Polyamine의 안전성 및 유효성 평가

Abstract

평가배경 ‘Polyamine(보험분류번호 노289)’은 2001. 5. 1.에 등재된 비급여 의료기술로 소화기암, 폐암, 유방암, 난소암, 전립선암 등 고형암 및 백혈병, 악성 림프종과 같은 혈액암 환자의 소변에서 폭넓게 검출되는 종양 표지자인 polyamine을 검출하는 의료기술이다. 건강보험심사평가원에서는 신의료기술평가 이전에 등재된 비급여 항목의 예비급여 도입 검토를 위하여 관련 학(협)회의 의견 수렴 절차를 진행하였다. 그 결과 ‘안전성 및 유효성 검증 필요’ 등으로 회신된 19개 항목에 대한 안전성 및 유효성 평가를 본원으로 의뢰하였고, 이에 포함된 ‘Polyamine’을 평가하게 되었다.

위원회 운영 총 6인으로 구성된 소위원회는 2019. 8. 31.까지 약 5개월간 총 4회의 회의를 통해 동 기술을 평가하여 검토결과를 제출하였으며, 2019년 의료기술재평가위원회(2019. 12. 13.)에서 ‘Polyamine’의 안전성 및 유효성에 대한 평가결과를 심의하였다.

평가 목적 및 방법

Ⅰ.평가목적 ‘Polyamine’은 식도암, 위암, 간암, 췌장암, 결장암, 직장암, 폐암, 유방암, 자궁암/자궁경부암, 난소암, 전립선암, 백혈병, 악성 림프종 환자를 대상으로 소변 검체를 이용하여 polyamine을 검출하는 검사로 동 기술의 안전성과 유효성을 평가하였다.

ⅠI.평가방법 동 검사의 안전성 및 유효성에 대하여 체계적 문헌고찰을 통해 평가하였다. 문헌검색은 코리아메드를 포함한 5개 국내 데이터베이스와 Ovid-MEDLINE, Ovid-EMBASE 및 Cochrane Library의 3개 국외 데이터베이스를 이용하였다. 검색전략에 따라 neoplasm, cancer, urinary polyamine 등의 검색어를 이용하여 총 1,098편의 문헌을 검색하였다. 이 중 중복 검색된 문헌 230편을 포함한 총 1,074편의 문헌을 제외하여 최종 24편(국내 6편, 국외 18편)을 평가에 포함하였다. 문헌검색부터 선택기준 적용 및 문헌의 질 평가는 소위원회와 2명의 평가자가 독립적으로 수행하였고, 문헌의 질 평가는 QUADAS-2를 이용하였다.

평가 결과 동 기술의 안전성과 유효성은 총 24편의 문헌으로 평가하였고, 모두 진단정확성 연구였다.

Ⅰ.안전성 체계적 문헌고찰 결과 요중 polyamine 검사의 안전성에 대해 보고한 문헌이 없었고 환자의 소변을 채취하여 검사하는 체외진단검사이므로, 검사수행에 따른 안전성에 문제가 없는 것으로 평가하였다.

ⅠI.유효성 진단정확성에 대해 보고한 문헌은 24편으로, 문헌에서 보고한 민감도와 특이도는 암종에 따라, 요중 polyamine 검사 항목에 따라 매우 넓은 범위의 값으로 보고되었다. 양성질환자 대비 암 환자 감별진단 시 개별 암종 안에서 민감도, 특이도 등 진단정확성 지표는 문헌마다 보고한 값에 차이가 컸다. 민감도의 경우 식도암 12.5-87.5%, 위암 12.5-87.5%, 간암 21.4-100.0%, 췌장암 45.0-93.4%, 결장직장암 23.1-92.1%, 폐암 25.0-100.0%, 유방암 0-33.6%, 자궁경부암 37.0-51.0%, 난소암 10.5-100%, 전립선암 72.2-73.3%, 백혈병 25-100%으로 보고되었다. 특이도는 식도암 13.1-93.2%, 위암 13.1-93.2%, 간암 85.2-93.2%, 췌장암 13.1-88.5%, 결장직장암 13.1-93.2%, 폐암 32.0-88.5%, 난소암 0-100%, 전립선암 76.9-93.3%으로 보고되었다. 정상군 대비 암 환자의 감별진단 시 민감도는 식도암 37.5%, 위암 41.1-72.7%, 간암 76.5%, 췌장암 100%, 결장암 및 결장직장암 60.0-91.3%, 폐암 100%, 난소암 64.9-100%였다. 특이도는 식도암 100%, 위암 73.3-100%, 간암 100%, 췌장암 100%, 결장암 및 결장직장암 73.3-100%, 폐암 73.3%, 난소암 4.8-61.9%였다. 비교검사와의 상관성에 대해 보고한 문헌은 10편이며, 보고된 비교검사는 위암에서 CA-19-9, 간암에서 AFP, 췌장암에서 CA-19-9 및 CA-125, 결장직장암에서 CEA 및 CA-19-9, 자궁경부암에서 SCCA, 전립선암에서 PSA이었다. 10편의 문헌에서는 요중 polyamine과 비교검사 간의 상관관계에 대해 매우 낮은 수준이거나 유의한 상관관계가 없다고 보고하였다. 검사로 인한 치료방법의 변화 등 요중 polyamine의 의료결과에의 영향을 보고한 문헌은 없었다.

결론 Polyamine 소위원회는 현재 문헌적 근거를 바탕으로 다음과 같이 평가 결과를 제언하였다. 체계적 문헌고찰 결과 ‘Polyamine’의 안전성에 대해 보고한 문헌은 없었고 소위원회는 검사 수행과 관련하여 안전성에 문제가 없다고 판단하였다. 동 기술의 유효성에 대해서는 24편의 진단정확성 연구를 통해 진단정확성, 비교검사와의 상관성, 의료결과에의 영향 별로 평가하였다. 진단정확성의 경우 암종 및 보고자에 따라 진단정확성에 있어서 차이가 컸고, 비교검사와의 상관성의 경우 상관성이 낮거나 유의하지 않았으며, 검사로 인한 치료방법의 변화 등 의료결과에의 영향을 보고한 문헌은 없었다. 또한 국내외 임상진료지침에서 동 기술에 대한 가이드라인을 확인할 수 없었다. 소위원회는 이를 바탕으로 ‘Polyamine’의 유효성이 매우 낮다고 판단하였다.

의료기술재평가위원회는 ‘Polyamine’에 대해 소위원회의 검토결과에 근거하여 다음과 같이 심의하였다(2019. 12. 13.). 의료기술재평가위원회는 식도암, 위암, 간암, 췌장암, 결장암, 직장암, 폐암, 유방암, 자궁암/자궁경부암, 난소암, 전립선암과 같은 고형암 및 백혈병, 악성 림프종과 같은 혈액암 환자의 암 진단, 경과 및 예후 평가 시 ‘Polyamine’을 권고하지 않는다(권고등급 II).

Background "Polyamine (classification ID No 289)" is used to detect polyamine, a tumor marker extensively detected in the urine of patients with solid cancers (such as cancer in the digestive system, lung cancer, breast cancer, ovarian cancer, and prostate cancer) or blood cancers (such as leukemia and malignant lymphoma). The technology was added to the no-coverage list on May 1, 2001. The Korea Health Insurance Review and Assessment Service (HIRA) sought the opinions of relevant academic societies (associations) on changing the coverage status of the items to preliminary coverage listed in the no-coverage list before the introduction of the Innovative Health Technology Assessment System. Subsequently, the HIRA requested the Korea National Evidence-based Healthcare Collaborating Agency (NECA) to perform a safety and effectiveness assessment of the 19 items for which the relevant academic societies (associations) recommended safety and effectiveness assessment. "Polyamine" was one of the 19 items.

Committee operation A subcommittee composed of 6 members held a total of 4 meetings to assess the said technology within 5 months until August 31, 2019, and presented the review results. During the 2019 Health Technology Reassessment Committee meeting (December 13, 2019), the assessment results on "Polyamine" safety and effectiveness were reviewed.

Purposes and Methods

I. Purposes "Polyamine" is a test used to detect polyamine in urine specimens in patients with esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, lung cancer, breast cancer, cervical cancer/uterine cervix carcinoma, ovarian cancer, prostate cancer, leukemia, and malignant lymphoma. The purpose of this report was to assess the safety and effectiveness of the said technology.

II. Methods The safety and effectiveness of the said test were assessed via a systematic review. A literature search was performed using 5 domestic databases, including KoreaMed, and 3 foreign databases (Ovid-MEDLINE, Ovid-EMBASE, and Cochrane Library). A total of 1,098 articles were obtained from the search, which used keywords such as neoplasm, cancer, and urinary polyamine. Of those, 1,074 articles (including 230 duplicates) were excluded and 24 (6 Korean and 18 foreign articles) were finally included in the review.

The subcommittee and 2 assessors independently performed the literature review and article search using an application based on the selection criteria and the evaluation of the quality of articles. Article quality was evaluated using QUADAS-2.

Results A total of 24 articles were reviewed to assess the safety and effectiveness of the said technology. All of the articles were diagnostic accuracy studies.

I. Safety None of the articles reported the safety of urine polyamine test. Because it is an ex-vivo diagnostic test using urine specimens, it was determined that safety would not be an issue.

II. Effectiveness All 24 articles reported diagnostic accuracy. The sensitivities and specificities reported in the articles varied widely depending on the cancer type as well as the urine polyamine test item. For the differential diagnosis of benign tumors and cancer, the ranges of diagnostic accuracy index values like sensitivity and specificity were wide across the articles, even for the same cancer type. The range of sensitivity was 12.5-87.5% for esophageal cancer, 12.5-87.5% for stomach cancer, 21.4-100.0% for liver cancer, 45.0-93.4% for pancreatic cancer, 23.1-92.1% for colorectal cancer, 25.0-100.0% for lung cancer, 0-33.6% for breast cancer, 37.0-51.0% for uterine cervix carcinoma, 10.5-100% for ovarian cancer, 72.2-73.3% for prostate cancer, and 25-100% for leukemia. The specificities were 13.1-93.2% for esophagus cancer, 13.1-93.2% for stomach cancer, 85.2-93.2% for liver cancer, 13.1-88.5% for pancreatic cancer, 13.1-93.2% for colorectal cancer, 32.0-88.5% for lung cancer, 0-100% for breast cancer, and 76.9-93.3% for prostate cancer. For the differential diagnoses for normal and cancer patients, the sensitivities were 37.5% for esophagus cancer, 41.1-72.7% for stomach cancer, 76.5% for liver cancer, 100% for pancreatic cancer, 60.0-91.3% for colon and colorectal cancers, 100% for lung cancer, and 64.9-100% for ovarian cancer. The specificities were 100% for esophagus cancer, 73.3-100% for stomach cancer, 100% for liver cancer, 100% for pancreatic cancer, 73.3-100% for colon and colorectal cancers, 73.3% for lung cancer, and 4.8-61.9% for ovarian cancer. Ten articles reported the correlations with comparison tests. The reported comparison tests were CA-19-9 for stomach cancer, AFP for liver cancer, CA-19-9 and CA-125 for pancreatic cancer, CEA and CA-19-9 for colorectal cancer, SCCA for uterine cervix carcinoma, and PSA for prostate cancer. The articles reported that the correlations between the outcomes of the urine polyamine test and a comparison test was very low or did not reach significance. The impact of the urine polyamine test on healthcare outcomes, such as a change in treatment approach, was not reported in any of the articles.

Conclusion Based on the current evidence found in the literature, the Polyamine subcommittee presented the following assessment results. The systematic review showed that no article reported the safety of "Polyamine," and the subcommittee determined that safety is not an issue for the test. The effectiveness, diagnostic accuracy, correlation with comparison tests, and impact on healthcare outcomes were evaluated using 24 articles. Diagnostic accuracy widely varied depending on cancer type as well as the researchers. The correlation between the test and a comparison test was low or did not reach significance. None of the articles reported the test's impact on healthcare outcomes such as a change in the treatment approach. In addition, the subcommittee did not find any recommendations for the technology in the clinical practice guidelines inside and outside Korea. Based on the findings, the subcommittee determined that the effectiveness of "Polyamine" is very low.

Based on the "Polyamine" subcommittee's review results, the Health Technology Reassessment Committee made the following decision (December 13, 2019). The Health Technology Reassessment Committee does not recommend the use of "Polyamine" for diagnosis, patient follow-up, and prognosis evaluation for solid cancers (such as the esophagus, stomach, liver, pancreatic, colon, rectal, lung, breast, uterus/uterine cervix, ovarian, and prostate cancers) or blood cancers (leukemia and malignant lymphoma) (Grade of recommendation - II)