간암 냉동제거술 - 개복술하

Abstract

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 개복술하 간암 냉동제거술에 대해 안전성 및 효과성에 대한 과학적 근거를 평가하고, 이를 제시하였다.

평가 방법 개복술하 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 Bias Assessment for Nonrandomized Studies를 사용하여 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 개복술하 간암 냉동제거술의 안전성과 효과성은 총 4편(비무작위 비교연구 4편)에 근거하여 평가하였다. 중재군 대상 환자 수는 총 372명으로, 2000년도 초반 연구 두 편에서는 원발성 및 전이성 간암 환자 중 종양 수 또는 위치에 따라 간 절제술이 불가능한 환자를 대상으로 하였다. 2015년 이후 문헌 2편은 원발성 간암 환자가 대상이었으며, 이 중 한편의 문헌에서 보고된 환자 선택기준은 암 크기 5cm 이하였다. 선택문헌의 비뚤림 위험평과 결과는 ‘낮음(Low)’이었다.

안전성 간암 환자를 대상으로 개복술하 냉동제거술의 안전성은 3편의 비교연구(비무작위 비교연구 3편)에서 보고한 합병증 발생률을 지표으로 평가하였다. 소위원회에서는 현재 냉동제거술에 사용되는 프로브는 초창기 문헌들에서 사용된 프로브와는 달라 동 기술의 안전성을 최근의 문헌에서 보고된 결과를 기준으로 평가하는 것이 합당하다는 의견이었다. 개복술하 냉동제거술과 고주파열치료술을 비교한 연구 중 한 편(2015년)의 연구에서는 주요 합병증 및 전체 합병증 발생에 있어 두 군간 유의한 차이가 없었으나, 다른 두 편(1999년, 2000년)의 연구에서는 합병증 발생률이 중재군에서 유의하게 높았다. 이러한 연구들을 메타분석 결과 합병증 발생에 있어 두 군간 유의한 차이는 없었다(2편; Odds Ratio (OR) 4.46; 95% Confidence interval (CI) 0.23, 87.32; I2=92%). 개복술하 냉동제거술과 극초단파열치료술을 비교한 1편의 개별 연구에서 주요 합병증 및 전체 합병증 발생에 있어 두 군간 유의한 차이가 없는 것으로 나타났다.

효과성 간암 환자를 대상으로 효과성은 생존율, 무병생존율, 무재발생존율, 국소종양진전을 지표로 평가하였다. 이 중 무병생존율을 보고한 문헌은 한편도 없었다. 체계적 문헌고찰을 수행한 결과, 해당 의료기술의 임상적 효과성을 보고하고 있는 4편의 비교연구(비무작위 비교연구 4편)를 확인할 수 있었다. 개복술하 냉동제거술과 고주파열치료술을 비교한 비무작위 비교연구에서 전체 생존율(1편), 무재발생존율(1편)은 두 군간 유의한 차이가 없다고 보고하였다. 국소종양진전을 보고한 2편의 연구 중 한편(2000년)의 연구에서는 두 군간 유의한 차이가 없었으나, 다른 한편(1999년)에서는 중재군에서 유의하게 높았다. 이러한 연구들을 메타분석 결과 두 군간 유의한 차이는 없었다(2편; OR 4.41; 95% CI 0.57, 33.94; I2=82%). 개복술하 냉동제거술과 극초단파열치료술을 비교한 비무작위 비교 연구에서 무재발생존율(1편)은 두 군간 유의한 차이가 없는 것으로 보고하였다. 전체 생존율과 국소종양진전을 보고한 문헌은 없었다.

결론 및 제언 소위원회에서는 현재 문헌적 근거를 토대로 다음과 같이 제언하였다. 간암 환자를 대상으로 시행한 개복술하 간암 냉동제거술은 다른 국소치료법(고주파열치료술 또는 극초단파열치료술)과 안전성을 비교한 3편에서의 결과가 일관되지 않았지만 가장 최신 문헌에서의 합병증 발생률이 중재군과 비교군(고주파열치료술)간 유의한 차이가 없었으며, 효과성도 전체 생존율, 무재발생존율, 국소종양진전에 있어 두 군간 유의한 차이는 없었다. 그러나 소위원회는 본 평가의 선택문헌에서의 중재법이 개복술하 간암 냉동제거술을 보고한 문헌이 1편, 복강경하/개복술하 간암 냉동제거술결과 구분이 불가능한 문헌이 1편, 경피적/복강경하/개복술하 간암 냉동제거술 결과 구분이 불가능한 문헌이 2편으로 현재 선택문헌만을 기준으로 개복술하 간암 냉동제거술의 안전성 및 효과성을 평가하기는 어렵다는 의견이었다. 다만, 소위원회에서는 1) 개복술하 간암 냉동제거술이 임상에서 단독으로 시술되기보다는 간 절제술시 함께 시행되는 점으로 미루어 봤을 때 앞으로도 개복술하 냉동제거술 단독 결과를 보고하는 문헌의 출판 가능성이 낮으며, 2) 경피적, 복강경하, 개복술하 간암 냉동제거술을 구분하지 않고 임상결과를 보고한 기존 문헌들을 비추어 볼 때 각 시술 경로별 중재법의 안전성과 효과성이 유사할 것으로 유추된다는 의견이다. 따라서 고주파열치료술, 극초단파열치료술과 같은 다른 국소치료법과 유사한 안전성과 효과성을 가진 의료기술로 판단한 경피적 간암 냉동제거술의 결과를 개복술하 간암 냉동제거술의 평가근거로 고려하는 것에 문제가 없다는 것이 소위원회의 추가적인 의견이다. 2022년 제5차 의료기술재평가위원회(2022.05.13.)에서는 소위원회 검토 결과에 근거하여 의료기술재평가사업 관리지침 제4조제10항에 의거 “개복술하 간암 냉동제거술”에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 개복술하 간암 냉동제거술이 임상에서 단독으로 시술되기보다는 간 절제술시 함께 수행되며, 다른 국소치료법과 유사한 안전성과 효과성을 가진 의료기술로 판단한 경피적 간암 냉동제거술의 결과를 개복술하 간암 냉동제거술의 평가근거로 고려하는 것에 문제가 없다는 소위원회 추가 의견을 바탕으로, 간암 환자에게 적용한 개복술하 간암 냉동제거술은 안전하고 효과적인 기술로 판단하여 ‘권고함’으로 심의하였다(권고등급: 권고함).

주요어 간암, 냉동제거술, 고주파열치료술, 극초단파열치료술

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 open cryosurgical ablation 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 open cryosurgical ablation 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 open cryosurgical ablation of liver cancer were evaluated based on a total of four studies (four articles on non-randomized controlled studies). The number of patients in the intervention group was 372 in total, and in two studies conducted in early 2000, the participants were those with unresectable carcinoma depending on the number or locations of the tumors, among patients with primary and metastatic liver cancer. In two studies conducted after 2015, the participants were patients with primary liver cancer, and the inclusion criteria of the patients reported in one of the article was size of tumor ≤ 5cm. The result of risk of bias assessment of the selected literature was “Low.”

Safety The safety of open cryoablation for liver cancer patients was evaluated with the complication rate reported in three comparative studies (three non-randomized controlled studies) as the outcome measure. The Sub-committee had the opinion that since the probes used in current technique of cryoablation are different from the probes used in publications in early stage, it would be reasonable to evaluate the safety of the technology based on the results reported from recent publications. In one study (2015) that compared open cryoablation and radiofrequency ablation, there was no significant difference between the two groups in the major complication rate and overall complication rate, but in the other two studies (1999, 2000), the complication rate was significantly higher in the intervention group. As a result of meta-analysis of these studies, there was no significant difference between the two groups in terms of the incidence of complications (two articles; Odds Ratio (OR) 4.46; 95% Confidence Interval (CI) 0.23, 87.32; I2=92%). In an individual study of one article comparing open cryoablation and microwave ablation, there was no significant difference between the two groups in terms of major complication rate and overall complication rate.

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, four comparative studies (four articles on non-randomized controlled studies) reporting the clinical effectiveness of the health technology were selected. Non-randomized controlled studies that compared open cryoablation and radiofrequency ablation reported no significant difference in OS (one article) and RFS (one article) between the two groups. Among the two studies that reported LTP, there was no significant difference between the two groups in one article (2000), but in the other article (1999), LTP was significantly higher in the intervention group. As a result of meta-analysis of these studies, there was no significant difference between the two groups (two articles; OR 4.41; 95% CI 0.57, 33.94; I2=82%). A non-randomized controlled study comparing open cryoablation and microwave ablation reported no significant difference in RFS (one article) between the two groups. There weas no published literature that reported OS and LTP between the two groups.

Conclusion and Suggestions Based on the evidence from the selected literature, the Sub-committee suggested the following. As a result of the assessment on the open cryoablation for liver cancer, the results from three articles that compared the safety with other locoregional therapies(radiofrequency ablation or microwave ablation) were not consistent. However, in the result reported by the most recently published literature, there was no significant difference in terms of complication rate between the intervention group and comparator group (radiofrequency ablation), and for assessment of effectiveness, there was no significant difference between the two groups in terms of OS, RFS, and LTP. Nevertheless, the Subcommittee was of the opinion that as for the intervention method used in the selected literature, there was one article that reported on open cryoablation for liver cancer, another article in which the differentiation of the outcomes between the laparoscopic/open cryoablation for liver cancer was not possible, and two articles in which the differentiation of the outcomes between the percutaneous/laparoscopic/open cryoablation for liver cancer was not possible. Therefore, it was considered that based on the articles selected in the present report only, it was difficult to perform the assessment of safety and effectiveness of the open cryoablation for liver cancer. Also, the Sub-committee has come to a consensus as follows: 1) Considering that open cryoablation for liver cancer is performed in combination with liver resection rather than on its own in clinical practice, it is considered unlikely that a paper reporting the outcomes of open cryoablation as a single mode of treatment will be published. 2) Considering that previous studies have reported clinical outcomes without differentiating between percutaneous, laparoscopic, or open cryosurgical ablation of liver cancer, it is inferred that the safety and effectiveness of the respective intervention method will be similar to each other. Therefore, the additional opinion of the Sub-committee is that there is no problem to consider the outcome of percutaneous cryosurgical ablation of liver cancer, which is determined as health technology with similar safety and effectiveness to those of other locoregional therapies such as radiofrequency ablation or microwave ablation, as the evidence for assessment of open cryosurgical ablation of liver cancer. Based on the results of the review by the Sub-committee, 5th Health Technology Reassessment Committee (May 13, 2022), the following is the result of the review for “Open Cryosurgical Ablation of Liver Cancer” in accordance with Article 4, Paragraph 10 of the Management Guidelines for Health Technology Reassessment Project. Based on the additional opinion of the Sub-committee that 1) open cryosurgical ablation of liver cancer is performed in combination with surgical resection rather than on its own in clinical practice and that 2) there is no problem to consider the outcome of percutaneous cryosurgical ablation of liver cancer, which is determined as health technology with similar safety and effectiveness to those of other locoregional therapies, as the evidence for assessment of open cryosurgical ablation of liver cancer, the review of the Health Technology Reassessment Committee determined that the Grade of Recommendation for the open cryosurgical ablation 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, Cryoablation, Radiofrequency ablation, Microwave ablation