고강도 초음파 집속술[전립선암]

Abstract

평가 배경 ‘고강도 초음파 집속술 [전립선암] (high intensity focused ultrasound, HIFU)’은 전립선암 조직에 직장을 통하여 고밀도의 강력한 초음파를 투사시켜 이때 발생된 고열로 전립선암을 치료하는 시술로서, 신의료기술평가제도가 확립되기 전인 2005년 비급여로 등재되었으며, 본 원의 내부 모니터링으로 발굴된 주제이다. 2022년 제3차 의료기술재평가위원회(2022.03.11.)에서는 보건의료 자원의 효율적 사용을 지원하기위한 근거를 제공하기 위하여, 체계적 문헌고찰을 통해 고강도 초음파 집속술 [전립선암]의 안전성 및 효과성에 대한 의과학적 근거를 재평가하고, 동 안건에 대하여 권고등급 결정을 수행하는 것으로 심의하였다.

평가 방법 전립선암 환자에서 고강도 초음파 집속술에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 비뇨의학과 3인, 근거기반의학 2인으로 구성된 “고강도 초음파 집속술 [전립선암] 재평가 소위원회(이하 ‘소위원회’)”의 심의를 거쳐 확정하였다. 체계적 문헌고찰의 핵심질문은 “전립선암 환자에서 고강도 초음파 집속술은 임상적으로 안전하고 효과적인가?”이었다. 본 핵심질문을 토대로 국외 3개, 국내 5개 데이터베이스에서 검색하였으며, 문헌선정 및 배제기준에 따라 두 명의 검토자가 독립적으로 선별하고 선택하였다. 문헌의 비뚤림위험 평가는 Risk of Bias Assessment for Nonrandomized Studies (RoBANS Ver 2.0) 도구를 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. 자료합성은 양적 합성이 가능한 경우 메타분석을 수행하였고, 불가능한 경우 질적 검토 방법을 적용하였으며, Grading of Recommendations Assessment, Development and Evaluation (GRADE) 방법을 이용하여 근거 수준을 평가하였다. 2022년 제11차 의료기술재평가위원회(2022.11.11.)에서는 소위원회의 검토 의견을 고려하여 최종 권고등급을 결정하였다.

평가 결과 동 평가에 최종 선택된 문헌은 모두 비무작위 연구(non-randomized studies, NRS)로 총 18편이었다. 선택문헌은 HIFU의 적용범위와 목적으로 구분한 결과, primary partial-gland ablation은 5편, primary whole-gland ablation은 8편, salvage whole-gland ablation 문헌은 5편이었으며, 대조군으로 설정한 전립선적출술, 냉동제거술, 방사선치료술과 비교하여 HIFU의 안전성과 효과성 결과를 제시하였다. 다중그룹 비교는 2편이었으며, 다중그룹 비교 연구의 경우는 대조군별로 결과를 제시하였다. 선택된 문헌들의 비뚤림위험 평가 결과, 대상군 비교가능성, 대상군 선정, 교란변수 영역 등에서 비뚤림위험이 대체로 높았다. 대상군 비교가능성, 대상군 선정, 교란변수 영역 등에서 비뚤림위험이 높았으므로 비뚤림위험 영역에서 한 단계 강등하였고 연구대상자 수가 적어 비정밀성 영역에서 한 단계 강등하여, 문헌에서 보고한 모든 결과지표의 근거수준은 낮음(low) 또는 매우 낮음(very low)으로 평가되었다.

안전성 Primary partial-gland HIFU 문헌 중 부작용 및 이상반응을 보고한 2편에서 HIFU군과 전립선적출술군 간 부작용 및 이상반응의 발생률에 있어 유의한 차이는 없었고, 냉동제거술군에 비해 HIFU군에서 급성 요폐와 급성 감염성 부고환염의 발생률이 유의하게 높았다. Primary whole-gland HIFU 문헌 중 부작용 및 이상반응을 보고한 5편에서 HIFU군이 전립선적출술군에 비해 급성 요폐의 발생률이 유의하게 높았으며, 냉동제거술군에 비해서는 요도 협착의 발생률이 유의하게 높았고, 방사선치료술군에 비해서는 급성 요폐, 요도 협착의 발생률이 유의하게 높았다. Salvage whole-gland HIFU 문헌 중 부작용 및 이상반응을 보고한 3편에서 HIFU군이 전립선적출술군에 비해 급성 요폐의 발생률이 유의하게 높았고, 냉동제거술군에 비해서는 유의하게 낮았다. 방사선치료술군과는 부작용 발생률에 유의한 차이가 없었다. 소위원회는 HIFU군에서 높게 보고된 급성 요폐는 시술 특성에 따른 일시적인 부작용으로 심각한 부작용은 아니며, 대부분의 안전성 지표에서 기존 기술과 유의한 차이가 없다고 평가하였다.

효과성 Primary partial-gland HIFU 문헌 중 생존율을 보고한 3편에서 무추가치료 생존율은 HIFU군과 전립선적출술군, 냉동제거술군 간 유의한 차이가 없었다. 재발률과 관련한 결과를 보고한 1편의 문헌에서 HIFU군의 치료실패율이 전립선적출술군에 비해 유의하게 높았다. 요실금과 발기기능을 보고한 2편의 연구에서 모두 전립선적출술군에 비해 HIFU에서의 결과가 유의하게 좋았다. 이외 전립선 증상을 보고한 문헌은 없었다. Primary whole-gland HIFU 문헌 중 생존율은 6편에서 보고되었다. 5년 전체 생존율은 HIFU군이 전립선적출술군에 비해 유의하게 낮았으며, 방사선치료술군과는 유의한 차이가 없었고, 무구제치료 생존율은 HIFU군과 전립선적출술군, 냉동치료술군 간 유의한 차이가 없었으며, 방사선치료술군에 비해서는 HIFU군에서 유의하게 높았다. 재발률을 보고한 5편에서 생화학적 재발률은 HIFU군과 전립선적출술군, 냉동제거술군, 방사선치료술군 간 모두 통계적으로 유의한 차이가 없었다. 4편에서 보고된 요실금 환자의 비율은 HIFU군이 전립선적출술군에 비해 유의하게 낮았으며, 냉동제거술군과 방사선치료술군과는 유의한 차이가 없었다. 4편에서 보고된 발기기능 International Index of Erectile Function (IIEF-5) 점수는 HIFU군이 전립선적출술군과 냉동제거술군에 비해 유의하게 좋았으며, 방사선치료술군과는 유의한 차이가 없었다. 전립선 증상을 보고한 4편에서 International Prostate Symptom Scale (IPSS) 점수는 HIFU군과 전립선적출술군, 냉동제거술군, 방사선치료술군 간 모두 통계적으로 유의한 차이가 없었다. Salvage whole-gland HIFU 문헌 중 생존율을 보고한 3편에서 전체 생존율은 HIFU군과 전립선적출술군, 냉동제거술군, 방사선치료술군 간 모두 통계적으로 유의한 차이가 없었다. 3편에서 보고된 생화학적 재발률은 HIFU군이 전립선적출술군에 비해 유의하게 낮았고 냉동제거술군에 비해서는 유의하게 높았으며, 방사선치료술군과는 유의한 차이가 없었다. 3편에서 보고한 요실금 환자의 비율은 HIFU군이 전립선적출술군과 냉동제거술군에 비해서는 유의하게 낮았으나, 방사선치료술군과는 유의한 차이가 없었다. 발기기능 및 전립선 증상을 보고한 문헌은 없었다.

결론 및 제언 고강도 초음파 집속술 [전립선암] 재평가 소위원회는 현재 평가 결과에 근거하여 다음과 같이 제언하였다. 1) 전립선암 환자에서 primary partial-gland ablation 목적의 고강도 초음파 집속술은 심각한 합병증이 보고되지 않고, 보고된 부작용 및 이상반응이 기존 기술과 유사한 수준으로 소위원회는 동 기술을 안전한 의료기술로 판단하였다. 생존율은 기존 기술과 유의한 차이가 없고 전립선암의 재발률은 고강도 초음파 집속술에서 높아 전립선암 primary partial-gland ablation 목적으로 동 기술의 효과는 제한적이라고 판단하였다. 다만, 소위원회는 고강도 초음파 집속술이 기존 기술에 비해 요실금과 발기기능 유지에 효과가 있어 전문의의 판단하에 제한적으로 사용될 수 있다고 제언하였다. 2) 전립선암 환자에서 primary whole-gland ablation 목적의 고강도 초음파 집속술은 심각한 합병증이 보고되지 않고, 보고된 부작용 및 이상반응이 기존 기술과 유사한 수준으로 소위원회는 동 기술을 안전한 의료기술로 판단하였다. 생존율은 전립선적출술에 비해 낮고 냉동제거술과 방사선치료술과는 차이가 없으며, 전립선암의 재발률에서는 기존 기술과 차이가 없어 전립선암 primary whole-gland ablation 목적으로 동 기술의 효과는 제한적이라고 판단하였다. 다만, 소위원회는 고강도 초음파 집속술이 기존 기술에 비해 요실금과 발기기능 유지에 효과가 있어 전문의의 판단하에 제한적으로 사용될 수 있다고 제언하였다. 3) 방사선 치료 후 재발한 전립선암 환자에서 salvage whole-gland ablation 목적의 고강도 초음파 집속술은 심각한 합병증이 보고되지 않고, 보고된 부작용 및 이상반응이 기존 기술과 유사한 수준으로 소위원회는 동 기술을 안전한 의료기술로 판단하였다. 생존율은 기존 기술과 유의한 차이가 없고 요실금에 효과가 있어 동 기술이 전립선암 salvage whole-gland ablation 목적으로 하나의 치료대안이 될 수 있다고 판단하였다. 2022년 제11차 의료기술재평가위원회(2022.11.11.)에서는 소위원회 검토 결과에 근거하여 의료기술재평가사업 관리지침 제4조제10항에 의거 “고강도 초음파 집속술 [전립선암]”에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 전립선암 환자에서 고강도 초음파 집속술은 기존 기술과 유사한 수준의 안전한 시술이지만 기존 기술과 효과성을 비교하였을 때 시술의 목적에 따라 전문의의 판단하에 선별된 환자에서 제한적으로 사용될 수 있다고 제언한 소위원회 결론에 동의하였다. 이에 의료기술재평가위원회는 전립선암 환자에서 고강도 초음파 집속술을 ‘조건부 권고함’으로 심의하였다(권고등급: 조건부 권고함).

주요어 전립선암, 고강도 초음파 집속술, 안전성, 효과성

Background High-intensity focused ultrasound (HIFU) is a procedure for treating prostate cancer using high heat generated when powerful high-density ultrasound is projected at the prostate cancer tissue through the rectum. It was registered as a non-coverage item in 2005, before the establishment of the New Health Technology Assessment system, and identified as an item for reassessment through internal monitoring by our institution. During the third session of the Committee of Health Technology Reassessment in 2022 (March 11, 2022), a decision was made to reassess the medical and scientific evidence on the safety and effectiveness of HIFU for prostate cancer through a systematic review and to determine the grade of recommendation for this item, so as to provide evidence that can support efficient use of healthcare resources.

Methods A systematic review was performed to assess the safety and effectiveness of HIFU for prostate cancer management. All assessment methods were finalized after a review by the “HIFU [prostate cancer] reassessment subcommittee” (hereinafter referred to as “subcommittee”) with consideration for the purpose of the assessment. The subcommittee comprised three experts in urology and two experts in evidence-based medicine. The key question in the systematic review was “Is HIFU clinically safe and effective for treating patients with prostate cancer?” Three international and five domestic databases were searched based on this key question, and two reviewers independently screened and selected the articles in accordance with the inclusion and exclusion criteria. Two reviewers independently performed a risk-of-bias (RoB) assessment using the Risk of Bias Assessment for Nonrandomized Studies (RoBANS) Ver 2.0 tool and reached a consensus. Data extraction was performed independently by two reviewers by using a predetermined format. Any disagreements were resolved by discussing the matter with a third person to reach a consensus. For data synthesis, a meta-analysis was performed if a quantitative synthesis was possible and a qualitative review was performed if not. In addition, the grade of recommendation was assessed using the Grading of Recommendations Assessment, Development and Evaluation method. During the 11th session of the Committee of Health Technology Reassessment in 2022 (November 11, 2022), the final grade of recommendation was determined based on the subcommittee findings.

Results Overall, 18 articles, all on non-randomized studies, were selected for this assessment. When the selected articles were classified by the scope and purpose of HIFU, there were five articles on primary partial-gland ablation, eight on primary whole-gland ablation, and five on salvage whole-gland ablation. The safety and effectiveness of HIFU were presented in comparison with those of prostatectomy, cryoablation, and radiotherapy, which were used as the controls. There were two articles on multigroup comparisons, which presented the results from comparisons with each control modality. The RoB assessment results showed generally high RoB in the domains of case-control comparability, selection of participants, and confounding variables. Due to the high RoB in the domains of case-control comparability, selection of participants, and confounding variables, the level of evidence was downgraded by one level. The level of evidence was also downgraded by one level for imprecision due to a small sample size. Accordingly, the level of evidence of outcomes reported in the articles was assessed to be low or very low.

Safety Among the articles on HIFU for primary partial-gland ablation, two articles reported adverse events (AEs) and adverse reactions (ARs). While there were no significant differences in the incidence rates of AEs and ARs between the HIFU and prostatectomy groups, the former showed significantly higher incidence rates of acute urinary retention and acute infectious epididymitis than the corresponding rates in the cryoablation group. Among the articles on HIFU for primary whole-gland ablation, five articles reported AEs and ARs. According to these articles, the HIFU group showed a significantly higher incidence of acute urinary retention than that in the prostatectomy group; a significantly higher incidence of urethral stricture than that in the cryoablation group; and a significantly higher incidence of acute urinary retention and urethral stricture than the corresponding incidence rates in the radiotherapy group. Among the articles on salvage whole-gland HIFU, three articles reported on AEs and ARs. In these articles, the HIFU group showed a significantly higher incidence of acute urinary retention than that in the prostatectomy group; a significantly lower incidence of acute urinary retention than that in the cryoablation group; and no significant difference in the incidence of AEs compared with that in the radiotherapy group. The subcommittee determined that acute urinary retention, the incidence of which was reported to be higher in the HIFU group, is a transient and not a serious AE owing to the nature of the procedure and that there were no significant differences in most safety indicators compared with those related to conventional techniques.

Effectiveness Among the articles on HIFU for primary partial-gland ablation, three articles reported the survival rate. According to these articles, there was no significant difference in survival rates among the HIFU, prostatectomy, and cryoablation groups. In one article that reported recurrence rates, the HIFU group showed a significantly higher treatment failure rate than that in the prostatectomy group. In two articles that reported urinary incontinence and erectile function, the HIFU group showed significantly better outcomes than those of the prostatectomy group. Meanwhile, there were no articles that reported other prostate symptoms. Among the articles on HIFU for primary whole-gland ablation, six articles reported on survival rate. The HIFU group showed a significantly lower 5-year overall survival rate than that in the prostatectomy group and no significant difference compared with that in the radiotherapy group. Further, there was no significant difference in the treatment-free survival rate among the HIFU, prostatectomy, and cryoablation groups. However, the HIFU group showed a significantly higher treatment-free survival rate than that in the radiotherapy group. In five articles that reported the recurrence rate, there were no statistically significant differences in biochemical recurrence rates among all four groups (HIFU, prostatectomy, cryoablation, and radiotherapy groups). In four articles that reported urinary incontinence, the HIFU group had a significantly lower percentage of patients with urinary incontinence than did the prostatectomy group and showed no significant difference compared with the cryoablation and radiotherapy groups. In four articles that reported erectile function, the HIFU group showed a significantly higher International Index of Erectile Function (IIEF-5) score than those in the prostatectomy and cryoablation groups and no significant difference compared with the score of the radiotherapy group. In four articles that reported prostate symptoms, there were no statistically significant differences in the International Prostate Symptom Scale scores among the four groups. Among the articles on salvage whole-gland HIFU, three articles reported the survival rate. There were no significant differences in overall survival rates among all the four groups. In three articles that reported the biochemical recurrence rate, the HIFU group showed a significantly lower rate than that in the prostatectomy group, a significantly higher rate than that in the cryoablation group, and no significant difference compared with the rate in the radiotherapy group. In three articles that reported urinary incontinence, the HIFU group showed a significantly lower percentage of patients with urinary incontinence than those in the prostatectomy and cryoablation groups and no significant difference compared with that in the radiotherapy group. Meanwhile, there were no articles that reported erectile function and prostate symptoms.

Conclusions and recommendations Based on the current assessment results, the subcommittee recommended the following: 1) With respect to HIFU for primary partial-gland ablation in patients with prostate cancer, there were no serious complications, and the reported AEs and ARs are at levels similar to that for the existing modalities. Accordingly, the subcommittee determined that this is a safe health modality. There was no significant difference in the survival rate compared with those related to the existing modalities, and HIFU was associated with a higher recurrence rate of prostate cancer. Accordingly, it was determined that this modality has limited effectiveness when applied for primary partial-gland ablation in patients with prostate cancer. Nevertheless, the subcommittee recommended that HIFU may be used on a limited basis, at the discretion of a specialist, since it can be effective in treating urinary incontinence and maintaining erectile function compared with the existing modalities. 2) Regarding the use of HIFU for primary whole-gland ablation in patients with prostate cancer, there were no serious complications, and the reported AEs and ARs are at levels similar to those for the existing modalities. Accordingly, the subcommittee determined that that this is a safe health modality. HIFU was associated with a lower survival rate than that associated with prostatectomy. However, the survival rates associated with HIFU, cryoablation, and radiotherapy were not different. In addition, there was no difference in the recurrence rate of prostate cancer associated with HIFU and the other existing modalities. Accordingly, it was determined that HIFU has limited effectiveness when applied for the purpose of primary whole-gland ablation in patients with prostate cancer. Nevertheless, the subcommittee recommended that HIFU may be used on a limited basis, at the discretion of a specialist, since it can be effective in treating urinary incontinence and maintaining erectile function compared with the existing modalities. 3) With respect to the use of HIFU for salvage whole-gland ablation in patients with recurrent prostate cancer after radiotherapy, there were no serious complications, and the reported AEs and ARs are at levels similar to those for the existing modalities. Accordingly, the subcommittee determined that HIFU is a safe health modality. There was no significant difference in the survival rate associated with HIFU and the other existing modalities, and HIFU was found to be effective in managing urinary incontinence. Accordingly, it was determined that HIFU, when used for salvage whole-gland ablation, could be a treatment option for prostate cancer. During the 11th session of the Committee of Health Technology Reassessment in 2022 (November 11, 2022), the following conclusions were made with regard to “HIFU [prostate cancer]” based on the subcommittee findings in accordance with Article 4-10 of the Guidelines for Management of Health Technology Reassessment Project. The Committee of Health Technology Reassessment concurred with the subcommittee's conclusion that HIFU may be used on a limited basis in select patients with prostate cancer, at the discretion of a specialist according to the purpose of the procedure, based on its effectiveness and safety compared with those of the existing modalities. Accordingly, the Committee of Health Technology Reassessment “conditionally recommends” the use of HIFU in patients with prostate cancer (grade of recommendation: conditionally recommended).

Keywords: Prostate Cancer, High-Intensity Focused Ultrasound, Safety, Effectiveness