Cryosurgical Ablation of Primary or Metastatic Liver Tumors

Policy Number: MA 1.121

Effective Date 9/1/2025

Policy

Cryosurgical ablation of either primary or metastatic tumors in the liver is considered investigational. There is insufficient evidence to support a general conclusion concerning the health outcomes of benefits associated with these procedures.

Cross-References:

• MP 1.088 Cryosurgical Ablation of Miscellaneous Solid Tumors other than Liver, Prostate or Dermatologic Tumors
• MP 1.055 Radiofrequency Ablation of Primary or Metastatic Liver Tumors
• MP 1.084 Radiofrequency Ablation of Miscellaneous Solid Tumors, Excluding Liver Tumors

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations as discussed in Section VI. Please see additional information below.

FEP PPO – Refer to FEP Medical Policy Manual. The FEP Medical Policy manual can be found at: https://www.fepblue.org/benefit-plans/medical-policies-and-utilization-management-guidelines/medical-policies

Description/background

Hepatic tumors can be primary or metastatic. 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 carcinoma (CRC) given the propensity of CRC to metastasize to the liver and the 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.

Treatment

Treatment of liver tumors is done to reduce endocrine-related symptoms, as well as prolong survival and reduce symptoms related to the hepatic mass.

Surgical resection with tumor-free margins or 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, 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 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 HCC.

Various ablative therapies for unresectable liver tumors have been evaluated: cryosurgical, radiofrequency (RFA), microwave ablation (MWA), and laser. Other therapies include transhepatic arterial embolization, chemoembolization, or radioembolization with yttrium-90 microspheres; microwave coagulation; and percutaneous ethanol injection.

Guided cryoablation via many imaging methods induces ice-ball formation and tumor necrosis and is an attractive option for treating unresectable liver tumors. There are several advantages to using cryoablation for the treatment of liver cancer: it can be performed percutaneously, intraoperatively, and laparoscopically; ice-ball formation can be monitored; it has little impact on nearby large blood vessels; and it induces a cryo-immunological response in situ.

Clinically, primary research has shown that percutaneous cryoablation of liver cancer is relatively safe and efficient, and it can be combined with other methods, such as radiation therapy, chemotherapy, and immunology, to control disease.

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.

Regulatory status

Several cryosurgical devices have been cleared by the U.S. Food and Drug Administration (FDA). For example, in 1996, the Endocare™ Cryocare System (Endocare) was cleared for marketing through the 510(k) process. Its 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.

Description/background

Hepatic tumors can be primary or metastatic. 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 carcinoma (CRC) given the propensity of CRC to metastasize to the liver and the 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.

Treatment

Treatment of liver tumors is done to reduce endocrine-related symptoms, as well as prolong survival and reduce symptoms related to the hepatic mass. Surgical resection with tumor-free margins or 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, 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 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 HCC.

Various ablative therapies for unresectable liver tumors have been evaluated: cryosurgical, radiofrequency (RFA), microwave ablation (MWA), and laser. Other therapies include transhepatic arterial embolization, chemoembolization, or radioembolization with yttrium-90 microspheres; microwave coagulation; and percutaneous ethanol injection.

Guided cryoablation via many imaging methods induces ice-ball formation and tumor necrosis and is an attractive option for treating unresectable liver tumors. There are several advantages to using cryoablation for the treatment of liver cancer: it can be performed percutaneously, intraoperatively, and laparoscopically; ice-ball formation can be monitored; it has little impact on nearby large blood vessels; and it induces a cryo-immunological response in situ.

Clinically, primary research has shown that percutaneous cryoablation of liver cancer is relatively safe and efficient, and it can be combined with other methods, such as radiation therapy, chemotherapy, and immunology, to control disease.

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.

Regulatory status

Several cryosurgical devices have been cleared by the U.S. Food and Drug Administration (FDA). For example, in 1996, the Endocare™ Cryocare System (Endocare) was cleared for marketing through the 510(k) process. Its 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.

Rationale

Summary of evidence

For individuals who have unresectable primary HCC amenable to locoregional therapy who receive cryosurgical ablation, the evidence includes a randomized controlled trial (RCT), several nonrandomized comparative studies, and multiple noncomparative studies. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The available RCT comparing cryoablation with radiofrequency ablation 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. 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 cryosurgical ablation, the evidence includes a Cochrane review and case series. Relevant outcomes are overall survival, 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 cryosurgical ablation, the evidence includes an RCT, several nonrandomized comparative and noncomparative studies, and systematic reviews of these studies. Relevant outcomes are overall survival, disease-specific survival, and treatment-related mortality and morbidity. The available RCT comparing surgical resection with cryoablation was judged at 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.

Definitions

• Denaturation: A change in conditions (temperature, addition of a substance) that causes irreversible change in a protein's structure, usually resulting in precipitation of the protein.
• Extrahepatic: Refers to outside or unrelated to the liver.
• Hepatic: Pertains to the liver.
• Hyperthermia: Refers to the use of microwave or radiofrequency energy to increase body temperature.
• Metastasis: The movement of body cells (esp. cancer cells) from one part of the body to another.
• Neuroendocrine malignancies: A diverse group of tumors, such as carcinoid, islet cell tumors, neuroblastoma, and small-cell carcinomas of the lung.
• Percutaneous: That which is passed or affected through the skin.

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as required by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These policies are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the members’ benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding information

Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement. The codes need to be in numerical order.

Investigational, and therefore not covered:

References

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2. 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): 1579-90. PMID 25284802
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. PMID 33960697
4. 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. PMID 31844951
5. 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. PMID 33297809
6. 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. PMID 32850395
7. 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): 1294-300. PMID 25287439
8. 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): 632-8. PMID 24529593
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11. 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): 674-84. PMID 22187145
12. Rong G, Bai W, Dong Z, et al. Long-term outcomes of percutaneous cryoablation for patients with hepatocellular carcinoma within Milan criteria. PLoS One. 2015; 10(4): e0123065. PMID 25849963
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16. Gurusamy KS, Ramamoorthy R, Sharma D, et al. Liver resection versus other treatments for neuroendocrine tumours in patients with resectable liver metastases. Cochrane Database Syst Rev. Apr 15, 2009; (2): CD007060. PMID 19370671
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18. Chung MH, Pisegna J, Spirt M, et al. Hepatic cytoreduction followed by a novel long-acting somatostatin analog: a paradigm for intractable neuroendocrine tumors metastatic to the liver. Surgery. Dec 2001; 130(6): 954-62. PMID 11742323
19. Al-Asfoor A, Fedorowicz Z, Lodge M. Resection versus no intervention or other surgical interventions for colorectal cancer liver metastases. Cochrane Database Syst Rev. Apr 16, 2008; (2): CD006039. PMID 18425932
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22. Gurusamy KS, Ramamoorthy R, Imber C, et al. Surgical resection versus non-surgical treatment for hepatic node positive patients with colorectal liver metastases. Cochrane Database Syst Rev. Jan 20, 2010; (1): CD006797. PMID 20091607
23. Pathak S, Jones R, Tang JM, et al. Ablative therapies for colorectal liver metastases: a systematic review. Colorectal Dis. Sep 2011; 13(9): e252-65. PMID 21689362
24. Ruers TJ, Joosten JJ, Wiering B, et al. Comparison between local ablative therapy and chemotherapy for non-resectable colorectal liver metastases: a prospective study. Ann Surg Oncol. Mar 2007; 14(3): 1161-9. PMID 17195903
25. Niu R, Yan TD, Zhu JC, et al. Recurrence and survival outcomes after hepatic resection with or without cryotherapy for liver metastases from colorectal carcinoma. Ann Surg Oncol. Jul 2007; 14(7): 2078-87. PMID 17473951
26. Joosten J, Jager G, Oyen W, et al. Cryosurgery and radiofrequency ablation for unresectable colorectal liver metastases. Eur J Surg Oncol. Dec 2005; 31(10): 1152-9. PMID 16126363
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29. Kornprat P, Jarnagin WR, DeMatteo RP, et al. Role of intraoperative thermoablation combined with resection in the treatment of hepatic metastasis from colorectal cancer. Arch Surg. Nov 2007; 142(11): 1087-92. PMID 18025338
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31. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hepatocellular Carcinoma. Version 3.2024.
32. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 1.2024.
33. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 5.2024.
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35. 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. PMID 28230008
36. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Cryosurgical Ablation of Unresectable Hepatic Tumors. TEC Assessments. 2000; Volume 15: Tab 14.
37. Sohn RL, Carlin AM, Steffes C, et al. The extent of cryosurgery increases the complication rate after hepatic cryoablation. Am Surg. Apr 2003; 69(4): 317-322; discussion 322-313. PMID 12716090
38. Shiina S, Sato K, Tateishi R, et al. Percutaneous Ablation for Hepatocellular Carcinoma: Comparison of Various Ablation Techniques and Surgery. Can J Gastroenterol Hepatol. 2018 Jun 3, 2018: 4756147. PMID 29974040.
39. Abdalla E, Stuart K. Overview of treatment approaches for hepatocellular carcinoma.
40. InterQual® Level of Care Criteria 2020. CP: Procedures: Ablation or Transarterial Therapy, Liver.
41. Curley S, Stuart K, Schwartz J, et al. Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates who are eligible for local ablation. UpToDate Online Updated October 31, 2024. Literature review through Oct 2024.
42. Shiina S, Sato K, Tateishi R, Shimizu M, Ohama H, Hatanaka T, Takawa M, Nagamatsu H, Imai Y. Percutaneous Ablation for Hepatocellular Carcinoma: Comparison of Various Ablation Techniques and Surgery. Can J Gastroenterol Hepatol. 2018 Jun 3; 2018: 4756147. doi: 10.1155/2018/4756147. PMID: 29974040; PMCID: PMC6008833.
43. Nault J, Sutter O, Nahon P, et al. Percutaneous Treatment of Hepatocellular Carcinoma: State of the Art and Innovations. J Hepatol. 2018 Apr; 68(4): 783-797. PMID 29031662.
44. Chen Z, Meng L, Zhang J, Zhang X. Progress in the cryoablation and cryoimmunotherapy for tumor. Front Immunol. 2023; 14: 1094009. Published 2023 Jan 25. doi: 10.3389/fimmu.2023.1094009. PMID: 36761748
45. Niu LZ, Li JL, Xu KC. Percutaneous Cryoablation for Liver Cancer. J Clin Transl Hepatol. 2014; 2(3): 182-188. doi: 10.14218/JCTH.2014.00017. PMID: 26355719
46. Kwak K, Yu B, Lewandowski RJ, Kim DH. Recent progress in cryoablation cancer therapy and nanoparticles mediated cryoablation. Theranostics. 2022; 12(5): 2175-2204. Published 2022 Feb 14. doi: 10.7150/thno.67530. PMID: 35265206
47. Blue Cross Blue Shield Association Medical Policy Reference Manual. 7.01.75, Cryosurgical Ablation of Primary or Metastatic Liver Tumors. October 2024.

Policy History

• MA 1.121 - MA version created policy; Complete Adoption.

Health care benefit programs issued or administered by Capital Blue Cross and/or its subsidiaries, Capital Advantage Insurance Company^®, Capital Advantage Assurance Company^® and Keystone Health Plan^® Central. Independent licensees of the Blue Cross BlueShield Association. Communications issued by Capital Blue Cross in its capacity as administrator of programs and provider relations for all companies.