CAM 70175

Cryosurgical Ablation of Primary or Metastatic Liver Tumors

Category:Surgery   Last Reviewed:January 2019
Department(s):Medical Affairs   Next Review:January 2020
Original Date:December 2000    

Description:
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.

For individuals who have unresectable primary hepatocellular carcinoma amenable to locoregional therapy who receive CSA, the evidence includes 1 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. Additional comparative evidence is needed to permit conclusions about the effectiveness of cryoablation compared with other locoregional therapies.  The evidence is insufficient to determine the effects of the technology on health outcomes.

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 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 the effects of the technology on health outcomes.

For individuals who have unresectable liver metastases from colorectal cancer amenable to locoregional therapy who have CSA, the evidence includes 1 RCT, a number of 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 the effects of the technology on health outcomes.

Background 
LIVER METATASES
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) 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.

Treatment 
Treatment of liver metastases is undertaken to reduce endocrine-related symptoms, in addition to prolonging survival and reducing symptoms related to the hepatic mass.

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 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.1. 2. 

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,3. 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, the EndocareCryocare System (Endocare, Irvine, CA) was cleared for marketing through the 510(k) process in December 1996 for “use in general surgery, dermatology, neurology, thoracic surgery, ENT [ears, nose, throat], gynecology, oncology, proctology and urology for the ablation of tissue, including liver metastases, skin lesions, warts and removal of prostate tissue.” Product code: GEH.

Related Policies
70191 Radiofrequency Ablation of Primary or Metastatic Liver Tumors
70192 Cryosurgical Ablation of Miscellaneous Solid Tumors Other Than Liver, Prostate or Dermatologic Tumors

70195 Radiofrequency Ablation of Miscellaneous Solid Tumors Excluding Liver Tumors
701133 Microwave Tumor Ablation
80103 Interferon Therapy
80111 Transcatheter Arterial Chemoembolization (TACE) to Treat Primary or Metastatic Liver Malignancies

80143 Radioembolization for Primary and Metastatic Tumors of the Liver 

Policy:
Cryosurgical ablation of either primary or metastatic tumors in the liver is INVESTIGATIONAL.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that certain U.S. Food and Drug Administration‒approved devices, drugs or biologics may not be considered investigational and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
The evidence review was created in December 2000 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through May 7, 2018.

This review was informed by a TEC Assessment (2000) that found insufficient data to permit conclusions on the effect of cryosurgery on health outcomes of patients with unresectable hepatocellular carcinoma (HCC), cholangiocarcinoma, or liver metastases.4.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

Hepatocellular Carcinoma 
Clinical Context and Therapy Purpose 
The purpose of cryosurgical ablation in patients who have unresectable primary HCC is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of cryosurgical ablation improve health outcomes for individuals with unresectable primary HCC?

The following PICOTS were used to select literature to inform this review. 

Patients 
The relevant population of interest is individuals with unresectable primary HCC amenable to locoregional therapy.

Interventions 
The therapy being considered is cryosurgical ablation. 

Comparators 
The following therapies are currently being used: radiofrequency ablation (RFA), microwave tumor ablation, and locoregional ablation other than RFA. 

Outcomes 
The general outcomes of interest are disease-free and overall survival. Other outcomes include recurrence rates, symptom reductions, and treatment-related adverse events. 

Timing 
In less than 20% of cases by some estimates can HCC be completely resected, so prognosis will vary by tumor stage at diagnosis. Estimates for disease-related mortality can range from 3 to 6 months, and sometimes longer. 

Setting 
Cryosurgical ablation is performed by a surgeon in an outpatient setting. 

Randomized Controlled Trials 
Wang et al (2015) reported on an RCT comparing cryoablation with RFA in 360 patients with HCC.5.  One hundred eighty treatment-naive patients with Child-Pugh class A or B cirrhosis and 1 or 2 HCC lesions 4 cm or less and without metastasis were randomized to each treatment group. Of the 360 patients enrolled, 310 patients were ineligible for surgical resection due to significant portal hypertension. The median follow-up for the cryoablation group was 25 months (range, 8-64 months) and 25 months (range, 5-65 months) for the RFA group (p=0.767). At 1, 2, and 3 years, local tumor progression rates were 3%, 7%, and 7% for cryoablation and 9%, 11%, and 11% for RFA, respectively (p=0.043). Overall survival (OS) rates at 1, 3, and 5 years for cryoablation were 97%, 67%, and 40%, and 97%, 66%, and 38% for RFA, respectively (p=0.747). Tumor-free survival rates at 1, 3, and 5 years were 89%, 54%, and 35% in the cryoablation group and 84%, 50%, and 34% in the RFA group, respectively (p=0.628). Major complications were experienced in 7 (3.9%) patients following cryoablation and in 6 (3.3%) patients following RFA (p=0.776).

Overall, trial strengths included its randomized design, a well-characterized patient population with few dropouts, intention-to-treat analysis, and evaluation of clinical outcomes. However, there did not appear to be an accounting of the disposition of all patients approached for enrollment. Additionally, there was a suboptimal randomization scheme, lack of allocation concealment, and some evidence for noncomparability of groups at baseline. The lack of any local tumor progression after approximately 14 months (extrapolated from the graph) in either group seems unusual. 

Nonrandomized Comparative Studies 
Ei et al (2015) reported on outcomes for consecutive patients with primary HCC treated with cryotherapy (n=55) or RFA or microwave coagulation therapy (n=64) using prospectively collected data.6. The choice of locally ablative therapy was made by a multidisciplinary team based on the following criteria: cryoablation for tumors near major hepatic veins, hepatic hilum, secondary branches of the portal pedicles, or other organs; RFA or microwave coagulation therapy for tumors of 1 cm or less; and patient preference. Groups were similar at baseline, with the exception that patients treated with cryotherapy had larger median tumor size (2.5 cm vs 1.9 cm, p<0.001). Rates of short-term complications did not differ significantly between groups. Over a median follow-up of 25 months, local recurrence-free survival was nonsignificantly higher in the cryoablation group (80% vs 68%, p=0.20). In a multivariable model to predict local recurrence, receiving cryoablation was significantly associated reduced risk of recurrence (adjusted hazard ratio, 0.3; 95% confidence interval, 0.1 to 0.9; p=0.02). For tumors greater than 2 cm in diameter, the 2-year local recurrence rate was lower for patients treated with cryoablation (21% vs 56%, p=0.006).

In a smaller, retrospective comparative study including 42 patients with HCC and cirrhosis, Dunne et al (2014) reported on short-term safety outcomes after cryoablation or RFA.7. Twenty- five patients underwent 33 cryoablation procedures, and 22 patients underwent 30 RFA procedures; 5 patients underwent both cryoablation and RFA procedures. No significant differences were observed in the overall complication rates, complication rates by severity, or specific complication types by cryoablation and RFA groups. 

Noncomparative Studies 
Noncomparative studies and systematic reviews of these studies have reported on outcomes after the use of cryotherapy for HCC. Although these studies may provide useful information about complications and longer term recurrences after cryoablation, they do not provide evidence of the comparative effectiveness of cryotherapy.

In a Cochrane review, Awad et al (2009) evaluated cryotherapy for HCC, identifying 2 prospective cohort studies and 2 retrospective studies but no RCTs or quasi-RCTs.8.  This review antedates Wang (2015). Only 1 study could be considered for the assessment of benefit. In that study, Adam et al (2002) stratified results by both the type of hepatic malignancy (primary or secondary) and the intervention group (percutaneous cryotherapy or percutaneous RFA).9. Sixty-four patients were treated based on the random availability of probes: 31 patients received cryotherapy and 33 received RFA. Of all patients treated, 26 (84%) of 31 who had cryotherapy and 24 (73%) of 33 who had RFA developed a local recurrence, all within 1 year. The distribution of primary cancers was not specified. Among the HCC patients, rates of initial tumor ablation were similar after cryosurgery (65%) or RFA (76%), but local recurrences were more frequent after cryosurgery (38%) than after RFA (17%). Survival at 1 year did not differ by ablative technique (cryosurgery, 66% vs RFA, 61%). The trial did not include controls managed with an established alternative. Cochrane reviewers concluded that there was no evidence to recommend or refute cryotherapy in the treatment of patients with HCC.

Since the 2009 Cochrane review, several studies have reported on series of patients with HCC treated using cryoablation. Yang et al (2012) reported on 300 patients treated between 2003 and 2006 with percutaneous argon-helium cryoablation for HCC.10. Complete tumor ablation occurred in 185 tumors in 135 patients with mean tumor diameter of 5.6 cm, while 223 tumors in 165 patients with a mean tumor diameter of 7.2 cm were incompletely ablated (p<0.001). Serious complications occurred in 19 (6.3%) patients, including liver hemorrhage in 5 patients, cryoshock syndrome in 6 patients, gastric bleeding in 4 patients, liver abscess in 1 patient, and intestinal fistula in 1 patient. Liver failure resulted in the death of 2 patients. Patients with incomplete ablation received additional treatment with transarterial catheter embolization or a multikinase inhibitor (sorafenib). During the median follow-up of 36.7 months (range, 6-63 months), the local tumor recurrence rate was 31%. Larger tumors and tumor location were significantly related to tumor recurrence (p=0.029 and 0.037, respectively). The OS rates were 80% at 1 year, 45% at 2 years, and 32% at 3 years.

Rong et al (2015) reported on longer term outcomes (median, 30.9 months) after cryoablation in a series of 866 patients with HCC treated at a single center in China.11. A total of 832 (96.1%) patients were considered to have a complete response after up to 3 cryoablation sessions. During follow-up, 502 (60.2%) patients with an initial complete response had a recurrence (n=99 11.9%. local, n=396 44.5%. distant intrahepatic, n=7 0.85. extrahepatic). Two hundred sixteen subjects died (mortality rate, 25.9%), corresponding to a 5-year OS rate of 59.5%.

In a study not included in the 2009 Cochrane review, Zhou et al (2009) categorized 124 patients with primary nonresectable HCC into early, middle, and advanced stage groups using Barcelona Clinic Liver Cancer staging classification.12.  After argon-helium cryoablation, the serum level of a-fetoprotein was reduced in 76 (82.6%), and 205 (92.3%) of 222 tumor lesions were diminished or unchanged. Median survival time was 31.35 months in the early-stage, 17.4 months in the middle-stage, and 6.8 months in the late-stage groups. As of April 2008, 14 patients had survived and 110 had died. To determine risk factors that predict metastasis and recurrence, Wang et al (2009) also studied a series of 156 patients with hepatitis B virus-related HCC and tumors smaller than 5 cm in diameter who underwent curative cryoablation.13.  One-, 2-, and 3-year OS rates were 92%, 82%, and 64%, respectively, and 1-, 2-, and 3-year recurrence-free survival rates were 72%, 56%, and 43%, respectively. The multivariate analysis showed that Child-Pugh class and expression of vascular endothelial growth factor in HCC tissues could be used as independent prognostic factors for OS. The expression of vascular endothelial growth factor in HCC tissues and hepatitis B virus basal core promoter variants were independent prognostic factors for recurrence-free survival. 

Section Summary: Hepatocellular Carcinoma 
The available RCT comparing cryoablation with 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 to RFA, trial limitations would suggest findings need to be replicated. Additional comparative evidence is needed to permit conclusions about the effectiveness of cryoablation compared with other locoregional therapies. 

Neuroendocrine Cancer Liver Metastases 
Neuroendocrine tumors are relatively slow-growing malignancies (mean survival time, 5-10 years) that commonly metastasize to the liver. As with other cancers, the most successful treatment of hepatic metastasis is resection with tumor-free margins, but treatment benefits for a slow-growing tumor must be weighed against the morbidity and mortality of major surgery.14. The intent of cryosurgery in these cases is to minimize or eliminate symptoms caused by liver metastases while avoiding the complications of open surgery.

Clinical Context and Therapy Purpose 
The purpose of cryosurgical ablation in patients who have unresectable liver metastases from neuroendocrine tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of cryosurgical ablation improve health outcomes for individuals with unresectable liver metastases from neuroendocrine tumors?

The following PICOTS were used to select literature to inform this review. 

Patients 
The relevant population of interest is individuals with unresectable liver metastases from neuroendocrine tumors amenable to locoregional therapy. 

Interventions 
The therapy being considered is cryosurgical ablation. 

Comparators 
The following therapies are currently being used: RFA, microwave tumor ablation, and locoregional ablation other than RFA. 

Outcomes 
The general outcomes of interest are disease-free and OS. Other outcomes include recurrence rates, symptom reductions, and treatment-related adverse events. Unlike other liver metastases, neuroendocrine tumors metastatic to the liver may cause systemic symptoms, including palpitations, flushing, and diarrhea, secondary to the release of neuropeptides. 

Timing 
Given the nature of neuroendocrine tumors, treatment outcomes can be measured over a 5- to 10-year period. 

Setting 
Cryosurgical ablation is performed by a surgeon in an outpatient setting. 

Systematic Reviews 
A Cochrane review by Gurusamy et al (2009) compared the benefits and harms of liver resection with those of other treatments in patients who had resectable liver metastases from gastro-entero-pancreatic neuroendocrine tumors.15. Trials comparing liver resection (alone or in combination with RFA or cryoablation) with other interventions (chemotherapy, hormonotherapy, or immunotherapy) and studies comparing liver resection with thermal ablation (RFA or cryoablation) were sought. Cochrane reviewers reported finding that none of the RCTs suitable for review nor any quasi-randomized, cohort, or case-control studies “could inform meaningfully.” No analysis was performed, and reviewers referred to only RFA in their discussion, noting that radiofrequency is not suitable for large tumors (ie, >5-6 cm), and that neuroendocrine liver metastases are frequently larger than that. They concluded that randomized trials comparing surgical resection with RFA in selected patients would be appropriate. 

Cohort Studies 
Saxena et al (2012) retrospectively reviewed data on 40 patients treated with cryoablation and surgical resection for hepatic metastases from neuroendocrine cancer.16. The median period of follow-up was 61 months (range, 1-162 months). One death occurred within 30 days of treatment. No other complications were reported. Median survival was 95 months, and the rate of survival was 92%, 73%, 61% and 40% at 1, 3, 5, and 10 years, respectively.

Chung et al (2001) reported on outcomes of cryosurgery for hepatic metastases from neuroendocrine cancer.17. This study used cytoreduction (resection, cryosurgery, RFA, or a combination of the three) and adjuvant therapy (octreotide, chemotherapy, radiotherapy, interferon-a) in 31 patients with neuroendocrine metastases to the liver and “progressive symptoms refractory to conventional therapy.” Following treatment, symptoms were eliminated in 87% of patients; median symptom-free interval was 60 months with octreotide and 16 months with alternatives. Because outcomes were not reported separately for different cytoreductive techniques, it was not possible to compare the benefits of cryosurgery with those of other cytoreductive approaches or octreotide alone. 

Section Summary: Neuroendocrine Cancer Liver Metastases 
The available evidence for unresectable liver metastases from neuroendocrine tumors amenable to locoregional therapy is very limited. Current evidence does not permit conclusions on whether this technology effects health outcomes. 

Liver Metastases From colorectal cancer 
Although multiple tumor types metastasize to the liver, colorectal cancer (CRC) is particularly likely to metastasize to the liver and has been the focus of the bulk of the literature on cryoablation for non-neuroendocrine tumor liver metastases.

Clinical Context and Therapy Purpose 
The purpose of cryosurgical ablation in patients who have unresectable liver metastases from CRC is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does use of cryosurgical ablation improve health outcomes for individuals with unresectable liver metastases from CRC?

The following PICOTS were used to select literature to inform this review.

Patients 
The relevant population of interest is individuals with unresectable liver metastases from CRC amenable to locoregional therapy. 

Interventions 
The therapy being considered is cryosurgical ablation. 

Comparators 
The following therapies are currently being used: RFA, microwave tumor ablation, and locoregional ablation other than RFA. 

Outcomes 
The general outcomes of interest are disease-free and OS. Other outcomes include recurrence rates, symptom reductions, and treatment-related adverse events. 

Timing 
In less than 20% of cases by some estimates can liver metastases from CRC be completely resected, so prognosis will vary by tumor stage at diagnosis. Estimates for disease-related mortality can range up to 2 years, with subsets of populations surviving 5 to 10 years. 

Setting 
Cryosurgical ablation is performed by a surgeon in an outpatient setting. 

Systematic Reviews 
A Cochrane review by Al-Asfoor et al (2008) compared outcomes of resection of CRC liver metastases with no intervention or other treatment modalities, including RFA and cryosurgery.18. Only RCTs reporting on patients who had curative surgery for adenocarcinoma of the colon or rectum, who had been diagnosed with liver metastases, and who were eligible for liver resection were considered. Only 1 randomized trial by Korpan (1997) was identified, a trial from the Ukraine that compared surgical resection with cryosurgery in 123 subjects, 82 of whom had liver metastases from primary CRCs and the remainder who had metastases from other primary tumors.19. Survival outcomes were not provided by type of cryogenic procedure or primary tumor site. Cochrane reviewers concluded that local ablative therapies were probably useful but that the therapy would need further evaluation in an RCT. A Cochrane review by Bale et al (2013) examined cryoablation for liver metastases from various sites, primarily colorectal.20. Only the Korpan RCT,19. included in the 2008 Cochrane review, met inclusion criteria. The Korpan trial was considered to have a high risk of bias, and reviewers found the available evidence was insufficient to determine whether there were any benefits with cryoablation over conventional surgery or no intervention.

A Cochrane review by Gurusamy et al (2010) compared liver resection (alone or in combination with RFA or cryoablation) with nonsurgical treatments (neoadjuvant chemotherapy, chemotherapy, or RFA) in patients with colorectal liver metastases and hepatic node involvement.21. No RCTs, quasi-randomized trials, or cohort studies were identified to address this clinical scenario.

Pathak et al (2011) reported on a systematic review of ablative therapies for CRC liver metastases.22. They selected 26 nonrandomized studies on cryoablation. Reviewers reported local recurrence rates in the studies ranging from 12% to 39%. Survival rates ranged from 46% to 92% at 1 year, 8% to 60% at 3 years, and 0% to 44% at 5 years. Mean survival rates at 1, 3, and 5 years were 84%, 37%, and 17%, respectively. Major complications ranged from 7% to 66%. Cryoshock was indicated to be of major concern. 

Case Series 
A few studies have compared cryotherapy with other treatments for liver metastases. Ruers et al (2007) reported on a consecutive series of 201 CRC patients, without extrahepatic disease, treated between 1995 and 2004 and who underwent laparotomy for surgical treatment of liver metastases.23. These patients were prospectively followed for survival and quality of life. During laparotomy, 3 groups were identified: patients in whom radical resection of metastases proved feasible, patients in whom resection was not feasible and received local ablative therapy (with or without resection), and patients in whom resection or local ablation was not feasible for technical reasons and who received systemic chemotherapy. The study reported that patients in the chemotherapy and local ablation groups were comparable for all prognostic variables tested. For the local ablation group, OS rates at 2 and 5 years were 56% and 27%, respectively (median, 31 months; n=45); for the chemotherapy group, 51% and 15%, respectively (median, 26 months; n=39; p=0.252). After resection, these rates were 83% and 51%, respectively (median, 61 months; n=117; p<0.001). Median disease-free survival (DFS) after local ablation was 9 months. The authors concluded that although OS of local ablation vs chemotherapy was not statistically significant, median DFS of 9 months suggested a beneficial effect of local tumor ablation. However, given the heterogeneity of the groups in this study, it is very difficult to compare outcomes among groups. Additionally, this study used both cryotherapy and RFA for local ablation, and results were reported for the combined group further limiting interpretation of specific results in cryoablation.

Niu et al (2007) analyzed data collected prospectively for 415 patients who underwent hepatic resection for metastatic CRC with or without cryoablation from 1990 to 2006.24. A decision about resectability was determined at the time of surgery. Patients who had resections and cryoablation were more likely to have bilobar disease (85% vs 27%, respectively) and to have 6 or more lesions (35% vs 3%, respectively). Additionally, 73% of this combined treatment group received hepatic arterial chemotherapy compared with 32% in the resection-only group. Median follow-up was 25 months (range, 1-124 months). The 30-day perioperative mortality rate was 3.1%. For the resection group, the median survival was 34 months, with 1-, 3-, and 5-year survival values rates of 88%, 47%, and 32%, respectively. The median survival for the resection plus cryotherapy group was 29 months, with 1-, 3-, and 5-year survival rates of 84%, 43%, and 24%, respectively (p=0.206). The overall recurrence rate was 66% for resection only, but 78% for resection plus cryotherapy. Five factors were independently associated with an improved survival: absence of extrahepatic disease at diagnosis, well- or moderately differentiated CRC, lesion size of 4 cm or less, a postoperative carcinoembryonic antigen of 5 ng/mL or less, and absence of liver recurrence. While the recurrence rates between groups did not differ, it is unclear how representative the patients who had resection plus cryotherapy were of the total sample of 415 patients. The comparability of the 2 groups is uncertain, especially given the differential use of hepatic arterial chemotherapy. In this study, a direct comparison was not made with chemotherapy. Finally, the 16-year duration of the study raises concerns about intercurrent changes that could have had affected the results.

In a relatively small study, Joosten et al (2005) reported on 58 patients with unresectable colorectal liver metastases where cryosurgical ablation or RFA was performed on patients ineligible for resection.25. Median follow-up was 26 and 25 months for cryosurgical ablation and RFA, respectively. One- and 2-year survival rates were 76% and 61% for cryosurgical ablation and 93% and 75% for RFA, respectively. In a lesion-based analysis, the local recurrence rate was 9% after cryosurgical ablation and 6% after RFA. Complication rates were 30% and 11% after cryosurgical ablation and RFA, respectively (p=0.052). While the small size of this study makes drawing conclusions difficult, results raise questions about the relative efficacy of both techniques.

A number of series have reported on outcomes for cryoablation for liver metastases from CRC. Summarized here are some of the larger and more recent series. Ng et al (2012) conducted a retrospective review of 293 patients treated between 1990 and 2009 for colorectal liver metastases with cryoablation with or without surgical resection.26. Perioperative death occurred in 10 (3%) patients and included liver abscess sepsis in 4 patients, cardiac events unrelated to treatment in 3 patients, and 1 case each of dilated cardiomyopathy, cerebrovascular event, and multiorgan failure. Median follow-up was 28 months (range, 0.1-220 months). OS rates were 87%, 41.8%, 24.2%, and 13.3% at 1, 3, 5, and 10 years, respectively.

Seifert et al (2005) reported on a series of patients with colorectal liver metastases treated from 1996 to 2002.27. In this series, 168 patients underwent resection, and 55 had cryosurgical ablation (in 25 of these patients, it was combined with resection). Twenty-nine percent (16/55) of the ablation group had prior liver resection compared with only 5% in the resection group. Twenty percent of both groups had extrahepatic disease at the time of surgery. With a median follow-up of 23 months, median and 5-year survival rates following resection and cryotherapy were comparable, with 29 months and 29 months and 23% and 26%, respectively. However, the median DFS times and 5-year DFS rates following resection were superior at 10 months and 19%, respectively, for resection compared with 6 months and 12%, respectively, for cryotherapy. Overall recurrence was 61% in the resection group and 76% in the cryotherapy group and liver recurrence was 45% and 71%, respectively. Study limitations included the small sample size, limited follow-up, and noncomparability of the groups.

Kornprat et al (2007) reported on thermoablation combined with resection in the treatment of hepatic metastasis from CRC.28. In this series, from 1998 to 2003, 665 patients with colorectal metastases underwent hepatic resection. Of these, 39 (5.9%) had additional intraoperative thermoablative procedures (19 RFA, 20 cryosurgical ablation). The overall morbidity rate was 41% (16/39). No RFA-related complications occurred; however, 3 patients developed an abscess at cryoablation sites. The median DFS was 12.3 months (range, 8.4-16.2 months). The local in situ recurrence rate according to the number of ablated tumors was 14% for RFA and 12% for cryosurgical ablation. Tumor size correlated directly with recurrence (p=0.02) in RFA- treated lesions.

Xu et al (2008) reported on a series of 326 patients with nonresectable hepatic colorectal metastases treated with 526 percutaneous cryosurgery procedures.29. At 3 months posttreatment, carcinoembryonic antigen levels decreased to the normal range in 197 (77.5%) of patients who had elevated markers before cryosurgery. Among 280 patients who had computed tomography follow-up, cryo-treated lesions showed complete response in 41 (14.6%) patients, partial response in 115 (41.1%), stable disease in 68 (24.3%), and disease progression in 56 (20%). During a median follow-up of 32 months (range, 7-61 months), the recurrence rate was 47.2%. The recurrence rate at the cryo-treated site was 6.4% for all cases. During median follow-up of 36 months, the median survival of all patients was 29 months (range, 3-62 months). OS rates were 78%, 62%, 41%, 34%, and 23% at 1, 2, 3, 4, and 5 years, respectively, after treatment. For patients with tumor sizes smaller than 3 cm, tumors in the right lobe of the liver, carcinoembryonic antigen levels less than 100 ng/dL, and post-cryosurgery transcatheter arterial chemoembolization had higher survival rates. 

Section Summary: Liver Metastases From CRC 
The available RCT comparing surgical resection with cryoablation was judged to be 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 on the effectiveness of cryoablation compared with other locoregional therapies. 

Summary of Evidence 
For individuals who have unresectable primary hepatocellular carcinoma amenable to locoregional therapy who receive CSA, 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. Additional comparative evidence is needed to permit conclusions about the effectiveness of cryoablation compared with other locoregional therapies. The evidence is insufficient to determine the effects of the technology on health outcomes. 

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 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 the effects of the technology on health outcomes.

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 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 the effects of the technology on health outcomes.

Clinical Input From Physician Specialty Societies and Academic Medical Centers 
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 2 physician specialty societies and 3 academic medical centers while this policy was under review in 2008. All reviewers supported the use of cryoablation for liver tumors and, in general, cited the studies reviewed in the Rationale section. Some reviewers considered cryoablation as one of several ablative techniques that could be used in these patients. 

Practice Guidelines and Position Statements 
The National Comprehensive Cancer Network (NCCN) indicates that ablative techniques may be used in the treatment of certain hepatic tumors. NCCN guidelines on hepatobiliary cancer (v.2.2018) 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.30. For hepatocellular carcinoma, 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 (radiofrequency, cryoablation, percutaneous alcohol injection, microwave):

  • 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 or systemic therapy.
  • Sorafenib should not be used as adjuvant therapy post-ablation.”

For intrahepatic cholangiocarcinoma (isolated intrahepatic mass), the guidelines recommend locoregional therapy using arterially directed therapies or external-beam radiotherapy (category 2B recommendations).

NCCN guidelines on neuroendocrine and adrenal tumors (v.2.2018) address the use of hepatic- directed therapies for patients with unresectable hepatic-predominant progressive metastatic neuroendocrine.31. These guidelines support consideration of ablative therapies such as RFA or cryoablation if near-complete tumor burden can be achieved (category 2B recommendation).

NCCN guidelines on the treatment of colon cancer with liver metastases (v.2.2018) 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” (category 2A recommendations).32. 

U.S. Preventive Services Task Force Recommendations 
Not applicable. 

Ongoing and Unpublished Clinical Trials 
A search of ClinicalTrials.gov in May 2018 did not identify any ongoing or unpublished trials that would likely influence this review. 

References:

  1. Li Z, Fu Y, Li Q, et al. Cryoablation plus chemotherapy in colorectal cancer patients with liver metastases. Tumour Biol. Nov 2014;35(11):10841-10848. PMID 25081377
  2. 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
  3. 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
  4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Cryosurgical Ablation of Unresectable Hepatic Tumors. TEC Assessments. 2000;Volume 15:Tab 14.
  5. 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. PMID 25284802
  6. 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. PMID 25287439
  7. 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. PMID 24529593
  8. Awad T, Thorlund K, Gluud C. Cryotherapy for hepatocellular carcinoma. Cochrane Database Syst Rev. Oct 07 2009(4):CD007611. PMID 19821432
  9. Adam R, Hagopian EJ, Linhares M, et al. A comparison of percutaneous cryosurgery and percutaneous radiofrequency for unresectable hepatic malignancies. Arch Surg. Dec 2002;137(12):1332-1339; discussion 1340. PMID 12470093
  10. Yang Y, Wang C, Lu Y, et al. Outcomes of ultrasound-guided percutaneous argon-helium cryoablation of hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. Dec 21 2012;19(6):674- 684. PMID 22187145
  11. 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. PMID 25849963 
  12. Zhou L, Yang YP, Feng YY, et al. Efficacy of argon-helium cryosurgical ablation on primary hepatocellular carcinoma: a pilot clinical study. Ai Zheng. Jan 2009;28(1):45-48. PMID 19448416
  13. Wang C, Lu Y, Chen Y, et al. Prognostic factors and recurrence of hepatitis B-related hepatocellular carcinoma after argon-helium cryoablation: a prospective study. Clin Exp Metastasis. Sep 26 2009;26(7):839-848. PMID 19784786
  14. Jaeck D, Oussoultzoglou E, Bachellier P, et al. Hepatic metastases of gastroenteropancreatic neuroendocrine tumors: safe hepatic surgery. World J Surg. Jun 2001;25(6):689-692. PMID 11376398
  15. 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
  16. 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. PMID 21654315
  17. 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):954-962. PMID 11742323
  18. 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
  19. Korpan NN. Hepatic cryosurgery for liver metastases. Long-term follow-up. Ann Surg. Feb 1997;225(2):193-201. PMID 9065296
  20. Bala MM, Riemsma RP, Wolff R, et al. Cryotherapy for liver metastases. Cochrane Database Syst Rev. Jun 05 2013;6(6):CD009058. PMID 23740609
  21. 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
  22. 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. PMID 21689362
  23. 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):1161-1169. PMID 17195903
  24. 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):2078-2087. PMID 17473951
  25. 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):1152-1159. PMID 16126363 
  26. 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. PMID 21913018
  27. Seifert JK, Springer A, Baier P, et al. Liver resection or cryotherapy for colorectal liver metastases: a prospective case control study. Int J Colorectal Dis. Nov 2005;20(6):507-520. PMID 15973545
  28. 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):1087-1092. PMID 18025338
  29. Xu KC, Niu LZ, He WB, et al. Percutaneous cryosurgery for the treatment of hepatic colorectal metastases. World J Gastroenterol. Mar 07 2008;14(9):1430-1436. PMID 18322961
  30. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 2.2018. https://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed June 8, 2018.
  31. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 2.2018. https://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf. Accessed June 8, 2018.
  32. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2018. https://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed June 8, 2018.

Coding Section

Codes Number Description
CPT 47371 Laparoscopy, surgical, ablation of 1 or more liver tumors(s); cryosurgical
  47381 Ablation, open, 1 or more liver tumor(s); cryosurgical
  47383 Ablation, 1 or more liver tumor(s), percutaneous, cryoablation (new code 01/01/15)
  76940 Ultrasound guidance for, and monitoring of, parenchymal tissue ablation
ICD-9 Procedure 50.23 Open ablation of liver lesion or tissue
  50.24 Percutaneous ablation of liver lesion or tissue
  50.25 laparoscopic ablation of liver lesion or tissue
  50.29 Other destruction of lesion of liver
ICD-9 Diagnosis 155.0 Malignant neoplasm of liver
  C78.7197.7 Secondary malignant neoplasm; liver
ICD-10-CM (effective 10/01/15) C22.0-C22.9 Malignant neoplasm of liver and intrahepatic bile duct
  C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct
ICD-10-PCS (effective 10/01/15)  0F500ZZ Surgical, hepatobiliary system and pancreas, destruction, liver, open
  0F503ZZ Medical & Surgical hepatobiliary system and pancreas destruction liver
  0F504ZZ Medical & Surgical hepatobiliary system and pancreas destruction liver percutaneous endoscopic
Type of Service Surgery  
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

01/17/2019 

Annual review, no change to policy intent. Updating background, rationale and references. 

02/13/2018

Annual review, no change to policy intent. Updating background, description, rationale and references. 

01/03/2017 

Annual review, no change to policy intent. Updating background to correct typo. 

01/28/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. Adding benefit applications and regulatory status. 

11/30/2015 

Changing review date for continuity issues. 

12/22/2014

Annual review, no change to policy intent. Updated description, related policies, rationale and references. Added coding.

12/3/2013

Annual review.  Updated rationale and references.  Also, added related policies. 


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