Coverage Policy Manual
Policy #: 1997255
Category: Surgery
Initiated: September 1997
Last Review: October 2018
  Hepatic Tumors, Ablative Procedures (Percutaneous Ethanol Injections, Acetic Acid Injections, and Interstitial Laser Photocoagulation)

Description:
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.
 
Percutaneous Ethanol Injection (PEI) is the intratumoral injection of absolute ethanol. It does not damage non-cancerous liver parenchyma.   PEI is performed under local anesthesia using a 21-gauge needle guided by ultrasound or computed tomography. Ethanol diffuses into the tumor cells and causes dehydration and protein denaturation, resulting in coagulative necrosis. This is followed by microvascular thrombosis and subsequent tumor ischemia.  PEI is limited to small lesions and requires multiple sessions because of its reduced diffusion capacity over intratumoral septa.  Percutaneous acetic acid has been used in a few trials.
 
Interstitial Laser Photocoagulation (ILP) (also known as laser-induced interstitial thermotherapy - LITT) is a minimally invasive cancer treatment technique, whereby optical energy from implanted optical fibers is used to therapeutically heat small, solid tumors.
 
  
RELATED POLICIES:
  • 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
  • 2012062 - Radiofrequency Ablation of Primary or Metastic Liver Tumors
 

Policy/
Coverage:
Percutaneous ethanol injections or injections of acetic acid are not covered based on benefit certificate primary coverage criteria for effectiveness.
 
Interstitial laser photocoagulation (ILP) (also known as laser-induced interstitial therapy - LITT) is not covered based on benefit certificate primary coverage criteria.  These interventions are currently being studied.
 
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:
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.  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.  
  
2012 Update
A review of literature was conducted on PubMed through September 2012.   
Bouza and colleagues (2009) reported on a study completed on the meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma.
The purpose of the study was to analyze the efficacy and safety of RFA versus that of ethanol injection (PEI), the percutaneous standard approach to treat nonsurgical HCC.  A systematic review and meta-analysis of randomised or quasi-randomised controlled trials published up to August 2008 in PubMed, ISI Web of Science and The Cochrane Library was done. Overall survival, local recurrence rate and adverse effects were considered as primary outcomes.  Studies were critically appraised and estimates of effect were calculated according to the random-effects model.   Six studies were eligible.  The studies reported data on 396 patients treated by RFA and 391 treated by PEI. In general, subjects were in Child-Pugh class A (74%) and had unresectable HCC (mean size 2.5 cm). Mean follow-up was 25 +/- 11 months. The survival rate showed a significant benefit for RFA over PEI at one, two, three and four years. The advantage in survival increased with time with Relative Risk values of: 1.28 (95%CI:1.12-1.45) and 1.24 (95%CI:1.05-1.48) for RFA versus PEI at 3- and 4-years respectively. Likewise, RFA achieved significantly lower rates of local recurrence (RR: 0.37, 95%CI: 0.23-0.59). The overall rate of adverse events was higher with RFA (RR:2.55, 95%CI: 1.8-3.6) yet no significant differences were found concerning major complications (RR:1.85, 95%CI: 0.68-5.01). There was not enough evidence supporting a better cost-effectiveness ratio for RFA compared to PEI.  Available evidence from adequate quality controlled studies support the superiority of RFA versus PEI, in terms of better survival and local control of the disease, for the treatment of patients with relatively preserved liver function and early-stage non-surgical HCC.  
 
Giorgio and colleagues (2000) conducted a study to evaluate the efficacy and complications of interstitial laser photocoagulation (ILP) under ultrasound (US) guidance as a technique for focal ablation of liver tumors in patients with normal and impaired hepatic function.  A total of 104 patients, 77 with 85 nodules of hepatocellular carcinoma on cirrhosis (29 in Child-Pugh A class, 43 in B e 5 in C class) and 27 patients with hepatic metastases (25 from colon, two from lung carcinoma) underwent ILP under US guidance.  Depending on tumor size up to four needles were inserted in the tumor and multiple laser illuminations were performed in one or multiple sessions.  Necrosis of the nodules was evaluated with triphasic contrast-enhanced CT.  Results: Ninety-four patients underwent a single ILP session and nine patients two sessions.  CT showed complete necrosis in 70 out of 85 HCC nodules in 65 treated patients and in 24 out of 31 patients with metastases.  Three Child C class patients dropped out the control of efficacy by CT because of severe liver failure associated in one case with transient paralytic ileum.  One of these patients died 2 months after treatment.  Two patients with metastasis dropped the completion of the treatment because of complication occurred after the ILP session (one paralytic ileum, one gastric hemorrhage).  Conclusions:  ILP under US guidance is effective in inducing complete necrosis in small and large liver tumors. Nevertheless, ILP can cause severe derangement of liver function in patients with advanced cirrhosis.
 
Holmer and colleagues (2006) reported on laser-induced interstitial thermotherapy in colorectal tumors and hepatic metastases.  The extent of tumor destruction achieved by this the therapeutic application of laser light depends primarily on light distribution in the target tissue.  Knowledge about optical properties is necessary to predict light distribution in the tissue for careful irradiation planning. The aim of this study was to compare the optical behavior of healthy colon tissue with that of colorectal carcinomas and their hepatic metastases in the native and coagulated state in order to test the effect of malignant degeneration, metastasis, and thermal coagulation on optical parameters.
 
Ninety tissue samples were taken from patients with a colorectal carcinoma and concomitant liver metastases: healthy colon tissue (n = 30); colon carcinoma (n = 30); liver metastases (n = 30). Optical properties were measured according to the single integrating sphere principle in the native state and after thermal coagulation in the wavelength range of 800-1,100 nm and analyzed by inverse Monte Carlo simulation.
 
The highest optical penetration depth for all tissue types was obtained at the end of the spectral range investigated.  Comparing healthy colon-to-colon carcinoma always revealed a significantly lower absorption and scattering coefficient in the tumor tissue. This resulted in a higher optical penetration depth of the laser light in the colon carcinoma tissue (P < 0.05). A direct comparison disclosed no agreement between the optical properties of the primary tumor and the liver metastases.  In the native state, colon carcinoma tissue had a lower scattering coefficient (P < 0.05), higher anisotropy factor, and optical penetration depth than liver metastases (P < 0.05).  The absorption coefficient did not differ significantly. The differences in the native state were equalized by tissue coagulation.  Conclusions: Colon carcinoma tissue has a higher optical penetration depth than healthy colon tissue, which speaks in favor of tumor selectivity for interstitial laser application, since large treatment volumes can be obtained in the tumor. The lack of agreement between primary tumors and their concomitant liver metastases indicates a modification of optical behavior through metastasis. Thermal coagulation of tissue leads to changes in the optical properties, which are clearly less pronounced in carcinoma tissue. The data obtained in this study clearly show that an individual irradiation schedule is necessary for effective and safe dosimetry in laser-induced thermotherapy (LITT).
 
Shankar et al. (2000) reported on the treatment of recurrent colorectal liver metastases by interstitial laser photocoagulation.   Hepatic resection improves survival in selected patients with colorectal liver metastases. The treatment of recurrent hepatic metastases after resection is controversial. Interstitial laser photocoagulation, performed under local anaesthesia, offers a minimally invasive option to repeat resection. The first series of patients with recurrent colorectal liver metastases treated with photo- coagulation is reported.
 
Nineteen patients (five women and 14 men, median age 57 (range 44-71) years) who developed recurrent colorectal liver metastases after hepatectomy (five with bilateral disease) were treated with photocoagulation between 1993 and 1997. Fifteen patients also received chemotherapy (14 systemic, one hepatic arterial) before photocoagulation. There were no major complications or deaths related to the treatment. Six patients developed minor complications related to the procedure but did not require any form of intervention. Median survival from commencement of photocoagulation was 16 (range 4-36) months.  Photocoagulation is a safe, minimally invasive therapy that may be used as an adjunct to chemotherapy and repeat resection in the treatment of recurrent colorectal liver metastases, and may lead to improved survival.
 
In a prospective non-randomized study, Wietzke-Braun et al (2004) examined the quality-of-life (QOL) and outcome of ultrasound-guided laser interstitial thermo-therapy (US-LITT) in patients with liver metastases of colorectal cancer.  A total of 45 patients with liver metastases of colorectal cancer were palliatively treated by US-LITT.  Patient survival was analyzed by the Kaplan-Meier method and the QOL questionnaire C30 of the European Organization for Research and Treatment of Cancer before, and 1 week, 1 month, and 6 months after initiation of US-LITT.  Median survival after initiation of US-LITT was 8.5 +/- 0.7 months with a range of 1.5 to 18 months.  Body weight was constant 1 month after US-LITT.  In the multi-variate analyses, QOL symptoms and functioning scales did not deteriorate in patients alive at 6 months after initiation of US-LITT.  Uni-variate analyses outlined a significant increase of the pain subscale before and at 1 week after US-LITT.  The authors concluded that this study first described the QOL in patients with liver metastases of colorectal cancer treated by US-LITT.  Potential benefits of the minimal invasive procedure could be prolonged survival time by preserved QOL, but this first impression needs to be verified in a comparative study.
 
Ansari et al. (2012) reviewed the current role of RFA in the treatment of liver tumors and compared it to PEI,  The conclusion was that liver resection still remains the gold standard for the treatment of liver tumors. RFA and PEI are feasible and of benefit in non-operable patients, and as bridging therapies before liver transplantation. RFA seems superior to PEI in HCC > 2 cm and the combination of both interventions may be of benefit in selected patients. Liver resection is superior to RFA for patients with HCC meeting the Milan criteria, but RFA can be employed in tumors ≤ 3 cm and where there is increased expected operative mortality. Using RFA as the primary treatment of resectable CLM is still not recommended; however, RFA may have a role in unresectable lesions and for patients unfit for surgery. Newer advancements in the field of local ablative therapies are to be expected, requiring constant evaluation of the different techniques. In the future, local ablative approaches may be combined with systematically administered molecular targeted therapies (e.g., sorafenib) to further improve the outcomes of patients with liver malignancies.
 
Giorgio et al (2011) recently conducted an RCT of percutaneous RFA and PEI in 285 HCC patients with tumors ≤ 3 cm. The primary endpoint was 5-year survival. In the RFA and PEI groups, the 5-year survival rates were 70% and 68%, respectively (not significant). The local recurrence rates were also not significantly different. The overall costs of RFA and PEI were 171  000 Euros and 1359 Euros, respectively (P < 0.0001). According to pooled data from two previous RCTs (Lin, 2004 & 2005), RFA and PEI are equally effective for tumors ≤ 2 cm (Germani, 2010).  However, the effect of RFA is more predictable than PEI when considering all tumor sizes. The meta-analysis by Bouza et al (2009) included a total of 396 patients treated by RFA and 391 treated by PEI.   RFA yielded a better overall survival (1 year, 2 year, 3 year, and 4 year), as well as disease-free survival (1 year, 2 year, and 3 year).  The risk of local recurrence was reduced in the RFA group. Total complications were increased for RFA, but major complications were not significantly different.  In terms of cost-effectiveness of PEI over RFA, data are still controversial.  Brunello et al (2008) reported that mean direct hospital costs were 6540 Euros for RFA treated patients and 4097 Euros for the PEI group (P < 0.001), whereas Seror et al (2006) reported that RFA was the most cost-effective option.
 
NCT00392366 - Laser Interstitial Thermal Therapy Under "Real Time" MRI Guidance for "Minimal Invasive" Treatment of Liver Metastasis,  has been completed but no results have bee reported.
 
In summary, no literature was identified that would support a change in the coverage statement.  There were no current clinical trials identified for these procedures.
 
2015 Update
A literature search conducted through September 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2015 retrospective cohort study by Yeh  and colleagues investigated whether TACE plus sequential curative therapy provided a survival benefit in patients with a single hepatocellular carcinoma (HCC) compared to curative surgery, radiofrequency ablation or percutaneous ethanol injection (Yeh, 2015).  A total of 470 patients with a diagnosis of single HCC between 2005 and 2010 were included. The 1-, 3-, and 5-year OS rates of all patients were 93%, 73%, and 60%, respectively. Child-Pugh class A (HR=2.04; 95% CI, 1.277 to 3.254; p=0.003), very early stage Barcelona Clinic Liver Cancer (BCLC; HR=2.03; 95% CI, 1.021 to 4.025; p=0.043), tumor size less than 5 cm (HR=1.75; 95% CI, 1.115 to 2.751; p=0.015), alpha fetoprotein (AFP) level less than 200 ng/mL (HR=2.07; 95% CI, 1.346 to 3.182; p=0.001), and curative-based therapy (HR=2.16; 95% CI, 1.442 to 3.224; p<0.001) were factors associated with better OS. The 1-, 3-, and 5- year disease-free survival (DFS) rates of all the patients were 75%, 54%, and 36%, respectively. Only Child-Pugh class A (HR=1.57; 95% CI, 1.068 to 2.294; p=0.022) and curative-based therapy (HR=1.51; 95% CI, 1.128 to 2.028; p=0.006) were significantly associated with better DFS. Neoadjuvant TACE did not provide benefit compared with curative therapy alone in subgroup analysis.
 
The evidence for radiofrequency ablation (RFA) in individuals with primary, unresectable, hepatocellular carcinoma consists of randomized trials and several systematic reviews and meta-analyses. Relevant outcomes are overall survival, disease-specific survival, recurrence-free survival, hospitalizations, treatment-related morbidity, morbid events, change in disease status and tumor recurrence. Surgical resection of HCC, compared to RFA, has shown superior survival (although with higher morbidity), supporting the use of RFA for unresectable HCC and in patients who are not candidates for surgical resection. Response rates 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. Therefore, the evidence is sufficient t determine qualitatively that RFA in individuals with primary, unresectable, hepatocellular carcinoma results in a meaningful improvement in the net health outcome.
 
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Lan and colleagues published a network meta-analysis comparing different interventional treatments for early stage HCC (Lan, 2016). A total of 21 RCTs were included that compared TACE, RFA, percutaneous ethanol injection, and hepatic resection, or combinations of treatments. These studies were all rated at a low to moderate risk of bias, with lack of blinding being the most substantial limitation. The primary outcome measures were overall survival at 1, 3, and 5 years post-treatment. The treatments and combinations of treatments were rank ordered according to the results on overall survival. At each time point, the combination of RFA + TACE was the number one ranked treatment. The combination of RFA + TACE ranked second highest at 1 and 3 years, and was third highest at 5 years, with hepatic resection ranked second at 5 years. RFA alone was ranked as the fourth highest treatment at 1 year and the fifth highest treatment at 3 and 5 years.
 
Section Summary: RFA as a Primary Treatment for Patients with Unresectable HCC
Randomized and nonrandomized trials have been performed comparing RFA to alternate treatments for HCC. RCTs of RFA versus hepatic resection report that resection is associated with greater overall survival, but also with more complications. RCT evidence has also established that RFA is more effective than PEI in this population, and a small amount of evidence reports that RFA may be better than cryoablation. The evidence on RFA versus TACE is limited and no conclusions can be drawn. This evidence supports the use hepatic resection as first line therapy for HCC, and the use of RFA in patients who are inoperable.
 
2017 Update
A literature search conducted through September 2017 did not reveal any new information that would prompt a change in the coverage statement.  
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in September 2017 did not identify any ongoing or unpublished trials that would likely influence this review.
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
47379Unlisted laparoscopic procedure, liver
47399Unlisted procedure, liver
76940Ultrasound guidance for, and monitoring of, parenchymal tissue ablation
77013Computed tomography guidance for, and monitoring of, parenchymal tissue ablation
77022Magnetic resonance guidance for, and monitoring of, parenchymal tissue ablation

References: Ansari D, Andersson R(2012) Radiofrequency ablation or percutaneous ethanol injection for the treatment of liver tumors World J Gastroenterol. 2012 March 14; 18(10): 1003–1008.

Bouza C, López-Cuadrado T, Alcázar R et al.(2009) Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma. BMC Gastroenterol. 2009 May 11;9:31.

Brunello F, Veltri A, Carucci P, et al.(2008) Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scand J Gastroenterol. 2008;43:727–735.

Feng Q, Chi Y, Liu Y, et al.(2015) Efficacy and safety of percutaneous radiofrequency ablation versus surgical resection for small hepatocellular carcinoma: a meta-analysis of 23 studies. J Cancer Res Clin Oncol. Jan 2015;141(1):1-9. PMID 24889505

Germani G, Pleguezuelo M, Gurusamy K, et al.(2010) Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: a meta-analysis. J Hepatol. 2010;52:380–388.3-5.

Giorgio A, Di Sarno A, De Stefano G, et al.(2011) Percutaneous radiofrequency ablation of hepatocellular carcinoma compared to percutaneous ethanol injection in treatment of cirrhotic patients: an Italian randomized controlled trial. Anticancer Res. 2011;31:2291–2295.

Holmer C, Lehmann KS, Risk J, et al.(2006) Colorectal tumors and hepatic metastases differ in their optical properties-relevance for dosimetry in laser-induced interstitial thermotherapy. Lasers Surg Med. 2006 Apr;38(4):296-304.

Ikeda M, Okada S, Ueno H et al.(2001) Radiofrequency ablation and percutaneous ethanol injection in patients with small hepatocellular carcinoma: a comparative study. Jpn J Clin Oncol 2001; 31(7):322-6.

Jansen MC, van Hillegersberg R, Chamuleau RA, et al.(2005) Outcome of regional and local ablative therapies for hepatocellular carcinoma: a collective review. Eur J Surg Oncol 2005; 31(4):331-47.

Lan T, Chang L, Mn R, et al.(2016) Comparative Efficacy of Interventional Therapies for Early-stage Hepatocellular Carcinoma: A PRISMA-compliant Systematic Review and Network Meta-analysis. Medicine (Baltimore). Apr 2016;95(15):e3185. PMID 27082558

Livraghi T, Goldberg SN, Lazzaroni S et al.(1999) Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999; 210(3): 655-61.

Livraghi T, Solbiati L, Meloni F et al.(2003) Quality of life and outcome of ultrasound-guided laser interstitial thermo-therapy for non-resectable liver metastases of colorectal cancer. Cancer 2003; 97(12):3027-35.

Majumdar A, Roccarina D, Thorburn D, et al.(2017) Management of people with early- or very early-stage hepatocellular carcinoma: an attempted network meta-analysis. Cochrane Database Syst Rev. Mar 28 2017;3:Cd011650. PMID 28351116

National Comprehensive Cancer Network (NCCN).(2017) NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2017. 2017; http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf.

National Comprehensive Cancer Network (NCCN).(2017) NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 2.2017. 2017; www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf.

National Comprehensive Cancer Network (NCCN).(2017) NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine Tumors. Version 2.2017. 2017; http://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf.

Riemsma RP, Bala MM, Wolff R, et al.(2013) Percutaneous ethanol injection for liver metastases. Cochrane Database Syst Rev. May 31 2013(5):CD008717. PMID 23728679

Seror O, N’Kontchou G, Tin Tin Htar M, et al.(2006) Ethanol versus radiofrequency ablation for the treatment of small hepatocellular carcinoma in patients with cirrhosis: a retrospective study of efficacy and cost. Gastroenterol Clin Biol. 2006;30:1265–1273.

Shiina S, Tateishi R, Imamura M, et al.(2012) Percutaneous ethanol injection for hepatocellular carcinoma: 20-year outcome and prognostic factors Liver Int. 2012 Oct;32(9):1434-42. doi: 10.1111/j.1478-3231.2012.02838.x.

Wietzke-Braun P, Schindler C, Raddatz D, et al.(2004) Quality of life and outcome of ultrasound-guided laser interstitial thermo-therapy for non-resectable liver metastases of colorectal cancer. Eur J Gastroenterol Hepatol. 2004 Apr;16(4):389-95.

Yeh ML, Huang CI, Huang CF, et al.(2015) Neoadjuvant transcatheter arterial chemoembolization does not provide survival benefit compared to curative therapy alone in single hepatocellular carcinoma. Kaohsiung J Med Sci. Feb 2015;31(2):77-82. PMID 25645985


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.