인간 부고환 단백 4 [정밀면역검사]

Abstract

평가배경 인간 부고환 단백 4 [정밀면역검사]는 골반부 종괴가 있는 난소암 의심 환자를 대상으로 난소암을 진단하기 위한 종양표지자 검사이다. 2014년 신의료기술평가 당시 난소암 진단 목적으로 암항원 125(Cancer antigen 125, 이하 ‘CA125’) 검사와 보완적 검사로서 안전성과 효과성이 있다고 평가되었다. 이후 2016년 선별급여(본인부담률 80%)로 등재되었고 적합성평가 주기가 5년 이상 지났다. 임상자문회의 재평가 적합성 검토 및 의료기술재평가위원회 우선순위 심의 결과, 임상에서 인간 부고환 단백 4 [정밀면역검사]가 CA125 검사와 함께 로마(Risk of Ovarian Malignancy Algorithm, 이하 ‘ROMA’)를 많이 사용하고 있으며, 민감도와 특이도가 높은 검사로 알려져 있어 의료기술재평가를 통한 확인이 필요하다는 의견이었다. 이에 인간 부고환 단백 4 [정밀면역검사] 임상적 안전성 및 효과성을 확인하고 효율적인 보건의료자원 사용을 위한 근거를 제공하기 위하여 의료기술재평가를 수행하였다.

평가방법 HE4 검사 안전성 및 효과성 평가는 체계적 문헌고찰을 수행하였다. 평가방법은 평가목적을 고려하여 “인간 부고환 단백4 [정밀면역검사] 소위원회”(이하 ‘소위원회’) 논의를 거쳐 확정하였다. 소위원회는 진단검사의학 2인, 산부인과 2인, 근거기반의학 1인 전문가로 구성하였다. 핵심질문은 “골반부 종괴가 있는 난소암 의심 환자에서 인간 부고환 단백 4 [정밀면역검사]는 난소암 진단에 있어 임상적으로 안전하고 효과적인가?”이다. 실제 임상현장에서 인간 부고환 단백 4 [정밀면역검사](Human epidudymis protein 4 검사, 이하 ‘HE4 검사’)는 CA125 검사의 보완검사(add-on)로서 CA125가 높은 난소암 의심 환자를 대상으로 양성 종양일 가능성을 배제하고자 사용하였다. 이 때 HE4와 CA125 수치를 대입한 ROMA를 이용하여 난소암을 진단하였다. 그리고 난소암 진단 이후 HE4 수치를 모니터링하여 치료경과를 관찰하거나 난소암 재발을 확인하였다. 이에 HE4 검사의 사용양상을 고려하여 ① HE4 검사의 일환으로 ROMA를 중재검사로 포함하고, ② 난소암 진단정확성과 더불어 치료경과 및 재발 확인 효과를 검토하였다. 다만, 동 평가 목적에 따라 HE4 검사와 ROMA 간 의료결과 비교는 평가에서 제외하였다. 체계적 문헌고찰은 핵심질문을 토대로 국외 3개, 국내 5개 데이터베이스에서 검색하였으며, 문헌 선택･배제 기준에 따라 두 명의 검토자가 독립적으로 문헌을 선정하고, 의견 불일치가 있을 경우 회의를 통해 의견일치를 이루었다. 문헌의 비뚤림위험 평가는 Quality assessment of diagnostic accuracy studies-2 (QUADAS-2)를 사용하였으며, 자료추출은 미리 정해놓은 자료추출 양식을 활용하였다. 문헌의 비뚤림위험 평가와 자료추출은 모두 두 명의 검토자가 독립적으로 수행하였으며, 의견 불일치가 있을 경우 논의하여 합의하였다. 진단정확성은 STATA/MP 14.2를 이용하여 메타분석을 시행하였고, 치료경과 및 재발확인은 문헌에서 보고하는 의료결과가 다양하여 질적 검토(qualitative review)를 시행하였다.

평가결과 인간 부고환 단백 4 [정밀면역검사] 안전성과 효과성은 총 46편(국외 46편, 국내 0편)에 근거하여 평가하였다. 연구대상자는 신체검진, 초음파검사 등을 통해 골반종괴 또는 부속기 종양이 확인된 난소암 의심 환자 13,093명이었고, 조직병리학적 검사에 따라 악성종양 환자 3,989명(30.5%), 양성종양 환자 9,104명(69.5%)이었다. 선택문헌 46편 모두 HE4 검사를 수행하였고, 검사방법은 효소면역측정법 11편, 화학발광미세입자면역측정법 14편, 전기화학발광면역측정법 20편이었고, 치료 경과 및 재발 확인을 보고한 1편에서는 검사방법을 언급하지 않았다. 비뚤림위험 평가결과, 환자선택에서는 50.0%(23편)가 비뚤림위험 ‘높음’으로 평가하였고, 적용성 우려에서 15.2%(7편)가 ‘높음’이었다. 중재검사의 비뚤림위험은 28.3%(13편)가 ‘높음’이었고, 적용성 우려 부분에서 41.3%(18편)가 ‘높음’이었다. 참고표준검사의 비뚤림위험 및 적용성 우려 부분에서는 모두 ‘낮음’이었고, 연구진행과 시점의 비뚤림위험은 97.8%(45편)가 ‘낮음’으로 평가하였다.

안전성 인간 부고환 단백 4 [정밀면역검사] 안전성은 검사 관련 이상반응을 확인하고자 하였으나 이를 보고한 문헌은 없었다.

효과성 인간 부고환 단백 4 [정밀면역검사] 효과성은 진단정확성과 치료경과 및 재발 확인을 CA125 검사와 비교하였다. 진단정확성을 보고한 문헌은 40편이었고, 폐경 여부를 구분하지 않은 전체 환자(32편), 폐경 전 환자(21편), 폐경 환자(19편)로 구분하여 보고하였다. 이 중 ROMA 진단정확성을 보고한 문헌은 31편이었다. 인간 부고환 단백 4 [정밀면역검사] 는 전체 환자(32편, 9,838명)에서 통합민감도 0.75 (95% 신뢰구간(Confidence interval, CI) 0.71~0.78), 통합특이도는 0.95(95% CI 0.92~0.97), 통합진단정확도(Area under the curve, AUC) 0.90 (95% CI 0.87~0.92)이었다. 폐경 전 환자(21편, 5,014명)에서 통합민감도 0.69 (95% CI 0.63~0.75), 통합특이도는 0.95 (95% CI 0.92~0.97), 통합AUC 0.89 (95% CI 0.86~0.91)였다. 폐경 환자(19편, 3,079명)에서 통합민감도는 0.78 (95% CI 0.72~0.83), 통합특이도 0.96 (95% CI 0.92~0.98), 통합AUC 0.92 (95% CI 0.90~0.94)였다. 인간 부고환 단백 4 [정밀면역검사] 는 전체 환자, 폐경 전 환자, 폐경 환자에서 모두 CA125 검사보다 통합민감도는 낮고, 통합특이도는 높았으며, 2014년 신의료기술평가 전후에 따른 HE4 검사의 통합민감도와 통합특이도는 통계적으로 유의한 차이가 없었다. ROMA는 전체 환자(24편, 7,645명)에서 통합민감도 0.84 (95% CI 0.80~0.87), 통합특이도 0.86 (95% CI 0.82~0.90), 통합AUC 0.91 (95% CI 0.88~0.93)이었다. 폐경 전 환자(19편, 4,724명)에서 통합민감도 0.77 (95% CI 0.70~0.83), 통합특이도 0.90 (95% CI 0.86~0.93), 통합AUC 0.91 (95% CI 0.88~0.93)이었다. 폐경 환자(18편, 2,840명)에서 통합민감도 0.89 (95% CI 0.84~0.92), 통합특이도 0.90 (95% CI 0.86~0.92), 통합AUC 0.95 (95% CI 0.93~0.97)였다. ROMA는 전체 환자 및 폐경 환자에서 통합민감도, 통합특이도 모두 CA125 검사보다 높았다. 폐경 전 환자에서는 ROMA 통합민감도가 CA125 검사보다 낮았으나, 통합특이도는 CA125 검사보다 높았다. 2014년 신의료기술평가 전후에 따른 ROMA의 통합민감도와 통합특이도는 통계적으로 유의한 차이가 없었다. 치료경과 및 재발 확인을 보고한 문헌은 7편으로 난소암 재발 또는 전이가 의심되는 경우 HE4 검사의 진단정확성(3편)과 종양감축술 또는 항암화학요법 후 임상양상과 HE4 변화(5편)를 CA125 검사와 비교하였다. 난소암 재발 또는 전이 진단에 있어 HE4의 민감도는 0.70~0.88, 특이도는 0.92~1.00으로 민감도와 특이도 모두 CA125 검사(민감도 0.35~0.78, 특이도 0.59~0.87)보다 높았다. 종양감축술 또는 항암화학요법 후 임상양상과 HE4와 CA125 변화를 비교한 결과 ① HE4와 CA125 모두 일차 종양감축술 후 정상범위로 감소하였고, ② 치료 후 추적관찰 기간 동안 재발․전이 환자에서 HE4와 CA125가 재발․전이 소견이 나타나기 전 또는 동시에 증가하고 임계값보다 높은 수준을 보였으나 HE4가 CA125 보다 약 3~8개월 먼저 증가하는 양상을 보였다.

결론 및 제언 소위원회는 현재 문헌에 근거하여 인간 부고환 단백 4 [정밀면역검사]의 안전성 및 효과성 결과를 다음과 같이 제시하였다. 인간 부고환 단백 4 [정밀면역검사]와 관련된 이상반응을 보고한 문헌은 없었으나 체외에서 이루어지는 검사로 혈액채취 과정 이외에는 인체에 직접적인 위해를 가하지 않으므로 검사 수행에 따른 안전성에는 문제가 없다고 판단하였다. 인간 부고환 단백 4 [정밀면역검사]는 CA125 검사보다 민감도는 낮으나 수용할 수 있는 수준이고, 특이도는 높아 CA125 검사 결과와 종합하여 난소암을 진단하는 것이 필요하였다. 이에, 동 검사가 골반부 종괴가 있는 난소암 의심 환자를 대상으로 난소암 진단에 있어 안전하고, CA125 검사와 보완적으로 사용하는 검사로서 효과적이라고 판단하였다. 추가적으로 난소암 재발･전이 발생 시 혈중 HE4 수치가 CA125 보다 민감하게 증가하는 양상을 보이므로 동 검사가 임상에서 난소암 치료 후 경과 관찰 및 재발 확인을 위해 도움이 된다는 의견을 제시하였다. 2023년 제5차 의료기술재평가위원회(2023.5.12.)에서는 소위원회 검토 결과에 근거하여 의료기술 재평가사업 관리지침 제4조제10항에 의거 “인간 부고환 단백4 [정밀면역검사]”에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 임상적 안전성과 효과성의 근거 및 그 외 평가항목 등을 종합적으로 고려하였을 때, 국내 임상상황에서 골반부 종괴가 있는 난소암 의심 환자를 대상으로 난소암 진단 시 CA125 검사의 보완검사로서 ‘인간 부고환 단백4 [정밀면역검사]’의 사용을 ‘권고함’으로 심의하였다(권고등급: 권고함).

주요어 난소종양, 인간 부고환 단백 4, 난소암 진단, 보완검사

Background The Human epididymis protein 4 (HE4) [High quality immunoassay] (hereafter referred to as “HE4 test”), is a tumor marker test utilized for diagnosing ovarian cancer in patients suspected of having the disease, particularly those presenting with a pelvic mass. During the New Health Technology Assessment in 2014, this test was assessed to be a safe and effective adjunct to the cancer antigen 125 (CA125) test in diagnosing ovarian cancer. Following this assessment, the HE4 test was included as a selective benefit item in healthcare, necessitating an 80% patient co-payment and more than five years have passed since the conformity assessment cycle. Based on a reassessment conformity review by the Clinical Advisory Board and a priority review by the Committee of Health Technology Reassessment, it was determined that the HE4 test should be verified by health technology reassessment because it, along with the CA125 test, commonly uses the Risk of Ovarian Malignancy Algorithm (ROMA) and is known to be a test with high sensitivity and specificity. The purpose of this reassessment was to re-evaluate the clinical safety and effectiveness of the HE4 test and to substantiate its role in the efficient use of public health resources.

Methods To assess the safety and effectiveness of the HE4 test, a systematic review was conducted. The methodology for this review was determined by the “HE4 test subcommittee” (hereafter referred to as the “Subcommittee”). This Subcommittee, composed of five members, two with expertise in laboratory medicine, two from obstetrics/gynecology, and one from evidence-based medicine, focused on a key question, “Is the HE4 test clinically safe and effective for diagnosing ovarian cancer in suspected patients with a pelvic mass?” In practical clinical settings, the HE4 test is used in tandem with the CA125 test to differentiate between benign and malignant tumors in patients with high CA125 levels. The assessment involved diagnosing ovarian cancer using the ROMA, which incorporates both HE4 and CA125 levels. The assessment involved diagnosing ovarian cancer using the ROMA, which incorporated both HE4 and CA125 levels. Additionally, HE4 levels were monitored post-diagnosis to observe the treatment course and check for the recurrence of ovarian cancer. The assessment included ROMA as a part of the intervention process, but comparisons between the health outcomes of the HE4 test and ROMA were not considered, in line with the assessment's objective.

For the literature review, three international and five domestic databases were searched based on the key question. The articles were independently screened and selected by two reviewers according to specific inclusion and exclusion criteria. In cases of disagreement, a third reviewer was consulted to reach a consensus. The risk of bias (RoB) in the selected studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Data extraction was conducted using a predetermined format. The RoB assessment and data extraction processes were independently carried out by the two reviewers, with any disagreements resolved through discussion. For the assessment of diagnostic accuracy, a meta-analysis was performed using STATA/MP 14.2. Due to the variability in reported health outcomes, a qualitative review was conducted for evaluating the effectiveness of the HE4 test in identifying the treatment course and recurrence of ovarian cancer.

Results In the comprehensive assessment of the HE4 test's safety and effectiveness, a total of 46 studies were analyzed, all conducted outside of Korea. These studies encompassed a population of 13,093 patients suspected of having ovarian cancer, each presenting with either a pelvic mass or an adnexal tumor confirmed through physical examination or ultrasonography. Of these patients, histopathological findings identified 3,989 individuals (30.5%) with malignant tumors and 9,104 (69.5%) with benign tumors. Various methodologies were employed in these studies to perform the HE4 test, including enzyme-linked immunosorbent assay (11 studies), chemiluminescence microparticle immunoassay (14 studies), and electrochemiluminescent immunoassay (20 studies). Notably, one study, which reported on the treatment course and recurrence, did not specify the test method used. In terms of the RoB assessment, it was found that the RoB was high in 50% of the studies (23 studies) in the patient selection domain. Concerns about applicability were also high in 15.2% of these studies (2 studies). Furthermore, the RoB was high in 28.3% of the studies (13 studies) with high applicability concerns in 41.3% (18 studies) in the index test domain. Both the RoB and concern about applicability were low in the reference standard domain, and the RoB was low in 97.8% of the studies (45 studies) in the flow and timing domain.

Safety Regarding the safety of the HE4 test, it was assessed based on any test-related adverse events (AEs). However, it was noted that none of the studies reported such adverse events, indicating a lack of specific data concerning the direct safety implications of the HE4 test.

Effectiveness The effectiveness of the HE4 test was assessed based on its diagnostic accuracy, effectiveness in monitoring the treatment course, and detecting recurrence, all in comparison to the CA125 test. Diagnostic accuracy was reported in 40 studies, categorizing the patients as all patients (32 studies), pre-menopausal patients (21 studies), and menopausal patients (19 studies). The diagnostic accuracy of the ROMA was reported in 31 studies. The results showed that the HE4 test had a pooled sensitivity, pooled specificity, and pooled area under the curve (AUC) of 0.75(95% confidence interval [CI] 0.71–0.78), 0.95 (95% CI 0.92–0.97), and 0.90 (95% CI 0.87–0.92), respectively, among all patients (9,838 patients in 32 studies); 0.69 (95% CI 0.63–0.75), 0.95 (95% CI 0.92–0.97), and 0.89 (95% CI 0.86–0.91), respectively, among pre-menopausal patients (5,014 patients in 21 studies); and 0.78 (95% CI 0.72–0.83), 0.96 (95% CI 0.92–0.98), and 0.92 (95% CI 0.90–0.94), respectively, among menopausal patients (3,079 patients in 19 studies). The HE4 test exhibited lower pooled sensitivity and higher pooled specificity compared to the CA125 test in all patient groups. Additionally, no statistically significant differences were observed in the pooled sensitivity and pooled specificity of the HE4 test between the periods before and after the new health technology assessment in 2014. For ROMA, the pooled sensitivity, pooled specificity, and pooled AUC were 0.8495% CI 0.80–0.87), 0.86 (95% CI 0.82–0.90), and 0.91 (95% CI 0.88–0.93), respectively, among all patients (7,645 patients in 24 studies); 0.77 (95% CI 0.70–0.83), 0.90 (95% CI 0.86–0.93), and 0.91 (95% CI 0.88–0.93), respectively, among pre-menopausal patients (4,724 patients in 19 studies); and 0.89 (95% CI 0.84–0.92), 0.90 (95% CI 0.86–0.92), and 0.95 (95% CI 0.93–0.97), respectively, among menopausal patients (2,840 patients in 18 studies). ROMA demonstrated higher pooled sensitivity and pooled specificity than the CA125 test among all patients and menopausal patients. Among pre-menopausal patients, ROMA showed lower pooled sensitivity and higher pooled specificity than the CA125 test. Similar to the HE4 test, there were no statistically significant differences in the pooled sensitivity and pooled specificity of ROMA between the periods before and after the 2014 health technology assessment. Regarding the treatment course and recurrence, seven studies reported on these aspects. They compared the diagnostic accuracy of the HE4 test in cases where ovarian cancer recurrence or metastasis was suspected (3 studies) and observed changes in HE4 level and clinical features after cytoreductive surgery or chemotherapy (5 studies) in comparison to the CA125 test. For the diagnosis of ovarian cancer recurrence or metastasis, the HE4 test demonstrated a sensitivity range of 0.70–0.88 and specificity range of 0.92–1.00, which were higher than those of the CA125 test (sensitivity: 0.35–0.78 and specificity: 0.59–0.87). In comparing clinical features and changes in HE4 and CA125 levels after cytoreductive surgery or chemotherapy, it was noted that both HE4 and CA125 levels reduced to the normal range after primary cytoreductive surgery. Furthermore, both HE4 and CA125 levels increased above threshold levels before or concurrently with the recurrence or metastasis findings in patients with recurrence or metastasis during the post-treatment follow-up period. Of the two markers, the HE4 level tended to increase approximately 3-8 months earlier than the CA125 level.

Conclusions and recommendations The Subcommittee conducted a thorough evaluation of the HE4 test, synthesizing the current evidence available in the literature to gauge its safety and efficacy. Despite the absence of studies specifically reporting AEs associated with the HE4 test, the Subcommittee concluded that the test is generally safe. This determination is rooted in the fact that the HE4 test is an in vitro blood assay, which inherently carries minimal risk to patients, aside from the standard blood collection procedure. Regarding effectiveness, the HE4 test demonstrated a slightly lower sensitivity compared to the CA125 test. However, its sensitivity levels were deemed clinically acceptable. Notably, the HE4 test exhibited superior specificity relative to the CA125 test. Based on these findings, the Subcommittee advocated for the combined use of HE4 and CA125 tests in the diagnosis of ovarian cancer in patients presenting with a pelvic mass, affirming the enhanced diagnostic efficacy of this approach. Furthermore, the Subcommittee highlighted the clinical utility of the HE4 test in the post-treatment monitoring phase, particularly in the detection of recurrence or metastasis in ovarian cancer cases. It was observed that the levels of HE4 in the blood exhibit a more pronounced increase compared to CA125 levels in instances of cancer recurrence or metastasis. In the fifth session of the Committee of Health Technology Reassessment in 2023 (on May 12, 2023), definitive conclusions were drawn regarding the HE4 test, informed by the Subcommittee's findings and in alignment with Article 4-10 of the Guidelines for Management of Health Technology Reassessment. The Committee of Health Technology Reassessment “recommended” the employment of the HE4 test as an auxiliary diagnostic tool alongside the CA125 test in the identification of ovarian cancer in suspected patients with a pelvic mass. This is based on a comprehensive evaluation of the test's clinical safety, efficacy, and other pertinent assessment criteria, particularly within the context of clinical practice in Korea (Grade of recommendation: Recommended).

Keywords: Ovarian tumor, Human epididymis protein 4, HE4, Diagnosis of ovarian cancer, Add-on test