Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2012062
Category:	Surgery
Initiated:	August 2017
Last Review:	August 2023

Radiofrequency Ablation of Primary or Metastatic Liver Tumors

Description:

Radiofrequency ablation of hepatic tumors was original included in CP 1997225 (Hepatic Tumors, Ablative Procedures) and has been moved to CP 2012062.

There are several ablative procedures that are used to treat lesions of hepatocellular carcinoma or metastatic hepatic lesions of colorectal cancer. Resection of these lesions is considered to be the most effective treatment but there are factors that preclude surgical intervention including the size and location of the tumor, inadequate viable liver tissue that would remain after surgery or co-morbid conditions.

Radiofrequency ablation (RFA) is a procedure in which a probe is inserted into the center of a tumor and heated locally by a high frequency, alternating current that flows from electrodes. The local heat treats the tissue adjacent to the probe, resulting in a 3 to 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 a local recurrence, it occurs at the edge of the treated tissue and, in some cases, is retreated. Radiofrequency ablation may be performed percutaneously, laparoscopically, or as an open procedure.

Hepatic tumors can arise either as primary liver cancer (hepatocellular cancer [HCC]) or by metastasis to the liver from other tissues. Local therapy for hepatic metastasis may be indicated when there is no extrahepatic disease, which rarely occurs for patients with primary cancers other than colorectal carcinoma or certain neuroendocrine malignancies. A study from 2016 determined that the incidence of liver cancer was higher among White individuals, Black individuals, and Hispanic individuals born after 1938 (Singh, 2020). The incidence of hepatocellular carcinoma was twice as high for US-born Hispanic men compared to Hispanic men born outside of the US. This may be due to the increased risk of smoking, hepatitis B or C infection, and diabetes among US-born Hispanic individuals.

Neuroendocrine tumors are tumors of cells that possess secretory granules and originate from the neuroectoderm. Neuroendocrine cells have roles both in the endocrine system and the nervous system. They produce and secrete a variety of regulatory hormones, or neuropeptides, which include neurotransmitters and growth factors. Overproduction of the specific neuropeptides produced by the cancerous cells causes a variety of symptoms depending on the hormone produced. They are rare, with an incidence of 2-4 per 100,000 per year.

Treatment options for hepatocellular carcinoma (HCC) range from potentially curative treatments, such as resection or liver transplantation, to nonsurgical options, which include ablative therapies (radiofrequency ablation [RFA], cryoablation, microwave ablation, percutaneous ethanol or acetic acid injection), transarterial chemoembolization, radiation therapy, and systemic therapy. Choice of therapy depends on the severity of the underlying liver disease, size and distribution of tumors, vascular supply, and patient overall health. Treatment of liver metastases is undertaken to prolong survival and to reduce endocrine-related symptoms and hepatic mass-related symptoms.

At present, surgical resection with adequate margins or liver transplantation constitutes the only treatments available with demonstrated curative potential for hepatic tumors. However, most hepatic tumors are unresectable at diagnosis, due either to their anatomic location, size, number of lesions, or underlying liver reserve. Comorbid conditions may also make patients unqualified for surgical resection.

Radiofrequency ablation (RFA) is a procedure in which a needle electrode is inserted into a tumor either percutaneously, through a laparoscope, or through an open incision. The electrode is heated by a high frequency, alternating current, which destroys tissue in a 3 to 5 cm sphere of the electrode. Radiofrequency ablation has been investigated as a treatment for unresectable hepatic tumors, both as a primary intervention and as a bridge to a liver transplant. In the latter setting, RFA is being tested to determine whether it can reduce the incidence of tumor progression in patients awaiting transplantation and thus maintain patients' candidacy for liver ablation, transhepatic arterial chemoembolization, microwave coagulation, percutaneous ethanol injection, and radioembolization (yttrium-90 microspheres).

Regulatory Status

Radiofrequency ablation devices have been cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process. Food and Drug Administration product code: GEI.

Related Policies:

1997255 – Hepatic Tumors, Ablative Procedures (Percutaneous Ethanol Injections, Acetic Acid Injections, Interstitial Laser Photocoagulation)
2003061 - Brachytherapy, Radioembolization of Primary & Metastatic Tumors of the Liver with Therapeutic Microspheres
2008006 - Transcatheter Arterial Chemoembolization (TACE) to Treat Primary or Metastatic Liver Malignancies
2011078 - Microwave Ablation of Tumors

Policy/
Coverage:

Effective August 2018

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Radiofrequency ablation of primary, inoperable (e.g., due to location of lesion[s] and/or comorbid conditions), hepatocellular carcinoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness under the following conditions:

as a primary treatment of hepatocellular carcinoma meeting the Milan criteria (a single tumor of ≤5 cm or up to 3 nodules <3 cm).
as a bridge to transplant, where the intent is to prevent further tumor growth and to maintain a patient’s candidacy for liver transplant.

Radiofrequency ablation as a primary treatment of inoperable hepatic metastases meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness under the following conditions:

metastases are of colorectal origin and meet the Milan criteria (a single tumor of ≤5 cm or up to 3 nodules <3 cm).
metastases are of neuroendocrine in origin and systemic therapy has failed to control symptoms.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Radiofrequency ablation of primary, inoperable, hepatocellular carcinoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness under the following conditions:

when there are more than 3 nodules or when not all sites of tumor foci can be adequately treated.
when used to downstage (downsize) hepatocellular carcinoma in patients being considered for liver transplant.

For members with contracts without primary coverage criteria, radiofrequency ablation of primary, inoperable, hepatocellular carcinoma is considered investigational under the following conditions:

when there are more than 3 nodules or when not all sites of tumor foci can be adequately treated.
when used to downstage (downsize) hepatocellular carcinoma in patients being considered for liver transplant.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Radiofrequency ablation of primary, operable hepatocellular carcinoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, Radiofrequency ablation of primary, operable hepatocellular carcinoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Radiofrequency ablation for hepatic metastasis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness under the following conditions:

hepatic metastases from colorectal cancer or neuroendocrine tumors that do not meet the criteria above; and
for hepatic metastases from other types of cancer except colorectal cancer or neuroendocrine tumors.

For members with contracts without primary coverage criteria, radiofrequency ablation for hepatic metastasis is considered investigational under the following conditions:

hepatic metastases from colorectal cancer or neuroendocrine tumors that do not meet the criteria above; and
for hepatic metastases from other types of cancer except colorectal cancer or neuroendocrine tumors.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective July 2017 to July 2018

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Radiofrequency ablation meets primary coverage criteria for effectiveness and is covered for patients with primary hepatocellular carcinoma or hepatic colorectal metastases when:

Tumors are unresectable and measure less than 5 cm;
There are less than five lesions:
Tumors are sufficiently isolated from adjacent organs to allow complete ablation;
Patients have asymptomatic disease; and
Patients have no extrahepatic disease.

Radiofrequency ablation of primary hepatocellular carcinoma meets primary coverage criteria for effectiveness and is covered as a bridge to transplant, where the intent is to prevent further tumor growth and to maintain a patient’s candidacy for liver transplant

Radiofrequency ablation may meet primary coverage criteria for effectiveness and is covered for hepatic metastases from neuroendocrine tumors in patients with symptomatic disease when systemic therapy has failed to control symptoms.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of any intervention for the treatment of hepatic metastases from cancers of primary sites other than colorectal cancer or neuroendocrine tumors that do not meet the criteria above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria the use of any intervention for the treatment of hepatic metastases from cancers of primary sites other than colorectal cancer or neuroendocrine tumors that do not meet the criteria above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective Prior to July 2017

Radiofrequency ablation meets primary coverage criteria for effectiveness and is covered for patients with primary hepatocellular carcinoma or hepatic colorectal metastases when:

Tumors are unresectable and measure less than 5 cm;
There are less than five lesions:
Tumors are sufficiently isolated from adjacent organs to allow complete ablation;
Patients have asymptomatic disease; and
Patients have no extrahepatic disease.

The use of any intervention for the treatment of hepatic metastases from cancers of primary sites other than colorectal cancer or neuroendocrine tumors that do not meet the criteria above is not covered based on benefit certificate primary coverage criteria for effectiveness.

For contracts without primary coverage criteria, any circumstance not noted above as covered, is considered investigational. Investigational services are an exclusion in the member certificate of coverage.

Rationale:

Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com.

Radiofrequency Ablation as a Primary Treatment of Unresectable Hepatocellular Liver Cancer

For treating patients with hepatocellular cancer (HCC), 3 studies, (Ikeda, 2001; Livraghi, 1999; Lencioni, 2003) including 1 randomized trial (Lencioni, 2003), compared RFA to percutaneous ethanol injection (PEI). The results of these trials suggest that in patients with small foci of HCC (no more than 3 lesions, each measuring no greater than 3 cm), RFA appears to be at least as good as and likely better than PEI in achieving complete ablation and preventing local recurrence. For this reason, the policy statement is revised to indicate that this indication for RFA would be considered medically necessary.

In contrast, although numerous case series were identified (Chung, 2001; DeBaere, 2000; Livrahgi, 2003), no comparative studies were found that compared RFA ablation of unresectable hepatocellular carcinoma to other methods of treatment.

There were insufficient data regarding the use of radiofrequency ablation combined with another therapy (i.e., resection) in the treatment of patients with hepatocellular carcinoma. Similarly, there were insufficient data regarding the use of RFA combined with another therapy (i.e., resection) in the treatment of patients with hepatic metastases.

A 2004 Cochrane review (Galandi) of RFA included the randomized Lencioni trial reviewed by the TEC assessment. The review concluded that the methodological quality of the trial was high, and that the results suggested that RFA was at least as good as PEI and perhaps better, consistent with the conclusions of the TEC Assessment. However, the Cochrane review concluded that RFA was a promising technique for treating small HCC, and that further randomized trials are needed.

Radiofrequency Ablation as a Bridge to Transplant for Unresectable Hepatocellular Cancer

In 2002, UNOS introduced a new liver allocation system—model for end-stage liver disease (MELD)—for adult patients awaiting liver transplant . The MELD score is a continuous disease severity scale incorporating bilirubin, prothrombin time (i.e., INR), and creatinine into an equation, producing a number that ranges from 1 to 40. Aside from those in fulminant liver failure, donor livers are prioritized to those with the highest MELD number. This scale accurately predicts the risk of dying from liver disease except for those with hepatocellular cancer (HCC), who often have low MELD scores since bilirubin, INR, and creatinine levels are near normal. Therefore, patients with HCC are assigned additional allocation points according to the size and number (T stage) of tumor nodules, as follows:

T1: one nodule <1.9 cm
T2: one nodule between 2.0–5.0 cm, or two or three nodules each <3.0 cm
T3: one nodule >5.0 cm, or two or three nodules with at least one >3.0 cm

In considering how to allocate the scarce donor organs, UNOS sought to balance risk of death on the waiting list against risk of recurrence after transplant. Patients with T1 lesions were considered at low risk of death on the waiting list, while those with T3 lesions are at high risk of post-transplant recurrence, and are generally not considered transplant candidates. Patients with T2 tumors have an increased risk of dying while on the waiting list compared with T1 lesions, and an acceptable risk of post-transplant tumor recurrence. Therefore, UNOS criteria prioritize T2 HCC by allocating additional points equivalent to a MELD score predicting a 15% probability of death within 3 months. The definition of T2 lesions are often referred to as the “Milan criteria,” in reference to a key 1996 study that examined the recurrence rate of HCC according to the size of the initial tumor (Mazzaferro, 1996). Note that liver transplantation for those with T3 HCC is not prohibited, but these patients do not receive any priority on the waiting list. All patients with HCC awaiting transplantation are reassessed at 3-month intervals. Those whose tumors have progressed and are no longer T2 tumors will lose the additional allocation points.

Therefore, the UNOS allocation system provides strong incentives to use locoregional therapies in 2 different settings:

To downsize T3 tumors to T2 status to meet the UNOS criteria for additional allocation points; or
To prevent progress of T2 tumors while on the waiting list to maintain the UNOS allocation points.

These 2 indications are discussed further here. It should be noted that the UNOS policy appears to implicitly recognize the role of locoregional therapy in the pretransplant setting. For example, section 3.6.4.4 (i) of the UNOS policy regarding the workup of patients with HCC states, as follows, “In addition, the patient must have at least one of the following: vascular blush corresponding to the area of suspicion seen on the above imaging studies, an alpha-fetoprotein level of >200 ng/ml, an arteriogram confirming a tumor, a biopsy confirming HCC, chemoembolization of lesion, radiofrequency, cryo, or chemical ablation of lesion.”

Locoregional Therapy as a Technique to Prevent Tumor Progression While on the Waiting List

Several studies have reported drop-out rates of wait-listed patients treated with locoregional therapy. However, lacking controlled data, it is difficult to assess contributions of locoregional therapy to time on the waiting list. In addition, in 2002, as discussed above, United Network for Organ Sharing (UNOS) revised its liver allocation policy, such that wait times for patients with HCC meeting the “Milan criteria” have now declined.

The majority of the literature has focused either on transcatheter arterial chemoembolization (TACE), or a variety of locoregional therapies. Given these limitations, the following case series have been reported. Fisher and colleagues reported on 33 patients who received multimodality ablation therapy, consisting primarily of radiofrequency ablation or TACE. Five patients (12%) were removed from the waiting list after waits of 5 to 14 months (Fisher, 2004). In this protocol, patients with tumors larger than 5 cm were not considered transplant candidates until the tumor was completely ablated using TACE, RFA, or another technique. Yamashiki and colleagues (2005) reported on 288 patients given various ablative therapies; the drop-out rate due to tumor progression at 1 and 3 years was 6.2% and 23%, respectively. Tumors greater than 3 cm affected the drop-out rate due to tumor progression. Mazzaferro (2004) reported on 50 patients with HCC who underwent RFA while awaiting transplantation; no patient had to be removed from the waiting list due to tumor progression over a mean wait time of 9.5 months. The median tumor size was 3 cm, and 80% of patients met the Milan criteria. Similarly, Lu and colleagues (2005) reported on 52 patients who underwent RFA as a bridge to transplantation, 42 of whom met the Milan criteria. After a mean of 12 months, 5.8% had dropped off the waiting list due to tumor progression.

Locoregional Therapies to Downgrade HCC Prior to Transplant

Yao and colleagues (2005) reported on a case series of 30 patients with HCC who underwent locoregional therapy specifically to downstage tumors to meet the University of California San Francisco (UCSF) criteria. Eligibility for locoregional therapy seeking to downstage patients included either 1) 1 nodule between 5 and 8 cm in diameter, 2) 2 or 3 nodules with at least 1 between 3 and 5 cm in diameter, with a sum of diameters no greater than 8 cm; or 3) 4 or 5 nodules all less than or equal to 3 cm, with a sum of diameters less than 8 cm. Among the 30 patients, 21 (70%) met the criteria for locoregional therapy and 16 of these were successfully downstaged and underwent transplantation. No tumors recurred at a median follow-up of 16 months. The authors concluded that downstaging can be successfully achieved in most patients, but that data regarding tumor recurrence requires longer follow-up.

Yao et al. (2008) analyzed longer-term outcome data on HCC downstaging in a cohort of 61 patients with tumor stage exceeding T2 criteria enrolled between June 2002 and January 2007. Eligibility criteria for downstaging included: 1) one lesion larger than 5 cm and up to 8 cm; 2) 2 to 3 lesions with at least 1 lesion larger than 3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or 3) 4 to 5 lesions with none larger than 3 cm, with total tumor diameter up to 8 cm. TACE and laparoscopic RFA (LRFA) either alone or in combination were the main methods used: 11 patients received LRFA alone, 14 received TACE and LRFA, and 9 received TACE and percutaneous RFA. A minimum observation period of 3 months after downstaging was required before liver transplant. Tumor downstaging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) received liver transplant, including 2 with live-donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent transplant, 13 had complete tumor necrosis, 17 met T2 criteria, and 5 exceeded T2 criteria. The Kaplan-Meier intention-to-treat survival at 1 and 4 years after downstaging were 87.5% and 69.3%, respectively. The 1-year and 4-year post-transplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median post-transplantation follow-up of 25 months. The only factor predicting treatment failure was pretreatment alpha-fetoprotein greater than 1,000 ng/mL. From this small series, the authors conclude that successful downstaging can be achieved with excellent post-transplant outcomes.

A national conference involving transplant physicians was held to better characterize the long-term outcomes of liver transplantation for patients with HCC and to discuss the policy of assigning increased priority for candidates with stage T2 HCC on the transplant waiting list in the U.S. Goals of the conference were to standardize pathology reporting, develop specific imaging criteria, expand the Milan Criteria (the criteria used to measure tumor size to determine if a patient qualifies for transplant), discuss locoregional therapy, define criteria for downstaging transplantation, and review current liver allocation system for HCC patients. Pomfret and colleagues summarized the conference findings and recommendations (Pomfret, 2010).

The workgroup on locoregional therapy found compelling evidence that pretransplant locoregional therapy decreases waitlist dropout, especially for patients who wait longer than 3-6 months for transplant. They note “there is a paucity of data comparing radiofrequency ablation (RFA) with transarterial therapies for the treatment of HCC prior to liver transplant and most single-center trials have a mixture of [locoregional therapies] included in the study population” and that, while early studies suggested a high rate of tumor seeding with percutaneous RFA, it is rare in larger series from experienced centers. The workgroup considering evidence to support expansion of MELD criteria for patients with HCC reported wide regional variation in the risk of death for patients without HCC. The “MELD score of the non-HCC patients was quite low in some regions. Post-transplant survival in HCC patients ranged from 25% in regions with few non-HCC patients with high MELD scores to greater than 70% in regions in which there was a greater need for liver transplant (higher MELD scores) in the non-HCC population.” The workgroup observed that there is extreme variability of the time to transplantation of patients with HCC in the country suggesting that management of patients on the waitlist and outcomes may vary. In addition, “Concern has been raised that short times to liver transplant may lead to an increase in post-transplant recurrence because the tumor biology [aggressiveness] has not had enough time to be expressed. The lack of national data on recurrence rates limits one’s ability to study this national experiment of nature based on the divergent waiting times for transplantation for HCC.” There was agreement that the allocation policy should result in similar risks of removal from the waiting list and similar transplant rates for HCC and non-HCC candidates. In addition, the allocation policy should select HCC candidates so that there are similar post-transplant outcomes for HCC and non-HCC recipients. There was a general consensus for the development of a calculated continuous HCC priority score for ranking HCC candidates on the list that would incorporate the calculated MELD score, alpha-fetoprotein, tumor size, and rate of tumor growth. Only candidates with at least stage T2 tumors would receive additional HCC priority points. The paper discusses pretransplant local regional therapy to allow patients to maintain transplant candidacy, as well as to downstage to meet MELD criteria. The workgroup on the role of downstaging in transplant candidates with HCC noted inconsistent outcomes reported in the literature and proposed a definition of downstaging that would include TACE and various ablative techniques but not resection. The group noted that only 2 regions have adopted a downstaging protocol.

Locoregional Therapies to Reduce Risk of Recurrence in Those with T3 tumors

An additional indication for locoregional therapies focuses on their use in patients with T3 tumors, specifically to reduce the incidence of recurrence post-transplant. If the incidence of recurrence can be reduced, then advocates have argued that the UNOS allocation criteria should not discriminate against patients with larger tumors (Sauer, 2005; Fernandez, 2003; Yao, 2002; Yao, 2001). Certainly some patients with T3 lesions apparently are cured with liver transplant, although most experience recurrent tumor. For example, in the seminal 1996 study (Mazzaferro, 1996), the 4-year recurrence-free survival was 92% in those who met the “Milan criteria” compared to 59% in those who did not; additional studies confirm this difference in recurrence-free survival rate (Sauer, 2005). However, other institutions have reported similar outcomes with expanded criteria. For example, Yao and colleagues at University of California at San Francisco reported similar recurrence-free survival after transplant in patients with T2 and a subset of those with T3 tumors. This T3 subset was defined as a single lesion <6.5 cm or <3 lesions with none greater than 3 cm and with a sum of tumor diameters <8 cm. These expanded criteria are known as the UCSF criteria (Merli, 2005).

The question is whether locoregional therapies (including both RFA and chemoembolization) may decrease the recurrence rate in patients meeting the UCSF criteria. Yao and colleagues (2005) published a detailed analysis of 121 patients with HCC who underwent transplantation. Seventy-eight patients (64%) had T2 lesions, while an additional 27 patients (22.3%) met the expanded UCSF criteria, termed T3A lesions. The rest had T1, T3B, or T4 lesions. Individual patients received a variety of pre-operative locoregional therapies, including TACE or ablative therapies, such as percutaneous ethanol injection (PEI), RFA, or combined therapies. A total of 38.7% of patients did not receive preoperative locoregional therapy. The 1- and 5-year recurrence-free survival was similar in those with T2 and T3A lesions, while the corresponding recurrence rates were significantly lower for those with T3B and T4 lesions.

The authors also compared recurrence-free survival of those who did and did not receive locoregional therapy. For those with T2 lesions, the recurrence rates were similar whether or not the patient received locoregional therapy. However, for T3 lesions (including both T3A and T3B), the 5-year recurrence-free survival was 85.9% for those who received locoregional therapy compared to 51.4% in those who did not. When the data for T2 and T3 lesions were grouped together, the 5-year recurrence-free survival was 93.8% for those who received locoregional therapy compared to 80.6% in those who did not. The authors concluded that preoperative locoregional therapy may confer a survival benefit in those with T2 or T3 lesions.

The authors note several limitations to the study, including the retrospective nature of the data, and the marginal statistical significance of the improved survival given the small numbers of patients in each subgroup. For example, only 19 patients were in the T3A (i.e., UCSF expanded criteria) subgroup. In addition, no protocol specified which type of locoregional therapy to offer different patients. These therapies are only offered to those patients with adequate liver reserve; such patients may have an improved outcome regardless of the preoperative management.

2007 Update

Radiofrequency Ablation as a Primary Treatment of Unresectable Liver Metastases from Colorectal Cancer

More than half of patients with colorectal cancer (CRC) will develop liver metastases, generally with a poor prognosis (Kemeny, 2006). A median survival of 21 months has been observed in patients with a single CRC liver metastasis; those with several unilobar lesions have median survival of 15 months; and, those with disseminated metastases have median survival of less than 1 year. A number of first-line systemic chemotherapy regimens have been used to treat metastatic CRC, with a 2-year survival rate of 25% for those treated with 5-fluorouracil (5-FU) or 5-FU plus leucovorin (Kemeny, 2006). With the introduction of newer agents, including irinotecan and oxaliplatin, and targeted drugs such as cetuximab and bevacizumab, 2-year survival rates have increased to 30%–39%, with marked improvement in overall survival duration. As the liver is often the only site of metastases from CRC, however, locoregional therapies have been investigated. Surgical resection is considered the gold standard for treatment of CRC liver metastases, with 5-year actuarial survival rates that historically range from 28% to 38%, but may reach 58% in appropriately selected, resectable patients without widely disseminated disease (McKay, 2006; Lencioni, 2005). However, only 10%–25% of patients with CRC metastases are eligible for surgical resection because of the extent and location of the lesions within the liver, or because of the presence of comorbid conditions or disseminated disease. Unresectable cases or those for whom surgery is contraindicated typically are treated with systemic chemotherapy, with poor results and considerable adverse side effects.

Alternatively, RFA has been proposed as an approach to treat metastatic CRC in the liver. Early clinical experience with RFA comprised case series to establish feasibility, safety, tolerability, and local therapeutic efficacy in short-term follow-up. A recent literature review encompassing 6 case series (N=446) showed that RFA of unresectable CRC metastases was associated with 1-, 2-, and 3-year survival rates that ranged from 87%–99%, 69%–77%, and 37%–58%, respectively (McKay, 2006). While these results suggest RFA may have clinical benefit in this setting, a primary caveat is the definition of the term “unresectable” in the different series, and that different surgeons may have different opinions on this issue. Further, differences in lesion size, number, distribution, prior treatments, RFA technology, and physician experience may affect results, making it difficult to compare results of different studies.

More recently, 2 groups have reported results of prospective studies in which RFA was compared with resection or systemic chemotherapy in well-defined consecutive cohorts of patients with localized CRC metastases and no evidence of additional metastatic disease. In the first study, Abdalla and coworkers (2004) examined recurrence and survival rates for clinically similar patients treated with hepatic resection only (n=190), resection plus RFA (n=101), RFA only (n=57, open laparotomy by hepatobiliary surgeon), and systemic chemotherapy alone (n=70). In the key relevant comparison, RFA versus chemotherapy in chemotherapy-naive patients with non-resectable CRC metastases (median 1 lesion per patient, range 1-8, median tumor size 2.5 cm), overall survival at 4 years was 22% in the RFA group compared with 10% in the chemotherapy group (p=0.005). Median survival was estimated at 25 months in the RFA group and 17 months in the chemotherapy group (p not reported). Recurrence anywhere in the liver at median follow-up of 21 months was 44% in the RFA group and 11% in the resection-only group (p<0.001), although the proportion of patients with distant recurrence as a component of failure was similar (41% resection, 40% RFA, p not significant).

In a second trial, a consecutive series of well-defined, previously untreated patients (n=201) without extrahepatic disease underwent laparotomy to determine therapeutic approach (Ruers, 2007). Three groups were identified: those amenable to hepatic resection (n=117); those for whom resection plus local ablation were indicated (RFA, n=27; cryoablation, n=18); and those deemed unresectable and unsuitable for local ablation (n=39) who received systemic chemotherapy. Median overall survival was 61 months (95% CI: 41-81 months) in resected patients (median 1 tumor per patient, range 1–9, median diameter 3.8 cm), 31 months (95% CI: 20–42 months) in locally ablated patients (median 4 tumors per patient, range 1-19, median diameter 3 cm per lesion), and 26 months (95% CI: 17–35 months) in the chemotherapy patients (median 4 tumors per patient, range 1–17, median diameter 4 cm per lesion, p not significant, ablated vs. chemotherapy). Results from 2 validated quality of life instruments (EuroQol-5D and EORTC QLQ C-30) showed that patients treated by local ablation returned to baseline values within 3 months, whereas those treated with chemotherapy remained significantly lower (i.e., worse quality of life) than baseline over 12 months post-treatment (p<0.05).

Local hepatic recurrence with RFA is a concern, but neither the impact on outcomes compared to systemic chemotherapy nor the role of re-treatment has been evaluated (Mulier, 2005). The potential role of adjuvant chemotherapy following RFA is being addressed in a phase III randomized trial (EORTC 40004, CLOCC trial, chemotherapy plus local ablation vs. chemotherapy), in which patients are randomized to receive systemic chemotherapy (oxaliplatin, 5-FU, and leucovorin) alone or combined with RFA (Ruers, 2007). Questions also exist about the best approach to perform RFA. A recent systematic review suggests that RFA at open laparotomy was clearly superior to the percutaneous route independent of tumor size or type (Mulier, 2005). However, there is no consensus among practitioners as to the best approach (i.e., via laparotomy, laparoscopy, or percutaneously).

2008 Update

A literature search performed through November 2008 did not identify any randomized or prospective comparative studies relevant to the use of RFA for any of the indications listed in the policy statements. A number of review articles summarizing clinical results for the use of RFA for primary or metastatic liver lesions are in general agreement with the policy statements (Curley, 2007; Mulier, 200; Gervais, 2008; Garrean, 2008; Hanje, 2008; Heckman, 2008). Therefore, the policy statements are unchanged.

The NCI PDQ lists RFA as one of several ablative options for patients with small (<5 cm), localized, unresectable primary liver cancer (http://www.cancer.gov/cancertopics/pdq/treatment/adult-primary-liver/HealthProfessional/page6).

Several phase II or III trials involving the use of RFA in the treatment of primary or metastatic liver cancer are underway (http://www.cancer.gov/search/ResultsClinicalTrialsAdvanced.aspx?protocolsearchid=5470565).

2012 Update:

In 2011, van Tilborg and colleagues reported long-term results in 100 patients with unresectable colorectal liver metastases who underwent a total of 126 RFA sessions (237 lesions). Lesion size ranged from 0.2-8.3 cm (mean 2.4 cm). The mean follow-up time was 29 months (range 6-93 months). Major complications (including abscess, hemorrhage, grounding pad burns, and diaphragm perforation) occurred in 8 patients. Factors that determined the success of the procedure included lesion size and the number and location of the lesions. Local tumor site recurrence was 5.6% for tumors less than 3 cm, 19.5% for tumors 3-5 cm, and 41.2% for those greater than 5 cm. Centrally located lesions recurred more often than peripheral ones, at 21.4% versus 6.5%, respectively, p=0.009. Mean survival time from the time of RFA was 56 months (95% CI: 45-67 months).

A review by Guenette and Dupuy in 2010 summarized the literature on the use of RFA for colorectal hepatic metastases. Approximately 17 studies in the literature with greater than 50 patients treated with RFA for colorectal hepatic metastases reported survival. Average tumor size, reported in 15 studies ranged from 2.1 cm-4.2 cm. Five-year overall survival (OS), reported in 12 studies, ranged from 2% to 55.3% with a mean of 24.5%. The largest study series included in the review was by Lencioni et al. and consisted of 423 patients with average tumor size of 2.7 cm, 4 or fewer metastases, each 5 cm or less in greatest dimension, and no extrahepatic disease (2004). Overall survival in the Lencioni et al. study at 1, 3 and 5 years was 86%, 47% and 24%, respectively. The authors of the Guenette/Dupuy review concluded that 5-year survival rates following RFA appear to rival those following resection but that long-term data associated with RFA and colorectal hepatic metastases is sparse, randomized trials have failed recruitment, and patients with resectable disease should undergo resection if possible. However, given the efficacy of RFA as compared to chemotherapy alone, RFA should be considered as a primary treatment option in patients with unresectable disease.

A 2011 systematic review by Pathak and colleagues assessed the long-term outcome and complication rates of various ablative therapies used in the management of colorectal liver metastases. The literature search was from 1994 to 2010, in all, 226 potentially relevant studies were identified, 75 of which met the inclusion criteria. The majority of the studies were single-arm, single-center, retrospective and prospective. There was wide variability in patient groups, adjuvant therapies, and management approaches within individual studies. Several studies combined results for colorectal and non-colorectal metastases, often reporting combined outcomes. Endpoints were not always reported uniformly, with varying definitions of survival time, recurrence time, and complication rates. Cryotherapy (26 studies) had local recurrence rates of 12-39%, with mean 1-, 3- and 5-year survival rates of 84%, 37% and 17%, respectively. The major complication rate ranged from 7% to 66%. Radiofrequency ablation (36 studies) had a local recurrence rate of 10-31%, with a mean 1-, 3- and 5-year survival of 85%, 36% and 24%, respectively, with major complication rate ranging from 0% to 33%. The authors concluded that ablative therapies offer significantly improved survival compared with palliative chemotherapy alone with 5-year survival rates of 17-24%, and that complication rates of commonly used techniques are low.

Radiofrequency Ablation as a Treatment of Unresectable Liver Metastases from Neuroendocrine Tumors

Most reports of radiofrequency treatment of neuroendocrine liver metastases include small numbers of patients or subsets of patients in reports of more than one ablative method or very small subsets of larger case series of patients with various diagnoses.

Berber and Siperstein (2008) analyzed a large series of liver tumors treated with RFA. Of 1,032 tumors in the study, 295 were neuroendocrine tumor metastases. The mean number of lesions treated was 5.6 (range: 1-16) and mean size was 2.3 cm (range: 0.5–10.0 cm). Local recurrence rates were lower in patients with neuroendocrine tumors than in patients with other tumor types; neuroendocrine tumors (19/295, 6%), colorectal metastases (161/480, 24%), noncolorectal, nonneuroendocrine metastases (28/126, 22%), and HCC (23/131, 18%). In patients with neuroendocrine tumors, 58% of the recurrences were evident at 1 year and 100% at 2 years versus 83% at 1 year and 97% at 2 years for colorectal metastases. Eight neuroendocrine tumors were eligible for repeat RFA; 7 were retreated, and one was not. Symptom control and survival were not reported in this study.

Mazzaglia et al. (2007) report on a series gathered over 10 years of 63 patients with neuroendocrine metastases who were treated with 80 sessions of LRFA. Tumor types were 36 carcinoid, 18 pancreatic islet cell, and 9 medullary thyroid cancer. Indications for enrollment in the study were liver metastases from neuroendocrine tumors, enlarging liver lesions, worsening of symptoms, and/or failure to respond to other treatment modalities, and predominance of disease in the liver; however, patients with additional minor extrahepatic disease were not excluded from the study. RFA was performed 1.6 years (range, 0.1-7.8 years) after diagnosis of liver metastases. Fourteen patients had repeat sessions for disease progression. The mean number of lesions treated at the first RFA session was 6 and the mean tumor size was 2.3 cm. One week after surgery, 92% of patients had at least partial symptom relief and 70% had complete relief. Symptom control lasted 11 +/- 2.3 months. Median survival times were 11 years post-diagnosis of primary tumor, 5.5 years post-diagnosis of neuroendocrine hepatic metastases, and 3.9 years post-first RFA treatment.

Elias et al. (2009) report on 16 patients who underwent a one-step procedure comprising a combination of hepatectomy and RFA for treatment of gastroenteropancreatic endocrine tumors. A mean of 15 +/- 9 liver tumors per patient were surgically removed, and a mean of 12 +/-8 were ablated using RFA. Three-year survival and disease-free survival rates were similar to those observed in the authors’ preliminary series of 47 patients who had hepatectomy with a median of 7 liver tumors per patient. Venkatesan and colleagues (2009) report on 6 patients treated for pheochromocytoma metastases. Complete ablation was achieved in 6 of 7 metastases. Mean follow-up was 12.3 months (range: 2.5-28 months).

Radiofrequency Ablation as a Primary Treatment of Unresectable Liver Metastases from Tumors other than Colorectal Cancer and Neuroendrocrine Tumors

Breast Cancer

A number of case series report RFA of breast cancer liver metastases. In a retrospective review, Meloni et al. assessed local control and intermediate- and long-term survival in 52 patients. (34) Inclusion criteria were fewer than 5 tumors, maximum tumor diameter of 5 cm or smaller, and disease confined to the liver or stable with medical therapy. Complete tumor necrosis was achieved in 97% of tumors. Median time to follow-up from diagnosis of liver metastasis and from RFA was 37.2 and 19.1 months, respectively. Local tumor progression occurred in 25% of patients, and new intrahepatic metastases developed in 53%. Overall median survival time, from the time the first liver metastasis was diagnosed, was 42 months, and 5-year survival was 32%. Patients with tumors 2.5 cm in diameter or larger had a worse prognosis than those with smaller tumors. The authors conclude that these survival rates are comparable to those reported in the literature for surgery or laser ablation. In another series of 43 breast cancer patients with 111 liver metastases, technical success was achieved in 107 metastases (96%). (35) During follow-up, local tumor progression was observed in 15 metastases. The estimated overall median survival was 58.6 months. Survival was significantly lower among patients with extrahepatic disease, with the exception of skeletal metastases.

A series of 19 patients was reported by Lawes et al. (36) Eight patients had disease confined to the liver, with 11 also having stable extrahepatic disease. At the time of the report, 7 patients, with disease confined to the liver at presentation, were alive, as were 6 with extra-hepatic disease; median follow-up after RFA was 15 months (range: 0-77 months). Survival at 30 months was 41.6%. RFA failed to control hepatic disease in 3 patients.

Other reports include 16 or fewer subjects. All of the authors report that RFA of breast cancer liver metastases is technically feasible and may provide a survival benefit in woman without extra-hepatic or stable extrahepatic disease (excluding bone metastases).

Sarcoma

Jones et al. evaluated RFA in a series of patients with sarcoma. (37) Thirteen gastrointestinal stromal tumor (GIST) patients and 12 with other histological subtypes received RFA for metastatic disease in the liver: 12 of these responded to the first RFA procedure and 1 achieved stable disease. Two GIST patients received RFA on 2 occasions to separate lesions within the liver, and both responded to the second RFA procedure. Of the other subtypes: 7 underwent RFA to liver lesions, 5 of these responded to RFA, 1 progressed and 1 was not assessable for response at the time of analysis. RFA was well-tolerated in this series of sarcoma patients. RFA may have a role in patients with GIST who have progression in a single metastasis but stable disease elsewhere. The authors advise that further larger studies are required to better define the role of this technique in this patient population.

A case series of 66 patients who underwent hepatic resection (n=35), resection and RFA (n=18), or RFA alone (n=13) was reported by Pawlik et al. (38) After a median follow-up of 35.8 months, 44 patients had recurrence (intrahepatic only, n=16; extrahepatic only, n=11; both, n=17). The 1-, 3-, and 5-year overall survival rates were 91.5%, 65.4%, and 27.1%, respectively. The authors recommend that patients with metastatic disease who can be rendered surgically free of disease be considered for potential hepatic resection.

Summary

For treating patients with unresectable HCC, numerous studies including randomized trials demonstrate that in patients with small foci of HCC (no more than 3 lesions), RFA appears to be better than ethanol injection in achieving complete ablation and preventing local recurrence. Three-year survival rates of 80% have been reported. Thus, the policy statement notes that this indication for RFA in patients with HCC who are not candidates for resection or transplant may be considered medically necessary.

A substantial body of literature has been published on the use of RFA to treat colorectal cancer metastases in the liver. Two prospective studies comprise good evidence that overall survival following RFA is at least equivalent and likely better than that obtained with currently accepted systemic chemotherapy in well-matched patients with unresectable hepatic metastatic colorectal cancer who do not have extrahepatic disease. Additional evidence from 1 comparative study suggests RFA has a lesser deleterious effect on quality of life than chemotherapy and that RFA patients recover quality of life significantly faster than chemotherapy recipients. Quicker recovery of quality of life may be viewed as a net health benefit when viewed in the context of expected survival durations of patients with metastatic cancer. In addition, results from a number of uncontrolled case series also suggest RFA of hepatic colorectal cancer metastases produces long-term survival that is at minimal equivalent and likely superior to historical outcomes achieved with systemic chemotherapy. Although indirect comparisons of series results are difficult, the body of data shows consistent change in direction and magnitude of effect that suggests an RFA benefit. It should be recognized, however, that patients treated with RFA in different series may have better prognosis than those who undergo chemotherapy, suggesting patient selection bias may at least partially explain the apparent better outcomes observed following RFA. Given the caveats outlined above, the available body of clinical evidence is sufficient to conclude that RFA of unresectable colorectal cancer metastases to the liver, absent extrahepatic metastatic disease, may be considered medically necessary according to the Policy Guidelines noted above.

Evidence shows that durable tumor and symptom control of neuroendocrine liver metastases can be achieved by radiofrequency ablation. This evidence is based on case series; neuroendocrine tumors are uncommon. T hus, a statement indicating that radiofrequency ablation of hepatic metastases of neuroendocrine tumors may be considered medically necessary in patients whose symptoms are not controlled by systemic therapy has been added.

Transplant clinicians find the evidence compelling that use of locoregional therapy reduces the dropout rate of patients with HCC awaiting a liver transplant. After listing for transplant, UNOS does not reassign status based on tumor shrinkage from locoregional therapy. A number of approaches are accepted for use in this situation, including TACE and RFA. Small case series conclude that patients managed on the transplant list with locoregional therapy have outcomes comparable to patients who do not receive pretransplant treatment. However, earlier liver transplant for HCC patients may reduce the need for RFA in this situation. Thus, given the strong clinical support, UNOS position, and clinical studies, the policy statement has been changed to indicate that radiofrequency ablation may be considered medically necessary as a bridge to liver transplant.

Currently, there is less evidence available for patients treated with RFA to specifically downsize (downstage) tumors (tumors of stage greater than T2) to meet priority transplant criteria, and its use for this application is considered investigational.

The published evidence for demonstrating improved health outcomes with RFA of other hepatic metastatic tumors (e.g., breast cancer and sarcoma) is lacking. Comparative trials are needed for these malignancies that may have associated systemic disease. Use of RFA in these tumors is considered investigational under this policy; the data are insufficient to change this policy statement.

2013 Update

A search of the MEDLINE database was conducted through September 2013. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.

Radiofrequency Ablation as a Primary Treatment of Unresectable Hepatocellular Liver Cancer

In a 2013, Shen and colleagues reported on a meta-analysis of 4 RCTs and quasi-RCTs, totaling 766 patients, to compare RFA to PEI for treatment of HCC nodules up to 3 cm (Shen, 2013). Overall survival was significantly longer for RFA than PEI at 3 years (hazard ratios [HR]: 0.66, 95% confidence interval [CI]: 0.48-0.90, p=0.009), and local recurrence risk was lower with RFA (HR: 0.38, 95% CI: 0.15-0.96, p=0.040). However, there was no difference in distant intrahepatic recurrence and RFA resulted in more complications.

In 2012, Xu et al. reported on a meta-analysis of 13 studies to compare RFA to surgical resection for early HCC Xu, 2012). Only 2 of the studies were RCTs. Surgical resection occurred in 1,233 patients and RFA was used in 1,302 patients. Surgical resection patients had significantly longer overall survival rates at 1, 3 and 5 years than RFA (odds ratio [OR]: 0.60, 95% confidence interval [CI]: 0.42 to 0.86, OR: 0.49, 95% CI: 0.36 to 0.65, and OR: 0.60, 95% CI: 0.43 to 0.84, respectively). When only HCC tumors <3 cm were analyzed, resection was still significantly better in overall survival than RFA at 1-, 3- and 5-years. Recurrence rates were also significantly lower in the surgical resection group at 1, 3 and 5 years than RFA (OR: 1.48, 95% CI: 1.05 to 2.08, OR: 1.76, 95% CI: 1.49 to 2.08, and OR: 1.68, (95% CI: 1.21 to 2.34, respectively). Local recurrence rates did not differ significantly between procedures. Complication rates were higher with resection than RFA (OR: 6.25, 95% CI: 3.12 to 12.52; p=0.000), but in a subanalysis of HCC <3 cm, complication rates were significantly lower with resection than RFA.

Tiong and Maddern conducted a systematic review of the literature from 2000 to 2010 and a meta-analysis of survival and disease recurrence after RFA for HCC (Tiong, 2011). Studies reporting on patients with HCC who were treated with RFA, either in comparison or in combination with other interventions, such as surgery or percutaneous ethanol injection (PEI), were eligible for inclusion. Outcome data collected were overall survival, disease-free survival and disease recurrence rates. Only RCTs, quasi-RCTs, and non-randomized comparative studies with more than 12 months’ follow-up were included. Forty-three articles, including 12 RCTs, were included in the review. The majority of the articles reported the use of RFA for unresectable HCC, often in combination with other treatments such as PEI, transarterial chemoembolization, and/or surgery. A meta-analysis of 5 RCTs showed that RFA was better than PEI, with higher overall and disease-free survival rates. Data on RFA compared to microwave ablation were inconclusive. The authors concluded that RFA can achieve good clinical outcomes for unresectable HCC.

In a 2013 meta-analysis comparing RFA to cryoablation for HCC, Huang and colleagues evaluated 3 prospective studies and 1 retrospective study (Huang, 2013). Included in the studies were 180 RFA and 253 cryoablation patients. RFA was found to be significantly superior to cryoablation in rates of complications (OR: 2.80, 95% CI: 1.54-5.09), local recurrence of patient (OR: 4.02, 95% CI: 1.93-8.39), and local recurrence of tumor (OR: 1.96, 95% CI: 1.12-3.42). However, mortality was not significantly different (OR 2.21, 95% CI: 0.45-10.8) between groups.

In 2012, Feng et al. reported on a randomized controlled trial of 84 RFA patients compared to 84 surgical resection patients with up to 2 HCC nodules less than 4 cm in size (Feng, 2012). Patients were followed for 3 years and overall survival and recurrence-free survival were not statistically different between groups, (p=0.342 and p=0.122, respectively).

Radiofrequency Ablation as a Primary Treatment of Unresectable Liver Metastases from Colorectal Cancer

A 2012 systematic review by Cirocchi et al. analyzed 17 nonrandomized studies and one abstract on a RCT from a 2010 American Society of Clinical Oncology (ASCO) meeting on RFA for CRC liver metastases (Cirocchi, 2012). The RCT reported progression-free survival was significantly higher in 60 patients receiving RFA plus chemotherapy when compared to 59 patients receiving only chemotherapy. The RCT did not report overall survival. This Cochrane review found different types of vulnerability in all reviewed studies. Of main concern was the imbalance of patient characteristics in the studies reviewed, as well as heterogeneity in the interventions, comparisons and outcomes. Therefore the authors concluded the evidence was insufficient to recommend RFA for CRC liver metastasis.

In 2013, Weng and colleagues reported on a systematic review and meta-analysis to compare RFA to liver resection for the treatment of CRC liver metastases (Weng, 2012). One prospective study and 12 retrospective studies were included in the analysis. Overall survival at 3 and 5 years was significantly longer in liver resection than RFA (risk ratio [RR]: 1.377, 95% CI: 1.246-1.522 and RR: 1.474, 95% CI: 1.284-1.692, respectively). Disease-free survival was also significantly longer in liver resection than RFA at 3 and 5 years (RR: 1.735, 95% CI: 1.483-2.029 and RR: 2.227, 95% CI: 1.823-2.720). While postoperative morbidity with liver resection was significantly higher than with RFA (RR: 2.495, 95% CI: 1.881-3.308), mortality was not significantly different between liver resection and RFA. Liver resection also still performed significantly better than RFA when data were analyzed in 3 subgroups: tumors <3 cm, solitary tumor and open or laparoscopic approach. However, hospital stays were significantly shorter (9.2 + 0.6 vs. 3.9 + 0.4, p<0.01) and rates of complications lower (18.3% vs. 3.9%, p<0.01) with RFA over liver resection. Interpretation of the meta-analysis is limited by the retrospective nature of the majority of studies.

2014 Update

A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Many systematic reviews and meta-analyses have been published on RFA for hepatocellular cancer (HCC). In a Cochrane review, Weis et al reviewed studies on RFA for HCC versus other HCC interventions (Weis, 2013). Moderate quality evidence demonstrated hepatic resection had superior survival outcomes than RFA, however, resection might have greater rates of complications and longer hospital stays. Other systematic reviews and metaanalyses have also found superior survival with hepatic resection but higher rates of complications than RFA (Feng, 2014; Wang, 2014; Qi, 2014). This reinforces the use of RFA for only unresectable HCC. The Cochrane review also reported finding moderate quality evidence demonstrating superior survival with RFA over percutaneous ethanol injection (PEI) (Weis, 2013) Evidence on RFA versus acetic acid injection, microwave ablation or laser ablation was insufficient to draw conclusions.

In a 2014 Health Technology Assessment, Loveman et al also found insufficient evidence to draw conclusions on the clinical effectiveness of ablative therapies, including RFA, for liver metastases (Loveman, 2014).

In 2014, Veltri et al analyzed 45 women treated with RFA for 87 breast cancer liver metastases of a mean size of 23 mm (Veltri, 2014). Complete ablation was seen on initial follow-up in 90% of tumors but tumor recurrence occurred in 19.7% within 8 months. RFA did not impact overall survival which at 1-year was 90% and at 3-years was 44%.

2017 Update

A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

In 2016, Liu and colleagues published a RCT that compared surgical resection to TACE plus RFA for HCC. A total of 200 patients within the Milan criteria were included in the trial and followed for 5 years (Liu, 2016). Tumor sizes ranged from 0.6 to 5.0 cm, with a median of 3.0 cm in the surgical resection group and 2.8 cm in the TACE plus RFA group. OS (p=0.007) and recurrence-free survival (p=0.026) were significantly higher in the surgical resection group (see Table 1). Local tumor progression occurred in 1 patient in the surgical resection group and in 18 in the TACE plus RFA group (p<0.001). There were no significant differences in recurrence or OS between the groups for HCC lesions 3.0 cm or smaller, but there were significant benefits for surgery in recurrence (p=0.032) and OS (p=0.012) in patients with lesions larger than 3 cm. Tumor size was an independent prognostic factor for recurrence-free survival (hazard ratio [HR], 1.76; p=0.006) along with hepatitis B DNA (HBV-DNA) and platelet count. HBV-DNA was a significant risk factor for OS. Complications were higher in the surgical resection group (23.0%) than in the TACE plus RFA group (11.0%; p=0.24). It cannot be determined from this trial whether RFA alone is as effective as surgical resection for these small tumors.

In 2017, Kutlu and colleagues compared outcomes for RFA, resection, or transplantation in patients from the Surveillance, Epidemiology, and End Results (SEER) database (Kutlu, 2017). A total of 1894 patients treated between 2004 and 2013 with HCC tumors measuring up to 50 mm met study criteria. Outcomes from the 3 treatments were compared for lesions 20 mm or smaller, 21 to 30 mm, 31 to 35 mm, or 31 to 50 mm in order to identify the upper limit of lesion size appropriate for RFA. Transplantation resulted in significant improvements in OS compared with RFA for all tumor sizes (p<0.001; see Table 2). In tumors up to 30 mm, there were no significant differences in OS between RFA and resection. However, OS was significantly lower with RFA compared to resection for tumors measuring 31 to 35 mm (adjusted HR=1.90; 95% confidence interval [CI], 1.07 to 3.38; p=0.028) or 31 to 50 mm (HR=1.69; 95% CI, 1.24 to 2.31; p=0.001). The study found that even a small increase in lesion size over 30 mm decreased OS compared with resection or transplantation.

Section Summary: Radiofrequency Ablation as a Treatment of Early-Stage Hepatocellular

Carcinoma

The evidence on RFA ablation as a primary treatment of early-stage resectable HCC includes RCTs, meta-analyses of these RCTs, and a database analysis. Results from these studies have suggested that RFA alone or RFA plus TACE may be as effective as resection for small HCC tumors, although the exact size cutoff has not been clearly established. The studies reviewed have suggested that RFA is inferior to hepatic resection for tumors of 5 cm or less, but may lead to OS rates similar to those for resection of tumors less than 3 cm. In a network analysis, TACE plus RFA was found to be more effective than surgery, TACE, or RFA alone. This network meta-analysis did not evaluate efficacy based on lesion size. In addition, the results of this network meta-analysis were based on indirect comparisons with heterogeneous populations and should be confirmed in a prospective randomized trial. Further study in a multicenter RCT would permit greater certainty whether RFA, with or without TACE, is as effective as surgical resection in treating HCC tumors 30 mm or smaller. (See evidence review 8.01.11 for further information on TACE.)

RFA AS A PRIMARY TREATMENT OF INOPERABLE HCC

The evidence includes RCTs comparing RFA to other nonsurgical interventions, as an adjunct to chemotherapy, and systematic reviews of the RCTs.

Systematic Reviews

Majumdar and colleagues published a Cochrane systematic review and network meta-analysis of management of early and very early stage HCC (Majumdar, 23017). Reviewers included 14 RCTs (total N=2533 patients) of nonsurgical treatments compared to each other, sham or no intervention in patients with unresectable HCC. The quality of the evidence was rated as low or very low for all outcomes. Follow-up ranged from 6 to 37 months. Compared with RFA, mortality was higher for percutaneous acetic acid injection (HR=1.8; 95% CI, 1.1 to 2.8; 1 trial; N=125) and PEI (HR=1.49; 95% CI, 1.2 to 1.9; 5 trials; n=882). No trials reported health-related quality of life.

Randomized Controlled Trials

Giorgio and colleagues reported on an RCT comparing RFA plus chemotherapy with chemotherapy alone in 99 patients with unresectable HCC invading the portal vein.17 The HCC nodules ranged in size from 2.1 to 6.5 cm. The primary outcome was OS at 3 years. OS rates at 1, 2, and 3 years were 60%, 35%, and 26% in the combined therapy group and 37% and 0% at 1 and 2 years in the chemotherapy-alone arm (HR=2.87; 95% CI, 1.61 to 5.39).

RFA to Prevent Tumor Progression

Lee and colleagues reported a 10-year intention-to-treat analysis of RFA to prevent progression and reduce the chance of posttransplant HCC (Lee, 2017).Patients were included in this analysis if they had cirrhosis with treatment-naive HCC, were on the transplant waiting list, and had RFA alone as a stand-alone treatment. Only tumors that could safely be treated with a 5-mm margin received RFA. Of 1016 patients who had HCC and were on the transplant waiting list, 121 were treated with RFA and were included in this analysis. Patients returned for follow-up with imaging every 3 to 6 months. The outcomes of interest were dropout rate from the waitlist, posttransplant recurrence, and OS at 10 years. The mean time on the waiting list was 10.2 months (range, 0.3-38 months). At the end of follow-up, 89 (73.6%) patients had undergone liver transplant, 16 (13.2%) were delisted, 14 (11.6%) died, and 2 (1.7%) remained on the waitlist. The number of patients who were delisted due to tumor was 9 (7.4%). Intention-to-treat analysis of all patients estimated 8-year OS at 60.0% and disease-specific survival at 89.5%. 89 patients with HCC who received RFA prior to liver transplant, 5 (5.6%) had HCC recurrence.

Randomized Controlled Studies

In 2012 and 2017, Ruers and colleagues published the results of a multicenter RCT that compared RFA plus systemic treatment to systemic treatment alone for unresectable colorectal liver metastases.39,40 This RCT, originally designed as a phase 3 study, was completed as a phase 2 study due to slow accrual

(N=119 patients). To be included in the trial, patients had to have nonresectable liver metastases with fewer than 10 nodes and without extrahepatic disease. In the experimental arm, RFA, with or without additional resection, was given in combination with systemic therapy. The primary end point was a 30- month survival higher than 38% in the experimental arm with ITT analysis. At 3 years, OS did not differ significantly between groups (see Table 3). However, there was a significant improvement in PFS, (HR=0.74; 95% CI, 0.42 to 0.95; p=0.025), which corresponded to a difference in PFS at 3 years from

10.6% in the systemic therapy arm to 27.6% in the combined treatment arm. At a median follow-up of 9.7 years, 39 (65%) of 60 patients in the combined treatment arm had died compared with 53 (89.8%) of 59 in the systemic treatment arm (HR=0.58; 95% CI, 0.38 to 0.88; p=0.01).

ONGOING AND UNPUBLISHED CLINICAL TRIALS

Some currently unpublished trials that might influence this review are listed below:

Ongoing:

(NCT03127072) A Prospective, Randomized, One-center Study Assessing Overall Survival Using RFA Plus Chemotherapy ± Target Therapy and Chemotherapy ± Target Therapy Alone in Patients With Unresectable Colorectal Cancer Liver Metastases; planned enrollment 200; projected completion date December 2021.

2019 Update

A literature search was conducted through July 2019. There was no new information identified that would prompt a change in the coverage statement.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through July 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Yu et al performed a meta-analysis focused on comparative OS and disease-free survival (DFS) between percutaneous RFA and partial hepatectomy in patients with primary HCC meeting Milan criteria (Yu, 2020). The analysis included only RCTs, accounting for 5 trials (N=761). The authors evaluated the quality of the included studies and judged 4 of 5 to be high quality based on the Jadad score. Overall survival and DFS were similar between groups, but RFA was associated with a higher long-term recurrence rate (2-year overall recurrence: relative risk [RR]=1.56, 95% confidence interval [CI]: 1.12 to 2.16; 5-year overall recurrence: RR=1.48, 95% CI: 1.19 to 1.84). Treatment-related complications with RFA were significantly lower compared to partial hepatectomy (RR=0.23; 95% CI: 0.09 to 0.56), but the analysis had a high degree of heterogeneity (I2=79%).

Li et al also evaluated the comparative efficacy of RFA and surgical resection in patients with HCC meeting Milan criteria with liver function Child-Pugh scores of grade A or B (Li, 2020). One RCT and 15 retrospective observational studies were included in their analysis. Surgical resection was associated with significantly improved OS and DFS rates. In a subgroup analysis stratified by tumor size, 5-year OS rates were significantly improved in patients receiving surgical resection in patients with tumors ≤3 cm and >3 cm. The authors noted that the observational studies, which comprised most of the data, had significant heterogeneity and were prone to potential selection biases.

Zhao et al compared outcomes for RFA, resection, or transplantation in patients from the Surveillance, Epidemiology, and End Results database (Zhao, 2019). A total of 7664 patients treated between 2004 and 2015 with a single HCC tumor measuring up to 50 mm met study criteria. Outcomes for the 3 treatment arms were evaluated for both the unadjusted population and a propensity score-adjusted population to account for differences in baseline characteristics between patients. Median follow-up for the whole cohort was 55 months for OS. In the overall cohort, liver transplantation was associated with an improved overall survival (5-year OS, 66%) compared to RFA and resection in both unadjusted and adjusted populations (5-year OS [adjusted], 66% vs 53% vs 52%, respectively), but no significant difference was found between RFA and resection. Stratification by tumor size generally showed more survival benefits with resection compared to RFA. Further analysis by prognostic factors found that RFA may be the preferred treatment strategy for patients with low tumor risk (eg, tumor size <20 mm, tumor grade 0, fibrosis score/F0) and good general health condition.

Additional observational studies published since the systematic reviews have reported inconsistent results, with some finding no difference in survival outcomes between RFA and resection (Lee,2017 and Cucchetti, 2017) and some finding resection to be superior to RFA, particularly in cases with tumor sizes measuring between 3 and 5 cm, though some studies favored resection in smaller tumors as well (Lee, 2017; Min, 2018; Lin, 2020; Zheng, 2020; and Chu, 2019).

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through July 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Jia et al performed a meta-analysis to compare clinical efficacy between RFA and surgical resection in patients with HCC meeting Milan criteria (Jia, 2021). The analysis only included RCTs, accounting for 8 trials (N=1177). There were no significant differences found between RFA and surgical resection in OS and disease-free survival (DFS) rates. In a subgroup analysis stratifying by tumor size, there was still no significant differences between the 2 therapies for both tumors ≤4 cm and >4 cm. Limitations of the analysis include inclusion of clinical trials with small sample sizes and a lack of double blinding as it is not feasible.

Shin et al compared the efficacy of surgical resection with local ablative therapies for HCC meeting Milan criteria (Shin, 2021). The analysis included 7 RCTs and 18 non-randomized trials (N=5629) that compared surgical resection with either RFA, microwave ablation, or RFA plus TACE. Four of the RCTs were judged to be at high risk of bias overall, due to either lack of reported randomization method or missing data. All non-randomized trials were classified as having a high risk for bias due to the missing data. There was no significant difference between surgical resection and RFA alone when the RCTs were analyzed; the 3- and 5-year OS favored surgical resection in the analysis of the non-randomized trials. A multiple treatment meta-analysis using a frequentist framework random effect model found that 5-year recurrence free survival was highest with surgical resection (hazard ratio [HR]=0.64, 95% confidence interval [CI]: 0.56 to 0.74 vs RFA), followed by RFA plus TACE (HR=0.70, 95% CI: 0.53 to 0.92 vs RFA); no difference was found between microwave ablation and RFA (HR=0.93, 95% CI, 0.63 to 1.37). However, the latter comparisons were limited by the number of trials evaluating RFA plus TACE (5 studies) and microwave ablation (2 studies).

An additional observational study published since the systematic reviews found resection to be superior to RFA, particularly in cases with tumor sizes measuring between 3 and 5 cm (Conticchio, 2021).

Yu et al performed a meta-analysis of RCTs comparing RFA with microwave ablation for the treatment of localized, very early- or early-stage HCC (Yu, 2021). Five RCTs comparing RFA (n=413) and microwave ablation (n=431) were identified. The OS between microwave ablation and RFA was not significantly different at 1 year (OR=0.705; 95% CI: 0.382 to 1.301) or 3 years (OR=0.972; 95% CI: 0.615 to 1.538). Similarly, there was no difference observed in recurrence-free survival between microwave ablation and RFA at 1 year (OR=1.167; 95% CI: 0.568 to 2.396) and 3 years (OR=0.981; 95% CI, 0.616 to 1.562). Among the procedure-related complications evaluated, there were no statistically significant differences between the 2 groups.

Han et al also evaluated RFA compared with microwave ablation for early-stage HCC in a meta-analysis but included both RCT and observational trial data (Han, 2020). There were 5 RCTs, 1 prospective cohort, and 20 retrospective cohorts included in the analysis, providing data for 2393 patients treated with RFA and 2003 treated with microwave ablation. The median 1-year, 3-year, and 5-year OS rates were 93.3%, 71.3%, and 57.4%, respectively, in the microwave ablation group compared with 89.5%, 68.1%, and 55.5%, respectively, in the RFA group. Pooled HR for OS did not show any difference between microwave ablation versus RFA (HR=0.891; 95% CI: 0.740 to 1.072). There was also no difference observed between groups for DFS (HR=1.014; 95% CI: 0.811 to 1.209).

Schullian et al reported on local control and long-term outcomes in 42 female patients treated with stereotactic RFA for breast cancer liver metastases (Schullian, 2021). The procedures were performed at a single center covering 110 breast cancer liver metastases (median tumor size, 3 cm) in 48 ablation sessions. Additionally, 18 (42.9%) patients had extrahepatic metastasis. The technical success rate was 100%, and 107 of the 110 liver metastases were successfully ablated on the first RFA. Four grade 1 (arterial bleeding from subcapsular liver vessels) and 1 grade 2 (major pleural effusion) periprocedural complications occurred. Local recurrence developed in 7.3% of the tumors after a median imaging follow-up of 10.9 months. The 1 year, 3 year, and 5 year OS rates from the date of the first RFA were 84.1%, 49.3%, and 20.8%, respectively, with a median OS of 32.3 months (95% CI: 20.6 to 50.3). The 1 year, 3 year, and 5 year DFS rates from the date of the first RFA were 45.3%, 22.3%, and 15.9%, respectively, with a median OS of 10.5 months (95% CI 6.8 to 25.0).

The American Association for the Study of Liver Diseases published a guideline on the treatment of hepatocellular carcinoma (Heimbach, 2019). For adults with Child-Pugh class cirrhosis and resectable T1 or T2 hepatocellular carcinoma (HCC), the guideline suggests using resection over radiofrequency ablation (RFA; moderate quality/certainty of evidence; conditional strength of recommendation). Technical remarks in the guideline note that "Stage T1 and T2 HCC include a wide range of tumor sizes from <1 cm to 5 cm, and the effectiveness of available therapies depend in large part on the size, number, and location of the tumors. Whereas smaller, single tumors (<2.5 cm) that are favorably located may be equally well treated by either resection or ablation, tumors larger than 2.5-3 cm, multifocal, or near major vascular or biliary structures may have limited ablative options." Additionally, the guideline highlighted that "[r]andomized trials performed to date comparing RFA to resection have been performed primarily in East Asian patients, in whom there is a higher etiologic prevalence of HBV [hepatitis B virus] (including noncirrhotic HBV–associated HCC) and a lower prevalence of other liver diseases such as NAFLD [non-alcoholic fatty liver disease] or HCV [hepatitis C virus] compared with Western patients. The impact of these demographic differences on oncologic outcomes of different therapies is unknown."

CPT/HCPCS:

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