전립선암 냉동제거술

Abstract

평가배경 ‘전립선암 냉동제거술’은 전립선암에 대한 일차적 치료 및 재수술 치료를 목적으로 아르곤 가스나 헬륨 가스를 프로브에 삽입하여 동결/해동 주기를 통해 암조직을 파괴하는 의료기술이다. 국내에서는 신의료기술평가제도가 확립되기 이전인 2005년 비급여로 등재된 이후, 2011년 건강보험 보장성 강화 정책에 따라 급여로 전환되어 현재까지 사용 중이다. 해당 의료기술은 과거 유관기관 수요조사에서 저가치 기술로 제기된 바 있었으며, 다시 내부 모니터링을 통해 재평가 주제로 발굴되었다. 재평가 대상선별을 위한 임상자문회의와 우선순위 심의를 거쳐 2022년 제8차 의료기술재평가위원회(’22.8.12.)에서 재평가 대상으로 최종 선정되었다.

평가 방법 본 평가는 국소 전립선암 환자의 치료에 사용되는 냉동제거술의 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “냉동제거술 통합 소위원회(이하 ‘소위원회’라 한다)”의 논의를 거쳐 확정하였으며, 핵심질문은 “국소 전립선암 환자에서 냉동제거술은 임상적으로 안전하고 효과적인가?”였다. 문헌검색은 국외 3개, 국내 5개 데이터베이스에서 수행하였으며, 문헌선정은 선택배제 기준에 따라 두 명의 검토자가 독립적으로 선별하고 선택하였다. 문헌의 비뚤림위험 평가는 연구유형에 따라 Cochrane의 Risk of Bias 및 Risk of Bias for Nonrandomized Studies (RoBANS Ver.2)를 사용하여 평가하였고, 자료추출은 미리 정해놓은 자료추출 양식을 활용하여 두 명의 검토자가 독립적으로 수행하였다. 의견 불일치가 있을 경우 제3자와 함께 논의하여 합의하였다. 자료 분석은 정량적 분석이 가능할 경우 메타분석을 수행하고 불가능한 경우 질적 검토를 수행하였다. 본 평가의 체계적 문헌고찰 결과는 GRADE (Grading of Recommendations Assessment, Development and Evaluation) 방법을 이용하여 근거 수준을 평가하였고, 의료기술재평가위원회는 평가결과를 토대로 권고등급을 결정하였다.

평가 결과 체계적 문헌고찰을 수행한 결과, 핵심질문을 충족하는 42편의 문헌(37개의 연구)이 선정되었다. 국소 전립선암을 대상으로 전체/부분 냉동제거술을 수행한 비교연구가 포함되었으며, 대조군으로는 능동감시, 고강도 초음파 집속술, 방사선 치료, 전립선절제술이 포함되었다. 비뚤림위험은 비무작위 비교연구에서 ‘대상군 비교 가능성’ 및 ‘교란변수’와 관련된 비뚤림위험이 다소 높게 나타났다

안전성 전립선암 냉동제거술의 안전성은 16개의 연구(무작위배정 비교임상시험(RCT) 2개, 비무작위 비교연구(NRS) 14개)에서 다양한 결과지표들로 보고하였으며, 해당 지표들은 전체 합병증, 비뇨생식기 합병증, 위장관 합병증으로 범주화하여 확인하였다. 전체 합병증을 보고한 연구는 10개(RCT 2개, NRS 8개)였다. 냉동제거술은 HIFU (High-Intensity Focused Ultrasound)(NRS 2개) 및 전립선절제술(NRS 1개)보다 전체 합병증이 유의하게 덜 발생하였으나, 능동감시(NRS 1개)보다는 합병증이 더 많이 발생하였고, 방사선 치료와 비교시(RCT 2개, NRS 4개) 두 군간 유의한 차이가 없었다. 요실금, 혈뇨, 요관 협착, 방광염, 발기부전과 같은 다양한 비뇨생식기 합병증을 보고한 연구는 13개(RCT 2개, NRS 11개)였다. 대부분의 결과지표에서 냉동제거술과 다른 치료법(능동감시, HIFU, 방사선 치료, 전립선절제술)은 비뇨생식기와 관련된 합병증 발생에 유의한 차이가 없었으며, 가장 많이 보고된 요실금에 대한 메타분석 결과 역시, 냉동제거술과 다른 치료법은 유의한 차이가 없었다. 그 외 일부 지표인 요도 협착 및 감염 질환은 냉동제거술에서, 음낭 부종 및 발기 부전은 대조군에서 더 적게 발생하여 각각 유의한 차이가 있었다. 직장요도루, 직장 통증, 혈변, 설사, 직장 손상과 같은 다양한 위장관 합병증을 보고한 연구는 7개(RCT 1개, NRS 6개)였다. 냉동제거술은 방사선 치료보다 전반적으로 위장관 합병증이 유의하게 적게 발생하거나 두 군간 유의한 차이가 없었으며(RCT 1개, NRS 3개), 그 외 다른 치료법(능동감시, HIFU, 전립선절제술)과 대체로 유의한 차이가 없었다. 가장 많이 보고된 직장요도루에 대한 메타분석 결과 역시, 다른 치료법들과 유의한 차이가 없었다.

효과성 전립선암 냉동제거술의 효과성은 30개의 연구(무작위배정 비교임상시험 2개, 비무작위 비교연구 28개)에서 보고하였다. 효과성은 크게 종양학적 의료결과, 기능 지표, 삶의 질로 나누어 확인하였다. 냉동제거술의 종양학적 의료결과는 세분화하여 전체 생존율, 암 특이 생존율, 무재발 생존율, 무전이 생존율, 재발의 지표를 통해 확인하였다. 전체 생존율을 보고한 연구는 8개(RCT 2개, NRS 6개)였다. 대체로 냉동제거술은 전립선절제술보다 전체 생존율이 유의하게 낮았지만(NRS 2/3개), 그 외 다른 치료법(능동감시, 방사선 치료)과 비교시 유의한 차이가 없었다. 암 특이 생존율을 보고한 연구는 9개(RCT 2개, NRS 7개)였다. 냉동제거술은 전립선절제술보다 암 특이 생존율이 유의하게 낮았지만(NRS 2개), 그 외 다른 치료법(능동감시, 방사선 치료)과 비교시 유의한 차이가 없었다. 무재발 생존율을 보고한 연구는 6개(RCT 1개, NRS 5개)였다. 대체로 냉동제거술은 방사선 치료보다 무재발 생존율이 유의하게 낮았으나(RCT 2개, NRS 2/3개), 전립선절제술과 비교한 2개 연구(NRS)에서는 연구결과가 각각 상반되게 나타났다. 그 외 다른 치료법(능동감시, HIFU)과 비교한 연구에서는(각 NRS 3개, NRS 2개) 무재발 생존율에 유의한 차이가 없었다. 무전이 생존율을 보고한 연구는 2개(NRS 2개)였다. 냉동제거술은 능동감시, 방사선 치료와 무전이 생존율에 있어 유의한 차이가 없었다. 재발(recurrence)을 보고한 연구는 15개(RCT 2개, NRS 13개)였다. 메타분석 결과, 냉동제거술은 HIFU보다 재발이 유의하게 더 많이 발생하였으나(OR 1.42; 95% CI 1.05, 1.19), 그 외 다른 치료법(능동감시, 방사선 치료, 전립선절제술)과는 유의한 차이가 없었다. 냉동제거술 후 전립선의 기능적 결과는 국제전립선증상점수(International Prostate Symptom Score, IPSS) 및 국제발기기능지수(International Index of Erectile Function, IIEF)를 이용하여 확인하였다. 국제전립선증상점수에 대한 메타분석 결과, 냉동제거술과 다른 치료법들(능동감시, HIFU, 방사선 치료, 전립선절제술)은 유의한 차이가 없었다. 국제발기기능지수의 메타분석 결과에서는 냉동제거술이 HIFU보다 유의하게 낮았으며(OR –0.89; 95% CI –1.52, -0.26), 그 외 다른 치료법(능동감시, 방사선 치료, 전립선절제술)과는 유의한 차이가 없었다. 전립선암 냉동제거술에 따른 삶의 질은 종합/일반적 기능, 비뇨기계 기능, 장 기능, 성적 기능으로 범주화하여 확인하였다. 삶의 질-종합/일반적 기능을 보고한 연구는 5개(RCT 1개, NRS 4개)였다. 대체로 냉동제거술은 다른 치료법들(능동감시, HIFU, 방사선 치료, 전립선절제술)과 종합/일반적 기능에 있어 유의한 차이가 없었으나, 방사선 치료와 비교한 1개의 무작위배정 비교임상시험의 장기 시점에서 냉동제거술의 종합/일반적 기능점수가 유의하게 더 높았다. 삶의 질-비뇨기계 기능을 보고한 연구는 7개(RCT 1개, NRS 6개)였다. 일부 연구(NRS 1/4개)에서는 냉동제거술이 전립선절제술보다 비뇨기계 기능점수가 유의하게 높았으나, 나머지 연구는 군간 통계적 유의성을 보고하지 않아 차이를 확인할 수 없었다. 그 외 다른 치료법(능동감시, 방사선 치료)과는 유의한 차이가 없었다. 삶의 질-장 기능을 보고한 연구는 6개(RCT 1개, NRS 5개)였다. 대체로 냉동제거술은 다른 치료법들(능동감시, 방사선 치료, 전립선절제술)과 장 기능에 있어 유의한 차이가 없거나 통계적 유의성을 확인할 수 없었으나, 방사선 치료와 비교한 1개 비무작위 비교연구의 단기 시점에서 냉동제거술의 장 기능 점슈가 유의하게 더 높았다. 삶의 질-성적 기능을 보고한 연구는 7개(RCT 1개, NRS 6개)였다. 냉동제거술은 전립선절제술과 비교시 성적 기능점수가 낮은 경향성을 보였으나 통계적 유의성은 보고하지 않았다. 반면 냉동제거술은 다른 치료법(능동감시, 방사선 치료)보다 성적 기능점수가 유의하게 낮다는 연구가 다수 확인되었다(각 NRS 2/5개, NRS 2/3개).

결론 및 제언 해당 소위원회는 현재 평가결과에 근거하여 다음과 같이 제언하였다. 체계적 문헌고찰 결과, 전립선암 냉동제거술은 요실금, 요관 협착, 발기부전과 같은 비뇨생식기 합병증 및 직장요도루, 직장 통증과 같은 위장관 합병증이 보고되었으나, 대부분의 연구에서 다른 치료법과 합병증 발생에 유의한 차이가 없고, 전립선절제술 및 HIFU보다 전체 합병증 발생이 유의하게 적어 안전한 의료기술로 평가하였다. 전립선암 냉동제거술은 전립선절제술보다 전체/암 특이 생존율이 유의하게 낮고 방사선 치료 또는 HIFU보다 재발이 유의하게 더 많았으나, 그 외 다른 종양학적 결과에서는 군간 유의한 차이가 없었다. 국제전립선증상점수 및 국제발기기능지수를 이용하여 확인한 전립선의 기능 결과는 대부분 다른 치료법과(능동감시, HIFU, 방사선 치료, 전립선절제술) 유의한 차이가 없었으나, 국제발기기능지수는 HIFU에서 냉동제거술보다 유의하게 더 좋았다. 삶의 질은 치료법간 장단점이 일부 확인되었으나 전반적으로 치료법간 차이가 없었다. 따라서 소위원회에서는 본 평가결과를 바탕으로 국소 전립선암 환자의 치료 목적으로 사용되는 ‘전립선암 냉동제거술’이 종양학적 결과에 있어서 전립선절제술보다는 열등하였으나, 능동감시, 방사선 치료 및 HIFU와 효과가 유사하고 안전한 의료기술로 평가하였다. 2023년 제3차 의료기술재평가위원회(2023.3.10.)에서는 소위원회 검토 결과에 근거하여 의료기술재평가사업 관리지침 제4조제10항에 의거 ‘전립선암 냉동제거술’에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 임상적 안전성과 효과성의 근거 및 그 외 평가항목 등을 종합적으로 고려하였을 때, 국내 임상상황에서 국소 전립선암 환자를 대상으로 사용하는 ‘냉동제거술’은 안전한 기술이며, 수술적 치료보다는 열등하였으나 그 외 다른 치료법과는 효과가 비슷한 의료기술로 ‘조건부 권고함’으로 심의하였다.

주요어 국소 전립선암, 냉동제거술, 안전성, 효과성, 경제성

Background Cryoablation for prostate cancer is a medical procedure designed to destroy cancerous tissues using freeze-thaw cycles, facilitated by argon or helium gas delivered through a probe. This method is primarily used in the initial and subsequent treatments of prostate cancer. Despite its initial classification as a non-benefit item in 2005 in Korea, prior to the establishment of the new health technology assessment system, cryoablation was reclassified as a benefit item in 2011. This change occurred due to the expansion of health insurance coverage policies, and the technology continues to be used as a benefit item today. Interestingly, while cryoablation was initially assessed as a low-value technology by relevant organizations, it was flagged for reassessment following internal monitoring. The Clinical Advisory Board, after conducting a candidate screening and a priority review, selected this technology for reassessment during the eighth session of the Committee of Health Technology Reassessment in 2022 (on August 12, 2022).

Methods To evaluate the safety and effectiveness of cryoablation in treating localized prostate cancer, a systematic review was conducted. The methods for this assessment were finalized after discussions within the “Integrated cryoablation subcommittee (hereafter referred to as the “Subcommittee”), focusing on the key question “Is cryoablation clinically safe and effective for patients with localized prostate cancer?” Articles were sourced from three international and five domestic databases. The inclusion and exclusion criteria were strictly followed by two independent reviewers during the article selection process. The risk of bias (RoB) in these studies was assessed using either the Cochrane RoB tool or the Risk of Bias for Nonrandomized Studies (RoBANS Ver.2), depending on the study design. Data extraction was independently carried out by two reviewers, and any disagreements were resolved through discussions with a third person to reach consensus. For data analysis, the approach was two-fold: a meta-analysis was performed if quantitative analysis was feasible; otherwise, a qualitative review was conducted. The systematic review results were then graded for evidence level using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. The Committee of Health Technology Reassessment used these results to determine their grade of recommendation

Results The systematic review yielded a total of 42 articles, encompassing 37 studies that met the key question criteria. These studies involved comparative analyses of complete or partial cryoablation for treating localized prostate cancer. Comparator interventions (controls) included in these studies were active surveillance, high-intensity focused ultrasound (HIFU), radiotherapy, and prostatectomy. In the RoB assessment, the RoB associated with the “possibility of the target group comparisons” and “confounding variables” was slightly high in randomized control trials (RCTs).

Safety In the realm of prostate cancer treatment, the safety profile of cryoablation has been documented in 16 studies, including two RCTs and 14 non-randomized studies (NRSs). These studies provided a comprehensive evaluation of various outcome indicators, which were systematically categorized into overall complications, genitourinary (GU) complications, and gastrointestinal (GI) complications. A total of 10 studies—comprising two RCTs and eight NRSs—reported on all types of complications. Cryoablation demonstrated a notably lower rate of overall complications when compared to high-intensity focused ultrasound (HIFU) and prostatectomy, as reported in two NRSs and one NRS, respectively. However, it exhibited a higher rate of overall complications than active surveillance, as indicated in one NRS. In contrast, when compared to radiotherapy (evaluated in two RCTs and four NRSs), cryoablation showed no significant difference in the rate of overall complications. Concerning GU complications, 13 studies (including two RCTs and 11 NRSs) reported on a variety of issues such as urinary incontinence, hematuria, ureteral stricture, cystitis, and erectile dysfunction. The majority of these outcome indicators revealed no significant disparity in GU complications between cryoablation and other treatment modalities (active surveillance, HIFU, radiotherapy, and prostatectomy). Furthermore, a meta-analysis specifically focusing on urinary incontinence—the most commonly reported GU complication—also found no significant difference between cryoablation and other treatments. However, for certain indicators like urethral stricture and infectious diseases, cryoablation was associated with a lower incidence compared to control groups, with these differences being statistically significant. In the assessment of GI complications, seven studies (one RCT and six NRSs) reported on conditions such as rectourethral fistula, rectal pain, bloody stools, diarrhea, and rectal injury. Overall, the incidence of GI complications was significantly lower in the cryoablation group compared to the radiotherapy group, or there was no significant difference between the two groups (one RCT and three NRSs). Additionally, cryoablation showed no significant difference in GI complications when compared to other treatment methods (active surveillance, HIFU, and prostatectomy). Notably, a meta-analysis focusing on rectourethral fistula—the most commonly reported GI complication—also indicated no significant difference between cryoablation and other treatment approaches.

Effectiveness The effectiveness of cryoablation in treating prostate cancer has been examined in 30 studies, including two RCTs and 28 NRSs. The assessment of effectiveness encompassed a range of factors, such as oncologic outcomes, functional indicators, and quality of life (QoL). The oncologic outcomes were further subdivided into categories including overall survival rate, cancer-specific survival rate, recurrence-free survival rate, metastasis-free survival rate, and recurrence. The overall survival rate was addressed in eight studies (two RCTs and six NRSs). In most instances, cryoablation displayed a significantly lower overall survival rate compared to prostatectomy, as indicated in two out of three NRSs. However, it showed no significant difference when compared to other treatment methods like active surveillance and radiotherapy. Regarding the cancer-specific survival rate, reported in nine studies (two RCTs and seven NRSs), cryoablation exhibited a significantly lower rate than prostatectomy (two NRSs), but again showed no notable difference compared to other treatments such as active surveillance and radiotherapy. In the context of recurrence-free survival rate, covered in six studies (one RCT and five NRSs), cryoablation generally had a significantly lower rate than radiotherapy (two RCTs and two out of three NRSs). Studies comparing cryoablation with prostatectomy (two NRSs) presented conflicting results. When compared with other treatment methods like active surveillance and HIFU (evaluated in three and two NRSs, respectively), there was no significant difference in recurrence-free survival rates. The metastasis-free survival rate was analyzed in two studies (both NRSs). Here, cryoablation showed no significant difference in comparison to active surveillance and radiotherapy. In terms of recurrence, 15 studies (two RCTs and 13 NRSs) were reviewed. Meta-analysis results indicated that cryoablation had a significantly higher rate of recurrences than HIFU (with an odds ratio [OR] of 1.42; 95% confidence interval [CI] 1.05, 1.19), but it did not differ significantly from other treatment methods (active surveillance, radiotherapy, and prostatectomy). Prostate functional outcomes post-cryoablation were assessed using the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF). The meta-analysis of IPSS showed no significant difference between cryoablation and other treatment methods (active surveillance, HIFU, radiotherapy, and prostatectomy). However, the meta-analysis of IIEF revealed that cryoablation resulted in a significantly lower score compared to HIFU (OR –0.89; 95% CI –1.52, -0.26), while showing no significant difference when compared to other treatments (active surveillance, radiotherapy, and prostatectomy). The assessment of QoL following cryoablation of prostate cancer was categorized into comprehensive/general, urinary, bowel, and sexual functions. QoL based on comprehensive/general function was reported in five studies (one RCT and four NRSs). Generally, cryoablation demonstrated no significant difference in comprehensive/general function compared to other treatment methods (active surveillance, HIFU, radiotherapy, and prostatectomy). However, one RCT that compared cryoablation with radiotherapy noted that cryoablation yielded significantly higher long-term comprehensive/general function scores. QoL based on urinary function was assessed in seven studies (one RCT and six NRSs). Some studies (one out of four NRSs) reported significantly higher urinary function scores for cryoablation compared to prostatectomy, but differences in the remaining studies were inconclusive as they did not report statistical significance between the groups. Moreover, there was no significant difference compared to other treatment methods (active surveillance and radiotherapy). For QoL based on bowel function, reported in six studies (one RCT and five NRSs), cryoablation generally showed no significant difference compared to other treatment methods (active surveillance, radiotherapy, and prostatectomy), or statistical significance could not be determined. However, one RCT comparing cryoablation and radiotherapy indicated that cryoablation resulted in significantly higher short-term bowel function scores. Regarding QoL based on sexual function, evaluated in seven studies (one RCT and six NRSs), cryoablation tended to show lower sexual function scores compared to prostatectomy, though statistical significance was not always reported. Conversely, many studies indicated that cryoablation had significantly lower sexual function scores compared to other treatment methods, such as active surveillance and radiotherapy (two out of five and two out of three NRSs, respectively).

Conclusions and recommendations Following an exhaustive evaluation, the Subcommittee has formulated the following recommendations based on the outcomes of the systematic review. systematic review elucidated that GU complications such as urinary incontinence, ureteral stricture, and erectile dysfunction, as well as GI complications including rectourethral fistula and rectal pain, were associated with cryoablation of prostate cancer. Notwithstanding these complications, the majority of studies indicated no significant disparities in complication rates between cryoablation and other prostate cancer treatment modalities. Remarkably, cryoablation was associated with substantially fewer overall complications compared to both prostatectomy and HIFU. Consequently, the Subcommittee concluded that cryoablation is a safe health technology. In terms of oncologic outcomes, cryoablation exhibited significantly lower overall and cancer-specific survival rates in comparison to prostatectomy and a higher incidence of recurrences relative to radiotherapy and HIFU. However, other oncologic outcomes did not demonstrate significant differences across treatment groups. Prostate functional outcomes, as measured by the IPSS and the IIEF, revealed no substantial differences between cryoablation and most other treatment methods (including active surveillance, HIFU, radiotherapy, and prostatectomy), although HIFU was noted to have a significantly better IIEF score compared to cryoablation. Regarding QoL, certain advantages and disadvantages were observed among different treatment methods, yet overall, no significant differences were discerned. In light of these findings, the Subcommittee deduced that cryoablation, when employed in the treatment of localized prostate cancer, is a safe health technology. While it is less effective than prostatectomy with respect to oncologic outcomes, its effectiveness is comparable to that of active surveillance, radiotherapy, and HIFU. During the third session of the Committee of Health Technology Reassessment in 2023 (on March 10, 2023), conclusions were drawn concerning cryoablation of prostate cancer, in alignment with the Subcommittee’s insights and Article 4-10 of the Guidelines for Management of Health Technology Reassessment. The Committee determined that cryoablation of prostate cancer is a safe technology and, despite its relative inferiority in effectiveness compared to surgical treatment, it is similarly effective to other treatment methods. Therefore, the Committee of Health Technology Reassessment “conditionally recommends” the use of cryoablation for treating patients with localized prostate cancer in Korea. This recommendation is predicated on a comprehensive evaluation of the evidence concerning its clinical safety and effectiveness, alongside other assessment criteria.

Keywords: Localized prostate cancer, Cryoablation, Safety, Effectiveness, Cost-effectiveness