평가 배경 

간암 냉동제거술(Cryosurgical Ablation of Liver Cancer)은 간세포암 또는 전이성 간암의 종양 환자에서 종양을 초저온으로 얼려 파괴하는 치료법으로서, 신의료기술평가 제도가 도입되기 전인 행위 비급여로 등재(2006.12.1.)된 후, 2016년 11월 선별급여 본인부담률 80%로 전환되어 현재까지 사용되고 있다(보건복지부 고시 제2016-212호(2016.11.18.)). 해당 의료기술은 내부 모니터링을 통해 발굴된 주제로, 대상선별 임상자문회의 및 우선순위 심의에서 재평가 적합성 및 필요성을 인정받아 의료기술평가 대상으로 선정되었다. 2021년 제9차 의료기술재평가위원회(2021.9.10.)에서는 경피적, 복강경하, 개복술하 간암 냉동제거술에 대해 평가계획서 및 소위원회 구성을 심의하였다.

이에 간암 냉동제거술에 대해 안전성 및 효과성에 대한 과학적 근거를 제공하고, 의료기술의 적정 사용 등 정책적 의사결정을 지원하고자 간암 냉동제거술의 재평가를 수행하였다. 본 보고서에는 경피적 간암 냉동제거술에 대해 안전성 및 효과성에 대한 과학적 근거를 평가하고, 이를 제시하였다.

평가 방법

경피적 간암 냉동제거술에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “간암 냉동제거술 평가 소위원회(이하 ‘소위원회’라 한다)”의 심의를 거쳐 확정하였다. 소위원회는 소화기내과 2인, 외과 2인, 영상의학과 2인, 근거기반의학 1인의 전문가 7인으로 구성하였다. 

체계적 문헌고찰은 핵심질문을 토대로 국외 3개, 국내 5개 데이터베이스에서 검색하여 문헌선정 및 배제기준에 따라 두 명의 검토자가 독립적으로 선별하고 선택하였다. 문헌의 비뚤림위험 평가는 Risk of Bias와 Risk of Bias Assessment for Nonrandomized Studies를 사용하였으며 두 명의 검토자가 독립적으로 수행하여 의견합의를 이루었다. 자료추출은 미리 정해놓은 자료추출 양식을 활용하여 두 명의 검토자가 독립적으로 수행하였으며, 의견 불일치가 있을 경우 제3자와 함께 논의하여 합의하였다. 자료분석은 정량적 분석(quantitative analysis)과 정성적(qualitative review) 분석을 적용하였다. 체계적 문헌고찰 결과의 근거 수준은 Grading of Recommendations Assessment, Development and Evaluation (GRADE) 접근 방법으로 평가하였다.

평가 결과

체계적 문헌고찰을 통해 경피적 간암 냉동제거술의 안전성과 효과성은 총 9편(무작위배정 비교임상시험 3편, 비무작위 비교연구 6편)에 근거하여 평가하였다. 중재군 대상 환자 수는 총 649명으로, 한 편의 문헌을 제외한 8편에서는 원발성 간암 환자를 대상으로 하였으며 2015년 이후 문헌들에서 보고된 환자 선택기준은 암 크기가 1cm 이상 5cm 이하, 암 부위는 3개 이하였다. 선택문헌의 비뚤림위험 평과결과는 ‘낮음(Low)’이었다.

안전성

간암 환자를 대상으로 경피적 냉동제거술의 안전성은 8편의 비교연구(무작위배정 비교임상시험 3편, 비무작위 비교연구 5편)에서 보고한 주요 합병증 및 경미한 합병증으로 평가하였다. 

경피적 냉동제거술과 고주파열치료술을 비교한 무작위배정 비교임상시험에서 보고된 병적 상태가 심각하여 사망 또는 장기간의 입원으로 이어지는 주요 합병증 발생에 대해 메타분석한 결과 두 군간 유의한 차이가 없었다(3편; Relative Risk (RR) 1.07; 95% Confidence interval (CI) 0.57, 2.03; I2=0%). 이 연구들에서는 고열(2편), 치료 후 통증(1편), 무증상 흉수(1편), 복수 악화(1편), 기타(시술 장비 관련 1편) 등 경미한 합병증 발생이 보고되었으며, 치료 후 통증 발생은 중재군인 냉동제거술에서 유의하게 낮았으나 나머지 경미한 합병증은 군간 유의한 차이가 없었다. 비무작위 비교연구에서도  병적 상태가 심각하여 사망 또는 장기간의 입원으로 이어지는 주요 합병증 발생에 대해 메타분석한 결과 두 군간 유의한 차이가 없는 것으로 나타났다(4편; Odds Ratio (OR) 0.57; 95% CI 0.19, 1.68; I2=14%). 다수의 비무작위 비교연구에서 다빈도로 보고된 경미한 합병증 중 혈전증(3편; OR 0.62; 95% CI 0.23, 1.71; I2=0%), 혈소판 감소증(2편; OR 3.85; 95% CI 0.61, 24.34; I2=0%), 치료 후 통증(1편), 복수악화(1편), 기타(시술 장비 관련 2편) 경미한 합병증 발생이 군간 유의한 차이가 없었다. 메타분석 결과 담도 합병증(2편; OR 0.22; 95% CI 0.08, 0.61; I2=0%)은 중재군인 냉동제거술에서 유의하게 낮았다. 

경피적 냉동제거술과 극초단파열치료술을 비교한 비무작위 비교연구에서 보고한 간 출혈, 간농양, pleural abscess seeding, 배액이 필요한 혈흉, 배액이 필요한 흉수 등의 주요 합병증 발생에 있어 메타분석 결과 두 군간 유의한 차이가 없는 것으로 나타났다(2편; OR 0.51; 95% CI 0.06, 4.77; I2=47%). 경미한 합병증은 한 편의 연구에서 보고된 시술 후 열 및 통증 발생은 중재군에서 유의하게 낮았으나, 각각 1편의 개별 연구에서 혈전증, 혈소판 감소증, 흉막삼출, 기타 경미한 합병증은 두 군간 유의한 차이가 없는 것으로 보고하였다. 

효과성 

간암 환자를 대상으로 효과성은 생존율, 무병생존율, 무재발생존율, 국소종양진전을 기준으로 평가하였다. 이 중 무병생존율을 보고한 문헌은 한편도 없었다. 체계적 문헌고찰을 수행한 결과, 해당 의료기술의 임상적 효과성을 보고한 9편의 비교연구(무작위배정 비교임상시험 3편, 비무작위 비교연구 6편)를 확인할 수 있었다.

경피적 간암 냉동제거술과 고주파열치료술을 비교한 무작위배정 비교임상시험에서 5년 전체 생존율(2편; RR 1.00; 95% CI 0.82, 1.23; I2=0%), 무재발생존율(2편; RR 1.31; 95% CI 0.81, 2.12; I2=0%), 국소종양진전(3편; RR 0.91; 95% CI 0.56, 1.48; I2=61%)은 메타분석 결과 두 군간 유의한 차이가 없었다. 비무작위 비교연구에서도 전체 생존율(1편), 무재발생존율(1편), 국소종양진전(2편; OR 1.69; 95% CI 0.72, 3.95; I2=0%)에 두 군간 유의한 차이가 없었다.

경피적 간암 냉동제거술과 극초단파열치료술을 비교한 비무작위 비교연구에서 전체 생존율(1편), 무재발생존율(2편)은 두 군간 유의한 차이가 없는 것으로 보고하였으며 한편의 연구에서 냉동제거술군에서 국소종양진전이 유의하게 낮았다고 보고하였다.

결론 및 제언

소위원회에서는 현재 문헌적 근거를 토대로 다음과 같이 제언하였다. 

간암 환자에서 경피적 냉동제거술은 다른 국소치료술(고주파열치료술 또는 극초단파열치료술)과 유사한 수준의 합병증 발생률을 보이는 안전한 의료기술이며, 국소종양진전에 있어서는 좀 더 유리한 경향성을 보였으나 전체 생존율과 무재발생존율에서 다른 국소치료술과 효과성이 유사한 수준의 의료기술로 평가하였다.  

2022년 제4차 의료기술재평가위원회(2022.04.15.)에서는 소위원회 검토 결과에 근거하여 의료기술재평가사업 관리지침 제4조제10항에 의거 “경피적 간암 냉동제거술”에 대해 다음과 같이 심의하였다. 

의료기술재평가위원회는 간암 환자에게 적용한 경피적 간암 냉동제거술은 안전하고 효과적인 기술로 판단하여 ‘권고함’으로 심의하였다(권고등급: 권고함). 

주요어

간암, 경피적 냉동제거술, 고주파열치료술, 극초단파열치료술

Liver cancer, Percutaneous Cryoablation, Radiofrequency ablation, Microwave ablation

Background

 “Cryosurgical Ablation of Liver Cancer” is a treatment method that employs extremely low temperature to destroy cancerous tissue of tumors in patients with hepatocellular carcinoma or metastatic liver cancer. Before the New Health Technology Assessment system was introduced, the technology was listed as a non-reimbursable treatment act (December 1, 2006), and then the national health insurance coverage status of the technology was changed to selective benefit with out-of-pocket coverage at 80% in November 2016, and the technology has been used in clinical practice to date (Notice No. 2016-212, Ministry of Health and Welfare (November 18, 2016)). This health technology was identified through internal monitoring and its adequacy and necessity for reassessment was acknowledged through the process of clinical advisory meeting and priority review, and it was finally selected as a technology subject to health technology reassessment (HRT). At the 9th Health Technology Reassessment Committee (September 10, 2021) in 2021, the assessment protocol and organization of the Sub-committee were reviewed for percutaneous, laparoscopic, and open cryosurgical ablation of liver cancer.

Therefore, in order to establish scientific evidence for safety and effectiveness of cryosurgical ablation of liver cancer and support policy decision-making such as optimal application of the health technology, HRT was conducted for the health technology of cryosurgical ablation of liver cancer. In this report, scientific evidence for safety and effectiveness of percutaneous cryoablation of liver cancer was reviewed for assessment and the result was presented.

Methods

A systematic review of the related literature was conducted for assessment of the safety and effectiveness of percutaneous cryoablation of liver cancer. All assessment methods were finalized after review by the Cryosurgical Ablation of Liver Cancer Assessment Sub-committee (Hereinafter Sub-committee) in consideration of the purpose of the assessment. The Sub-committee consisted of a total of seven experts: two in Gastroenterology, two in General Surgery, two in Radiology, and one in Evidence-Based Medicine.

In the process of systematic review, based on the key question , three international and five domestic databases were used for literature search and the articles were selected based on independent screening by two reviewers according to the inclusion/exclusion criteria for the related literature. The Risk of Bias Assessment for Nonrandomized Studies tool was used for risk of bias assessment of the literature. For data extraction, a predefined format was used. Both the risk of bias assessment and data extraction  were conducted independently by two reviewers, and in case of disagreement, the two reviewers held discussions with a third party to draw consensus on the matter.

For methods of data analysis, quantitative analysis and qualitative review were applied. The evidence level of the results of systematic review was assessed using the approach of Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Results

Through the systematic review, safety and effectiveness of percutaneous cryoablation of liver cancer were evaluated based on a total of nine studies (three randomized controlled trials, six non-randomized controlled studies). The number of patients in the intervention group was 649 in total, and in eight studies apart from one study, the participants were patients with primary liver cancer. In studies conducted after 2015, the inclusion criteria of the patients reported in the articles was size of tumor ≤ 5cm and the number of tumors ≤ 3. The result of risk of bias assessment of the selected literature was “Low.”

Safety

The safety of percutaneous cryoablation for liver cancer patients was evaluated with incidence of major complications and minor complications reported in eight comparative studies (three randomized controlled trials, five non-randomized controlled studies) as the outcome measures.

In randomized controlled trials comparing percutaneous cryoablation and radiofrequency ablation, results of meta-analysis showed that there was no significant difference between the two groups for major complications with serious morbidity resulting in deaths or prolonged hospital stay (Three articles; Relative Risk (RR) 1.07; 95% Confidence Interval (CI) 0.57, 2.03; I2=0%). In these studies, minor complications were reported such as sustained high fever (two articles), post-procedural pain (one article), asymptomatic pleural effusion (one article), worsening ascites (one article), and others (one article related to equipment used for the procedure). The incidence of post-procedural pain was significantly lower in the percutaneous cryoablation group, which is the intervention group, but there was no significant difference between the two groups in terms of other minor complications.  In non-randomized controlled studies, results of meta-analysis showed that there was no significant difference between the two groups for major complications with serious morbidity resulting in deaths or prolonged hospital stay (four articles; Odds Ratio (OR) 0.57; 95% CI 0.19, 1.68; I2=14%). Among minor complications frequently reported in a number of non-randomized controlled studies, thrombosis(three articles; OR 0.62; 95% CI 0.23, 1.71; I2=0%), thrombocytopenia(two articles; OR 3.85; 95% CI 0.61, 24.34; I2=0%), post-procedural pain (one article), worsening ascites(one article), and others (two articles related to equipment used for the procedure) showed no significant differences between the two groups. As a result of meta-analysis, incidence of biliary complications(two articles; OR 0.22; 95% CI 0.08, 0.61; I2=0%) was significantly lower in cryoablation group, which is the intervention group.

In non-randomized controlled studies comparing percutaneous cryoablation and microwave ablation, the results of meta-analysis showed that there was no significant difference between the two groups in terms of incidence of major complication such as hepatic hemorrhage, liver abscess formation, pleural abscess seeding, hemothorax requiring drainage, and pleural effusion requiring drainage (two articles; OR 0.51; 95% CI 0.06, 4.77; I2=47%). In terms of minor complications, in one study, the reported incidence of post-procedural fever and pain was significantly lower in the intervention group, but in individual studies with one article each, there was no significant difference between the two groups in terms of incidence of thrombosis, thrombocytopenia, pleural effusion, and other minor complications.  

Effectiveness

For liver cancer patients, effectiveness was evaluated with overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), and local tumor progression (LTP) as outcome measures. None of the literature reported DFS. As a result of systematic review, nine comparative studies (three randomized controlled trials, six non-randomized controlled studies) that reported the clinical effectiveness of the health technology were selected.

In randomized controlled trials that compared percutaneous cryoablation of liver cancer and radiofrequency ablation, as a result of meta-analysis, the 5-year OS (two articles; RR 1.00; 95% CI 0.82, 1.23; I2=0%), RFS(two articles; RR 1.31; 95% CI 0.81, 2.12; I2=0%), and LTP(three articles; RR 0.91; 95% CI 0.56, 1.48; I2=61%) showed no significant difference between the two groups. In non-randomized controlled studies, there was no significant difference between the two groups in terms of OS(one article), RFS(one article), and LTP(two articles; OR 1.69; 95% CI 0.72, 3.95; I2=0%)

In non-randomized controlled studies comparing percutaneous cryoablation of liver cancer and microwave ablation, it was reported that there was no significant difference between the two groups in terms of OS (one article) and RFS(two articles), and in one study, the cryoablation group was reported to show a significantly lower LTP compared to the microwave ablation group.  

Conclusion and Suggestions

Based on the evidence from the selected literature, the Sub-committee suggested the following.

In liver cancer patients, the assessment concluded that percutaneous cryoablation is a safe health technology that shows a similar level of incidence of complications to other locoregional therapies (radiofrequency ablation or microwave ablation). It was assessed to show more favorable outcomes in terms of LTP, but in terms of OS and RFS, the assessment determined that the technology had a similar level of effectiveness to other locoregional therapies.

Based on the results of the review by the Sub-committee, at the 4th Health Technology Reassessment Committee (April 15, 2022) in 2022, the following is the result of the review for “Percutaneous Cryoablation of Liver Cancer” in accordance with Article 4, Paragraph 10 of the Management Guidelines for Health Technology Reassessment Project

The review of the Health Technology Reassessment Committee determined that the Grade of Recommendation for the percutaneous cryoablation of liver cancer applied for patients with liver cancer was “Recommend,” based on the assessment that the technology is safe and effective (Grade of Recommendation: Recommend).

Keywords

Liver cancer, Percutaneous Cryoablation, Radiofrequency ablation, Microwave  ablation

요약문 (국문) i

알기 쉬운 의료기술재평가 Ⅰ

Ⅰ. 서론 1

 1. 평가배경 1

  1.1 의료기술 개요 1

  1.2 국내외 보험 및 행위등재 현황 3

  1.3 질병 특성 및 현존하는 의료기술 4

  1.4 국내외 임상진료지침 6

  1.5 체계적 문헌고찰 현황 6

 2. 평가목적 7

Ⅱ. 평가 방법 8

 1. 체계적 문헌고찰 8

  1.1 개요 8

  1.2 핵심질문 8

  1.3 문헌검색 9

  1.4 문헌선정 10

  1.5 비뚤림위험 평가 11

  1.6 자료추출 11

  1.7 자료합성 11

  1.8 근거수준 평가 12

 2. 권고등급 결정 12

Ⅲ. 평가결과 13

 1. 문헌선정 결과 13

  1.1 문헌선정 개요 13

  1.2 선택문헌 특성 14

  1.3 비뚤림위험 평가 결과 18

 2. 분석 결과 20

  2.1 안전성 20

  2.2 효과성 27

  2.3 GRADE 근거 평가 34

Ⅳ. 결과요약 및 결론 39

 1. 평가결과 요약 39

  1.1 안전성 39

  1.2 효과성 40

 2. 결론 40

Ⅴ. 참고문헌 42

Ⅵ. 부록 43

 1. 의료기술재평가위원회 43

 2. 소위원회 44

 3. 문헌검색현황 45

 4. 비뚤림위험 평가 및 자료추출 양식 49

 5. 최종선택문헌  52