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1 VIII 폐암스크리닝 Pros 장승훈 한림대학교의과대학내과학교실, 한림대학교성심병원호흡기 - 알레르기내과 Lung cancer is a leading cause of cancer-death in many countries. About 70% of patients are diagnosed with advanced stage which is causing poor survival outcome. Early detection and curative intervention of lung cancer are desperately needed to reduce disease specific mortality. Recently, the National Lung Screening Trial from USA, a nation-wide randomized controlled trial reported 20% of lung cancer specific mortality reduction with low-dose CT (LDCT) screening for high risk participants who were current or former smokers, aged 55 to 74, compared with chest radiography screening. LDCT screening may have potential benefits and harms. This is a brief review about pros for LDCT screening and future directions for improving screening performance. Key Words: Low dose CT, Lung cancer, Screening Corresponding author: Seung Hun Jang, M.D., Ph.D. Division of Pulmonary, Allergy and Critical Care Medicine, Hallym University Sacred Heart Hospital, 22, Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang 14068, Korea Tel: , Fax: , chestor@hallym.or.kr 1. 서론 2013년, 전세계폐암발생환자는 180만명, 폐암사망자는 160만명으로추정되어세계적으로폐암은가장흔하게발생하는암이며가장사망자가많은암이다 1. 한국중암암등록본부의 2012년연보에의하면우리나라에서폐암은 60세이상의남녀에서가장흔하게발생하는암으로보고되었다. 한국에서의흡연율은지속적으로감소하는추세이지만발암물질의잠복기, 인구고령화, 산업화에의한환경오염의증가로인하여폐암유병률은향후 20여년동안지속적으로증가할것으로예상된다. 한국을포함한선진국의주요폐암조직형분포는역사적으로공통된변화양상을보이는데편평상피암의지속적인감소와선암의꾸준한상승이특징이다 2-5. 폐암주요조직형발생빈도의변화는임상적양상에도영향을미쳐서폐암의발생부위가기관지중심성이아닌비중심성폐실질에서초기병변이시작되는것이많아졌다는것을의미하며이부위의병소를잘발견할수있는흉부전산화단층촬영 (computed tomography, CT) 의역할이중요해졌다. 폐암은다른암에비해예후가좋지않아연령표준화 5년생존율은선진국과개발도상국모두에서 10 20% 정도에불과하여췌장암다음으로불량한예후를보인다 6. 폐암의예후를결정하는가장중요한요소는병기이며그외에고령, 남성, 흑인종, 낮은경제사회학적지위가불량한예후인자로알려져있다 7. 병기에따른폐암의 5년상대생존율은병기가증가할수록급격히낮아져서한국의통계를보면국한병기의생존율은 46.3% 에이르지만원격전이가있는 4기폐암에서는 4.8% 까지감소한다 8. 폐실질에는감각신경이분포하지않으므로폐암에의한증상이나타나서병원을방문할때면이미국소적으로진행하거나원격전이된상태로발견되는경우가많아서진단당시수술이가능한경우는전체폐암의 25 30% 에불과하므로증상이나타나기전수술이가능한상태에서폐암을 36

2 조기진단해야할필요가절실하다. 2. 폐암검진의역사 폐암검진의역사는흉부영상진단법의발전사와맥을같이한다 년대부터흉부 x-선을이용한폐암검진의역사가시작되어 1980년대에정점을이루다가미국에서 1993년 2001년까지대상자가모집되었으며매우잘계획되고시행된 PLCO (The Prostate, Lung, Colorectal, and Ovarian, PLCO) 무작위대조군연구를마지막으로더이상의후속연구는없는것같다. PLCO 연구이전에시행된연구들은모두흉부 x-선검진군에서대조군에비하여폐암사망률을낮추지못한다는공통된연구결과들을보여주었고, 이들을메타분석한결과도마찬가지였다 년대에주류를이루던폐암조직형이기관지중심성발생을보이는편평상피암인것에착안하여흉부 x-선에객담암세포검사를추가하여폐암검진을시행해도대조군에비하여폐암사망률을낮추지못하는것은마찬가지였다 10. PLCO 연구는미국에서 세인 154,901 명을등록시켜진행된대규모연구로서 4년동안매년흉부 x-선촬영을시행한군과특별한일이없으면검사를하지않는일상적인진료행태를취한군을 13년간추적하며비교하였는데, 양군의폐암발생률, 폐암사망률, 전체사망률에차이가없다는것을보여주어흉부 x-선폐암검진의무용성을다시한번보여주었다 11. 흉부저선량 CT (low dose CT, LDCT) 가폐암검진에본격적으로도입된시기는 1992년 ELCAP (Early Lung Cancer Action Project) 연구부터다. 1990년대에시행된 LDCT 폐암검진은비교군이없는관찰연구로서 LDCT를이용하여폐암진단율과조기폐암발견율이향상된다는것을관찰하였다. 2000년대초부터 LDCT 를이용한 DANTE, DLCST, MILD 연구등몇개의대조임상시험이진행되었는데어떤연구도 LDCT를시행함으로써폐암사망률을낮춘다는것을입증하지못했다 이들연구들을메타분석하여도 ( 연구참여자 9,467 명 ) 폐암조기검진으로폐암사망률이낮아지는관찰할수없었는데, 각각의연구디자인이검진대상군설정, 추적검사등에서다소상호이질적이고통계적유의성을가질만큼연구의규모가크지않았던것들이문제점으로지적된다. 폐암조기검진이유용성논쟁에서답보상태를보이던중, 미국의 33개의료기관에서무려 53,454 명을대상으로매우잘조직되고시행된 LDCT 와흉부 x-선의폐암조기검진효과를비교한무작위대조임상시험 (National Lung Screening Trial, NLST) 에서 LDCT 시행군의폐암사망률과전체사망률이의미있게감소되는것이입증된이후 LDCT를이용한폐암조기검진논의가탄력을받게되었다 15. 네덜란드에서 15,822 명을대상으로, 또다른잘조직된 LDCT 폐암검진연구가 (NEtherland-Leuven Longkanker Screenings ONderzoek, NELSON trial) 등록을마치고조만간그결과를발표할예정이다 National Lung Screening Trial (NLST) 의설계와결과 NLST 는 30갑년이상의흡력을가지는현재또는과거흡연자중에서금연기간이 15년을경과하지않은 55 74세의미국인을 LDCT 또는흉부 x-선을 2년간매년시행하는양군으로무작위배정하고폐암사망률과전체사망률을비교한임상연구다. 연구참여의중요한제외기준은객혈, 1년간 6.8 kg 이상체중감소등현증폐암일수있는증상을가진사람들과폐암검진중발견된결절에대한침습적진단이나치료과정을견딜수없을정도의불량한체력을가진사람들이었다 년 8월 2004년 4월까지 53,454명이연구에참여하여 2008년 12월 31일까지추적되었으며, 추적기간의중앙값은 6.5년이었다. LDCT 시행군에서흉부 x-선시행군과비교하여의미있게폐암발생률증가 (4.0% vs. 3.6%, HR 1.13, 95% 신뢰구간 ), 20.0% 의폐암사망률감소 (1.3% vs. 1.6%, p=0.004), 6.7% 의전체사망률감소 (7.1% vs. 7.6%, p=0.02) 를보여주었다 15. 이는인류역사상최초이자유일하게폐암조기검진의유용성을입증한연구로기록되었다. 비록이것이 LDCT를이용한폐암조기검진의유용성을입증한유일한연구이나, 대규모로매우잘설계되고, 수행되어서이를근거로미국의여러유관조직과우리나라에서폐암검진권고안을제시하고있다 17,18. 일본과유럽의여러국가들에서는아직공식적인폐암검진권고안을발표하지않고 37

3 NELSON 연구결과가발표되기를기다리는분위기다. NLST의임상적의미는폐암발생의고위험군에서 LDCT 선별검사로써폐암사망률을의미있게감소시킬수있었다는점이다. LDCT 선별검사의효율성은상당히낮아서 1명의폐암사망자를줄이기위하여필요한검진자의수 (Number Needed to Screen, NNS) 는 320명, 1명의전체사망자를줄이기위하여필요한 NNS는무려 960명이나되었다 15. 연구결과및후속분석결과위양성결절의발견율이높아서불필요한추가검사및의료비용지출로연결될수있고, 방사선피폭에의한이차적발암가능성이제시되었으며과진단과검사유소견자인경우정신적스트레스가일시적으로증가하는것으로조사되었다. LDCT 검진중발생하는방사선노출은 msv정도로흉부 x-선 msv보다많지만일반적인흉부 CT 9 10 msv보다현저히적다. 미국에서 55 80세의고위험군을대상으로매년 LDCT 검진을시행한다고가정하였을때방사선노출로인한폐암사망이 24/100,000 명이발생하고 521/100,000명의검진에의한폐암사망예방효과가있을것으로계산되어방사선위해보다검진의득이더큰것으로조사된바있다 19. 이에대한상세한논의는폐암스크리닝 cons에서상세히다루어질것이다. 4. LDCT 폐암선별검사의성적을제고하기위한전략들 LDCT 선별검사를시행함으로써예방되는폐암사망은폐암발생고위험자일수록집중적으로발생하는것으로조사되었다. 연령, 체질량지수, 암발생가족력, 흡연량, 폐기종여부로폐암발생예측모델을만들고폐암발생위험도에따라 5분위로나누었을때, 폐암발생위험도가높은군일수록 LDCT 선별검사로써폐암사망도더많이예방하는것으로나타났다 (p=0.01 for trend). LDCT 선별검사로예방되는폐암사망을 100% 로간주했을때폐암발생위험상위 60% 에서 88% 의예방효과가나타나고, 그다음위험군 20% 에서 11%, 하위 20% 에서는불과 1% 의비율을차지했다 (Figure 1) 20. 이러한사실은천문학적비용이드는 LDCT 선별검사를폐암발생고위험군에집중한다면검진의비용-효과적효율성을제고할수있다는것을시사한다. 현재까지시행된거의모든선별검사는연구마다조금상이한기준을제시하기는하지만연령과흡연력에기초하여고위험군을정의하였다. 이는고령자일수록, 흡연량이많을수록폐암발생위험이폭증한다는기존의역학연구들에근거한판단이다. 그러나폐암발생의위험이연령과흡연력에의해서만결정되지않는다는것은잘알려진사실이다. 폐암발생에관여하는다른중요한요소들은간접흡연, 직업력, 가족력, 라돈가스노출, 만성폐쇄성폐질환, 폐결핵같은기저폐질환, 환경오염, 방사선노출등이 Figure 1. Prevented lung cancer death according to the risk of lung cancer development in NLST. 88% of prevented lung cancer death was achieved in the upper 60% risk group of NLST population, while only 1% of prevented lung cancer death in the lower 20% risk group of the population. NLST, National Lung Screening Trial. 38

4 있다. 여러선행연구들은연령, 흡연력과같은고정된고위험군설정보다는여러위험요소들로구성된폐암발생예측모델을개발하고이를이용하여보다정밀하게고위험군을선정하면폐암검진의효율성을개선할수있다고보고하고있다 21. 이런맥락으로가장최근에보고된연구는 PLCO, NLST 연구참여자, 미국국민건강면접조사 (National Health Interview Survey, HHIS) 자료를이용하여폐암발생예측모델을개발하고이를미국민들에게적용한결과에대한것이었다 (Figure 2). 이연구결과에의하면 NLST 의고위험군선별기준을적용했을때계산되는검진대상자들숫자만큼개발된예측모델로고위험미국민들을선정하고이들에게검진을시행한다면 LDCT 선별검사로써폐암사망예방을 20% 더향상시킬수있고, 검진의효율성에해당하는 NNS를 17% 더감소시킬수있다는계산결과를도출하여연령, 흡연력으로고착된고위험군선정기준보다여러위험인자들을두루감안하여정밀한폐암발생예측모델을개발하는것이더좋다는것을다시한번입증하였다 22. 이방법을적용하면연령, 흡연력만으로선정된검진대상군중에서 36% 정도에해당되는상대적으로폐암발생위험이적은검진대상자를 (5년간폐암발생위험 1.3%) 보다위험성이높은대상자로 (5년간폐암발생위험 3.2%) 치환할수있는것으로추정되었다. 현재 United Kingdom Lung Cancer Screening (UKLS) trial은폐암발생예측모델 (Liverpool Lung Project Risk Prediction Model) 에근거하여검진대상자를모집하고있는 LDCT 검진군과일반적인진료행위를비교하는무작위대조임상시험으로서총 32,000명정도를모집할예정이고현재 4,055명의시범연구대상자가참여하여분석된바있다 23,24. LDCT 검진의비용-효과적효율성을결정하는또다른중요한요소는비석회화결절의판정기준이다. NLST 에서는 4 mm 이상의결절을유소견자의기준으로하였는데, 초회검진 LDCT에서 26.6% 의유소견자가발견되었다. 의미있는결절의크기, 성장속도등을고려하여제시된 Lung-RADS (Lung imaging Reporting and Data System) 는고형결절의크기가 6 mm 이상일때유소견자로정의한다. Lung-RADS 기준에의한카테고리 3 4를검진유소견자로정의하고이기준을 NLST 연구집단에적용하였을때는초회검진 LDCT에서 13.6% 만이유소견자로분류되어약 50% 정도유소견자비율을줄일수있었음에도불구하고검사의민감도는 NLST 기준일때 95.5% 에서 Lung-RADS 기준일때 84.9% 로 10% 정도의감소만보였다 25. 이는 LDCT 검진에서유소견자를분류하는기준이비용-효과적 Figure 2. Impact of lung cancer development prediction model on the eligible population selection for LDCT screening. About 36% of USPSTF recommended population based on the fixed criteria by age and smoking dose (NLST criteria) would be replaced by higher risk-based population if the eligible population is selected based on lung cancer development prediction model in USA with the assumption of same screening cost. The replaced USPSTF recommended population has 1.3%/5-year risk of lung cancer development (647 NNS), while risk-based population has 3.2%/5-year risk of lung cancer development (226 NNS). LDCT, low dose CT; USPSTF, US Preventive Services Task Force; LC, lung cancer; NNS, Number Needed to Screen. 39

5 효율성을결정하는중요한요소임을시사한다. 생체표지자를이용하여폐암발생고위험군을예측하고 LDCT 검진대상자를선별할수있다면불필요한검진을획기적으로줄일수있을것이다. 이에대한몇가지시도가있었으나아직까지는만족할만한생체표지자가발굴되지못하고있는실정이다. 그중가능성이보이는한가지연구결과를소개하면 MILD 연구참여대상자의혈장에서몇가지폐암관련 microrna 를찾아내고그조합으로 microrna signature classifier (MSC) 를만든다음이를이용하여고위험-중위험군또는저위험군으로분류하고위험도에따른 LDCT 검진의성적표를비교한연구가있었다 26. MSC가고위험- 중위험군으로분류된경우에는 60/222 (27.0%) 에서폐암이발견되었고, 저위험군으로분류된경우에는 9/717 (1.2%) 에서만폐암이발견되어 MSC 의음성예측도가 99% 나되었다. 이와같은결과는다른연구를통하여다시검증될가치가있을것이다. 5. 성공적인폐암조기검진정착을위한조건들 폐암조기검진의성공을위하여중요한것은 1) 효율적인검진대상군-폐암발생고위험군의선정기준설정, 2) 검진참여자와의료진을대상으로폐암검진의이득, 위해, 검진시스템, 금연에대한교육, 3) LDCT 영상자료의품질, 저장관리, 4) LDCT 영상의정확한판독, 5) 의료진상호간, 환자-의료진간명확한의사소통, 6) 폐결절발견시진단, 치료를위한의료전달체계의수립, 7) 의료비용의사회적분담문제해결, 8) 폐암검진의효율성제고를위한연구사업들-예를들면폐암발생고위험군선별을위한생체표지자개발, 적절한 LDCT 시행주기, 최소침습적진단, 치료법개발에대한연구등이다 27. 검진참여자들에게는금연교육이필수적이고, LDCT 의유용성과함께잠재적위해에대해서도정보를제공해야하며의료진과검진참여자의합의가이루어진상태에서검진이시행되어야한다. 6. 결론 LDCT 폐암선별검사는매우잘조직되고시행된비교임상시험에서폐암사망률과전체사망률을의미있게감소시킬수있는것으로입증된검진방법이다. 다만고비용과비효율성, 검진참여중예상하지못한합병증이발생할수있으므로검진효율성을높이고자하는부단한노력과이러한문제들에대하여검진참여자에게정보를제공하고의료진과상호합의한상태에서진행되는것이바람직하다. References 1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, et al. The global burden of cancer JAMA Oncol 2015;1: Park JY, Jang SH. Epidemiology of lung cancer in Korea: recent trends. Tuberc Respir Dis (Seoul) 2016;79: Lortet-Tieulent J, Soerjomataram I, Ferlay J, Rutherford M, Weiderpass E, Bray F. International trends in lung cancer incidence by histological subtype: adenocarcinoma stabilizing in men but still increasing in women. Lung Cancer 2014;84: Toyoda Y, Nakayama T, Ioka A, Tsukuma H. Trends in lung cancer incidence by histological type in Osaka, Japan. Jpn J Clin Oncol 2008;38: Zhou C. Lung cancer molecular epidemiology in China: recent trends. Transl Lung Cancer Res 2014;3: Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival : analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015;385: Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD. Epidemiology of lung cancer: diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e1S-29S. 40

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon