신장암 냉동제거술

Abstract

평가배경 “신장암 냉동제거술”은 신장암에 대한 일차적 치료 및 재수술 치료를 목적으로, 아르곤 가스와 헬륨 가스를 냉동프로브에 삽입하여 동결/해동 주기를 통해 암조직을 파괴하는 의료기술이다. 국내에서는 신의료기술평가제도가 확립되기 이전인 2005년에 비급여로 등재되었으며, 이후 2011년 건강보험 보장성 강화 정책에 따라 급여로 전환되어 임상에서 사용하고 있다. 해당 의료기술은 행위 급여 항목 중에 과거 유관기관 수요조사에서 저가치 기술로 제기된 바 있어, 내부 모니터링을 통해 재평가 주제로 발굴하였으며, 재평가 대상선별을 위한 임상자문회의와 우선순위 심의를 거쳐 2022년 제8차 의료기술재평가위원회(‘22.8.12.)에서 재평가 대상으로 최종 선정하였다. 본 평가의 목적은 신장암 환자에서 냉동제거술의 안전성 및 효과성 등에 대한 의과학적 근거평가를 통해 의료기술의 적정사용 등을 지원하고자 하였다.

평가방법 신장암 냉동제거술에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “냉동제거술 통합 소위원회(이하 ‘소위원회’라 한다)”의 심의를 거쳐 확정하였다. 소위원회 구성은 비뇨의학과 2인, 신장내과 1인, 종양내과 1인, 영상의학과 3인, 흉부외과 2인, 호흡기내과 1인, 근거기반의학 2인 전문가로 구성하였다. 평가의 핵심질문은 “신장암 환자에서 냉동제거술은 임상적으로 안전하고 효과적인가?”이었고 안전성은 시술 관련 합병증을, 효과성은 종양학적 결과, 신장기능, 환자 관련 결과 지표로 평가하였다. 체계적 문헌고찰은 핵심질문을 토대로 국외 3개, 국내 5개 데이터베이스에서 검색하였으며, 문헌선정 및 배제기준에 따라 두 명의 검토자가 독립적으로 선별하고 선택하였다. 문헌의 비뚤림위험 평가는 Risk of Bias for Nonrandomized Studies (RoBANS Ver 2.0)을 사용하였고, 자료추출은 미리 정해놓은 자료추출 양식을 활용하였다. 문헌의 비뚤림위험 평가와 자료추출은 모두 두 명의 검토자가 독립적으로 수행하였으며, 의견 불일치가 있을 경우 논의하여 합의하였다. 자료분석은 질적 검토(qualitative review) 및 정량적 분석(quantitative analysis)을 수행하였다.

평가결과 체계적 문헌고찰 결과, 안전성 및 효과성 평가는 총 19편(후향적 코호트 연구 18편, 전향적 코호트 연구1편)을 토대로 검토하였다. 선택문헌의 연구대상자는 종양크기가 대부분 3cm 또는 4cm미만의 작은 신장암 환자로, 비교기술은 부분 신절제술(partial nephrectomy), 고주파 열치료술(radiofrequency ablation)이었다. 비뚤림위험은 비무작위 비교연구에서 선택비뚤림 관련 ‘대상군 비교가능성’, ‘대상군 선정’ 항목과 ‘교란변수’ 및 ‘평가자의 눈가림’ 항목의 비뚤림 위험이 다소 높거나 불확실로 평가하였다.

안전성 안전성은 총 14편을 토대로, 시술 관련 합병증, 시술 후 재원기간, 혈액손실 지표를 검토하였다. 시술 관련 합병증으로는 요 누출, 요관 손상, 신 주위 농양 등의 비뇨생식계 관련 문제, 호흡기계(기흉, 폐렴 등), 혈전증, 출혈, 장 손상과 같은 기관·장기 손상 등의 사례 등이 확인되었으며, 전체 합병증과 중증도 분류(Clavien-Dindo grade)에 따라 중대한(major), 경미한(minor) 합병증으로 구분하여 살펴보았다. 부분 신절제술과 비교한 연구에서 전체 합병증(11편)은 신장암 냉동제거술군이 더 낮게 발생하는 경향이 있으나 통계적으로 유의하지 않았다(오즈비(Odds ratio, OR) 0.64, 95% 신뢰구간(Confidence interval, CI) 0.41-1.01, I2=75%, p=0.06). 중대한 합병증(5편) 및 경미한 합병증(5편)에서도 두 군간의 유의한 차이는 없었다. 고주파 열치료술과 비교한 연구에서 전체 합병증(2편)은 신장암 냉동제거술군에서 낮게 발생하는 경향이 있으나 두 군간의 유의한 차이는 없었다(OR 0.56, 95% CI 0.26-1.23, I2=0%, p=0.15). 중대한 합병증 및 경미한 합병증은 1편에서 보고되었고, 두 군간 유의한 차이는 없었다. 시술 후 재원기간은 총 12편에서 보고하였으며, 신장암 냉동제거술은 부분 신절제술과 비교시(11편) 대부분의 연구에서 재원기간이 짧거나 유사하였고, 고주파 열치료술(1편)과는 유의한 차이가 없었다. 추정된 혈액손실은 총 5편에서 보고하였으며, 신장암 냉동제거술은 부분 신절제술에 비해 혈액손실량은 유의하게 적었다.

효과성 효과성은 총 16편을 토대로 i) 종양학적 의료결과로 생존, 재발, 전이, 시술성공(technical success : 사전에 계획한 종양의 완전 소작), ii) 신 기능(추정 사구체여과율(estimated Glomerular Filtration Rate, eGFR)) 감소, 혈청 크레아티닌 증가, 말기신장질환 발생), iii) 환자 결과(진통제 사용 등)를 검토하였다. 생존 결과는 총 5편에서 보고하였으며, 전체 생존율, 무질병 생존율, 암특이 생존율, 무재발 생존율로 세분화하여 결과 지표를 확인하였다. 부분 신절제술의 비교는 총 4편에서 보고하였고, 전체생존율(4편)은 신장암 냉동제거술군 82-96.6%, 비교군 86-100%로 모든 연구에서 군간의 유의한 차이는 없었다. 5년 무질병 생존율(2편)은 중재군 64-93%, 비교군 92-96%로 1편은 중재군에서 유의하게 낮았고, 다른 1편은 군간 차이는 없었다. 2-7년 암특이 생존율(2편), 무재발 생존율(2편)은 중재군은 각 82-93%, 83-92%, 비교군은 100%로 중재군에서 낮았다. 고주파 열치료술의 비교는 총 1편에서 보고하였고, 전체 생존율 및 암특이 생존율은 신장암 냉동제거술군 각 94.4%, 98%, 비교군은 각 100%이었다. 재발은 총 14편에서 보고하였다. 메타분석한 결과, 신장암 냉동제거술은 부분 신절제술과 비교시(11편) 재발 발생은 냉동제거술군에서 유의하게 높았고(OR 5.12, 95% CI 1.34-19.55, I2=53%, p=0.02), 고주파 열치료술과 비교시(3편) 냉동제거술군에서 재발 발생이 낮았으나, 통계적으로 유의하지 않았다(OR 0.55, 95% CI 0.10-3.08, I2=74%, p=0.14). 전이는 부분 신절제술과 비교한 총 5편에서 보고하였으며, 신장암 냉동제거술군에서 비교적 많이 발생하였으나 통계적으로 유의하지 않았다(OR 3.37, 95% 0.57-19.92, I2=48%, p=0.18). 시술성공은 고주파 열치료술과 비교한 총 2편에서 보고하였으며, 신장암 냉동제거술군에서 완전소작율이 높았으나, 통계적으로 유의하지 않았다(OR 1.49, 95% CI 0.66-3.34, I2=0%, p=0.34). 신기능은 총 11편에서 보고하였다. 부분 신절제술과의 비교시(10편), eGFR 감소(4편) 및 혈청 크레아티닌 증가(6편)는 1편을 제외한 대부분 연구에서 두 군간의 차이는 없었다. 고주파 열치료술과 비교된 1편에서는 두 군 모두 시술전후 유의한 차이는 없었다. 환자결과는 총 2편에서 보고하였다. 부분 신절제술과 비교시(1편) 진통제 사용은 군간의 차이는 없었다. 고주파 열치료술과 비교시(1편) 환자만족도는 군간의 차이는 없었으며, 진통제 사용 및 완전회복/업무 복귀에 소요되는 시간은 비교군에서 적거나 짧았다.

경제성 총 4편에서 신장암 냉동제거술의 경제성과 관련된 결과를 보고하였다. 모든 연구는 미국에서 수행된 연구로 메디케어(Medicare) 자료 또는 병원자료를 바탕으로 치료방법에 따른 의료비용을 확인하였다. 신장암 냉동제거술은 대체로 경피적 방법의 냉동제거술, 고주파 열치료술 보다는 의료비용은 높았고, 외과적 부분 신절제술(복강경하 포함)과 비교한 경우 의료비용은 낮거나 유사하였고, 외과적 고주파 열치료술과는 유사하였다.

결론 및 제언 소위원회는 현재 문헌에 근거하여 “신장암 냉동제거술”의 안전성 및 효과성 결과를 다음과 같이 제시하였다. 신장암 냉동제거술은 부분 신절제술, 고주파 열치료술과 비교하여 전체적으로 합병증 발생이 적거나 유사하였고, 시술 후 입원기간은 짧거나 유사한 것으로 보고되어 안전한 의료기술로 판단하였다. 신장암 냉동제거술의 효과성은 재발, 전이 측면에서 냉동제거술이 부분 신절제술보다 치료성적이 좋지 않았으나, 유사한 수준의 전체 생존, 신장 기능 결과를 나타내었다. 다른 국소치료법인 고주파 열치료술과는 유사한 수준의 생존 및 시술성공 등의 종양학적 결과, 신장기능 결과를 보였다. 이에 소위원회에서는 신장암의 국소치료로 사용되는 신장암 냉동제거술은 표준 수술치료인 부분 신절제술보다 재발 등 종양학적 결과의 치료성적이 좋지 않았으나, 다른 국소치료법 (고주파 열치료술)과 종양학적 결과 및 신장 기능 결과가 유사하여, 선택문헌의 연구대상자인 ‘4cm 미만의 작은 신장암 환자’에서 냉동제거술을 효과적인 의료기술로 평가하였다. 2023년 제3차 의료기술재평가위원회(2023.3.10.)에서는 소위원회 검토 결과에 근거하여 의료기술 재평가사업 관리지침 제4조제10항에 의거 “신장암 냉동제거술”에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 임상적 안전성과 효과성의 근거 및 그 외 평가항목 등을 종합적으로 고려하였을 때, 국내 임상상황에서 표준적 수술이 어려운 상태의 작은 신장암 환자를 대상으로 냉동제거술의 사용을 ‘조건부 권고함’으로 심의하였다.

주요어 신장암, 냉동제거술, 안전성, 효과성

Background Cryoablation of renal masses, a medical technology for destroying cancerous tissues through freeze/thaw cycles using argon or helium gas in a cryoprobe, is used for both primary and reoperation treatments of renal masses. In Korea, this health technology was listed as a non-benefit item in 2005, prior to the establishment of the new health technology assessment system. However, its status changed to a benefit item in 2011, following the expanded health insurance coverage policy and is now being used in clinical practice. This health technology. Although it was previously assessed as a low-value technology in a demand survey, it has been subjected to reassessment based on internal monitoring. The Clinical Advisory Board conducted reassessment candidate screening and a priority review, leading to the selection of this technology for reassessment during the eighth session of the Committee of Health Technology Reassessment in 2022 (on August 12, 2022). The aim of this reassessment is to provide support for the appropriate use of this health technology, based on medical and scientific evidence of its safety and effectiveness for patients with renal masses.

Methods The safety and effectiveness of cryoablation of renal masses were assessed through a systematic review. The methods for this assessment were finalized post-review by the “Integrated cryoablation subcommittee (hereafter referred to as the “Subcommittee”), with considerations for the assessment's purpose. This Subcommittee comprised experts in various fields: two from urology, one from nephrology, one from oncology, three from radiology, two from thoracic surgery, one from pulmonology, and two from evidence-based medicine. The central question of the assessment was, “Is cryoablation clinically safe and effective for patients with renal masses?” Safety was evaluated based on procedure-related complications, while effectiveness was measured through oncologic outcomes, renal function, and patient-related outcomes. For the literature review, three international and five domestic databases were searched based on the key question. Two reviewers independently screened and selected articles based on the inclusion and exclusion criteria. The Risk of Bias for Nonrandomized Studies (RoBANS Ver.2) was used for the risk of bias (RoB) assessment, and data extraction was done using a pre-determined format. The RoB assessment and data extraction were independently conducted by two reviewers, and any disagreements were resolved through discussion to reach a consensus. Data were analyzed both qualitatively and quantitatively.

Results In this systematic review, the focus was placed on the safety and effectiveness of cryoablation, examined through a total of 19 studies. This ensemble of research comprised 18 retrospective cohort studies and one prospective cohort study. The patient populations under study were specifically those presenting with small renal masses, measuring less than 3 or 4 cm. The comparative interventions employed in these studies were partial nephrectomy and radiofrequency ablation. Within the framework of the RoB assessment, particular attention was paid to the selection bias domain, which encompasses elements such as comparisons of target groups, the process of patient selection, the presence of confounding variables, and the extent of assessor blinding. In this realm, the RoB was deemed slightly high or uncertain, particularly in studies that were not randomized.

Safety The safety profile of cryoablation was meticulously evaluated across 14 studies, with specific focus on procedure-related complications, the length of hospital stay post-procedure, and the extent of blood loss. The spectrum of procedure-related complications investigated included genitourinary issues like urinary leakage, ureteral injury, and peri-renal abscess, as well as systemic or organ-specific complications such as respiratory issues (pneumothorax, pneumonia, etc.), thrombosis, bleeding, and bowel injury. These complications were further categorized into overall, major, and minor complications, following the established Clavien-Dindo grade classification system. In the comparative analysis with partial nephrectomy, the overall complications (n=11) in the cryoablation group tended to be lower, although this difference did not attain statistical significance (Odds ratio [OR]: 0.64, 95% confidence interval [CI]: 0.41-1.01, I2=75%, p=0.06). The comparison also extended to major (n=5) and minor complications (n=5), with no significant differences found between the two groups. Similarly, when cryoablation was compared with radiofrequency ablation, the overall complications (n=2) tended to be lower in the cryoablation group, yet without significant difference between the two groups (OR: 0.56, 95% CI: 0.26-1.23, I2=0%, p=0.15). Major and minor complications were reported in one study, which reported no significant difference between the two groups. In terms of hospital stay, as reported in 12 studies, the duration was generally shorter or similar in the cryoablation group when compared to the partial nephrectomy group (n=11), while one study reported no significant difference as compared to the radiofrequency ablation group (n=1). Additionally, the estimated blood loss was significantly less in the cryoablation group, as reported in five studies.

Effectiveness The effectiveness of cryoablation, explored in 16 studies, encompassed a range of outcomes: 1) oncologic outcomes, including survival, recurrence, metastasis, and procedural success (technical success: defined as the pre-planned complete ablation of the tumor); 2) renal function outcomes, monitored through changes in estimated glomerular filtration rate (eGFR) and serum creatinine (sCr) levels, as well as the onset of end-stage renal disease; and 3) patient outcomes, particularly analgesic use. The survival outcomes, as detailed in five studies, were examined by overall, disease-free, cancer-specific, and recurrence-free survival rates. In the comparison with partial nephrectomy, covered in four studies, the overall survival rates (n=4) in the cryoablation group ranged from 82% to 96.6%, compared to 86% to 100% in the control group, with all studies reporting no significant differences between the two groups. However, the 5-year disease-free survival rate (n=2) was 64-93% in the intervention group and 92-96% in the control group, showed more variability, with one study indicating a significantly lower 5-year disease-free survival rate in the intervention group and the other study reporting no significant difference between the two groups. The cancer-specific (n=2) and recurrence-free survival rates (n=2) over 2-7 years were also slightly lower in the cryoablation group compared to 100% in the control group. In a single study comparing cryoablation with radiofrequency ablation, the overall and cancer-specific survival rates of 94.4% and 98%, respectively, in the cryoablation of renal masses and 100% each in the control group. Recurrence, a key metric in oncological studies, was the subject of 14 studies. A meta-analysis indicated that recurrence was significantly higher in the cryoablation group compared to the partial nephrectomy group, but not significantly different when compared to the radiofrequency ablation group. Metastasis, reported in five studies comparing cryoablation with partial nephrectomy, showed a higher rate in the cryoablation group, but this difference was not statistically significant. Metastasis was reported in five studies that compared cryoablation of renal masses with partial nephrectomy. The results showed a higher rate of metastasis in the cryoablation of renal masses group, but the difference was not statistically significant (OR: 3.37, 95% CI: 0.57-19.92, I2=48%, p=0.18). Procedure success, compared in two studies with radiofrequency ablation, indicated a higher rate of complete ablation in the cryoablation group, yet without a significant difference (OR: 1.49, 95% CI: 0.66-3.34, I2=0%, p=0.34). A total of 11 studies reported on renal function. In comparisons between cryoablation and partial nephrectomy across 10 studies, four found a decrease in eGFR and six reported an increase in sCr levels, but most studies, except one, reported no difference between the two groups. One study comparing cryoablation with radiofrequency ablation, indicated no significant difference between before and after the procedure. Regarding patient outcomes, two studies were noted. One comparing cryoablation to partial nephrectomy showed no difference in analgesic use between the two groups. Another study, comparing cryoablation to radiofrequency ablation, found similar patient satisfaction in both groups. However, the control group reported less analgesic use and a shorter duration for recovery and return to work.

Cost-effectiveness In the realm of cost-effectiveness, an analytical review of four studies, all conducted in the United States, was undertaken to discern the economic implications of cryoablation for renal masses. These studies, grounded in data sourced from Medicare and hospital records, explored the financial impact of various treatment modalities. The economic evaluation revealed that cryoablation generally incurred higher costs than percutaneous cryoablation and radiofrequency ablation. However, when compared to surgical partial nephrectomy, including laparoscopic surgery, cryoablation presented a lower or similar cost profile. Additionally, the cost of cryoablation was found to be on par with that of surgical radiofrequency ablation.

Conclusions and recommendations The Subcommittee, after a comprehensive review of the current literature, presented a nuanced appraisal of the safety and effectiveness of cryoablation for renal masses. The safety assessment underscored cryoablation as a safe health technology, highlighting its lower or comparable rate of overall complications and a shorter or similar duration of hospital stay post-procedure, especially when juxtaposed with partial nephrectomy and radiofrequency ablation. In terms of effectiveness, the Subcommittee observed that cryoablation, while exhibiting slightly poorer treatment outcomes compared to partial nephrectomy, demonstrated comparable levels of overall survival and renal function. Furthermore, when compared to another local treatment method, radiofrequency ablation, cryoablation showed parallel outcomes in oncological metrics (including survival and procedural success) and renal function. Consequently, the Subcommittee concluded that although cryoablation, when utilized as a local treatment for renal masses, might exhibit certain limitations in treatment outcomes (notably in oncological outcomes and recurrence) compared to the standard surgical approach of partial nephrectomy, it still stands as an effective health technology. This conclusion is particularly pertinent for patients with small renal masses (less than 4 cm), the primary demographic in the selected studies, given its similar oncological and renal function outcomes compared to radiofrequency ablation. In the third session of the Committee of Health Technology Reassessment in 2023 (on March 10, 2023), deliberations, informed by the findings of the Subcommittee and aligning with Article 4-10 of the Guidelines for Management of Health Technology Reassessment were made. The Committee of Health Technology Reassessment “conditionally recommends” the use of cryoablation for patients with small renal masses, especially in cases where traditional surgical options are not viable, based on a thorough evaluation of the clinical safety, effectiveness, and other pertinent factors within the specific clinical context of Korea.

Keywords: Renal masses, Cryoablation, Safety, Effectiveness