010 to assess the clinical efficacy and safety of image-guided percutaneous RFA of central RCC with adjunctive pyeloperfusion.19 OS was 96.0% (95% CI, 88.4% to 100.0%) and progression-free survival at 5 years was 80.9% (95% CI, 65.8% to 95.9%). The investigators found that complications were significantly higher for tumors located within 5 mm of the renal pelvis or 0 mm of a major calyx (28.6% vs 4.0%; p<0.05) and major complications occurred in 5 (12.8%) of 39 RFA sessions. They concluded that image-guided percutaneous RFA combined with pyeloperfusion had satisfactory clinical efficacy in the treatment of renal tumor but may be associated with significant major complications. The retrospective design and the small sample base are limitations to this analysis.

Over 10 years, Dvorak et al. (2017) retrospectively evaluated the technical success as well as mid-term and long-term efficacy and safety of RFA and microwave ablation with guided CT in 64 patients with small, non-central renal tumors.20 Ninety-one ablation procedures were performed on 68 tumors, 12 to 60 mm in size. Treatment was successful in 50 (73.5%) tumors; a second procedure was successful in 13 (19.1%) cases; and for the 5 largest tumors (range, 45-60 mm; 7.4%), a third treatment was required. Investigators concluded that percutaneous ablation is safe and effective in treating small, non-central renal tumors of the T1a group. The retrospective study design is the major limitation of this study.

Pantelidou et al. (2016) retrospectively compared the oncologic outcomes of RFA with robotic-assisted PN for the treatment of T1 stage RCC.21 Sixty-three cases were included in each treatment group. Baseline renal function for those who received RFA was poorer; and there was an imbalance between groups in the number of patients with tumors in a single kidney (16/63 RFA patients vs 1/63 PN patients; p<0.001). Postprocedure renal function decline at 30 days was significantly smaller in the RFA group (-0.8 mL/min/1.73 mvs -16.1 mL/min/1.73 m2; p<0.001). The robotic-assisted PN group experienced more minor complications (10/63 vs 4/63, p=0.15) and the RFA group had a higher local recurrence (6/63 vs 1/63, p=0.11). The authors concluded that both RFA and RNA offered good oncologic outcomes for T1 RCC with low morbidity. The retrospective study design, the tertiary center location's specific referral procedures, a loss of follow-up case data, and the heterogeneous patient demographics are study limitations.

A publication by Iannuccilli et al. (2016) reported a mean 34.1-months follow-up (range, 1 to 131 months) of RFA with intent to cure in 203 patients with renal tumors.22 Patients referred for RFA at high-risk or had refused surgery. Smaller tumors were treated with a single electrode with a 2 or 3 cm active tip. Larger tumors were treated with a cluster electrode with 3 active tips. Patients were assessed annually for the appearance of residual tumor at the treatment site, and 26 (13%) had residual disease. Treatment effectiveness was 87% during follow-up. The likelihood of recurrence was increased for tumors 3.5 cm or larger, clear cell subtype, and treatment temperature of 70° or less. All-cause mortality increased with increasing tumor size. The median survival was 7 years for patients with tumors less than 4 cm, with 80% survival at 5 years. Major complications, including urinary stricture or urine leak, occurred in 8 (3.9%) treatments.

Section Summary: Localized Renal Cell Carcinoma
The evidence on RFA for small renal tumors (≤ 4 cm) includes an RCT, meta-analyses, retrospective and cohort studies, and case series, that have compared RFA with nephrectomy or cryoablation. A 2014 meta-analysis that included 1 RCT and 5 cohort studies found that RFA was as effective as nephrectomy for small renal tumors, with a reduction in complications. Another, more recent, meta-analysis (2019) found that PN was superior to ablative techniques (the study included RFA but also cryoablation and microwave ablation) in overall mortality and local recurrence but not in cancer-specific mortality. It also found fewer complications and improved renal function with ablation. The correlation between tumor size and RFA efficacy has been demonstrated by a large case series with a mean 34-month follow-up; it found that residual disease and mortality increased with tumors over 4 cm. Long-term follow up in one single center study found that RFA resulted in similar cancer-specific survival outcomes as PN in patients with cT1a renal tumors.

Primary Pulmonary and Nonpulmonary Tumors
Clinical Context and Therapy Purpose
Surgery is the current treatment of choice in patients with stage I primary non-small-cell lung cancer (NSCLC; stage I includes Ia [T1N0M0] and 1b [T2N0M0]). Approximately 20% of patients present with stage I disease, although this number is expected to increase as a result of screening programs, advances in imaging modalities and widespread use of CT scans for other indications. Postsurgical recurrence rates of stage I NSCLC have been reported as between 20% and 30%, with most occurring at distant sites; locoregional recurrences occur in approximately 12%. Large differences in survival outcome are observed after surgery in stage I patients, with 5-year OS rates ranging from 77% for small T1 tumors to 35% for large T2 tumors. Untreated, stage I NSCLC has a 5-year OS rate range from 6% to 14%.

Patients with early-stage NSCLC who are not surgical candidates may be candidates for radiotherapy with curative intent. In 2 large retrospective radiotherapy series, patients with the inoperable disease treated with definitive radiotherapy achieved 5-year survival rates of 10% and 27%. In both studies, patients with T1 N0 tumors had better 5-year survival rates of 60% and 32%, respectively.

Stereotactic body radiotherapy has gained more widespread use as a treatment option because it is a high-precision mode of therapy that delivers very high doses of radiation. Two- to 3-year local control rates of stage I NSCLC with stereotactic body radiotherapy have ranged from 80% to 95%. Stereotactic body radiotherapy has been investigated in patients unfit to undergo surgery, with survival rates similar to surgical outcomes.

RFA also is being investigated in patients with small primary lung cancers or lung metastases who are deemed medically inoperable.

The purpose of RFA in patients who have inoperable primary pulmonary tumors or nonpulmonary tumors metastatic to the lung is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in individuals with inoperable primary pulmonary tumors or nonpulmonary tumors metastatic to the lung?

The following PICO was used to select literature to inform this review.

Patients
The relevant population of interest is individuals with inoperable primary pulmonary tumors or nonpulmonary tumors metastatic to the lung.

Interventions
The therapy being considered is RFA, which is administered in an outpatient setting by oncologists and radiologists.

Comparators
The following practice is currently being used treat primary pulmonary tumors or nonpulmonary tumors metastatic to the lung: radiotherapy, which is administered in an outpatient setting by oncologists and radiologists.

Outcomes
The general outcomes of interest are OS, tumor recurrence, and treatment-related adverse events (e.g., pneumothorax). Patients would be followed for at least 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
In a systematic review of RFA, surgery, and stereotactic body radiotherapy for colorectal cancer (CRC) lung metastases, Schlijper et al. (2014) did not identify any randomized trials, and evidence was insufficient to draw conclusions on the comparative effectiveness of these therapies.23

In comparative effectiveness review conducted for the Agency for Healthcare Research and Quality, Ratko et al. (2013) assessed local nonsurgical therapies for stage I NSCLC.24 In this review, no comparative RFA studies were identified. Reviewers found that available evidence was insufficient to draw conclusions on the comparative effectiveness of local nonsurgical therapies for NSCLC, including RFA.

In a review of 16 studies, Bilal et al. (2012) compared RFA with stereotactic ablative radiotherapy in patients with inoperable early-stage NSCLC.25 Reviewers found that OS rates for RFA and stereotactic ablative radiotherapy were similar in patients at 1 year (68.2% to 95% vs 81% to 85.7%) and 3 years (36% to 87.5% vs 42.7% to 56%), all respectively. However, survival rates at 5 years were lower with RFA (20.1% to 27%) than with stereotactic body radiotherapy (47%). These findings were drawn from comparisons of results of uncontrolled case series and retrospective reviews.

In an evidence-based review by Chan et al. (2011), 46 studies on RFA for lung tumors were evaluated, which included 2,905 ablations in 1584 patients with a mean tumor size of 2.8 cm.26 Twenty-four studies reported rates of local recurrence, which occurred in 282 (12.2%) cases at a mean follow-up of 13 months (range, 3 to 45 months). Primary lung cancer rates of local recurrence did not differ significantly (22.2%) from metastases (18.1%). Twenty-one studies reported mean OS rates of 59.4% at a mean follow-up of 17.7 months. The mean cancer-specific survival rate was 82.6%, at a mean follow-up of 17.4 months. The mean overall morbidity was 24.6% and most commonly included pneumothorax (28.3%), pleural effusion (14.8%), and pain (14.1%). Mortality related to the RFA procedure was 0.21%, overall.

Prospective Studies
Huang et al. (2011) prospectively followed 329 consecutive patients treated with RFA for lung tumors (237 primary, 92 metastatic).27 Complications were experienced by 34.3% (113) of patients, most commonly pneumothorax (19.1%). OS rates at 2 and 5 years were 35.3% and 20.1%, respectively. The risk of local progression did not differ significantly for tumors less than 4 cm but was statistically significant for tumors greater than 4 cm.

Zemlyak et al. (2010) prospectively compared 3 treatments for medically inoperable patients with stage I NSCLC: RFA in 12 patients, sublobar resection in 25 patients, and percutaneous cryoablation in 27 patients.28 At 3-year follow-up, survival rates did not differ significantly between groups. OS and cancer-specific 3-year survival rates were 87.5%, 87.1%, and 77% and 87.5%, 90.6%, and 90.2%, respectively, in the 3 groups. The authors concluded that all 3 procedures were reasonable options for treating lung tumors in patients unfit for major surgery. The authors also noted that because surgeons chose the treatment option with patient input for this study, selection bias limited study interpretation.

Inoperable Lung Tumors
In a prospective, single-arm, multicenter trial from 7 centers in Europe, the U.S., and Australia, Lencioni et al. (2008) reported the technical success, safety, response of tumors, and survival in 106 patients with 183 lung tumors.29 All patients were considered unsuitable for surgery and unfit for radiotherapy or chemotherapy. Tumors measured less than 3.5 cm (mean, 1.7 cm) and included patients with NSCLC (n=22), colorectal metastases (n=41), and other metastases (n=16). The technical success rate was 99%. Patients were followed for 2 years, and a confirmed complete response lasting at least 1 year was observed in 88% of assessable patients, with no differences in response rate between those with primary and metastatic tumors. OS rates in patients with NSCLC were 70% at 1 year (95% CI, 51% to 83%; cancer-specific survival, 92% [78% to 98%]), and 48% at 2 years (95% CI, 30% to 65%; cancer-specific survival, 73% [54% to 86%]). OS rates in patients with metastatic CRC were 89% at 1 year (95% CI, 76% to 95%; cancer-specific survival, 91% [78% to 96%]) and 66% at 2 years (95% CI, 53% to 79%; cancer-specific survival 68% [54% to 80%]). OS rates in patients with other metastases were 92% at 1 year (95% CI, 65% to 99%; cancer-specific survival, 93% [67% to 99%]) and 64% at 2 years (95% CI, 43% to 82%; cancer-specific survival, 67% [48% to 84%]). Patients with stage I NSCLC (n=13) had an OS rate of 75% (95% CI, 45% to 92%) at 2 years (cancer-specific, 92%; 95% CI, 66% to 99%). No differences in response rates were seen between patients with NSCLC or lung metastases.

Zhu et al. (2009) assessed the incidence and risk factors of various pulmonary neoplastic complications after RFA.30 They prospectively evaluated the clinical and treatment-related data for 129 consecutive percutaneous RFA treatment sessions for 100 patients with inoperable lung tumors. There was no postprocedural mortality. The overall morbidity rate was 43% (55/129). The most common adverse event was a pneumothorax, occurring in 32% (41/129) of treatment sessions. Other significant complications included pleuritic chest pain (18%), hemoptysis (7%), pleural effusions (12%), and chest drain insertion (20%). Both univariate and multivariate analyses identified more than 2 lesions ablated per session as a significant risk factor for overall morbidity, pneumothorax, and chest drain insertion. The length of the ablation probe trajectory greater than 3 cm was an additional independent risk factor for overall morbidity and pneumothorax.

Pennathur et al. (2009) reported on 100 patients with inoperable lung tumors.31 Forty-six patients had primary lung neoplasm, 25 had recurrent cancer, and 29 had pulmonary metastases. The mean follow-up was 17 months. Median OS for all patients was 23 months. The probability of 2-year OS for primary lung cancer patients, recurrent cancer patients, and metastatic cancer patients were 50% (95% CI, 33% to 65%), 55% (95% CI, 25% to 77%), and 41% (95% CI, 19% to 62%), respectively.

Section Summary: Primary Pulmonary and Nonpulmonary Tumors
The evidence on RFA for primary NSCLC and nonpulmonary tumors metastatic to the lung includes prospective and observational studies and systematic reviews of those studies. No RCTs identified compared treatment approaches. For inoperable lung tumors, a multicenter study found that RFA for tumors less than 3.5 cm can lead to a complete response in as many as 88% of patients for at least 1 year. Two-year survival has been reported to range from 41% to 75% in case series. Survival at 1 and 2 years appears to be similar, following treatment with RFA or stereotactic ablative radiotherapy in patients with inoperable lung tumors. Survival rates at 5 years were lower with RFA (20.1% to 27%) than with stereotactic ablative radiotherapy (47%), but this finding was drawn from comparisons of uncontrolled case series and retrospective reviews. Prospective comparison in an RCT would permit greater certainty for this finding but the studies are consistent with some effect of RFA on lung tumors.

Breast Tumors
Clinical Context and Therapy Purpose
The treatment of small cancers of the breast has evolved from total mastectomy to more conservative treatment options such as lumpectomy, with more acceptable cosmetic outcomes and preservation of the breast. The selection of the surgical approach balances the patient's desire for breast conservation and the need for tumor-free margins in resected tissue. Minimally invasive nonsurgical techniques such as RFA are appealing if they can produce local control and survival equivalent to breast-conserving surgical alternatives. Nonsurgical ablative techniques pose difficulties such as the inability to determine tumor size, complete tumor cell death, and local recurrence. Additionally, RFA can burn the skin and damage to muscle, possibly limiting use in patients with tumors near the skin or chest wall.

The purpose of RFA in patients who have breast tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in individuals with breast tumors?

The following PICO was used to select literature to inform this review.

Patients
The relevant population of interest is individuals with breast tumors.

Interventions
The therapy being considered is RFA, which is administered in an outpatient setting by oncologists and radiologists.

Comparators
The following practices are currently being used as treatment options for small cancers of the breast breast cancer: radiotherapy and surgical excision, which are administered in an outpatient or hospital setting by oncologists, radiologists, and surgeons.

Outcomes
The general outcomes of interest are tumor recurrence, reduction in medication, and treatment-related adverse events.

Patients would be followed for up to 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Peek et al. (2017) conducted a systematic review and meta-analysis of all studies evaluating the role of ablative techniques in the treatment of breast cancer published between 1994 and 2016.32 Selection criteria included at least 10 patients with breast cancer treated with RFA, high-intensity ultrasound, or cryo-, laser, or microwave ablation; 63 studies ( N=1,608 patients) were identified through PubMed and PubMed library databases. Fifty studies reported complete ablation, and RFA had the highest rate of complete ablation (87.1% [491/564]) as well as the shortest treatment time (15.6 minutes). A major limitation of this systematic review was the authors' inability to perform a comparative meta-analysis due to the inclusion of only 4 RCTs and 1 retrospective analysis that compared 2 or more of techniques. There was also considerable heterogeneity across included studies.

Zhao and Wu (2010) conducted a systematic review of 38 studies on ablation techniques for breast cancer treatment published from 1994 to 2009.33 Nine studies focused on RFA. Reviewers included small tumors ranging in size from 0.5 to 7 cm. Tumor resection was performed immediately after ablation or up to 4 weeks after RFA. Complete coagulation necrosis rates of 76% to 100% were reported. The results suggested RFA for breast cancer tumors is feasible but further studies with longer follow-up on survival, tumor recurrence, and cosmetic outcomes would be needed to establish clinical efficacy.

In another review, Soukup et al. (2010) examined 17 studies on RFA for the treatment of breast tumors and found RFA is feasible.34 Even though few adverse events and complications occurred with breast RFA, incomplete tumor ablation remains a concern.

Clinical Studies
Retrospectively, Ito et al. (2018) studied the safety and efficacy of percutaneous RFA of breast carcinomas in 386 patients from 10 institutions treated with RFA between 2003 and 2009.35 Patients were followed for a median of 50 months and ipsilateral breast tumor recurrence was more frequent in patients with initial tumor sizes of 2 cm or more (10% [3/30]) than those with initial tumors 2 cm or less (2.3% [8/355]; p=0.015). Ipsilateral breast tumor recurrence rates 5 years after RFA were 97%, 94%, and 87% in patients with initial tumor sizes of 1 cm or less, 1.1 to 2.0 cm, and greater than 2 cm, respectively. The authors concluded that RFA was safe for tumors of 2 cm or less. The retrospective design and lack of data on ipsilateral breast tumor recurrence for different types of chemotherapy and endocrine therapy and analyses to ascertain whether adjuvant chemotherapy or endocrine therapy influenced outcomes are the limitations of this study.

The efficacy and safety of using ultrasound-guided RFA for multiple breast fibroadenoma as an alternative to surgical resection were retrospectively analyzed by Li et al. (2016).36 From 2014 to 2016, 65 patients with 256 nodules were treated with ultrasound-guided RFA and complete ablation was achieved for 251 nodules (98.04%) after the first month of treatment; after the first and third months, tumor volume overall was reduced by 39.06% and 75.99%, respectively. The study reported minimal to no complications such as skin burns, hematoma, or nipple discharge. The retrospective design and short follow-up time limited the conclusions drawn from this study.

Wilson et al. (2012) reported on 73 patients with invasive breast cancer who had a lumpectomy followed immediately by RFA to the lumpectomy bed.37 The average breast tumor size was 1.0 cm (range, 0.2-2.6 cm) and follow-up averaged 51 months. Disease-free survival was 100%, 92%, and 86% at 1, 3, and 5 years, respectively. One patient had tumor recurrence within 5 cm of the lumpectomy site, and 3 patients had ipsilateral breast recurrences.

In a phase 1/2 study reported by Kinoshita et al. (2011), 49 patients were treated with RFA for breast tumors (mean size, 1.7 cm) followed immediately with surgical resection.38 Complete ablation was achieved in 30 (61%) patients. The complete ablation rate increased to 83% in 24 patients with tumor sizes of 2 cm or less in diameter. Adverse events related to the procedure included 3 muscle and 2 skin burns.

Imoto et al. (2009) reported on a series of 30 patients with T1N0 breast cancer who had sentinel node biopsy followed by RFA and breast-conserving surgery.39 Twenty-six patients showed pathologic degenerative changes in tumor specimens, and, in 24 of 26 cases, tumor cell viability was diagnosed. Two patients had skin burns, and 7 had muscle burn related to RFA.

In a 2-stage, phase 2 clinical trial reported by Garbay et al. (2008), patients with histologically confirmed noninflammatory and 3 cm or less ipsilateral breast tumor recurrence were treated with RFA followed by mastectomy.40 The study was ended early due to lack of efficacy of the technique tested.

Section Summary: Breast Tumors
Systematic reviews, retrospective studies, and observational studies have reported varied and incomplete ablation rates as well as concerns about postablation tumor cell viability. Long-term improvements in health outcomes have not been demonstrated. Additionally, available studies have not compared RFA with conventional breast-conserving procedures. For small breast tumors, further study, with long-term follow-up, is needed to determine whether RFA can provide local control and survival rates compared with conventional breast-conserving treatment.

Benign Thyroid Nodules
Clinical Context and Therapy Purpose
Surgical resection is the primary treatment choice for medically unresponsive, symptomatic benign thyroid tumors and thyroid carcinomas. However, techniques for ablation of thyroid tumors (e.g., RFA, microwave ablation) are being investigated.

The purpose of RFA in patients who have benign thyroid tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in individuals with benign thyroid tumors?

The following PICO was used to select literature to inform this review.

Patients
The relevant population of interest is individuals with large or symptomatic benign thyroid tumors. Patients with a benign cytology diagnosis or those very unlikely to be malignant (e.g., purely cystic nodule) should undergo surveillance with the frequency determined by the level of suspicion for a missed malignancy.41 Medical or surgical intervention is considered if the nodules are large (>4 cm), causing compressive or structural symptoms, or if there is clinical concern.

Interventions
The therapy being considered is RFA, which is administered in an outpatient setting by oncologists and radiologists.

Comparators
The following practices are currently being used to treat large or symptomatic benign thyroid tumors in the United States: percutaneous ethanol injection (PEI) and surgical excision, which are administered in an outpatient or hospital setting by oncologists, radiologists, and surgeons.

Outcomes
The general outcomes of interest are a reduction in nodule volume, hyper- and hypothyroidism, and treatment-related adverse events (e.g., voice changes).

Patients would be followed for at least 5 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Cho et al. (2020) evaluated the efficacy of thermal ablation (RFA and laser ablation) for the treatment of benign thyroid nodules.42 The analysis demonstrated long-term maintenance (up to 36 months) of volume reduction. Further, RFA was found to be superior to laser ablation. The volume reduction rate for RFA at last follow up was 92.2%, whereas in the laser ablation group, the volume reduction rate peaked at 12 months (52.3%) and was at 43.3% at last follow up.

To evaluate the efficiency of RFA for the treatment of benign thyroid nodules, Chen et al. (2016) conducted a systematic review and meta-analysis and found that RFA was associated with a significant decrease in nodule volume at months 1, 3, 6, 12, and last follow-up. 43

Fuller et al. (2014) reported on a systematic review of studies on RFA for benign thyroid tumors.44 After RFA, statistically significant improvements were reported in combined symptom improvement and cosmetic scores on the 0 to 6 scale (mean, -2.96; 95% CI, -2.66 to -3.25) and withdrawal from methimazole (odds ratio, 40.34; 95% CI, 7.78 to 209.09). Twelve adverse events were reported, 2 of which were considered significant but did not require hospitalization.

Table 3 includes a comparison of studies included in the systematic reviews; the analysis by Cho et al. (2020) contains the fewest number of included studies as a minimum follow up duration of 3 years was required for inclusion. Table 4 summarizes the characteristics of the systematic reviews and Table 5 contains the available results for nodule size reduction and complication rates. All of the systematic reviews are limited by high heterogeneity, inclusion of mostly single-center retrospective and/or noncontrolled studies, and generalizability concerns as included studies were mainly conducted in the Republic of Korea and Italy. They are further limited by a lack of comparison to surgical excision or PEI.

Table 3. Comparison of Meta-Analyses Assessing Radiofrequency Ablation for Benign Thyroid Nodules  

Study Cho (2020)*42 Chen (2016)43 Fuller (2014)44
Aldea Martinez (2019)    
Deandrea (2019)    
Jung (2018)    
Sim (2017)    
Cesareo (2015)    
Sung (2015)    
Che (2015)    
Ugurlu (2015)    
Ji Hong (2015)    
Valcavi (2015)    
Bernardi (2014)    
Turtulici (2014)    
Yoon (2014)    
Lim (2013)  
Ha (2013)    
Sung (2013)  
Huh (2012)    
Faggiano (2012)  
Jang (2012)    
Kim (2012)    
Baek (2010)  
Lee (2010)    
Spiezia (2009)  
Jeong (2008)    
Deandrea (2008)  
Kim (2006)  

*Studies addressing RFA only included.

Table 4. Characteristics of Meta-Analyses Assessing Radiofrequency Ablation for Benign Thyroid Nodules  

Study Dates Trials Participants N (Range) Design Duration
Cho (2020)42 2010-2019 12 Patients with a benign thyroid nodule treated with thermal ablation (RFA [5 studies] or laser [7 studies]) 1208 (24-276) 2 prospective and 10 retrospective cohorts At least 3 years
Chen (2016)43 2006-2016 20 Patients with a benign thyroid nodule treated with RFA 1090 (11-236) Prospective and retrospective cohorts Varied, 6-49.4 months
Fuller (2014)44 2006-2013 9 Patients with a benign thyroid nodule treated with RFA 284 (15-94) Prospective studies (5 observational, 4 randomized trials) Varied, 3-12 months

RFA: radiofrequency ablation 

Table 5. Key Results of Meta-Analyses Assessing Radiofrequency Ablation for Benign Thyroid Nodules  

Study Reduction in nodule size from baseline Complication rate
Cho (2020)42 Relative volume reduction, VRR  
Total N, nodules (patients) 695 (680) 695 (680)
Pooled effect (95% CI) 6 mo: 64.5% (56.1% to 72.1%)
12 mo: 76.9% (65% to 85.7%)
24 mo: 80.1% (66.4% to 89.2%)
36 mo: 80.3% (66% to 89.5%)
4.6%
I2 (p) 73.7%-95.9%  
Chen (2016)43 Absolute volume reduction, SMD  
Total N, nodules (patients) 1406 (1090)  
Pooled effect (95% CI) 1 mo: 0.83 (0.47 to 1.19)
3 mo: 1.31 (0.76 to 1.85)
6 mo: 1.25 (0.90 to 1.59)
12 mo: 4.16 (2.25 to 6.07)
 
I2 (p) 90.3%-98.7%  
Fuller (2014)44 Absolute volume reduction, SMD (follow up time frame not specified)  
Total N, nodules (patients) 284 (276)  
Pooled effect (95% CI) -9.77 mL (-13.83 to -5.72)  
I2 (p) 98% (<0.00001)  

CI: confidence interval; SMD: standard mean difference; VRR: volume reduction rate.

Section Summary: Benign Thyroid Tumors
Evidence on the treatment of benign thyroid nodules includes randomized and nonrandomized trials, case series, and systematic reviews of these studies. Systematic reviews have demonstrated that RFA results in a significant reduction in thyroid nodule size with a 2020 review showing that these changes remain durable through at least 36 months. Complication rates are generally low, but include voice changes. The data are limited by significant heterogeneity in meta-analyses, a lack of generalizability to populations outside Republic of Korea and Italy, and a lack of comparators more relevant to practice in the United States.

Miscellaneous Solid Tumors
Clinical Context and Therapy Purpose
RFA has been investigated for use in individuals with different lesions in different anatomic sites. These anatomic sites include but are not limited to, breast and head and neck.

In patients with head and neck cancer with recurrent disease, surgical salvage attempts are poor in terms of local control, survival, and QOL; further, these recurrent tumors are often untreatable with standard salvage therapies. Palliative chemotherapy or comfort measures may be offered. The safety and efficacy of RFA have been investigated as an option for palliative treatment in these situations.

The purpose of RFA in patients who have miscellaneous solid tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of RFA improve the net health outcome in individuals with miscellaneous solid tumors?

The following PICO was used to select literature to inform this review.

Patients
The relevant population of interest is individuals with miscellaneous solid tumors (e.g., head and neck, thyroid cancer, pancreas).

Interventions
The therapy being considered is RFA, which is administered in an outpatient setting by oncologists and radiologists.

Comparators
The following practices are currently being used to treat miscellaneous solid tumors: surgical excision or other local treatments specific to the tumor type, which are administered in an outpatient or hospital setting by oncologists, radiologists, and surgeons.

Outcomes
The general outcomes of interest vary by disease state but include OS, tumor recurrence, and reductions in pain.

Patient follow-up will vary by disease state.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Thyroid Cancer
Kim et al. (2015) reported on a comparative review of 73 patients with recurrent thyroid cancer smaller than 2 cm who had been treated with RFA (n=27) or repeat surgery (n=46).45 RFA was performed in cases of patient refusal to undergo surgery or poor medical condition. Data were weighted to minimize potential confounders. The 3-year recurrence-free survival rates were similar for RFA (92.6%) and surgery (92.2%, p=0.681). Posttreatment hoarseness rate did not differ between the RFA (7.3%) and surgery (9.0%) groups. Posttreatment hypocalcemia occurred only in the surgery group (11.6%).

Head and Neck Cancer
Owen et al. (2011) reported on RFA for 13 patients with recurrent and/or unresectable head and neck cancer who failed curative treatment.46 Median patient survival was 127 days. While the stable disease was reported in 8 patients after RFA, and QOL scores improved, 3 deaths occurred (1 carotid hemorrhage, 2 strokes).

A case series of RFA for 14 patients with recurrent advanced head and neck malignancies was reported by Brook et al. (2008).47 Tumor targeting and electrode deployment were successful in all cases, and 4 of 6 patients who completed QOL assessments showed improvement. Three major complications (in 27 [11%] applications) occurred 7 days to 2 weeks postprocedure. They included stroke, carotid artery rupture leading to death, and threatened carotid artery rupture with subsequent stroke. Retrospective analysis of intraprocedural CT scans revealed that the retractable electrodes were within 1 cm of the carotid artery during ablation in these cases.

A case series by Owen et al. (2004) showed that palliative CT-guided RFA provided subjective improvement with regard to pain, appearance, and function in 12 patients who had recurrent and advanced head and neck malignancies and were not candidates for radiotherapy or surgery.48 The procedure appeared reasonably safe and feasible for this indication.

Other Tumors
A prospective observational study by Rey et al. (2019) assessed the effectiveness of transvaginal ultrasound-guided RFA of myomas in reducing tumor volume and eliminating metrorrhagia associated with myomas.49 The study included 205 women with symptomatic type II/III uterine submucosal or intramural cavity-distorting myomas undergoing RFA. The preoperative mean standard deviation volume of the myomas was 122.4 (182.5) cm3 (95% CI, 82.1 to 162.8). Mean myoma volume decreased significantly at 1 (85.2 [147.9] cm3; p=0.001), 3 (67.3 [138.0] cm3; p=0.001), 6 (59.3 [135.3] cm3; p=0.001, and 12 months (49.6 [121.4] cm3; p=0.001). At 12 months, the mean volume reduction was 60% compared with preoperative volume. All patients returned to normal menstruation at a mean follow-up of 3 months and 12 months. Of the 205 patients, 201 (98.04%) were satisfied with the procedure. The investigators conceded that a larger population with a longer follow-up is needed but their study suggests that transvaginal ultrasound-guided RFA of myomas is effective and safe for treating select patients with metrorrhagia secondary to myomas.

In a large series, Yin et al. (2015) evaluated the effectiveness and safety of RFA for uterine myomas in a 10-year retrospective cohort study.50 From 2001 to 2011, a total of 1,216 patients treated for uterine myomas were divided into 2 groups. Group A consisted of 476 premenopausal patients (average age, 36 years) who had an average of 1.7 myomas with an average diameter of 4.5 cm. Group B consisted of 740 menopausal patients (average age, 48 years) with an average of 2.6 myomas with an average diameter of 5.0 cm. Patients were followed for a mean of 36 months. At 1, 3, 6, 12, and 24 months after RFA, the average diameters of myomas in group A were 3.8, 3.0, 2.7, 2.4, and 2.2 cm, respectively; 48% (227/476) of patients had a residual tumor at 12 months. In group B, myoma diameters were 4.7, 3.7, 3.3, 2.3, and 2.3 cm, respectively; 59% (435/740) of patients had trace disease at 12 months. Three months after RFA treatment, myoma volumes were significantly reduced in both groups (p<0.01), although group B had a higher rate of residual tumor 12 months after RFA than group A (p<0.05). Clinical symptoms and health-related QOL were significantly improved after RFA in both groups. The postoperative recurrence rate of uterine myomas was significantly higher in group A at 10.7% (51/476) than in group B at 2.4% (18/740; p<0.05).

Liu et al. (2020) retrospectively evaluated the clinical outcomes of percutaneous ultrasound-guided RFA in the treatment of adrenal metastasis as compared to adrenalectomy.51 Of the 60 patients included, 29 received RFA and 31 received adrenalectomy. The first technical success rate for RFA was 72.4%; 5 of the 8 patients had a repeat RFA and 4 of those achieved a complete response. In the adrenalectomy group, all patients achieved a R0 resection. Major complications were reported in 1 patient in the RFA group (ventricular fibrillation) and 2 patients in the adrenalectomy group (ascites, surgical site infection). The 1-, 2-, and 3-year local tumor progression rates after RFA were 17.1%, 30.9% and 44.7%, respectively, compared to 6.5%, 6.5% and 6.5% in adrenalectomy group (p=0.028). There was no significant difference between groups for mean OS (2.3 ± 0.3 years for RFA and 3.9 ± 0.6 years for adrenalectomy, p=0.057).Limitations of the study includes its retrospective design, potential selection bias on which patients received each treatment, and a high prevalence of patients with adrenal metastasis secondary to hepatocellular carcinoma, which exceeded the expected number of cases based on global prevalence rates.

Liu et al. (2016) retrospectively compared laparoscopic adrenalectomy with CT-guided percutaneous RFA for the treatment of aldosterone-producing adenoma, evaluating short-term and long-term outcomes of normalized aldosterone-to-renin ratio, hypokalemia, and hypertension.15 Of 63 patients, 27 were in the laparoscopic adrenalectomy group and 36 were in the RFA group. Primary aldosteronism was seen in 33 of 36 patients treated with RFA and all 27 who had laparoscopic adrenalectomy (p=0.180), within a median follow-up of 5 to 7 years. RFA was associated with faster recovery postprocedure, but hypertension was less frequently resolved using RFA (13/36 patients) compared with laparoscopic adrenalectomy (19/27 patients; p=0.007). The use of posture test and CT for subtype classification of primary aldosteronism is the major limitation of the study, as well as the retrospective design.

Retrospectively, Yang et al. (2016) compared the efficacy and safety of RFA with laparoscopic adrenalectomy in treating aldosterone-producing adenoma of the adrenal gland.52 From 2009 to 2013, 25 patients diagnosed with unilateral adrenal aldosterone-producing adenoma and similar tumor size (<25 mm) were allocated to a control group (n=18) that underwent laparoscopic adrenalectomy and a test group (n=7) that underwent CT-guided percutaneous RFA. Complete tumor ablation on follow-up CT scan and normalization of serum aldosterone-to-renin were the primary outcomes compared in this study. Success in the RFA group reached 100% within 3 to 6 months, compared with 94.4% in the laparoscopic adrenalectomy group, and normalization ability was statistically equivalent in both groups. The study's retrospective design and small sample are the main limitations of this study.

Hasegawa et al. (2020) conducted a prospective, single-arm, multicenter study to evaluate the efficacy of RFA in patients with surgically resectable CRC lung metastases measuring 3 cm or smaller.53 A total of 70 patients with CRC and 100 lung metastases were enrolled. All tumors were considered technically resectable, but all not all patients were clinically able to undergo surgery. A total of 85 initial RFA sessions were performed for 100 target lung metastases. The 3-year OS rate after RFA was 84%. Primary and secondary technical success rates for RFA were 96% and 100%, respectively. Over a mean follow-up of 57 ± 32 months, local tumor progression was found in 6 patients (9%) at 6 to 19 months after the initial RFA. The 3-year progression-free survival rate was 41%. Grade 2 pnemothorax occurred after 18 of the 88 RFA sessions. The study is limited by its lack of a comparator arm.

A single-arm, retrospective, paired-comparison study by Locklin et al. (2004) evaluated the short-term efficacy of RFA in reducing pain and improving function in patients with unresectable, painful soft tissue neoplasms recalcitrant to conventional therapies.54 Patients had tumors located in a variety of sites including chest wall, pelvis, breast, perirectal, renal, aortocaval, retroperitoneal, and superficial soft tissues. All had failed conventional methods of palliation or experienced dose-limiting adverse events from pain medication. Although not all Brief Pain Inventory scores were statistically significant, all mean scores trended down over time after ablation. Complications from RFA were minor or insignificant in all but one patient who had skin breakdown and infection of an ablated superficial tumor site.

Additional research has addressed the use of RFA in solid malignancies55,56 and in the pancreas.57-59 A systematic review by Rombouts et al. (2015) has examined studies of ablative therapies, including RFA, in patients with locally advanced pancreatic cancer.60 No RCTs were identified, and conclusions limited by the sparse evidence available on RFA in this setting.

Stereotactic radiofrequency thermocoagulation for epileptogenic hypothalamic hamartomas was described in a retrospective analysis by Kameyama et al. (2009) who evaluated 25 patients with gelastic seizures (a rare type of seizure).61 Other seizure types were exhibited in 22 (88.0%) patients, precocious puberty in 8 (32.0%), behavioral disorder in 10 (40.0%), and mental disability in 14 (56.0%). Gelastic seizures resolved in all but 2 patients. Complete seizure freedom was achieved in 19 (76.0%) patients. These patients experienced resolution of all seizure types and behavioral disorder and also demonstrated intellectual improvement.

Preliminary results of endoscopic RFA of rectosigmoid tumors have been described by Vavra et al. (2009).62 Twelve patients were treated with the Endoblate RFA device, with 10 patients having surgical resection after ablation. Histology of the resected specimens showed that, on average, 82% (range, 60% to 99%) of the tumor mass was destroyed in the ablation zone.

Small case series on RFA for colorectal and rectal carcinoma have demonstrated a debulking role for RFA.63,64 These case series did not permit comparison with an available alternative.

Section Summary: Miscellaneous Solid Tumor
Evidence on the use of RFA to treat other types of solid tumors consists of a small number of case series, prospective studies, or retrospective comparative studies. Reporting on outcomes is limited. The evidence base does not support a conclusion on the effects of RFA for the tumor types included in this evidence review.

Summary of Evidence
Bone Tumors
For individuals who have painful osteolytic bone metastases who have failed or are poor candidates for standard treatments who receive RFA, the evidence includes case series. Relevant outcomes are symptoms, change in disease status, quality of life (QOL), medication use, and treatment-related morbidity. Case series have shown clinically significant pain relief and reduction in opioid use following treatment of painful osteolytic metastases. The population is comprised of patients with few or no treatment options, for whom short-term pain relief is an appropriate clinical outcome. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have painful osteoid osteomas who receive RFA, the evidence includes numerous observational studies and systematic reviews of these studies. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. In a systematic review of thermal ablation techniques, clinical success (pain-free) was achieved in 94% to 98% of patients. Most patients (89% to 96%) remained pain-free when assessed during longer-term follow-up. Another systematic review reported similar success rates noting an average 8.3% failure rate among patients receiving computed tomography-guided RFA. Although no randomized trials of RFA for osteoid osteomas have been performed, the uncontrolled studies have demonstrated RFA can provide adequate symptom relief with minimal complications, for a population for whom short-term symptom relief and avoidance of invasive procedures are appropriate clinical outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Localized Renal Cell Carcinoma
For individuals who have localized renal cell carcinoma that is no more than 4 cm in size who receive RFA, the evidence includes a randomized controlled trial (RCT), numerous observational studies, and systematic reviews of these studies. Relevant outcomes are overall survival (OS), change in disease status, QOL, and treatment-related morbidity. A recent meta-analysis that included only an RCT and cohort studies found that RFA was as effective as nephrectomy for small renal tumors, with a reduction in complications. Another recent meta-analysis found that partial nephrectomy was superior to ablative techniques (the study included RFA but also cryoablation and microwave ablation) in overall mortality and local recurrence but not in cancer-specific mortality. It also found fewer complications and improved renal function with ablation. Although inconsistent, the evidence does suggest that, for small renal tumors, RFA may result in a similar rate of disease progression with a lower complication rate than nephrectomy. However, comparative trials are needed to determine with greater certainty the effects of these treatments in the same patient population. The evidence is insufficient to determine the effects of the technology on health outcomes.

Inoperable Primary Pulmonary and Nonpulmonary Tumors
For individuals who have inoperable primary pulmonary tumors or nonpulmonary tumors metastatic to the lung who receive RFA, the evidence includes prospective observational studies and systematic reviews of these studies. Relevant outcomes are OS, change in disease status, QOL, and treatment-related morbidity. A multicenter study found that for tumors less than 3.5 cm in size, RFA can lead to a complete response in as many as 88% of patients for at least 1 year. Two-year survival rates have been reported to range from 41% to 75% in case series, with 5-year survival rates of 20% to 27%. In general, the evidence suggests that RFA results in adequate survival and tumor control in patients who are not surgical candidates, with low morbidity rates. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Breast Tumors
For individuals who have breast tumors who receive RFA, the evidence includes observational studies and systematic reviews of these studies. Relevant outcomes are OS, change in disease status, QOL, and treatment-related morbidity. Evidence has reported varied and incomplete ablation rates with concerns about postablation tumor cell viability. Long-term improvements in health outcomes have not been demonstrated. Additionally, available studies do not permit comparisons with conventional breast-conserving procedures. Further studies, with long-term follow-up, should focus on whether RFA of the breast for small tumors can provide local control and survival rates compared with conventional breast-conserving treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

Benign Thyroid Tumors
For individuals who have benign thyroid tumors who receive RFA, the evidence includes RCTs, prospective studies, case series, and systematic reviews of these studies. Relevant outcomes are symptoms, change in disease status, QOL, medication use, and treatment-related morbidity. Systematic reviews have demonstrated that RFA results in a significant reduction in thyroid nodule size with a 2020 review showing that these changes remain durable through at least 36 months. Complication rates are generally low, but include voice changes. The data are limited by significant heterogeneity in meta-analyses, a lack of generalizability to populations outside Republic of Korea and Italy, and a lack of comparators more relevant to practice in the United States. Further studies comparing RFA to percutaneous ethanol injection or surgery would be more informative in determining the potential utility of RFA in patients with symptomatic or large benign thyroid tumors as these are the recommended treatment options per the American Thyroid Association. The evidence is insufficient to determine the effects of the technology on health outcomes.

Miscellaneous Solid Tumors
For individuals who have miscellaneous tumors (e.g., head and neck, thyroid cancer, pancreas) who receive RFA, the evidence includes a few case series, prospective observational studies, and retrospective comparative studies. Relevant outcomes are OS, change in disease status, QOL, and treatment-related morbidity. There is a limited evidence base for these tumor types. Reporting on outcomes or comparisons with other treatments is limited. These studies do not permit conclusions on the health benefits of RFA. The evidence is insufficient to determine the impact of technology on health outcomes.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2010 Input
In response to requests, input was received from 2 physician specialty societies (4 reviewers) and 2 academic medical centers (4 reviewers) while this policy was under review in 2010. Input was similar to that received in 2009, except support for the use of radiofrequency ablation (RFA) to treat lung tumors was declined (only 1 respondent indicated this was an option in tumors metastatic to lung). One respondent also indicated a potential use for adrenal tumors. Input supported RFA for localized renal cell carcinoma no more than 4 cm in size when preservation of kidney function is necessary and a standard surgical approach would likely substantially worsen kidney function or when the patient is not considered a surgical candidate.

2009 Input
In response to requests, input was received from 1 physician specialty society (4 reviews) and from 2 academic medical centers (3 reviews) while this policy was under review in 2009. All reviewers supported the use of RFA in the treatment of painful bone metastases that have failed standard treatment and in the treatment of osteoid osteomas. Reviewers were divided over the use of RFA for lung tumors, although several agreed that, while it may be useful in a select population of patients, it should be used in the clinical trial setting. Reviewers were also split with regard to RFA in the treatment of renal tumors, with some supporting its use in a select population of patients. With the exception of 1 disagreement and 1 nonresponse, the reviewers agreed to the investigational statement on the use of RFA in all other tumors outside the liver that are addressed in this policy.

Practice Guidelines and Position Statements
American College of Chest Physicians
The American College of Chest Physicians (2013) guidelines on the treatment of stage I and II non-small-cell lung cancer (NSCLC) have indicated RFA has been used effectively in clinical stage I NSCLC.65 Therefore, in medically inoperable patients, peripheral NSCLC tumors less than 3 cm may be treated with RFA. The College also collaborated with the Society of Thoracic Surgeons to develop consensus guidelines on the treatment of high-risk patients with stage I NSCLC.66 These 2012 consensus guidelines indicated RFA is an alternative treatment option for patients who are not surgical candidates due to severe medical comorbidity.

American Urological Association
The American Urological Association (2017) guideline on renal masses and localized renal cancer affirms that partial nephrectomy should be prioritized for management of cT1a renal masses when intervention is indicated.67 Thermal ablation should be considered "as an alternate approach for the management of cT1a renal masses <3 cm in size."

American Thyroid Association
The American Thyroid Association (2015) guideline on management of thyroid nodules and differentiated thyroid cancer. 41 Patients with a benign cytology diagnosis or those very unlikely to be malignant (e.g., purely cystic nodule) should undergo surveillance with the frequency determined by the level of suspicion for a missed malignancy. Medical or surgical intervention is considered if the nodules are large (>4 cm), causing compressive or structural symptoms, or if there is clinical concern. Recurrent cystic thyroid nodules with benign cytology should be considered for surgical removal or percutaneous ethanol injection. For differentiated thyroid cancer, "localized treatments with thermal (radiofrequency or cryo-) ablation, ethanol ablation, or chemoembolization may be beneficial in patients with a single or a few metastases and in those with metastases at high risk of local complications."

National Comprehensive Cancer Network
The NCCN guidelines for the treatment of non-small cell lung cancer (v.6.2020) state:.68 "For medically operable disease, resection is the preferred local treatment modality (other modalities include SABR, thermal ablation such as radiofrequency ablation and cryotherapy)."

The NCCN guidelines for thyroid carcinoma (v.2.2020) indicate that local therapies such as RFA may be considered for locoregional recurrence of thyroid carcinoma-papillary carcinoma in select patients with limited burden nodal disease. Additionally, local therapies, including RFA, can be considered in those with metastatic disease.68

The NCCN guidelines (v.1.2021) for renal cancer indicate that “[t]hermal ablation (e.g., cryosurgery, radiofrequency ablation) is an option for the management of patients with clinical stage T1 renal lesions. Thermal ablation is an option for masses <3 cm, but it may also be an option for larger masses in select patients. Ablation in masses >3 cm is associated with higher rates of local recurrence/persistence and complications."68

The NCCN colon cancer guidelines (v.4.2020), which are currently under discussion, state that “for the local treatment of resectable metastatic disease, patients with liver or lung oligometastases can be considered for tumor ablation therapy".69 Evidence on the use of RFA as a reasonable treatment option for non-surgical candidates and those with recurrent disease after hepatectomy with small liver metastases that can be treated with clear margins is growing.”

The NCCN guidelines for head and neck cancers (v.2.2020)70 and pancreatic adenocarcinoma (v.1.2020) do not mention RFA71.

National Institute for Health and Care Excellence
The NICE guidance (2004) on osteoid osteoma indicated that "current evidence on the safety and efficacy of computed tomography (CT)-guided thermocoagulation of osteoid osteoma appears adequate to support its use...."72

Updated NICE guidance (2010) on renal cancer has indicated that "evidence on the safety and efficacy of percutaneous radiofrequency ablation (RFA) … in the short and medium term appears adequate to support the use of this procedure provided that patients are followed up in the long term."72

The NICE guidance (2010) on RFA for primary and secondary lung cancers has stated: "[C]urrent evidence on the efficacy of percutaneous radiofrequency ablation (RFA) … is adequate in terms of tumor control."73 The NICE also indicated RFA might "be used in patients with small, early-stage lung cancers or small numbers of lung metastases who are unsuitable for, or prefer not to undergo, surgery. It may also have a place in multi-modality treatment of more advanced primary lung cancers." The guidance warned of serious complications (eg, pneumothorax) among lung cancer patients.

The NICE guidance (2016) on benign thyroid nodules stated: "Current evidence on the safety and efficacy of ultrasound-guided percutaneous radiofrequency ablation … is adequate to support the use of this procedure…."74

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials  

NCT No. Trial Name Planned Enrollment Completion Date
Unpublished      
NCT01051037 Phase II Study Evaluating Safety and Efficacy of Stereotactic Body Radiotherapy and Radiofrequency Ablation for Medically Inoperable and Recurrent Lung Tumors Near Central Airways 17 Dec 2017
(completed)

NCT: national clinical trial.

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Coding Section

CodesNumberDescription
CPT 20982 Ablation therapy for reduction or eradication of 1 or more bone tumors (eg, metastasis) including adjacent soft tissue when involved by tumor extension, percutaneous, including imaging guidance when performed; radiofrequency
  32998 Ablation therapy for reduction or eradication of 1 or more pulmonary tumor(s) including pleura or chest wall when involved by tumor extension, percutaneous, including image guidance when performed radiofrequency, unilateral
  41530 Submucosal ablation of the tongue base, radiofrequency, 1 or more sites, per session
  50542 Laparoscopy, surgical; ablation of renal mass lesion(s)
  50592 Ablation, 1 or more renal tumor(s), percutaneous, unilateral, radiofrequency
HCPCS No code  
ICD-10-CM C25.0-C25.9 Malignant neoplasm of pancreas code range
  C50.0-C50.9 Malignant neoplasm of breast code range
  C64.0-C64.9 Malignant neoplasm of kidney, except renal pelvis code range
  C34.0-C34.92 Malignant neoplasm of lung, primary, code range
  C73 Malignant neoplasm of Thyroid
  C76.0 Malignant neoplasm of head, face and neck
  C78.00-C78.02 Malignant neoplasm of lung, secondary, code range
  C79.51-C79.52 Secondary malignant neoplasm of bone and bone marrow code range
  D16.0-D16.9 Benign neoplasm of bone and articular cartilage code range (includes osteoid osteoma)
ICD-10-PCS 0T500ZZ, 0T503ZZ, 0T504ZZ, 0T507ZZ, 0T508ZZ, 0T510ZZ, 0T513ZZ, 0T514ZZ, 0T517ZZ, 0T518ZZ, 0T530ZZ, 0T533ZZ, 0T534ZZ, 0T537ZZ, 0T538ZZ, 0T540ZZ, 0T543ZZ, 0T544ZZ, 0T547ZZ, 0T548ZZ Surgical, urinary system, destruction, kidney (right or left) or kidney pelvis (right or left); codes by approach (open, percutaneous, percutaneous endoscopic, via natural or artificial opening, via natural or artificial opening endoscopic)
  0P500ZZ, 0P503ZZ, 0P504ZZ, 0P510ZZ, 0P513ZZ, 0P514ZZ, 0P520ZZ, 0P523ZZ, 0P524ZZ, 0P550ZZ, 0P553ZZ, 0P554ZZ, 0P560ZZ, 0P563ZZ, 0P564ZZ, 0P570ZZ, 0P573ZZ, 0P574ZZ, 0P580ZZ, 0P583ZZ, 0P584ZZ, 0P590ZZ, 0P593ZZ, 0P594ZZ, 0P5B0ZZ, 0P5B3ZZ, 0P5B4ZZ, 0P5C0ZZ, 0P5C3ZZ, 0P5C4ZZ, 0P5D0ZZ, 0P5D3ZZ, 0P5D4ZZ, 0P5F0ZZ, 0P5F3ZZ, 0P5F4ZZ, 0P5G0ZZ, 0P5G3ZZ, 0P5G4ZZ, 0P5H0ZZ, 0P5H3ZZ, 0P5H4ZZ, 0P5J0ZZ, 0P5J3ZZ, 0P5J4ZZ, 0P5K0ZZ, 0P5K3ZZ, 0P5K4ZZ, 0P5L0ZZ, 0P5L3ZZ, 0P5L4ZZ, 0P5M0ZZ, 0P5M3ZZ, 0P5M4ZZ, 0P5N0ZZ, 0P5N3ZZ, 0P5N4ZZ, 0P5P0ZZ, 0P5P3ZZ, 0P5P4ZZ, 0P5Q0ZZ, 0P5Q3ZZ, 0P5Q4ZZ, 0P530ZZ, 0P533ZZ, 0P534ZZ, 0P540ZZ, 0P543ZZ, 0P544ZZ, 0P5R0ZZ, 0P5R3ZZ, 0P5R4ZZ, 0P5S0ZZ, 0P5S3ZZ, 0P5S4ZZ, 0P5T0ZZ, 0P5T3ZZ, 0P5T4ZZ, 0P5V0ZZ, 0P5V3ZZ, 0P5V4ZZ Surgical, upper bones, destruction, codes by anatomic location and approach (open, percutaneous, or percutaneous endoscopic)
  0Q560ZZ, 0Q563ZZ, 0Q564ZZ, 0Q570ZZ, 0Q573ZZ, 0Q574ZZ, 0Q580ZZ, 0Q583ZZ, 0Q584ZZ, 0Q590ZZ, 0Q593ZZ, 0Q594ZZ, 0Q5B0ZZ, 0Q5B3ZZ, 0Q5B4ZZ, 0Q5C0ZZ, 0Q5C3ZZ, 0Q5C4ZZ, 0Q5D0ZZ, 0Q5D3ZZ, 0Q5D4ZZ, 0Q5F0ZZ, 0Q5F3ZZ, 0Q5F4ZZ, 0Q5G0ZZ, 0Q5G3ZZ, 0Q5G4ZZ, 0Q5H0ZZ, 0Q5H3ZZ, 0Q5H4ZZ, 0Q5J0ZZ, 0Q5J3ZZ, 0Q5J4ZZ, 0Q5K0ZZ, 0Q5K3ZZ, 0Q5K4ZZ, 0Q5L0ZZ, 0Q5L3ZZ, 0Q5L4ZZ, 0Q5M0ZZ, 0Q5M3ZZ, 0Q5M4ZZ, 0Q5N0ZZ, 0Q5N3ZZ, 0Q5N4ZZ, 0Q5P0ZZ, 0Q5P3ZZ, 0Q5P4ZZ, 0Q500ZZ, 0Q503ZZ, 0Q504ZZ, 0Q510ZZ, 0Q513ZZ, 0Q514ZZ, 0Q520ZZ, 0Q523ZZ, 0Q524ZZ, 0Q530ZZ, 0Q533ZZ, 0Q534ZZ, 0Q540ZZ, 0Q543ZZ, 0Q544ZZ, 0Q550ZZ, 0Q553ZZ, 0Q554ZZ, 0Q5Q0ZZ, 0Q5Q3ZZ, 0Q5Q4ZZ, 0Q5R0ZZ, 0Q5R3ZZ, 0Q5R4ZZ, 0Q5S0ZZ, 0Q5S3ZZ, 0Q5S4ZZ Surgical, lower bones, destruction, codes by anatomic location and approach (open, percutaneous, or percutaneous endoscopic)
Type of service Surgery  
Place of service Outpatient/inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/01/2021 

Annual review, no change to policy intent. Updating rationale, references, guidelines and coding. 

07/28/2020 

Annual review, no change to policy intent. Updating background, guidelines, CPT coding, rationale and references. 

07/01/2019 

Annual review, no change to policy intent. Updating background, rationale and references. 

07/27/2018 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

07/03/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references.

07/13/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

07/30/2015 

Annual review, no change to policy intent. Updated background, description, guidelines, rationale and references. Added coding.

07/08/2014

Annual review. Updated rationale and references. Added related policies. No change to policy intent.


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