신장암 경피적 냉동제거술

Abstract

평가배경 “신장암 경피적 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 경피적 냉동제거술의 안전성 및 효과성 등에 대한 의과학적 근거평가를 통해 의료기술의 적정사용 등을 지원하고자 하였다.

평가방법 신장암 경피적 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 경피적 냉동제거술은 임상적으로 안전하고 효과적인가?”이었고 안전성은 시술관련 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 RoBANS ver 2.0을 사용하여 진행하였으며, 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 40편(연구수 36편) (후향적 코호트 연구 39편, 전향적 코호트 연구1편)을 토대로 검토하였다. 선택문헌의 연구대상자는 종양크기가 대부분 3cm 또는 4cm 미만의 작은 신장암 환자로, 비교기술은 부분 신절제술(Partial Nephrectomy), 고주파 열치료술(Radiofrequency ablation), 초단파소작술(Microwave ablation), 능동감시(Active surveillance)였다. 비뚤림위험은 비무작위 비교연구에서 선택비뚤림 관련 ‘대상군 비교가능성’, ‘대상군 선정’ 항목과 ‘교란변수’ 및 ‘평가자의 눈가림’ 항목의 비뚤림 위험이 다소 높거나 불확실로 평가하였다.

안전성 안전성은 총 28편을 토대로, 시술 관련 합병증, 시술 후 재원기간 지표를 검토하였다. 시술 관련 합병증으로는 출혈/혈종, 요 누출, 농양, 정맥혈전색전증, 패혈증 등을 확인하였고, 전체 합병증과 중증도 분류(Clavien-Dindo grade, SIR 분류 등)에 따라 중대한(major), 경미한(minor) 합병증으로 구분하여 살펴보았다. 부분 신절제술과 비교한 연구(12편)에서 전체 합병증(9편)은 신장암 경피적 냉동제거술군에서 낮게 발생하는 경향이 있었으나(오즈비(Odds ratio, OR) 0.80, 95% 신뢰구간(Confidence interval, CI) 0.58-1.10, I2=13%, p=0.17), 두 군간 유의한 차이는 없었다. 중대한 합병증(11편) 및 경미한 합병증(10편)에서도 중재군이 덜 발생하였으나 두 군간의 유의한 차이는 없었다. 고주파 열치료술과 비교한 연구(15편)에서 전체 합병증(9편; OR 0.97, 95% CI 0.69-1.36, I2=3%, p=0.86), 경미한 합병증(9편; OR 0.89, 95% CI 0.61-1.28, I2=0%, p=0.52)은 두 군간의 유의한 차이는 없었다. 중대한 합병증(11편)은 신장암 경피적 냉동제거술군에서 발생오즈비가 유의하게 높았다(OR 1.68, 95% CI 1.11-2.53, I2=0%, p=0.01). 초단파소작술과 비교한 연구(6편)에서 전체 합병증(3편; OR 1.30, 95% CI 0.76-2.24, I2=0%, p=0.33), 중대한 합병증(6편; OR 0.97, 95% CI 0.47-2.02, I2=0%, p=0.94), 경미한 합병증(2편; OR 1.46, 95% CI 0.52-4.10, I2=0%, p=0.47)은 두 군간 유의한 차이는 없었다. 시술 후 재원기간은 총 12편에서 보고하였고, 부분 신절제술(7편) 및 초단파소작술(1편)과 비교시 경피적 냉동제거술군이 유의하게 재원기간이 짧았으며, 고주파 열치료술(5편)과는 대부분 유사하였다.

효과성 효과성은 총 34편을 토대로 i) 종양학적 의료결과로 생존, 재발, 전이, 시술성공(technical success, primary efficacy), 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 19편에서 보고하였으며, 전체 생존율, 무재발 생존율, 무전이 생존율, 암특이 생존율, 무질병 생존율, 무진행 생존율, 치료무실패 생존율 지표로 세분화하여 결과 지표를 확인하였다. 부분 신절제술과의 비교는 총 11편에서 확인하였고, 5년 시점의 결과로 전체생존율(6편)은 신장암 경피적 냉동제거술군 56-91.7%, 비교군 78-98.9%, 무재발 생존율(7편)은 중재군 85-98.5%, 비교군 93-98.7%, 무전이 생존율(3편)은 중재군 90-100%, 비교군 94-100%, 암특이 생존율(4편)은 중재군 91-100%, 비교군 98-100%, 무질병 생존율(1편)은 중재군 79.5%, 비교군 92.8%로 경피적 냉동제거술군에서 낮거나 유사하였다. 고주파 열치료술과의 비교는 총 12편에서 확인하였고, 5년 시점의 결과로 전체생존율(4편)은 신장암 경피적 냉동제거술군 87.8-98.5%, 비교군 79.4-95.7%, 무전이 생존율(2편)은 중재군 96.7-100%, 비교군 92.3-97.3%, 암특이 생존율(3편)은 중재군 96.4-100%, 비교군 92.3-100%, 무질병 생존율(1편)은 중재군 79.5%, 비교군 80.8%로 유사하였다. 초단파소작술과의 비교는 총 2편에서 확인하였고, 3년 전체생존율 및 무재발 생존율 결과는 두 군간유의한 차이는 없었다. 능동감시와의 비교는 총 1편에서 확인하였고, 5년 시점의 전체생존율, 암특이 생존율, 치료무실패 생존율 지표에서 두 군간 유의한 차이는 없었다. 재발은 총 18편에서 보고하였다. 부분 신절제술(7편), 초단파소작술(3편)과 비교시 신장암 경피적 냉동제거술군에서 재발 발생 오즈비가 높은 경향이 있었으나 통계적으로 유의하지 않았고(부분 신절제술과 비교시 OR 2.03, 95% CI 0.87-4.75, I2=75%, p=0.10 / 초단파소작술과 비교시 OR 2.48, 95% CI 0.74-8.30, I2=14%, p=0.14), 고주파 열치료술과의 비교시(11편) 냉동제거술군에서 재발 발생의 오즈값이 낮았으나 통계적으로 유의하지 않았다(OR 0.68. 95% CI 0.46-1.01, I2=0%, p=0.05). 전이는 총 3편에서 보고하였다. 부분 신절제술(2편) 및 고주파 열치료술(1편)과 비교시 전이 발생에 두 군간 유의한 차이는 없었다. 시술성공은 총 13편에서 보고하였다. 완전소작(technical success)은 고주파 열치료술(8편) 및 초단파소작술(4편)과 비교시 군간의 유의한 차이는 없었다. 일차 성공률(primary efficacy rate)은 고주파 열치료술 (3편)보다는 높았으나 통계적으로 유의하지는 않았다. 초단파소작술(2편)과 비교시 1편은 중재군에서 낮았고, 다른 1편은 군간 차이는 없었다. 신기능은 총 16편에서 보고하였다. 부분 신절제술과의 비교한 9편 중 3편은 비교군에서 유의한 eGFR 감소를, 3편은 중재군에서 eGFR 유의한 감소 및 sCr 증가를 보고하였고, 그 외 다수 연구(5편)에서는 두 군간의 차이는 없는 것으로 나타났다. 고주파 열치료술(10편), 초단파소작술(4편)과 비교한 대부분의 연구에서 eGFR 및 sCr 변화량은 두 군간 차이는 없었다. 환자결과는 총 4편에서 보고하였다. 진정제 사용은 고주파 열치료술과 비교한 4편 중 2편은 중재군에서 낮았고, 다른 2편은 군간의 차이가 없었으며, 초단파소작술과 비교한 1편에서는 중재군에서 많이 사용하였다. 환자만족도 및 완전 회복까지 복귀시간(1편)은 고주파 열치료술과 유의한 차이는 없었고, 업무 복귀 소요시간은 비교군에서 짧았다.

경제성 총 7편에서 신장암 경피적 냉동제거술의 경제성과 관련된 결과를 보고하였다. 모든 연구는 미국에서 수행된 연구로 메디케어(Medicare) 자료 또는 병원자료를 바탕으로 치료방법에 따른 의료비용을 확인하였다. 대부분 연구에서 신장암 경피적 냉동제거술은 부분 신절제술(개복하 부분 신절제술, 로봇 보조 복강경 부분 신절제술)과 비교하여 저렴한 비용으로 수행가능한 효과적인 기술로 제시하였다.

결론 및 제언 소위원회는 현재 문헌에 근거하여 “신장암 경피적 냉동제거술”의 안전성 및 효과성 결과를 다음과 같이 제시하였다. 신장암 경피적 냉동제거술은 고주파 열치료술과 비교시 중대한 합병증이 중재군에서 비교적 높게 발생하였으나, 그 외 부분 신절제술, 초단파소작술과 비교하여 합병증 발생에 유의한 차이가 없었고, 시술 후 입원기간은 짧거나 유사한 수준으로 보고되어 안전한 의료기술로 판단하였다. 신장암 경피적 냉동제거술의 효과성은 생존, 재발 측면에서 경피적 냉동제거술이 부분 신절제술보다 치료성적이 좋지 않은 경향이 있었으나 통계적으로 유의하지 않았고, 유사한 수준의 신장 기능 결과를 나타내었다. 다른 국소치료법에 해당되는 고주파 열치료술, 초단파소작술과는 유사한 수준의 생존 및 시술성공 등의 종양학적 결과, 신장기능 결과를 보였다. 이에 소위원회에서는 신장암의 국소치료로 사용되는 신장암 경피적 냉동제거술은 표준 수술치료인 부분 신절제술 보다는 종양학적 결과의 치료성적이 좋지 않았으나, 다른 국소치료법(고주파 열치료술, 초단파소작술)과 종양학적 결과 및 신장 기능 결과가 유사하여, 선택문헌의 연구대상자인 ‘4cm 미만의 작은 신장암 환자’에서 경피적 냉동제거술을 효과적인 의료기술로 평가하였다. 2023년 제3차 의료기술재평가위원회(2023.3.10.)에서는 소위원회 검토 결과에 근거하여 의료기술 재평가사업 관리지침 제4조제10항에 의거 “신장암 경피적 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 경피적 냉동제거술의 사용을 ‘조건부 권고함’으로 심의하였다.

주요어 신장암, 경피적 냉동제거술, 안전성, 효과성

Background Percutaneous 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 percutaneous 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 percutaneous 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 The systematic review involved an assessment of safety and effectiveness based on a total of 36 studies, which included 40 articles (39 articles on retrospective cohort studies and one article on prospective cohort studies). The study population in these articles consisted of patients with small renal masses (less than 3 or 4 cm). Comparator interventions (controls) included partial nephrectomy, radiofrequency ablation, microwave ablation, and active surveillance. In the RoB assessment, the risk of selection bias, including target group comparisons, patient selection, confounding variables, and assessor blinding, was found to be slightly high or uncertain in non-randomized studies.

Safety Safety was evaluated based on 28 studies that reported on procedure-related complications and the length of post-procedure hospital stays. The complications examined included bleeding/hematoma, urinary leakage, abscess, venous thromboembolism, and sepsis. These were categorized into overall complications and major/minor complications based on severity classification systems like the Clavien-Dindo grade and SIR classification. When compared with partial nephrectomy in 12 studies, overall complications (n=9) tended to be lower in the percutaneous cryoablation group (Odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.58-1.10, I2=13%, p=0.17), but without a significant difference between the two groups. Major complications (n=11) and minor complications (n=10) also showed lower incidences in the intervention group, but again without a significant difference between the two groups. In comparison with radiofrequency ablation across 15 studies, there were no significant differences in overall complications (n=9; OR: 0.97, 95% CI: 0.69-1.36, I2=3%, p=0.86) and minor complications (n=9; OR: 0.89, 95% CI: 0.61-1.28, I2=0%, p=0.52) between the two groups. However, the percutaneous cryoablation group had a significantly higher OR for major complications (n=11; OR: 1.68, 95% CI: 1.11-2.53, I2=0%, p=0.01). When compared with microwave ablation in 6 studies, no significant differences were found in overall complications (n=3; OR: 1.30, 95% CI: 0.76-2.24, I2=0%, p=0.33), major complications (n=6; OR: 0.97, 95% CI: 0.47-2.02, I2=0%, p=0.94), and minor complications (n=2; OR: 1.46, 95% CI: 0.52-4.10, I2=0%, p=0.47) between the two groups. The length of post-procedure hospital stay, reported in 12 studies, was significantly shorter for the percutaneous cryoablation group compared to the partial nephrectomy (n=7) and microwave ablation (n=1) groups, but similar to the radiofrequency ablation group (n=5).

Effectiveness The efficacy was evaluated in a comprehensive synthesis of 34 studies. These studies collectively probed into: 1) oncologic outcomes, including survival, recurrence, metastasis, and procedure success (technical success and primary efficacy); 2) renal function, specifically examining the decrement in estimated glomerular filtration rate (eGFR), escalation in serum creatinine (sCr) levels, and the emergence of end-stage renal disease; and 3) patient outcomes, primarily analgesic utilization. The efficacy was evaluated in a comprehensive synthesis of 34 studies. These studies collectively probed into: 1) oncologic outcomes, including survival, recurrence, metastasis, and procedure success (technical success and primary efficacy); 2) renal function, specifically examining the decrement in estimated glomerular filtration rate (eGFR), escalation in serum creatinine (sCr) levels, and the emergence of end-stage renal disease; and 3) patient-oriented outcomes, primarily analgesic utilization. The evaluation of survival outcomes, encapsulated in 19 studies, were examined by overall, recurrence-free, metastasis-free, cancer-specific, disease-free, progression-free, and treatment failure-free survival rates. The juxtaposition with partial nephrectomy, found in 11 studies, revealed a 5-year overall survival rate (in six studies) ranging from 56% to 91.7% in the cryoablation cohort versus 78% to 98.9% in the control group. The recurrence-free survival rate (in seven studies) oscillated between 85% and 98.5% for the intervention group and 93% to 98.7% for the controls. Metastasis-free survival rates (in three studies) spanned from 90% to 100% in the intervention group, compared to 94% to 100% in the control group. The cancer-specific survival rate (in 4 studies) was reported to be 91% to 100% in the cryoablation group and 98% to 100% in the control group. Additionally, a single study indicated a disease-free survival rate of 79.5% in the intervention group against 92.8% in the control group. These results collectively underscored that the survival rates in the percutaneous cryoablation cohort were either comparable to or slightly lower than those in various control groups. In terms of comparisons with radiofrequency ablation, as detailed in 12 studies, the 5-year overall survival rate (reported in four studies) spanned 87.8% to 98.5% in the cryoablation group and 79.4% to 95.7% in the control group. The metastasis-free survival rate (in two studies) ranged from 96.7% to 100% in the intervention group and 92.3% to 97.3% in the control group. The cancer-specific survival rate (in three studies) was documented as 96.4% to 100% in the intervention group and 92.3% to 100% in the control group. Furthermore, a single study reported a disease-free survival rate of 79.5% in the intervention group compared to 80.8% in the control group. Two studies comparing percutaneous cryoablation with microwave ablation articulated no significant differences in the 3-year overall and recurrence-free survival rates. Additionally, a solitary study comparing the treatment with active surveillance unveiled no significant disparities in 5-year overall survival, cancer-specific survival, and treatment failure-free survival rates. Recurrence was the focal point in 18 studies. When juxtaposed with partial nephrectomy (seven studies) and microwave ablation (three studies), the percutaneous cryoablation cohort tended to exhibit a higher OR for recurrence, albeit without reaching statistical significance (partial nephrectomy: OR 2.03, 95% CI 0.87-4.75, I2=75%, p=0.10; microwave ablation: OR 2.48, 95% CI 0.74-8.30, I2=14%, p=0.14). In contrast, compared to radiofrequency ablation (11 studies), the OR for recurrence was lower in the cryoablation group, yet this difference did not attain statistical significance (OR 0.68, 95% CI 0.46-1.01, I2=0%, p=0.05).

Metastasis was reported in three studies. When compared to partial nephrectomy (two studies) and radiofrequency ablation (one study), there were no significant differences in metastasis rates between the groups. The success of the procedure, as reported in 13 studies, revealed no significant disparities in complete ablation (technical success) when compared to radiofrequency ablation (eight studies) and microwave ablation (four studies). The percutaneous cryoablation group did exhibit a higher primary efficacy rate than the radiofrequency ablation group (three studies), but this difference did not reach statistical significance. Against microwave ablation (two studies), one study reported lower procedure success in the intervention group, while the other found no difference. Renal function was assessed in 16 studies. Among nine studies comparing with partial nephrectomy, three reported a significant decrease in eGFR in the control group, and three noted a significant decrease in eGFR and an increase in sCr in the intervention group. However, a substantial number of studies (five studies) reported no differences between the two groups. The majority of studies comparing with radiofrequency ablation (10 studies) or microwave ablation (four studies) indicated no significant differences in changes in eGFR and sCr levels between the groups. Patient outcomes, as chronicled in four studies, presented mixed results. Of the four studies comparing with radiofrequency ablation, two reported lower sedative use in the intervention group, while the other two found no significant differences. In one study comparing with microwave ablation, sedative use was higher in the intervention group. In another study comparing with radiofrequency ablation, there were no significant differences in patient satisfaction and time to full recovery, though the time required to return to work was shorter in the control group.

Cost-effectiveness Regarding cost-effectiveness, a series of seven conducted studies in the United States provided insights into the economic aspects of percutaneous cryoablation of renal masses. These studies, grounded in data sourced from Medicare and hospital records, explored the financial implications of various treatment methodologies. The preponderance of evidence from these studies converges on the conclusion that percutaneous cryoablation, when compared to alternatives such as open partial nephrectomy and robot-assisted laparoscopic partial nephrectomy, emerges as a more cost-effective technique, offering similar medical benefits at a reduced financial burden.

Conclusions and recommendations The Subcommittee, after an exhaustive review of the extant literature, arrived at a nuanced understanding of the safety and efficacy of percutaneous cryoablation for renal masses. Despite the observation that major complications were relatively more prevalent in the percutaneous cryoablation cohort compared to those undergoing radiofrequency ablation, the overall safety profile of the technique was affirmed. This assertion stems from the finding that the incidence of complications was not significantly higher than that observed in partial nephrectomy and microwave ablation groups, coupled with the advantage of shorter or equivalent durations of hospitalization post-procedure. Regarding the effectiveness of percutaneous cryoablation, the analysis yielded a complex picture. While the technique demonstrated less favorable outcomes in terms of survival and recurrence rates compared to partial nephrectomy, these differences did not reach statistical significance. Notably, the renal function outcomes were similar to those observed with partial nephrectomy. Furthermore, when juxtaposed with other localized treatment methodologies such as radiofrequency ablation and microwave ablation, percutaneous cryoablation showed comparable levels of oncologic outcomes, encompassing survival and procedural success, alongside renal function outcomes. In light of these findings, the Subcommittee posited that despite certain shortcomings in treatment outcomes, notably in oncologic efficacy, when benchmarked against the standard surgical treatment of partial nephrectomy, percutaneous cryoablation retains its status as an efficacious health technology. This is particularly relevant for patients harboring small renal masses (less than 4 cm), a demographic that constituted the primary focus of the studies under review. The comparative analysis with other local treatment methods, namely radiofrequency ablation and microwave ablation, further buttresses this conclusion. In the third session of the Committee of Health Technology Reassessment in 2023 (on March 10, 2023), deliberations centered around the findings of the Subcommittee, guided by Article 4-10 of the Guidelines for Management of Health Technology Reassessment. The Committee of Health Technology Reassessment “conditionally recommends” the use of percutaneous cryoablation for patients with small renal masses, particularly in scenarios where conventional surgical options are deemed infeasible. This recommendation is predicated on a holistic assessment of the technique's clinical safety and effectiveness, among other evaluative criteria, tailored to the specific clinical context of Korea.

Keywords: Renal masses, Percutaneous cryoablation, Safety, Effectiveness