Radiofrequency Ablation, Where It Stands in Interventional Radiology Today

Abstract

Radiofrequency ablation (RFA) is one of the first developed minimally invasive definitive cancer therapies. The safety and efficacy of RFA is well documented and has led to its incorporation into multiple international societal guidelines. By expanding on the body of knowledge acquired during the clinical use of RFA, alternative ablative technologies have emerged and are successfully competing for locoregional therapy market share. The adaption of newer ablative technologies is leading to a rapid decline in the utilization of RFA by interventional radiologists despite the lack of proven superiority. In their 2010 article, Hong and Georgiades stated “… RFA is likely to remain the mainstay of ablations for small tumors until sufficient experience emerges for the widespread acceptance for alternative ablative modalities.” Within a decade of this publication, has this time arrived?

Radiofrequency ablation (RFA) is one of the first developed minimally invasive definitive cancer therapies. The safety and efficacy of RFA is well documented and has led to its incorporation into multiple international societal guidelines. By expanding on the body of knowledge acquired during the clinical use of RFA, alternative ablative technologies have emerged and are successfully competing for locoregional therapy market share. The adaption of newer ablative technologies is leading to a rapid decline in the utilization of RFA by interventional radiologists despite the lack of proven superiority. ¹

Why have some interventionalists veered from RFA utilization? The answer is multifactorial. Monopolar RFA requires a more cumbersome setup with grounding pads and larger gauge multi-tined probes which add complexity. In addition, there are limitations of charring and heat sink with RFA. Microwave ablation (MWA) is a major competitor to RFA and designed to improve on the limitations of RFA. MWA benefits have yet to be proven in randomized controlled trials (RCTs). The convenience of MWA has led to rapid adoption subsequently reducing trainee exposure to RFA and further decline in RFA utilization.

In their 2010 article, Hong and Georgiades stated “… RFA is likely to remain the mainstay of ablations for small tumors until sufficient experience emerges for the widespread acceptance for alternative ablative modalities.” ² Within a decade of this publication, has this time arrived?

History in Brief

The utilization of radiofrequency length sound waves to heat tissue was first described in 1891 by D'Arsonval and by 1928 this led to the creation of an intraoperative electrocautery Bovie knife. ³ The initial reports of using RFA specifically for the percutaneous ablation of tumor was described in 1990 with case reports from two authors using a modified Bovie knife with an insulated needle. ^{4 5} In 1992, McGahan et al published the first RFA study for percutaneous liver tumor ablation in humans followed by Goldberg et al in 1995 with a study on RFA tissue ablation in the rabbit lung. ^{6 7} Advancements in engineering led to radiofrequency generators that produced wavelengths of 200 to 1,200 MHz that could be passed through insulated needles.

As of today, there are three Food and Drug Administration (FDA)-approved RFA generators for visceral tumors: the Rita device (Rita Medical Systems, Inc., Freemont, CA), the LeVeen RF ablation system (Boston Scientific, Natick, MA), and the “Cool-tip” electrode (Covidien, Boulder, CO). ⁸

Pulmonary Lesions

RFA is performed in lung lesions for both primary and metastatic neoplastic disease and is incorporated into multiple cancer treatment guidelines. ^{9 10} Unlike resection or external beam radiotherapy, RFA can be reapplied to previous treatments without compromise to residual pulmonary function. ¹¹ In 2008, Lencioni et al published their prospective, intention-to-treat, multicenter clinical trial (RAPTURE) for the treatment of non-small-cell lung cancer or pulmonary metastases in 106 patients. The RAPTURE trial suggested that RFA could be competitive with surgery and/or radiation therapy outcomes in properly selected patients. ¹² In 2015, Dupuy et al published their ALLIANCE trial findings for inoperable biopsy-proven stage 1a non-small cell lung cancer treated with RFA. The 2-year overall survival rates reported were similar to those reported after stereotactic body radiotherapy in similar patients. ¹¹

The majority of data used to support the use of pulmonary MWA is single-institutional experiences and case studies such as Healey et al's 2017 retrospective review of 108 patients treated with MWA. They demonstrated technical success was 11 times more likely with MWA for tumors less than 3 cm than that for greater than 3 cm. ¹³ The only RCT of MWA versus RFA (LUMIRA) was performed in patients with stage IV lung cancer and reported survival outcomes that were not significantly different. ¹⁴

Cryoablation can also be used for pulmonary ablation. This technique offers improved intraprocedural ablation zone visualization but requires additional probes to achieve equivalent ablation sizes as compared with RFA. The best comparative data for cryoablation to RFA comes from the ECLIPSE trial and the ongoing SOLSTICE trial. de Baere et al's multicenter prospective, single-arm ECLIPSE trial included 60 lung metastases treated during 48 cryoablation sessions and demonstrated a 1-year survival of 97.5%. ¹⁵ The ongoing SOLSTICE clinical study constitutes the largest multicenter, prospective study on safety and efficacy for cryoablation treatment of lung metastases. Preliminary results indicate an acceptable safety profile for the treatment of lung metastases ≤3.5 cm. ¹⁶

A meta-analysis published in 2018 reviewed 34 studies accounting for 1,840 patients with 2,520 lung lesions. The meta-analysis evaluated safety and efficacy for RFA, cryoablation, and MWA. ¹⁷ MWA and RFA were significantly more effective than cryoablation and there were no significant difference between MWA and RFA outcomes. The study was limited by its heterogeneous population obscuring the overall survival rate among different ablation modalities.

In medically inoperative patients, National Comprehensive Cancer Network guidelines version 5.2019 sanction the use of radiation therapies and thermal ablation (“such as RFA and cryoablation”) ⁹ in patients with non-small cell lung cancer stage 1a (peripheral T1abc, N0), multiple lung cancers (N0–1), recurrent disease, or metastases.

For pulmonary lesions ≤3 cm, RFA has the most robust clinical data to support its continued use. Cryoablation and MWA are accumulating comparative data to RFA, but no RCTs have been reported.

Hepatic Lesions

For hepatocellular carcinoma (HCC) and metastatic disease, resection is the only curative option. However, only 15 to 20% of patients with liver metastases and less than 30% of patients with HCC are resection candidates. ^{18 19} RFA is recommended in both primary and metastatic disease by multiple international treatment guidelines. ^{20 21 22} Unlike external beam radiation therapy and other ablative modalities, there have been four RCTs comparing RFA to surgical resection for the treatment of HCC. ^{23 24 25 26} In three of the four studies, RFA and surgery had equivalent overall survival and disease-free survival in patients with solitary HCC up to 5 cm. Adverse events occurred more frequently and with greater severity in the surgical resection groups. ^{23 24 25} Ruers et al's trial compared the outcomes of 119 patients with unresectable colorectal liver metastases treated with either systemic therapy alone or in combination with RFA. Patients who underwent RFA with systemic therapy had significantly longer progression-free survival than those who received systemic therapy alone. ²⁷

Several studies have failed to demonstrate MWA's superiority to RFA in the treatment of liver lesions in both local control and overall survival. ^{28 29 30 31 32} In a randomized controlled, single-blinded phase 2 trial performed in France and Switzerland, Vietti Violi et al did not find that MWA was more effective than RFA for the treatment of HCC lesions of 4 cm or smaller. The number of treated lesions with local tumor progression at 2 years was low in both MWA and RFA. ³³ Zhang et al in 2013 compared MWA to RFA for HCC up to 5 cm in diameter and demonstrated that there was no significant difference in complete ablation, local tumor progression, overall survival, or disease-free survival. ²⁹

The potential complication of “cryoshock” from vascular injury and tissue ischemic hypoxia was seen in the earlier generations of cryoablation systems with large lesions, suggesting inferiority in both efficacy and safety when compared with RFA. ^{34 35} However, Wang et al conducted multicenter RCT of newer generation cryoablation systems versus RFA for HCC in 2014 and found equally safe and effective with similar 5-year survival rates. ³⁶

RFA has substantial clinical data and has international guideline support for the treatment of hepatic lesions ≤3 cm. Despite the potential advantage of larger ablation zones with MWA, for lesions ≥3 cm, all ablation modalities demonstrate decreased efficacy. Cryoablation may offer improved visualization of ablation zones and the potential for use adjacent to critical structures to improve clinical outcomes, ^{37 38 39} but additional data are required.

Renal Cell Carcinoma

RFA is an accepted thermal ablation modality and alternative surgery for the management of T1a renal masses less than 3 cm. ^{40 41 42} Some guidelines consider MWA experimental. ^{41 42} Ablation is considered a nephron-sparing procedure and recommended over surgery for those who are high-risk surgical candidates, diminished renal function, multiple renal tumors, solitary functioning kidney, prior partial or total nephrectomy, tumors within a renal transplant, or are at risk of developing additional renal masses (i.e., Von Hippel–Lindau disease or familial renal cell carcinoma [RCC]) ^{40 41 42}

There have been no RCTs for the treatment of T1a renal masses using ablation. In patients with an initial tumor size ≤3 cm, the primary success rate with RFA is reported at 93 to 98%. ^{43 44} Stern et al showed in their retrospective cohort study for sporadic T1a renal tumors that RFA resulted in similar disease-free probability compared with partial nephrectomy at a 3-year follow-up. ⁴⁵ Chang et al also demonstrated comparable 5-year overall survival and disease-free survival in their retrospective cohort study for RFA versus partial nephrectomy, in stage T1a RCC. ⁴⁶

Guan et al compared MWA with partial nephrectomy for small renal masses and observed a similar overall local recurrence-free survival at 3 years. ⁴⁷ The kidney is a highly perfused organ which may affect the ablation zone by “heat sink” and should be considered when treating tumors close to the renal sinus. ⁴⁸ While the rapid heating with MWA may overcome the heat sink effect, in Thompson et al's case series of T1a RCC lesions treated with MWA, they reported a complication rate of 19.2% including two ureteropelvic junction obstructions with one case of bleeding requiring embolization. ⁴⁹ Unpredictable ablation zones limited the clinical efficacy of early-generation MWA platforms and increased the risk of complications. New-generation devices have been designed to address these shortcomings.

In patients with an initial tumor size ≤3 cm, the primary success rate with cryoablation is reported at 93%. ⁵⁰ A 5-year, single-arm, prospective study on biopsy-proven RCC treated with cryoablation was performed by Georgiades and Rodriguez and included 134 consecutive patients. The reported 5-year efficacy was 99.2, 99.2, 98.9, 98.5, and 97.0%, for years 1 to 5, respectively. ⁵¹ The largest retrospective series to date comparing percutaneous cryoablation and RFA with partial nephrectomy for T1 renal masses was performed by Thompson et al, finding similar local recurrence-free survival for RFA, cryoablation, and partial nephrectomy. ⁵²

RFA and cryoablation demonstrate similar outcomes in the treatment of T1a lesions. ⁵³ With insufficient data, MWA requires further investigation to confirm equivalent outcomes for T1a lesions.

Musculoskeletal System

While the use of RFA to treat osteoid osteoma (OO) was first described in 1989, the first reported case of complete relief of pain was by Rosenthal et al in 1992. ^{54 55} RFA to treat OO-related pain has an efficacy of nearly 90% in observational studies and is considered the gold standard in the treatment of painful OO refractory to medical treatment. ⁵⁶

Percutaneous ablation of musculoskeletal (MSK) metastases can be used in reduction of pain, prevention of pathological fractures in load-bearing osseous lesions, and can provide durable local tumor control. ^{57 58 59} While external beam radiation therapy is accepted as first-line therapy for metastatic osseous lesions, radiation achieves pain relief in approximately 60% of patients and may be temporary. ⁶⁰ Prospective trials showing the efficacy of ablation in bone lesions have been performed with RFA and cryoablation. Only retrospective data have been published on the use of MWA devices in MSK metastases at this time. ⁶¹ Tumor ablation may be combined with methacrylate cement placement in axial load–bearing areas to assist in pain reduction. This can be performed immediately after RFA ablation which is an advantage over cryoablation as delayed necrotic formation and prolong thawing times may inhibit distribution of the cement. ^{62 63}

There are far less data for the use of ablation in MSK lesions than in lung, hepatic, and renal lesions. That data which have been published are strongest for RFA and cryoablation. Seven new FDA-approved RFA generators have come on the market over the past 15 years specifically for osseous ablation. This speaks to the acceptance of RFA in osseous ablation, as there are no dedicated cryoablation or MWA generators for osseous lesions.

Utilization Trends

According to the Medtech 360 Interventional Oncology Devices U.S. Market Analysis from 2016, the percutaneous ablation market will be dominated by a single technology, MWA, by 2024. ¹ It predicts MWA will consume both RFA device sales and procedure volumes, and will represent more than half of the ablation market. Fig. 1 provides a graphical representation of the sales and predicted utilization outlooks for ablation in the various disease states covered previously.

Fig. 1.

Graphical representation of the sales and predicted utilization outlooks for ablation in the various disease states covered previously.

While RFA for pulmonary and MSK ablative therapies over the 2014–2024 period is expected to increase, RFA for hepatic ablation is expected to substantially decline.

Radiofrequency Ablation Outside of Interventional Radiology

FDA AccessGUDID (Global Unique Device Identification Database) has 31,355 registered “RFA”-approved devices and associate medical accessories. Similar searches for “Cryoablation” and “Microwave Ablation” yield 16,065 and 15,995 register products, respectively. ⁶⁴

Listed within the clinicaltrials.gov database are 958 trials using RFA, 291 using cryoablation, and 102 using MWA; search criteria are described in Table 1 . ⁶⁵ The ongoing and actively recruiting trials in pulmonary ablation for primary and metastatic lesions are split between RFA (12) and cryoablation (18) with MWA having fewer (7). For hepatic ablation of primary and metastatic lesions, RFA has 47 trials worldwide and MWA has 34. The largest location for RFA research in liver-directed therapy is in East Asia where currently 25 trials are registered as opposed to 10 in the United States. Cryoablation is the main focus of ongoing clinical trial in renal and bone ablation ( Table 2 ).

Table 1. Search criteria for current registered ongoing ablation clinical trial for treatment of various cancers from Clinicaltrials.gov.

Condition/disease	Other terms	Status
			Hepatocellular carcinoma Hepatic metastasis Cholangiocarcinoma Lung carcinoma Lung metastasis Renal cell carcinoma Osteoid osteoma Bone metastasis	Radiofrequency ablation Microwave ablation Cryoablation Irreversible electroporation	Recruiting Completed

Table 2. Current registered ongoing ablation therapy clinical trials in HCC, lung cancer, RCC, and bone tumor treatment.

Condition	Ablation treatment	Total no. of trials	Continent/Country
			USA	East Asia	Canada	Japan	Europe	Africa	Others
HCC	RFA	28	2	20	–	–	6	–	–
	MWA	23	2	14	–	–	5	1	–
	Cryoablation	1	1	–	–	–	–	–	–
	IRE	6	–	4	–	–	2	–	–
CC	RFA	4	1	1	–	–	1	–	1
	MWA	2	1	–	–	–	1	–	–
	Cryoablation	1	1	–	–	–	–	–	–
Hepatic metastasis	RFA	15	7	4	1	1	2	–	–
	MWA	9	1	2	–	–	6	–	–
	Cryoablation	7	4	1	–	–	–	–	2
	IRE	1	–	–	–	–	1	–	–
Lung carcinoma	RFA	8	5	2	–	1	2	–	–
	MWA	6	–	4	–	–	2	–	–
	Cryoablation	12	6	5	–	–	2	–	–
	IRE	4	1	3	–	–	–	–	–
Lung metastasis	RFA	4	2	1	–	1	2	–	–
	MWA	1	–	1	–	–	–	–	–
	Cryoablation	6	5	1	–	–	2	–	–
	IRE	1	1	–	–	–	–	–	–
RCC	RFA	5	2	1	–	–	1	–	1
	MWA	4	1	2	–	–	1	–
	Cryoablation	11	5	2	–	–	3	–	1
	IRE	1	–	–	–	–	1	–	–
Osteoid osteoma	RFA	1	–	–	–	–	1	–	–
Bone metastasis	RFA	1	1	–	–	–	–	–	–
	Cryoablation	3	3	–	1	–	2	–	–

Abbreviations: CA, cryoablation; CC, cholangiocarcinoma; HCC, hepatocellular carcinoma; IRE, irreversible electroporation; MWA, microwave ablation; RCC, renal cell carcinoma; RFA, radiofrequency ablation.

RFA is employed outside of visceral tumor therapy in the fields of vascular surgery, pain management, cardiology, gastroenterology, dermatology, and obstetrics/gynecology to name a few. RFA is a well-established tool for the treatment for various cardiac arrhythmias through ectopic tissue ablation. It is used in the treatment of refractory back pain as RFA neurolysis/rhizotomy to treat facet joint pain. Additional uses of pain control ablation include genicular nerve ablation for arthritic knee pain, sacroiliac joint pain neurolysis, ablation of Morton's neuroma, ingrown toe nails, and intervertebral discs. ^{66 67 68}

Endoscopic application of RFA is possible with the Habib Endo HBP catheter for benign and malignant biliary interventions and with the BARRX Anorectal RFA Wand for the treatment of high-grade anal squamous intraepithelial neoplasia. Additional endoscopic treatments using RFA include refractory gastroesophageal reflux disease and ablation of low- and high-grade Barrett's esophagus. ^{69 70 71 72}

In dermatology, RFA is used to improve skin texture, laxity, and wrinkles. ⁷³ RFA ablation of redundant soft palate tissue is an alternative to surgery for obstructive sleep apnea and snoring. ^{74 75}

In the field of obstetrics/gynecology, RFA has historically been used for endometrial ablation. In 2012, the FDA approved the Acessa RFA device for uterine fibroid ablation as an alternative to surgery. RFA has been described in the selective reduction of complicated monochorionic pregnancies. ^{76 77}

Summary

RFA is a safe and effective technology that has reshaped the paradigm of medical therapies. The selection bias in the existing literature and in clinical practice continues to limit the comparison of ablation technologies. As interventionalists continue to transition away from RFA, direct comparisons of new technologies to RFA will be less likely, thus limiting the level of evidence supporting their clinical validity.