Latest Review Date: September 2024

POLICY:

Cryosurgical ablation (CSA) is considered investigational when used for the treatment of liver tumors.

DESCRIPTION OF PROCEDURE OR SERVICE:

Cryosurgical ablation (CSA) involves the freezing of target tissues, often by inserting a probe through which coolant is circulated into the tumor. CSA can be performed as an open surgical technique or percutaneously or laparoscopically, typically with ultrasound guidance.

Liver Metastases

Hepatic tumors can be due to primary liver cancer or metastases to the liver from nonhepatic primary tumors. Primary liver cancer can arise from hepatocellular tissue (hepatocellular carcinoma [HCC]) or intrahepatic biliary ducts (cholangiocarcinoma). Multiple tumors metastasize to the liver, but there is particular interest in the treatment of hepatic metastases from colorectal cancer (CRC) given the propensity of CRC to metastasize to the liver and its high prevalence. Liver metastases from neuroendocrine tumors present a unique clinical situation. Neuroendocrine cells produce and secrete a variety of regulatory hormones (or neuropeptides), which include neurotransmitters and growth factors. Overproduction of the specific neuropeptides by cancerous cells causes various symptoms, depending on the hormone produced. In the U.S, the incidence rates of liver cancer are estimated to continually increase through 2030. Some racial groups are more affected by liver cancer than others due to differences in the prevalence of risk factors and disparities in access to quality care; the mortality rate for African Americans with HCC is higher than other racial groups in the U.S.

Treatment

Surgical resection with tumor-free margins and liver transplantation are the primary treatments available that have curative potential. Many hepatic tumors are unresectable at diagnosis, due either to their anatomic location, size, the number of lesions, or underlying liver reserve. Local therapy for hepatic metastasis is indicated only when there is no extrahepatic disease, which rarely occurs for patients with primary cancers other than CRC or certain neuroendocrine malignancies. For liver metastases from CRC, postsurgical adjuvant chemotherapy has been reported to decrease recurrence rates and prolong the time to recurrence. Combined systemic and hepatic arterial chemotherapy may increase disease-free intervals for patients with hepatic metastases from CRC but apparently is not beneficial for those with unresectable hepatocellular carcinoma.

Various locoregional therapies for unresectable liver tumors have been evaluated: cryosurgical ablation (cryosurgery); radiofrequency ablation; laser ablation; transhepatic arterial embolization, chemoembolization, or radioembolization with yttrium-90 microspheres; microwave coagulation; and percutaneous ethanol injection. Cryosurgical ablation occurs in tissue that has been frozen by at least 3 mechanisms: (1) formation of ice crystals within cells, thereby disrupting membranes and interrupting cellular metabolism among other processes; (2) coagulation of blood, thereby interrupting blood flow to the tissue, in turn causing ischemia and apoptosis; and (3) induction of apoptosis.

Recent studies, including a small randomized controlled trial and case series, have reported on experience with cryosurgical and other ablative methods used in combination with subtotal resection and/or procedures such as transarterial chemoembolization.

Procedure-Related Complications

Cryosurgery is not a benign procedure. Treatment-related deaths occur in approximately 2% of study populations and are most often caused by cryoshock, liver failure, hemorrhage, pneumonia/sepsis, and acute myocardial infarction. Clinically significant nonfatal complication rates in the reviewed studies ranged from 0% to 83% and were generally due to the same causes as treatment-related deaths. The likelihood of complications arising from cryosurgery might be predicted, in part, by the extent of the procedure, but much of the treatment-related morbidity and mortality reflect the generally poor health status of patients with advanced hepatic disease.

KEY POINTS:

The most recent literature update was performed through July 31, 2024.

Summary of Evidence

For individuals who have unresectable primary hepatocellular carcinoma (HCC) amenable to locoregional therapy who receive cryosurgical ablation (CSA), the evidence includes two meta-analyses, one randomized controlled trial (RCT), several nonrandomized comparative studies, and multiple noncomparative studies. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. The available RCT comparing cryoablation with radiofrequency ablation (RFA) demonstrated lower rates of local tumor progression with cryoablation but no differences in survival outcomes between groups. Although this trial provided suggestive evidence that cryoablation is comparable with radiofrequency ablation, trial limitations would suggest findings need to be replicated. Nonrandomized comparative studies have failed to find consistent benefit with cryoablation in outcomes related to tumor recurrence and survival. Evidence from two meta-analyses suggests equivalent OS and progression-free survival to RFA and superiority for combined transarterial chemoembolization (TACE) plus CSA over TACE alone for OS and tumor progression. Additional randomized comparative evidence is needed to permit conclusions about the effectiveness of cryoablation compared with other locoregional therapies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have unresectable liver metastases from neuroendocrine tumors amenable to locoregional therapy who receive CSA, the evidence includes a Cochrane review and case series. Relevant outcomes are OS, disease-specific survival, symptoms, and treatment-related mortality and morbidity. The available evidence base is very limited. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have unresectable liver metastases from colorectal cancer amenable to locoregional therapy who have CSA, the evidence includes an RCT, several nonrandomized comparative and noncomparative studies, and systematic reviews of these studies. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. The available RCT comparing surgical resection with cryoablation was judged as high-risk of bias. Some nonrandomized comparative studies have reported improved survival outcomes for patients managed with cryotherapy compared with those managed with resection alone; however, these studies were subject to bias in the selection of patients for treatments. Additional controlled studies are needed to permit conclusions about the effectiveness of cryoablation compared with other locoregional therapies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) indicates that ablative techniques may be used in the treatment of certain hepatic tumors. The NCCN guidelines on hepatocellular carcinoma (v.2.2024) include cryoablation in a list of ablative techniques, along with radiofrequency ablation (RFA), percutaneous alcohol ablation, and microwave ablation; however, the literature cited in the guidelines reports on only RFA and ethanol ablation. For hepatocellular carcinoma, the NCCN makes the following category 2A recommendation:

"All patients with HCC [hepatocellular carcinoma] should be evaluated for potential curative therapies (resection, transplantation, and for small lesions, ablative strategies). Locoregional therapy should be considered in patients who are not candidates for surgical curative treatments, or as a part of a strategy to bridge patients for other curative therapies.

Ablation (microwave/radiofrequency, surgical, or percutaneous ethanol injection):

• All tumors should be amenable to ablation such that the tumor and, in the case of thermal ablation, a margin of normal tissue is treated. A margin is not expected following percutaneous ethanol injection.
• Tumors should be in a location accessible for percutaneous/laparoscopic/open approaches for ablation.
• Caution should be exercised when ablating lesions near major vessels, major bile ducts, diaphragm, and other intra-abdominal organs.
• Ablation alone may be curative in treating tumors ≤3 cm. In well-selected patients with small properly located tumors, ablation should be considered as definitive treatment in the context of a multidisciplinary review. Lesions 3 to 5 cm may be treated to prolong survival using arterially directed therapies, or with combination of an arterially directed therapy and ablation as long as tumor location is accessible for ablation.
• Unresectable/inoperable lesions >5 cm should be considered for treatment using arterially directed, systemic therapy or RT [radiation therapy]."

The NCCN guidelines on biliary tract cancer (v.3.2024) recommend that patients with intrahepatic cholangiocarcinoma should be evaluated for potentially curative therapies such as ablation, arterially directed therapies, and RT. Specific recommendations for ablation include (category 2A recommendation):

• "All tumors should be amenable to complete ablation so that the tumor and a margin of normal tissue up to 1 cm can be treated."
• "For small single tumors <3 cm, whether recurrent or primary, thermal ablation is a reasonable alternative to surgical resection, particularly in patients with high-risk disease."
• "Options for ablation include cryoablation, radiofrequency ablation, microwave ablation, and irreversible electroporation."

The NCCN guidelines on neuroendocrine and adrenal tumors (v.1.2024) address the use of hepatic-directed therapies for patients with unresectable hepatic-predominant progressive metastatic neuroendocrine. These guidelines support consideration of ablative therapies such as RFA or cryoablation if near-complete tumor burden can be achieved (category 2B recommendation).

For ablative therapy, the NCCN makes the following category 2B recommendation:

"Percutaneous thermal ablation, often using microwave energy (radiofrequency and cryoablation are also acceptable), can be considered for oligometastatic liver disease, generally up to four lesions each smaller than 3 cm. Feasibility considerations include safe percutaneous imaging-guided approach to the target lesions, and proximity to vessels, bile ducts, or adjacent non-target structures that may require hydro- or aero-dissection for displacement."

The NCCN guidelines on the treatment of colon cancer with liver metastases (v.4.2024) consider patients with liver oligometastases as candidates for tumor ablation therapy. Ablative techniques include RFA, microwave ablation, cryoablation, percutaneous ethanol injection, and electro-coagulation. Use of surgery, ablation, or the combination "with the goal of less-than-complete resection/ablation of all known sites of disease, is not recommended other than in the scope of a clinical trial" (category 2A recommendations).

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Cryosurgery, Cryosurgical ablation of liver, CSA, cryoablation

APPROVED BY GOVERNING BODIES

Several cryosurgical devices have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. Use includes general surgery, urology, gynecology, oncology, neurology, dermatology, ENT[ears, nose, throat], proctology, pulmonary surgery, and thoracic surgery. The system is designed to freeze/ablate tissue by the application of extreme cold temperatures.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply.  Refer to member’s benefit plan.  

CURRENT CODING

CPT Codes:

REFERENCES:

1. Bala MM, Riemsma RP, Wolff R, et al. Cryotherapy for liver metastases. Cochrane Database Syst Rev. Jun 05 2013;6(6): CD009058.

2. Cha SY, Kang TW, Min JH, et al. RF Ablation Versus Cryoablation for Small Perivascular Hepatocellular Carcinoma: Propensity Score Analyses of Mid-Term Outcomes. Cardiovasc Intervent Radiol. Mar 2020; 43(3): 434-444.

3. Chen L, Ren Y, Sun T, et al. The efficacy of radiofrequency ablation versus cryoablation in the treatment of single hepatocellular carcinoma: A population-based study. Cancer Med. Jun 2021; 10(11): 3715-3725.
4. Dunne RM, Shyn PB, Sung JC, et al. Percutaneous treatment of hepatocellular carcinoma in patients with cirrhosis: a comparison of the safety of cryoablation and radiofrequency ablation. Eur J Radiol. Apr 2014;83(4):632-638.
5. Ei S, Hibi T, Tanabe M, et al. Cryoablation provides superior local control of primary hepatocellular carcinomas of >2 cm compared with radiofrequency ablation and microwave coagulation therapy: an underestimated tool in the toolbox. Ann Surg Oncol. Apr 2015;22(4):1294-1300.
6. Huang C, Zhuang W, Feng H, et al. Analysis of therapeutic effectiveness and prognostic factor on argon-helium cryoablation combined with transcatheter arterial chemoembolization for the treatment of advanced hepatocellular carcinoma. J Cancer Res Ther. Dec 2016;12(Supplement):C148-c152.
7. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
8. Keshavarz P, Raman SS. Comparison of combined transarterial chemoembolization and ablations in patients with hepatocellular carcinoma: a systematic review and meta-analysis. Abdom Radiol (NY). Mar 2022; 47(3): 1009-1023.
9. Kim HI, An J, Han S, et al. Loco-regional therapies competing with radiofrequency ablation in potential indications for hepatocellular carcinoma: a network meta-analysis. Clin Mol Hepatol. Oct 2023; 29(4): 1013-1028.
10. Ko SE, Lee MW, Rhim H, et al. Comparison of procedure-related complications between percutaneous cryoablation and radiofrequency ablation for treating periductal hepatocellular carcinoma. Int J Hyperthermia. Nov 17 2020; 37(1): 1354-1361.
11. Li Z, Fu Y, Li Q, et al. Cryoablation plus chemotherapy in colorectal cancer patients with liver metastases. Tumour Biol. Nov2014;35(11):10841-10848.
12. Luo J, Dong Z, Xie H, et al. Efficacy and safety of percutaneous cryoablation for elderly patients with small hepatocellular carcinoma: A prospective multicenter study. Liver Int. Apr 2022; 42(4): 918-929. 
13. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: HepatocellularCarcinoma. Version 2.2024. www.nccn.org/professionals/physician_gls/PDF/hcc.pdf.
14. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Biliary Tract Cancers. Version 3.2024. www.nccn.org/professionals/physician_gls/PDF/btc.pdf. 
15. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 1.2024. www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf. 
16. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 4.2024. www.nccn.org/professionals/physician_gls/PDF/colon.pdf. 
17. Ng KM, Chua TC, Saxena A, et al. Two decades of experience with hepatic cryotherapy for advanced colorectal metastases. Ann Surg Oncol. Apr 2012;19(4):1276-1283.
18. Pathak S, Jones R, Tang JM, et al. Ablative therapies for colorectal liver metastases: a systematic review. Colorectal Dis. Sep 2011;13(9):e252-265.
19. Rong G, Bai W, Dong Z, et al. Long-term outcomes of percutaneous cryoablation for patients with hepatocellular carcinoma within Milan criteria. PLoS One. Apr 2015;10(4):e0123065.
20. Saxena A, Chua TC, Chu F, et al. Optimizing the surgical effort in patients with advanced neuroendocrine neoplasm hepatic metastases: a critical analysis of 40 patients treated by hepatic resection and cryoablation. Am J Clin Oncol. Oct 2012;35(5):439-445.
21. Singh SK, Singh R. Liver cancer incidence and mortality: Disparities based on age, ethnicity, health and nutrition, molecular factors, and geography. Cancer Health Disparities. Mar 2020; 4: e1-e10. 
22. Wang C, Wang H, Yang W, et al. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology. May 2015;61(5):1579-1590.
23. Wang Y, Li W, Man W, et al. Comparison of Efficacy and Safety of TACE Combined with Microwave Ablation and TACE Combined with Cryoablation in the Treatment of Large Hepatocellular Carcinoma. Comput Intell Neurosci. 2022; 2022: 9783113.
24. Wei J, Cui W, Fan W, et al. Unresectable Hepatocellular Carcinoma: Transcatheter Arterial Chemoembolization Combined With Microwave Ablation vs. Combined With Cryoablation. Front Oncol. 2020; 10: 1285.
25. Yang Y, Wang C, Lu Y, et al. Outcomes of ultrasound-guided percutaneous argon-helium cryoablation of hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. Nov 2012;19(6):674-684.

POLICY HISTORY:

Medical Policy Panel, September 2019

Medical Policy Group, October 2019 (5): Created separate MP for cryosurgical ablation of primary or metastatic liver tumors. All information regarding cryosurgical ablation pulled from MP 070 and transferred to this policy. Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. No change in Policy Statement.  

Medical Policy Panel, September 2020

Medical Policy Group, September 2020 (5): Updates to Key Points, Practice Guidelines and Position Statements, and References. No change to Policy Statement.

Medical Policy Panel, September 2021

Medical Policy Group, September 2021 (5): Updates to Description, Key Points, Practice Guidelines and Position Statements, Approved by Governing Bodies, and References. Policy statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Panel, September 2022

Medical Policy Group, September 2022 (5): Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. No change to Policy Statement.

Medical Policy Panel, September 2023

Medical Policy Group, September 2023 (11): Updates to Key Points, Benefit Application, and References. No change to Policy Statement.

Medical Policy Panel, September 2024

Medical Policy Group, September 2024 (11): Updates to Description, Key Points, and References. No change to Policy Statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.