방사선 온열치료 - 소화기종양

Abstract

평가 배경 ‘방사선 온열치료’는 신체 조직을 고온(최대 45℃)에 노출시켜 정상 조직에 대한 손상을 최소화하면서 암세포를 치사시키는 암 치료법으로 방사선 요법 또는 항암요법과 함께 사용하며 암세포를 손상, 치사시키거나 방사선 또는 항암제에 더 예민하게 반응하도록 하는 기술이다. 2005년 1월부터 행위비급여 항목으로 사용되고 있으며, 건강보험심사평가원 예비급여부에서 해당 기술의 급여적용 타당성 판단 등 의사결정에 필요한 근거자료를 도출하기 위해 해당 행위의 재평가를 의뢰하였다. 본 평가의 목적은 소화기종양 환자에서 방사선 온열치료의 임상적 안전성 및 효과성 등에 대한 과학적 근거를 제공하고 이를 통해 의료기술의 적정사용 등 정책적 의사결정을 지원하는 것이다.

평가 방법 소화기종양 환자에서 방사선 온열치료에 대한 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “방사선 온열치료 소위원회(이하 ‘소위원회’라 한다)”의 심의를 거쳐 확정하였다. 소위원회 구성은 산부인과, 외과, 비뇨기과, 신경외과, 정형외과, 흉부외과 등 평가대상 암종 임상분과 각 1인과 방사선종양학과 1인, 혈액종양내과 1인, 영상의학과 1인, 근거기반의학 1인 등 총 10인으로 구성하였다. 평가의 핵심질문은 “소화기종양 환자에서 방사선 또는 항암요법과 병행하는 온열치료는 임상적으로 안전하고 효과적인가?”이었고, 안전성은 온열치료 관련 이상반응과 보고된 독성을 결과지표로 하였고, 효과성은 생존율, 관해율, 재발률, 삶의 질 등을 결과지표로 평가하였다. 체계적 문헌고찰은 핵심질문을 토대로 국외 3개, 국내 5개 데이터베이스에서 검색하였으며, 문헌 선정과정은 문헌선택 및 배제기준에 따라 2명의 평가자가 독립적으로 수행하고, 의견의 불일치가 있는 경우에는 평가자 간 합의를 통해 최종 논문을 결정하였다. 문헌의 비뚤림위험 평가는 Cochrane의 Risk of Bias (RoB) 및 Risk of Bias Assessment tool for Non-randomised Study (RoBANS) 2.0을 사용하여 평가하였으며, 최종 선택된 문헌을 대상으로 2명의 평가자가 독립적으로 평가를 실시하였으며, 의견이 불일치한 경우 평가자 간 합의를 통해 일치된 결과를 도출하였다. 모든 자료는 연구단위로 추출하였다. 본 평가에서 수행한 체계적 문헌고찰 결과는 암종 단위로 결과제시 및 Grading of Recommendations Assessment, Development and Evaluation (GRADE) 방법을 이용하여 근거 수준을 평가하고, 평가 결과를 토대로 권고등급을 결정하였다.

평가 결과 방사선 온열치료와 관련한 소화기종양 문헌은 총 16편이었으며 위암 2편, 췌장암 2편, 담관암 1편, 간암 2편, 대장암 1편, 항문직장암 8편이었다.

위암 위암에서 최종 선택된 문헌은 무작위배정임상연구(Randomized controlled trial, RCT) 2편이었다. 두 편 모두 중국에서 수행되었으며 총 환자수는 187명이었다. 평균 연령은 52~64세이었으며 각각 방사선요법과 화학요법에 온열치료를 병행하여 치료법을 중재군으로 하였다. 온열치료는 42℃ 전후에서 45~60분간 주 2회 수행하였으며 고주파를 열원으로 하는 온열치료 기기를 사용하였다.

위암 안전성 위암 2편의 연구에서 온열치료와 직접적으로 관련이 있는 이상반응을 보고한 경우는 없었으며 그 외 위장관계, 신장/간장계, 혈액학적 독성을 보고하였다. 위장관계 독성은 2편의 연구에서 등급에 따라 보고하였으며 3등급 이상의 오심/구토는 중재군 및 비교군에서 각각 2편(5.9%), 3편(8.8%) 발생하였고 3등급 이상의 복통은 각각 3편(8.8%), 2편(5.9%)이었다. 3등급 이상의 위장관 독성은 중재군에서 1편(1.8%), 비교군에서 3편(4.8%)이었고 양 군에서 유의한 차이를 보이지 않았다(p=0.469). 신장 및 간장 손상 발생은 중재군과 비교군 간에 유의한 차이가 없었고 3등급 이상의 독성을 발생하지 않았다. 혈액계 독성으로 보고된 골수억제는 군 간 차이가 없었다. 문헌 수의 제약으로 소위원회에서는 위암에서 온열치료의 안전성을 판단하기에 근거가 불충분한 것으로 평가하였다.

위암 효과성 온열치료 효과성은 생존율, 관해율 관련 결과지표로 평가하였다. 2편의 연구에서 보고한 전체 생존율의 결과는 서로 방향성이 달랐으며 제한적인 자료값으로 인해 합성할 수 없었다. 한 편의 문헌에서는 중재군의 전체 생존기간 중앙값이 14개월, 비교군의 전체 생존기간은 9개월로 중재군에서의 전체 생존기간이 유의하게 높았으나(p = 0.03) 다른 문헌에서는 2년 전체 생존율이 중재군 60.0%, 비교군 70.8%로 군 간 유의한 차이가 없었다(p = 0.056). 무국소진행 생존율은 군 간 차이를 확인할 수 없었다. 치료반응에서 완전관해율, 부분관해율, 불변율, 병변진행율은 군 간 유의한 차이가 없었으나 객관적 반응율(p = 0.044)과 질병조절률(상대위험비(Relative risk, (RR)) 1.27, 95% Confidence Interval(CI) 1.06~1.53, I2 = 87%)은 중재군에서 유의한 개선효과를 확인할 수 있었다.

췌장암 췌장암에서 최종 선택된 문헌은 비무작위배정연구(Non-randomized controlled trial, NRCT) 1편, NRS 1편으로 총 2편이었다. NRCT 연구는 유럽에서 원발성 또는 재발성 췌장암 환자 68명을 대상으로 수행되었으며 방사선 및 화학요법과 온열치료의 병용요법을 중재군으로 하였다. 온열치료는 42℃ 이상에서 60분간 주 2회 수행하였다. NRS 연구는 13명의 절제 불가능한 국소 진행성 췌장암 환자를 포함하였으며 온열치료는 41℃에서 50분간 주 1~2회씩 총 5~6회 수행하였다.

췌장암 안전성 2편의 연구에서 안전성을 보고하였으며 보고된 이상반응 중 온열치료와 직접적으로 관련있는 것은 없었다. 3등급 이상의 위장염이 보고되었으나 통계적 유의성은 평가하지 않았다. 혈액계 독성으로 백혈구 감소증, 빈혈, 혈액독성이 등급에 따라 보고되었다. 2등급 백혈구 감소증은 중재군과 비교군에서 각각 3편(7.5%), 2편(7.1%)였으며 빈혈은 각각 2편씩 발생하였고 3등급 이상의 독성은 각 군에서 2편씩(중재군 40.0%, 비교군 25.0%) 발생하였다. 이러한 위장관계, 혈액계 독성은 온열치료 관련 부작용이라기보다 방사선 또는 화학요법으로 인한 부작용으로 소위원회에서는 판단하였다.

췌장암 효과성 2편의 문헌에서 전체 생존율만을 보고하였다. NRCT 문헌에서 1년 생존율은 중재군 64.7%, 비교군 61.5%였으며 생존기간 중앙값은 중재군에서 15개월(범위 6~20개월), 비교군에서 11개월(범위 5~13개월)로 중재군에서 유의하게 높았다(p = 0.025). NRS에서도 1년 전체 생존율이 비교군 대비 온열치료 병용중재군에서 유의하게 높았다(RR 15.97, 95% CI 12.87~19.83) .

담관암 담관암에서 최종 선택된 문헌은 NRCT 1편이었다. 진행성 간문부 담관암 환자 43명을 대상으로 간동맥주입화학요법(Hepatic arterial infusion chemotherapy, HAIC)을 포함하는 화학요법과 온열치료를 함께 사용하였을 때의 효과를 확인하였다. 환자의 연령은 중앙값 61~64세였고 온열치료는 HAIC와 동시에, 41.5~43℃에서 수행하였다.

담관암 안전성 최종 선택된 1편의 문헌에서 안전성이 보고되었다. 온열치료와 관련하여 경증의 배꼽 통증은 45편(34.6%) 발생하였고 피부 발진은 32편(24.6%) 발생하였다. 항암치료 관련 이상반응으로 위장관 출혈 및 대퇴부 출혈이 양 군에서 2~4편 발생하였으나 군 간 유의성은 없었다. 3~4등급의 혈액계 독성 및 비혈액계 독성 역시 발생하였으나 중재군과 비교군 간의 유의한 차이는 없었다. 하지만 문헌 수의 제약으로 소위원회에서는 담관암에서 온열치료의 안전성을 평가하기에 근거가 불충분한 것으로 판단하였다.

담관암 효과성 담관암에서 온열치료의 효과성은 생존율과 관해율 지표로 평가하였다. 전체 생존기간은 중재군에서 중앙값 20.3개월(95% CI 16.3~24.3), 비교군은 13.2개월(95% CI 10.2~16.2)로 온열치료를 포함하는 중재군에서 생존기간이 유의하게 높았다(p = 0.004). 위험비(Hazard ratio, 이하 HR)는 2.63 (95% CI 1.31~5.27)으로 온열치료를 포함하는 중재군이 생존율이 유의하게 높았다(p = 0.007). 무진행 생존율 역시 중재군에서 중앙값 16.5개월, 비교군에서 10.2개월로 중재군에서 유의하게 증가하였다(p < 0.001). 치료반응과 관련하여 객관적 반응율(p = 0.005)과 질병조절율(p = 0.039)이 비교군 대비 중재군에서 유의하게 높았다.

간암 간암에서 최종 선택된 문헌은 RCT 2편이었다. 2편 모두 중군에서 수행되었으며 진행성 간세포암 환자 178명을 대상으로 방사선치료와 온열치료의 병용 또는 경동맥화학색전술(Transcatherter arterial chemoembolization, 이하 TACE)과 온열치료의 병용을 중재치료로 하였다. 온열치료는 41~43℃에서 수행하였으며 치료시간은 30~60분이었다. 비뚤림위험을 평가한 결과, 2편 모두 무작위 배정순서 생성과 배정순서 은폐에 대한 언급이 없어 이 항목에 대한 비뚤림위험을 ‘불확실’로 평가하였다. 그리고 1편의 문헌에서 연구비 출처에 대한 언급이 없어 민간연구 지원 비뚤림위험을 ‘불확실’로 평가하였으며 그 외 비뚤림위험은 모두 ‘낮음’이었다.

간암 안전성 최종 선택된 3편의 문헌 중 1편에서만 안전성이 보고되었다. 온열치료와 직접적으로 관련있는 이상반응은 보고되지 않았다. 전체 이상반응은 TACE와 온열치료 중재군에서 7편(14.3%), TACE 단독치료 비교군에서 17편(35.0%) 발생하여 중재군에서 유의하게 낮았다(p = 0.019). 그러나 개별 이상반응(기흉, 복강출혈, 간농양, 담관 손상)으로 비교하였을 때에는 중재군과 비교군 간의 유의한 차이는 없었다.

간암 효과성 간암에서 온열치료의 효과성은 생존율, 관해율, 재발률, 삶의 질 지표를 토대로 평가하였다. 전체 생존율을 보고한 2편의 문헌을 메타분석하였을 때 RR 값은 0.96(95% CI 0.75~0.23, I2 = 0.0%)으로 온열치료 여부가 전체 생존율에 영향을 주지 않았다. 관해율 지표에서 객관적 반응율과 질병조절율에 대해 메타분석을 수행한 결과, 객관적 반응률의 RR 값은 1.39(95% CI 0.90~2.15, I2 = 0.0%), 질병 조절률 RR 값 1.19(95% CI 0.89~1.60, I2 = 0.0%)로 중재군과 비교군 간에 유의한 차이가 없었다. 1년 재발률은 중재군에서 27.5%, 비교군에서 40.0%로 중재군에서 유의하게 낮았다(p < 0.001). 삶의 질은 Quality of life – liver cancer (QOL-LC) 도구를 이용하여 측정하였으며 치료완료 후 중재군과 비교군의 역할, 신체, 감정, 인지, 사회 기능 5개 영역 삶의 질을 비교하였을 때 모두 중재군에서 유의하게향상되었다(p < 0.001).

대장암 대장암에서 최종 선택된 문헌은 NRS 1편이었다. 중국에서 수행되었으며 중기 및 진행성 대장암 환자 105명을 대상으로 항암화학요법 및 방사선 온열치료의 병용중재와 항암화학요법 단독치료를 비교하였다. 온열치료는 41~43℃에서 46~60분 간 총 4회 수행되었다. ROBANS를 이용한 비뚤림위험 평가 결과, 교란변수에 대한 언급이 없어 교란변수 비뚤림위험이 ‘불확실’한 것으로 평가하였다. 그 외 대상군 비교 가능성, 대상군 선정, 노출측정, 평가자 눈가림, 결과평가 눈가림, 불완전한 결과자료, 선택적 결과보고, 민간 연구 지원 비뚤림위험은 모두 ‘낮음’으로 평가하였다.

대장암 안전성 온열치료와 직접적으로 관련된 이상반응은 보고되지 않았다. 전체 이상반응은 중재군과 비교군 간의 유의한 차이가 없었으며 위장관계, 혈액계 독성과 피로감 발생에서도 두 군간 차이는 없었다. 그러나 피부 관련 독성으로 중재군에서 버짐 발생이 1편(1.8%) 보고되었다. 대장암에서 방사선 온열치료와 관련한 문헌이 NRS 1편 밖에 없어서 소위원회에서는 대장암에서 온열치료의 안전성을 평가하기에 근거가 불충분한 것으로 판단하였다.

대장암 효과성 대장암에서 온열치료의 효과성은 생존율과 관해율, 삶의 질 결과지표로 평가하였다. 3년 전체 생존율은 중재군 16.4%, 비교군 12.5%로 중재군에서 유의하게 높았다(p = 0.05). 관해율의 경우, 완전관해율, 안정병변율, 병변진행율은 군 간 유의성이 없었으나 부분관해율(RR 1.69, 95% CI 1.04~2.75, p = 0.04)과 객관적 반응율(RR 1.75, 95% CI 1.13~2.70, p = 0.01)이 중재군에서 더 높았다. 삶의 질은 The European organization for research and treatment of cancer Core Quality of Life Questionnaire(EORTC QLQ-C30)을 이용하여 평가하였으며 치료 후 중재군과 비교군의 삶의 질을 비교하였을 때, 평가한 모든 영역(감정/역할/인지/신체/사회적 기능)에서 중재군이 더 개선된 효과를 나타내었다(p < 0.05).

항문직장암 항문직장암에서 최종 선택된 문헌은 RCT 2편, NRCT 6편이었다. NRCT 문헌 중 선행연구의 하위그룹분석 연구 또는 추적관찰연구가 포함되어 있어 연구 수는 4편이었다. 항문직장암 6편의 연구 중 4편의 연구가 유럽에서 수행되었고 2편의 연구는 한국에서 수행되었다. 직장암 대상 연구는 5편, 항문암 연구는 1편이었으며, 연구에 포함된 환자수는 총 964명으로 RCT와 NRCT에 포함된 환자수는 각각 189명, 775명이었다. 평균 연령은 57~68세였으며 온열치료는 39.5~42℃에서 60분 전후로 주 1~2회 수행되었다. NRCT 문헌 중 2편의 문헌에서 환자의 기저특성에 차이를 보여 대상군 비교 가능성 비뚤림위험이 ‘높음’으로 평가, 해당 항목의 비뚤림위험이 33.3%로 나타났다.

항문직장암 안전성 항문직장암에서 안전성을 보고한 문헌은 RCT 1편과 NRCT 3편이었다. 온열치료 관련 독성으로, 3등급 독성이 2건(3.2%)이 보고되었으며 3등급 이상의 피부 관련 독성은 중재군에서 3.7~30.0%, 비교군에서 0~25.8%이었다. 위장관계 독성으로 조기문합누출, 지연문합누출, 무합협착, 소장폐쇄, 설사 및 구토, 장폐색으로 인한 수술이 보고되었으나 중재군과 비교군 간에 유의한 차이는 없었다. 그러나 NRCT 1편에서 보고한 위장관 독성은 등급별 독성 발생에서 군 간 유의한 차이를 타나내었다(p = 0.01). 혈액계 독성의 경우, 한 편의 문헌에서는 백혈구 및 호중구 감소증 발생에 있어서 군 간 차이가 없었으나 다른 한 편에서는 조기 혈독성(p = 0.03), 후기 모세혈관확장증(p = 0.009) 발생이 중재군에서 유의하게 높았다. 후기 변실금, 비뇨생식기 독성은 군 간 차이가 없었다.

항문직장암 효과성 항문직장암에서 온열치료의 효과성은 RCT 2편, NRCT 4편에서 보고하였으며 생존율과 관해율, 재발률, 삶의 질 결과지표로 평가하였다. RCT 문헌에서 보고한 3년 전체 생존율은 중재군 72.2%, 비교군 62.2%로 군 간 유의한 차이가 없었으며(p = 0.44) 완전관해율과 국소 조절율 역시 군 간 유의한 차이가 없었다. 삶의 질은 gastrointestinal QoL Index (GIQLI) 도구를 이용하였으며 장기시점에서의 삶의 질은 온열치료를 포함하는 중재군에서 비교군보다 유의하게 낮았다(Standardized mean difference (SMD) –0.85 (95% CI –1.47~-0.24), p = 0.007). NRCT 문헌에서 전체 생존율을 보고한 문헌은 3편이 있었으며 메타분석 수행 결과, RR값은 1.08(95% CI 0.91~1.28, I2 = 0.0%)로 온열치료 유무가 생존율에 영향을 미치지 못하였다. 무질병 생존율(RR 1.14, 95% CI 0.92~1.41, I2 = 0.0%)과 무국소재발 생존율(RR 1.03,95% CI 0.85~1.25, I2 = 24.8%)도 방사선 온열치료 병용에 따른 차이를 보이지 않았다. 완전관해율의 RR 값은 2.04(95% CI 0.94~4.45, I2 = 0.0%)로 유의한 개선이 보이지 않았다.

결론 및 제언

위암 위암에서 방사선요법 및/또는 화학요법과 온열치료의 병용중재군과 방사선요법 및/또는 화학요법의 비교군을 체계적 문헌고찰로 비교한 결과, 온열치료와 직접적으로 관련이 있는 이상반응은 보고되지 않았으며 위장관계, 신장 및 간장계, 혈액계 독성이 발생하였으나 양 군의 차이가 유의하지 않았다. 효과성은 전체 생존율을 보고한 2편의 문헌에서 결과의 방향성이 상이하였고 무국소진행 생존율은 중재군에서 유의하게 높았다. 완전관해율, 부분관해율, 객관적 반응율은 모두 온열치료에 따른 유의한 차이를 확인할 수 없었다. 소위원회에서는 본 평가결과, 위암 환자에서 온열치료를 병용중재로 하는 선택문헌이 RCT 2편으로 확인되어 안전성 및 효과성을 판단하기에는 근거가 불충분한 것으로 평가하였다(근거의 신뢰수준, Low).

췌장암 췌장암에서 방사선화학요법과 온열치료의 병용요법와 방사선화학 단독요법을 체계적 문헌고찰을 통해 비교한 결과, 온열치료와 직접적으로 관련있는 이상반응은 보고되지 않았으며 위장관계, 혈액 독성 발생에 있어서 양 군간 유의한 차이를 보이지 않았다. 효과성은 전체 생존율을 보고하였으며 NRCT 문헌 1편과 NRS 1편에서 온열치료를 포함하는 중재군이 비교군보다 전체 생존율이 유의하게 개선되었다. 본 평가결과, 소위원회에서는 췌장암 환자에서 방사선화학요법과 온열치료의 병용요법에 관한 연구가 NRCT와 NRS 각 1편씩 총 2편이 있어 안전성과 효과성을 판단하기에 근거가 불충분한 것으로 평가하였다(근거의 신뢰수군, Very low ~ Low).

담관암 담관암에서 화학요법과 방사선 온열치료의 병용 중재군과 화학요법 단독군을 체계적 문헌고찰을 통해 비교한 결과, 온열치료 관련 이상반응으로 경증의 배꼽(hilar) 통증 및 피부발진이 발생하였다. 항암치료 관련 이상반응이나 혈액계 및 비혈액계 독성이 보고되었으나 중재군과 비교군 간 유의한 차이가 없었다. 효과성은 전체 생존율 및 무질병 생존율은 온열치료를 포함한 병용중재군이 비교군보다 유의하게 향상되었다. 완전관해율 및 부분관해율은 양 군에서 유의한 차이를 보이지 않았다. 본 평가결과, 소위원회에서는 담관암 환자에서 화학요법과 방사선 온열치료의 중재 연구가 NRCT 1편만 있어 안전성과 효과성을 판단하기에 근거가 불충분한 것으로 평가하였다(근거의 신뢰수준, Low)

간암 간암에서 방사선요법 또는 경동맥화학색전술과 온열치료의 병용치료를 체계적 문헌고찰을 통해 비교한 결과, 온열치료와 직접적으로 관련있는 이상반응은 보고되지 않았으며 호흡기계 및 위장관계 독성과 간농양이 발생하였으나 중재군과 비교군 간 독성 발생에 유의한 차이 없었다. 효과성에 있어서 전체 생존율 및 완전관해율, 부분관해율 모두 비교군 대비 중재군에서 유의한 차이를 보이지 않았다. 본 평가결과, 소위원회에서는 간암에서 온열치료의 병용요법 연구는 RCT 2편으로 안전성 및 효과성을 판단하기에 근거가 불충분한 것으로 평가하였다(근거의 신뢰수준, Moderate).

대장암 대장암에서 화학요법과 온열치료의 병용요법을 체계적 문헌고찰을 통해 평가한 결과, 온열치료와 직접적으로 관련있는 이상반응은 보고되지 않았으나 피부 관련 독성으로 중재군에서 버짐 1편이 보고되었다. 전체 이상반응을 포함하여 위장관계, 혈액계, 피부 관련 독성에서 양 군 간 유의한 차이는 없었다. 효과성에 있어서 전체 생존율은 중재군과 비교군 간 유의한 차이가 없었다. 1편의 연구에서 보고된 전체 생존율은 온열치료를 포함하는 중재군에서 유의하게 향상되었으며 완전관해율은 군 간 차이를 보이지 않았으나 부분관해율은 중재군에서 유의하게 높았다. 본 평가결과, 대장암 환자에서 온열치료 병용요법 연구는 NRS 1편으로 소위원회에서는 안전성 및 효과성을 판단하기에 근거가 불충분한 것으로 평가하였다(근거의 신뢰수준, Low).

항문직장암 항문직장암에서 방사선화학요법과 온열치료의 병용요법에 대한 체계적 문헌고찰을 통해 평가한 결과, 온열치료 관련하여 3등급 이상 독성은 2편 발생하였으며 그 외 피부 관련, 혈액계 및 비뇨기계 독성은 양 군 간 유의한 차이가 없었던 점을 고려하여 온열치료는 안전한 기술로 판단하였다. 효과성은 전체 생존율, 무질병 생존율, 무국소재발 생존율, 완전관해율 모두 온열치료 병용에 따른 유의한 차이는 없었다. 본 평가결과, 소위원회에서는 항문직장암 환자에서 방사선화학요법과 온열치료의 병용중재는 온도 관찰 하에서 안전한 기술이며 효과성은 방사선화학요법 대비 추가적인 치료효과가 없는 기술로 평가하였다(근거의 신뢰수준, Very Low~Moderate). 2021년 제12차 의료기술재평가위원회(2021.12.10.)에서는 소위원회 검토 결과와 관련하여 논의를 하여 의료기술재평가사업 관리지침 제4조제10항에 의거 “소화기종양 환자에서 온열치료”에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 방사선 온열치료는 방사선요법 및(또는) 항암화학요법과 병행하여 보조적으로 사용하는 기술로, 암종에 따라 근거가 불충분하거나 근거가 있는 경우에는 추가적인 치료효과를 확인할 수 없었다는 소위원회 결론에 동의하고, 방사선 온열치료를 암종으로 분리하지 않고 종합적으로 심의하기로 하였다. 의료기술재평가위원회는 방사선 온열치료가 2004년 비급여 항목으로 고시되어 10년 이상 사용되어 왔음에도 근거가 충분하지 않음을 고려하여 암환자에서의 방사선 온열치료를 “권고하지 않음”으로 심의하였다(권고등급: 권고하지 않음).

주요어 온열치료, 위암, 췌장암, 담관암, 간암, 대장암, 항문직장암

Hyperthermia Combined with Radiation Therapy—Gastrointestinal Tumors

Background Hyperthermia combined with radiation therapy is a cancer treatment intended to kill cancer cells while minimizing damage to normal tissues. It involves exposing body tissues to high temperatures (up to 45℃), which damage or kill cancer cells or make them more susceptible to radiation or chemotherapy. As it has been considered an out-of-pocket treatment since January 2005, the Preliminary Benefit Department of the Health Insurance Review and Assessment Service requested a reassessment of the act to obtain the necessary data for decision-making, such as determining the feasibility of applying the technique. This assessment aimed to provide scientific evidence for the clinical safety and effectiveness of hyperthermia combined with radiation therapy in patients with gastrointestinal tumors and to support policy decisions related to the appropriate use of health technology.

Methods A systematic literature review was conducted to evaluate the safety and effectiveness of hyperthermia with radiation in patients with gastrointestinal tumors. All assessment methods were finalized after deliberation by the Subcommittee on Hyperthermia Combined with Radiation Therapy (hereinafter referred to as the "Subcommittee"), considering the purpose of the assessment. The subcommittee consisted of 10 members: one each from clinical departments of obstetrics and gynecology, surgery, urology, neurosurgery, orthopedic surgery, and thoracic surgery; one from radiation oncology; one from hematology and oncology; one from radiology; and one from evidence-based medicine. The key question in the assessment was: "Is hyperthermia combined with radiation therapy or chemotherapy clinically safe and effective in patients with gastrointestinal tumors?" Safety was assessed based on adverse events and reported toxicity associated with hyperthermia, and effectiveness was assessed based on the survival rate, remission rate, recurrence rate, and quality of life (QoL) as indicators. Based on the key question, three overseas and five domestic databases were used for the systematic literature review. Studies were selected independently by two assessors according to the literature inclusion and exclusion criteria. In the event of any disagreement, consensus was reached by discussion among the assessors. The risk-of-bias (ROB) in the included studies was assessed two assessors independently using Cochrane's Risk-of-Bias tool and the Risk-of-Bias Assessment tool for Non-randomized Studies (RoBANS) 2.0. In the event of any disagreement, decisions were made by achieving consensus through discussion among the assessors. All data were extracted by study unit. For the results of the systematic literature review, the level of evidence was assessed by presenting the results by using the Grading of Recommendations, Assessment, Development, and Evaluation. The recommendation grade was determined based on the assessment results.

Results A total of 16 studies on gastrointestinal tumors related to hyperthermia combined with radiation therapy were identified; there were two studies on stomach neoplasms, two on pancreatic neoplasms, one on bile duct neoplasms, two on liver neoplasms, one on colonic neoplasms, and eight on rectal neoplasms.

Stomach neoplasms The studies on stomach neoplasms included two randomized controlled trials (RCTs). Both studies were conducted in China and included a total of 187 patients. The average age of patients ranged from 52 to 64 years. The intervention group was treated with hyperthermia combined with radiation therapy and/or chemotherapy. Hyperthermia involved exposure to a temperature of 42℃ for 45–60 min per session, in two sessions per week, using a radio-frequency hyperthermia device.

Safety in patients with stomach neoplasms In two studies on stomach neoplasms, no adverse event directly related to hyperthermia was reported, although other gastrointestinal, renal/hepatic, and hematological toxicities were reported. Two studies reported on gastrointestinal toxicity according to grade. In the intervention and control groups, respectively, two (5.9%) and three (8.8%) patients experienced severe nausea and vomiting of grade 3 or more, and three (8.8%) and two (5.9%) patients experienced severe abdominal pain of grade 3 or more. In the intervention and control groups, respectively, one (1.8%) and three (4.8%) patients experienced severe gastrointestinal toxicity of grade 3 or more, with no statistically significant difference between the groups. There was no statistically significant difference in kidney and liver damage between the intervention and control groups, and there was no severe toxicity of grade 3 or more. Myelosuppression reported as hematologic toxicity was not statistically significantly different between the groups. Due to the limited number of studies, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with stomach neoplasms.

Effectiveness against stomach neoplasms The effectiveness of hyperthermia was assessed based on the survival rate and remission rate-related indices. The results of the overall survival (OS) reported in the two studies had different directions and could not be synthesized due to limited data values. In one study, the median OS in the intervention group was 14 months and that in the comparison group was 9 months, indicating that the OS in the intervention group was significantly higher (p = 0.03). In the other study, the 2-year OS was 60.0% in the intervention group and 70.8% in the control group, with no significant difference between the groups (p = 0.056). No significant difference in local progression-free survival (LPFS) between the groups was identified. There was no significant difference between the groups in terms of treatment response, such as the complete remission rate, partial remission rate, invariance rate, and progressive disease (PD). However, the objective response rate (p = 0.044) and disease control rate (relative risk [RR] 1.27, 95% confidence interval [CI] 1.06–1.53, I2 = 87%) showed significant improvement in the intervention group.

Pancreatic neoplasms The two studies on pancreatic neoplasms that were finally selected included one non-RCT (NRCT) and one non-randomized study (NRS). The NRCT was conducted in Europe with 68 patients with primary or recurrent pancreatic cancer, and the intervention group was treated using hyperthermia combined with radiation therapy and/or chemotherapy. Hyperthermia involved exposure to a temperature of 42℃ for 60 min per session, two sessions per week. The NRS included 13 patients with unresectable locally advanced pancreatic cancer. Hyperthermia involved exposure to a temperature of 41℃ for 50 min per session, for one to two sessions per week, for a total of five to six sessions.

Safety in patients with pancreatic neoplasms Two studies provided safety-related reports. There was no adverse event directly related to hyperthermia. Severe gastroenteritis of grade 3 or more was reported, although statistical significance was not assessed. As for hematologic toxicity, leukopenia, anemia, and hemotoxicity were reported according to grade. Grade 2 leukopenia occurred in three (7.5%) and two cases (7.1%) in the intervention and control groups, respectively. Two cases of anemia occurred in each group. Two cases of severe toxicities of grade 3 or more occurred in each group (40.0% in the intervention group and 25.0% in the control group). The Subcommittee determined that such gastrointestinal and hematological toxicities were adverse events of radiation therapy and/or chemotherapy rather than being related to hyperthermia.

Effectiveness against pancreatic neoplasms Two studies only reported the OS. In the NRCT, the 1-year OS was 64.7% in the intervention group and 61.5% in the comparison group. The median survival time was 15 months (from 6 to 20 months) in the intervention group and 11 months (from 5 to 13 months) in the control group, which was significantly higher in the intervention group (p = 0.025). In the NRS, the 1-year OS was significantly higher in the intervention group than in the control group (RR 15.97, 95% CI 12.87–19.83).

Bile duct neoplasms One NRCT on bile duct neoplasms was selected. The effect of chemotherapy, including hepatic arterial infusion chemotherapy (HAIC), combined with hyperthermia was examined in 43 patients with advanced hilar cholangiocarcinoma. The median age of patients was 61 to 64 years. Hyperthermia involved exposure to a temperature of 41.5–43℃ simultaneously with HAIC.

Safety in patients with bile duct neoplasms The one study on bile duct neoplasms that was finally selected provided safety-related reports. In relation to hyperthermia, mild umbilical pain occurred in 45 cases (34.6%) and skin rash occurred in 32 (24.6%). As adverse events related to chemotherapy, gastrointestinal bleeding and femoral bleeding occurred in two to four cases in both groups, although there was no significant difference between the groups. Grade 3–4 hematologic and non-hematologic toxicities also occurred, although there was no statistically significant difference between the intervention and control groups. Due to the limited number of studies, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with bile duct neoplasms.

Effectiveness against bile duct neoplasms The effectiveness of hyperthermia against bile duct neoplasms was assessed based on the survival rate and remission rate indicators. The median OS time was 20.3 months (95% CI 16.3–24.3) in the intervention group and 13.2 months (95% CI 10.2–16.2) in the control group, which was significantly higher in the intervention group using hyperthermia (p = 0.004). The hazard ratio (HR) was 2.63 (95% CI 1.31–5.27), and the survival rate was significantly higher in the intervention group using hyperthermia (p = 0.007). The PFS also significantly increased in the intervention group, with a median value of 16.5 months in the intervention group and 10.2 months in the control group (p < 0.001). In relation to treatment response, the objective response rate (p = 0.005) and disease control rate (p = 0.039) were significantly higher in the intervention group than in the control group.

Liver neoplasms The relevant studies on liver neoplasms included two RCTs. Both studies were conducted in China, involving 178 patients with advanced hepatocellular carcinoma. The intervention was hyperthermia combined with radiation therapy or transcatheter arterial chemoembolization (TACE). Hyperthermia involved exposure to a temperature of 41–43℃ for 30–60 min. As a result of assessing the ROB in both studies, there was no mention of allocation concealment, which was in turn assessed as “uncertain.” The ROB for private research support was also assessed as “uncertain” in one of the studies that had no mention of sources of research grants. The ROB was assessed as “low” for all other indicators.

Safety in patients with liver neoplasms Only one of the three studies on liver neoplasms finally selected provided safety-related reports. There were no adverse events directly associated with hyperthermia. A total of seven adverse events (14.3%) occurred in the intervention group using TACE combined with hyperthermia, and in 17 cases in the control group using TACE alone (35.0%). Thus, the number of adverse events was significantly smaller in the intervention group (p = 0.019). However, there was no significant difference between the intervention and control groups in terms of individual adverse events (pneumothorax, abdominal hemorrhage, liver abscess, and bile duct damage).

Effectiveness against liver neoplasms The effectiveness of hyperthermia on liver neoplasms was assessed based on the survival rate, remission rate, recurrence rate, and QoL indicators. In a meta-analysis of two studies reporting OS, the RR was 0.96 (95% CI 0.75–0.23, I2 = 0.0%), and hyperthermia did not affect the OS. In a meta-analysis, the RR of the objective response rate was 1.39 (95% CI 0.90–2.15, I2 = 0.0%) and the RR of the disease control rate was 1.19 (95% CI 0.89–1.60, I2 = 0.0%), indicating no significant difference between the intervention and control groups. The 1-year recurrence rate was 27.5% in the intervention group and 40.0% in the control group. This was significantly lower in the intervention group (p < 0.001). QoL was measured using the Quality of Life—Liver Cancer scale. After completion of treatment, the QoL in the five domains of the role, physical, emotional, cognitive, and social functions was compared between the intervention and control groups. The intervention group showed a significant improvement in all domains after treatment (p < 0.001).

Colonic neoplasms One NRS on colonic neoplasms was selected for this review. The study was conducted in China and involved 105 patients with mid-stage or advanced colorectal cancer. The intervention group, using hyperthermia with radiation therapy and/or chemotherapy, was compared with a control group using radiation therapy and/or chemotherapy alone. Hyperthermia involved exposure to a temperature of 41–43℃ for 46–60 min, for a total of four times. ROB assessment using the ROBANS made no mention of confounders, and the ROB for confounders was in turn assessed as “uncertain.” The ROB was “low” for all other indicators, such as target group comparisons, target group selection, exposure measurement, blinding of assessors, outcome assessment, incomplete outcome data, selective outcome reporting, and private research support.

Safety in patients with colonic neoplasms No adverse events directly associated with hyperthermia were reported. There was no significant difference in the overall adverse events between the intervention and control groups, with no difference between the two groups in terms of gastrointestinal and hematologic toxicities and fatigue. However, in terms of skin-related toxicity, one case (1.8%) of psoriasis was reported in the intervention group. As there was only one NRS related to hyperthermia with radiation therapy in patients with colonic neoplasms, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia in patients with colonic neoplasms.

Effectiveness against colonic neoplasms The effectiveness of hyperthermia on colonic neoplasms was assessed based on the survival rate, remission rate, and QoL indicators. The 3-year OS was 16.4% in the intervention group and 12.5% in the control group, which was significantly higher in the intervention group (p = 0.05). The groups did not differ significantly in terms of the complete remission rate, stable disease (SD), or PD, although the partial remission rate (RR 1.69, 95% CI 1.04–2.75, p = 0.04) and objective response rate (RR 1.75, 95% CI 1.13–2.70, p = 0.01) were higher in the intervention group. The QoL was assessed by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire. When we compared the QoL in the intervention and control groups after treatment, the intervention group showed an improvement in all domains (emotional/role/cognitive/physical/social functions) assessed (p < 0.05).

Rectal neoplasms The studies on rectal neoplasms included two RCTs and six NRCTs. As the NRCTs included subgroup analyses of follow-up studies of previous reports, the number of studies was actually four. Four of six studies on rectal neoplasms were conducted in Europe, and two were conducted in South Korea. There were six studies on rectal cancer and one on anal cancer. The total number of patients included in the studies was 964, with 189 in the RCTs and 775 in the NRCTs. The average age of the patients was 57–68 years. Hyperthermia involved exposure to a temperature of 39.5–42℃ for around 60 min, once or twice per week. As two of the NRCTs showed a difference in the baseline characteristics of patients, the ROB of the target group comparability was assessed as “high,” at 33.3%.

Safety in patients with rectal neoplasms One RCT and three NRCTs on rectal neoplasms made safety-related reports. For hyperthermia-related toxicity, two cases of grade 3 toxicities (3.2%) were reported, and severe skin-related toxicity of grade 3 or more was reported in 3.7–30.0% of the subjects in the intervention group and in 0–25.8% of those in the control group. Early anastomosis leakage, delayed anastomosis leakage, non-stenosis, small intestine obstruction, diarrhea and vomiting, and surgery due to intestinal obstruction were reported as gastrointestinal toxicities, although there was no significant difference between the intervention and control groups. However, the gastrointestinal toxicity reported in one NRCT showed a significant difference between the groups in terms of the occurrence of toxicity by grade (p = 0.01). For hematologic toxicity, there was no difference between the groups in the occurrence of leukopenia and neutropenia in one study, although in the other study, the occurrence of early hemotoxicity (p = 0.03) and late telangiectasia (p = 0.009) was significantly higher in the intervention group. There was no significant difference between the groups in late fecal incontinence or urogenital toxicity.

Effectiveness against rectal neoplasms The effectiveness of hyperthermia against rectal neoplasms was reported in two RCTs and four NRCTs, where the survival rate, remission rate, recurrence rate, and QoL indicators were used for assessment. The 3-year OS reported in the RCTs was 72.2% in the intervention group and 62.2% in the control group, and there was no significant difference between the groups (p = 0.44). There was also no significant difference in the complete remission rate or local control rate between the groups. The QoL was assessed by using the Gastrointestinal QoL Index. The long-term QoL was significantly lower in the intervention group that used hyperthermia than in the control group (standardized mean difference -0.85 [95% CI -1.47 to -0.24], p = 0.007). In a meta-analysis of three NRCTs reporting OS, the RR was 1.08 (95% CI 0.91–1.28, I2 = 0.0%), indicating that hyperthermia did not affect the OS. The disease-free survival (DFS) (RR 1.14, 95% CI 0.92–1.41, I2 = 0.0%) and LRFS (RR 1.03,95% CI 0.85–1.25, I2 = 24.8%) did not differ between the groups depending on the use of hyperthermia. The RR of the complete remission rate was 2.04 (95% CI 0.94–4.45, I2 = 0.0%), indicating that use of hyperthermia conferred no significant improvement.

Conclusions and Recommendations

Stomach neoplasms As a result of this systematic literature review comparing an intervention group using hyperthermia combined with radiation therapy and/or chemotherapy and a control group using radiation therapy and/or chemotherapy in patients with stomach neoplasms, no adverse events directly associated with hyperthermia were reported, and the gastrointestinal, renal, hepatic, and blood toxicities showed no significant difference between the two groups. The results of the OS reported in the two studies had different directions, and the LPFS was significantly higher in the intervention group. No significant difference according to hyperthermia was identified in terms of the complete remission rate, partial remission rate, and objective response rate. Based on this assessment, the Subcommittee determined that there was insufficient evidence for judging the safety and effectiveness of the combination therapy involving hyperthermia in patients with stomach neoplasms in the two RCTs selected (confidence level of evidence: low).

Pancreatic neoplasms This systematic literature review on hyperthermia combined with radiation therapy and/or chemotherapy compared with radiation therapy and/or chemotherapy alone in patients with pancreatic neoplasms showed that were no adverse events directly associated with hyperthermia, with no significant difference between the groups in terms of gastrointestinal and blood toxicities. The effectiveness was assessed by the OS, which was significantly increased in the intervention group using hyperthermia than in the control group, based on one NRCT and one NRS. Based on this assessment, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with pancreatic neoplasms in the single NRCT and single NRS selected (confidence level of evidence: very low to moderate).

Bile duct neoplasms This systematic literature review on hyperthermia combined with radiation therapy and/or chemotherapy compared with chemotherapy alone in patients with bile duct neoplasms, found that mild hilar pain and skin rash occurred as adverse events related to hyperthermia. While adverse events related to chemotherapy and hematologic and non-hematologic toxicities were reported, there was no significant difference between the intervention and control groups. In terms of effectiveness, the OS and DFS were significantly improved in the intervention group using hyperthermia as compared with the control group. There was no significant difference in the complete and partial remission rates between the two groups. Based on this assessment, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia combined with radiation therapy and/or chemotherapy in patients with bile duct neoplasms based only one NRCT selected (confidence level of evidence: low)

Liver neoplasms This systematic literature review on hyperthermia combined with TACE or radiation therapy compared with TACE or radiation therapy alone in patients with liver neoplasms revealed no adverse events directly associated with hyperthermia, with no significant difference between the groups in terms of respiratory and gastrointestinal toxicities or liver abscess. In terms of effectiveness, there was no significant difference in the OS, complete remission rate, or partial remission rate in the intervention group compared with the control group. Based on this assessment, the Subcommittee determined that there was insufficient evidence for judging the safety and effectiveness of hyperthermia in patients with liver neoplasms from the two RCTs selected for literature review (confidence level of evidence: moderate).

Colonic neoplasms This systematic literature review on hyperthermia combined with radiation therapy and/or chemotherapy in patients with colonic neoplasms found no adverse events directly associated with hyperthermia, although one case of psoriasis was reported as a skin-related toxicity in the intervention group. There were no significant differences between the two groups in terms of gastrointestinal, blood, and skin-related toxicities, including overall adverse events. In terms of effectiveness, the OS was not significantly different between the intervention and control groups. The OS reported in one study was significantly improved in the intervention group using hyperthermia. While the complete remission rate showed no significant difference between the groups, the partial remission rate was significantly higher in the intervention group. Based on this assessment, the Subcommittee determined that there was not enough evidence for judging the safety and effectiveness of hyperthermia in patients with colonic neoplasms from the one NRS selected for literature review (confidence level of evidence: low).

Rectal neoplasms This systematic literature review on hyperthermia combined with radiation therapy and/or chemotherapy in patients with rectal neoplasms found two cases of severe adverse events of grade 3 or more directly associated with hyperthermia. Considering that there was no significant difference between the two groups in terms of skin, hematologic, and urinary system toxicities, hyperthermia was judged to be a safe technique. The indices for effectiveness, such as OS, DFS, LRFS, and complete remission rate, did not show a significant difference between the groups. As a result of this assessment, the Subcommittee evaluated hyperthermia combined with radiation therapy and/or chemotherapy in patients with rectal neoplasms as a safe technique with a controlled temperature. However, it was assessed as a technique with no additional therapeutic effect as compared with radiation and/or chemotherapy alone (confidence level of evidence: very low to moderate). The 12th Health Technology Reassessment Committee in 2021 (December 10, 2021) reviewed "hyperthermia in patients with gastrointestinal tumors" as follows in accordance with Article 4, Paragraph 10 of the Health Technology Reassessment Project Management Guidelines based on the results of the Subcommittee review: The Health Technology Reassessment Committee agreed with the decision of the Subcommittee that hyperthermia was a technique that could be used as an adjuvant to radiation therapy and/or chemotherapy, but found that either there was insufficient evidence for additional therapeutic effects or no additional therapeutic effects were confirmed for any evidence presented depending on cancer type. It was decided to review radiation hyperthermia comprehensively, without analyzing it by separate cancer types. The Health Technology Reassessment Committee determined that hyperthermia combined with radiation therapy in cancer patients was “not recommended” due to a lack of evidence, even though it had been used for more than 10 years since being designated as an out-of-pocket item in 2004 (recommendation level: not recommended).

Keywords: Colonic neoplasms, Induced hyperthermia, Liver neoplasms, Pancreatic neoplasms, Rectal neoplasms, Stomach neoplasms