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경피적에탄올주입술 서울대학교의과대학내과학교실, 간연구소 김윤준 Percutaneous ethanol injection therapy (PEIT), a potent non-surgical treatment tool for hepatocellular carcinoma (HCC), has been developed to manage small neoplasms. Intratumoral injection of only a few milliliters of ethanol with an ultrasonographic guidance allows PEIT to necrotize tumors completely and to reach reasonable survival rates comparable to radiofrequency ablation or liver resection. Advantages of PEIT include insignificant mortality, minimal damage to normal parenchyma, relatively low cost and easy availability; disadvantages include high local recurrence and minor complications such as fever and portal vein thrombosis. Recently with the introduction of single-session percutaneous ethanol injection, range of indications for PEIT is becoming wider. Furthermore, combined therapy of PEIT with transcatheter arterial chemoembolization (TACE) or other local ablation techniques is now being studied and performed with a satisfactory prospect. Key words: Liver, Interventional procedures, Liver neoplasms, Therapy, Percutaneous ethanol injection 서 론 간세포암 (Hepatocellular carcinoma, HCC) 은전세계에서다섯번째로흔한암이자세번째로흔한암사망의원인으로, 대부분의경우간경변증이나간염등의기저질환을가진사람에게서발생한다. 1,2 1980 년대에초음파를통한선별검사가실시됨에따라이러한위험군에서간세포암의조기진단이가능해지면서, 간세포암환자에게가능한치료의선택폭이매우넓어졌다. 3 부분적간절제술은시행이크게증가된치료법중하나다. 4 영상기법의발달로종양의특성과정확한위치파악이가능해지고수술기법의발전으로간절제술로인한합병증및사망률이감소하면서외과의사들은더욱넓은범위의간세포암에간절제술을적용할수있게되었다. 5 하지만여전히많은환자들에서는간절제술이최선의선택이아님은분명하다. 여러개의간세포암을가지고있거나, 공존하는간경화로인해간의잔여기능이떨어져있는환자가상당수이기때문이다. 6,7 그리하여여러연구자들은간세포암이침범하지않은간실질의손실을최소화할방법을강구하기시작하였고, 중재적영상기법을활용하여종양조직에화학물질이나고주파등으로직접손상을가하 63

2013 년대한간학회추계 Single Topic Symposium 는국소절제술의개념이대두되었다. 8 그중가장먼저제안된방법은경피적에탄올주입술 (Percutaneous ethanol injection therapy, PEIT) 이다. 9 경피적에탄올주입술은무시할만한합병증과높은효율로작은간세포암에서사용될수있는강력한치료적도구로떠올랐고, 정확히만시행된다면병변의완전한절제까지기대할수있다. 10 이후전신마취하의단회경피적에탄올주입술 (Single session PEIT) 의개발로더큰크기와많은개수의간세포암또한치료가가능해졌다. 11 원리및기법 경피적에탄올주입술에서는 95% 의무균에틸알코올을사용한다. 에탄올은종양세포사이를확산을통해이동하여작용한다. 알코올은세포질내의단백질을즉시탈수시켜변성되게함으로써세포의응고괴사를일으켜섬유화를유발한다. 또한주변의혈관을따라들어가혈관내피세포의괴사와혈소판응집을촉진하여미세혈관에혈전을만들고종양조직의허혈을유도한다. 간세포암은기질적으로혈관이많고주변의경화된간실질보다연하기때문에, 주입된에탄올은간세포암에쉽게확산되어풍부한혈관을따라고르게분포돼작용하게된다. 3,8 경피적에탄올주입술은실시간으로에탄올확산을감시해야하고종양의중심에바늘을정확히위치시켜야하므로, 대부분의경우초음파유도하에실시한다. 고전적인기법은보통각각 3 cm 이하의 3개이하의종양에서사용하는것이일반적이고, 종양의크기가클수록필요한시술의회차가늘어난다. 이경우시술은국소마취로도충분하며, 외래기반으로도시행될수있다. 환자에게간혹오심, 구토가나타날수있으므로환자는금식을유지하여야한다. 피부소독및국소마취후초음파유도하에 21-22G 의얇은바늘이삽입될때환자는숨을참도록요청받는다. 에탄올은종양의크기및혈관분포의정도, 격막의유무, 환자의상태등에따라 1-8 ml 내외로주입된다. 에탄올이성공적으로주입되면초음파상에서고에코의점으로확인할수있다. 종양내에서의에탄올의관류가충분하고혈관신생이확인되지않을경우치료를종료한다. 한세션당약 10-20분정도의시간이소요된다. 3,12-14 단회경피적에탄올주입술은주로간문맥이나간정맥의혈전을동반하지않는간전체부피의 30% 이하의중등도의간세포암을치료하는데에적용된다. 단회기법에서환자는기도삽관을통한기계적호흡및전신마취상태에서시술을시행받는다. 치료는주로가장깊숙이위치한종양, 중심부의종양, 주변부의종양순서로실시하는데, 에탄올확산의고에코성으로인해주변부부터치료를시작할경우추후중심부의초음파유도가어려워지기때문이다. 고전적인기법보다훨씬많은에탄올을사용하기때문에, 간정맥으로직접에탄올이주입되지않도록주의해야한다. 종양이전부고에코성으로보이게되면치료를종료하며, 종양의크기와개수에따라약 20-60분의시간이소요된다. 11 64

김윤준 경피적에탄올주입술 현재간세포암치료에서의역할 다른간세포암의치료와비교해볼때, 경피적에탄올주입술이가지는장점에는여러가지가있다. 먼저경피적에탄올주입술은위험도와합병증발생확률이매우낮은시술로알려져있다. 1,066명의환자를대상으로한 Stasi 등의연구에서, 시술로인한사망률은 0.09% 로미미한수준에그쳤다. 15 경피적에탄올주입술은가격면에서도효율적이고기법도간단하여대부분의작은기관에서도시행이가능하다. 이탈리아의경우간절제술에 3만달러, 간이식에 12만 5천달러의비용이소비되는반면, 경피적에탄올주입술은 1천달러정도면시행받을수있다. 13 또한, 경피적에탄올주입술은간절제나경동맥화학색전술 (Transcatheter arterial chemoembolization, TACE) 에비해종양조직이아닌정상간실질에가해지는손실이적어간기능이나쁜환자에서도시행할수있으며, 그러므로시술후병변이재발하거나새로운병변이발생하더라도쉽게반복적인시행을할수있다. 3 경피적에탄올주입술의치료효과는여러연구에서초음파및조영증강 CT 영상을통해평가되었다. 고주파절제술 (Radiofrequency ablation, RFA) 과비교한초기의연구들에서경피적에탄올주입술의완전관해율은 70-94% 로, 이는고주파절제술의 90.3-100% 와비교하여도유의한차이를보이지않을정도로높은수준의국소적효율을나타냈다. 16,17 추후두기법사이의생존율을비교한 Lencioni 등의연구에서시술후의 1년, 2년생존율은고주파절제술에서각각 100% 와 98%, 경피적에탄올주입술에서각각 96% 와 88% (p=0.138) 로역시큰차이가없었다. 18 한편 1.2-6.0 cm의단일혹은여러종괴를가진환자들을대상으로한 Shiina 등의연구에서는, 종양의직경이 3 cm 이하인경우와 4 cm 이상인경우 (p<0.0002), 종양의개수가 3개이하인경우와 4개이상인경우 (p<0.02) 에생존율에상당한차이가나타나는것이밝혀짐으로써, 작고적은종괴를가진초기단계의간세포암에서경피적에탄올주입술을시행하는것이유리하다는것이알려졌다. 14 문제점및향후발전방향 경피적에탄올주입술의흔한부작용에는주사부위의통증및 37-39 정도의발열이있다. 통증은대개수분안에사라지지만환자가오른쪽어깨나상복부쪽으로뻗치는심한통증을호소할경우에는진통제투여가필요할수있다. 발열은주로종양조직의괴사가가장많이일어나는초회의에탄올주입시에많이발생한다. 3,19 이외의부작용들은흔하지않다. 간혹에탄올이혈관으로누출되는경우내피세포손상에의해혈전이발생할수있는데, 이는 1-3개월내로대부분소실되며임상적으로큰문제가되지않는다. 20 또한병변이횡격막에가까이있는경우기술적인문제로흉막삼출이나기흉이발생할수있다. 21 주입바늘을통한종양의확산, 담관손상으로인한황달및담관염, 간경색, 복강내출혈등의심각한합병증은매우드물지만치명적일수있다. 22,23 경피적에탄올주입술의가장큰문제점중하나는간세포암의높은재발율이다. 국소재발율은 3cm보 65

2013 년대한간학회추계 Single Topic Symposium 다작은암에서는 33%, 3 cm 보다큰암에서는 43% 에달한다. 24,25 5 년간의새로운병변의발생은 Shiina 등 14 이 64%, Lencioni 등 26 이 78%, University of Chiba에서 3 87% 까지보고한바있다. Lencioni 등의무작위연구에서는고주파절제술을받은환자군에서각각 98% 와 96%, 경피적에탄올주입술을받은환자군에서 각각 83% 와 62% (p=0.002) 의 1 년및 2 년무재발생존율을나타내었다. 18 이러한잦은재발이나타나는 것은경피적에탄올주입술이위성결절이위치한주변간조직까지의넓은안전한계를확보하기어렵기때문이며, 격막이나피막이있는경우에탄올이그를뚫고균질하게퍼지기가힘들기때문이다. 8,27 이러한단점을보완하기위하여, 최근에는경피적에탄올주입술과경동맥화학색전술을같이활용하는방법이제안되었다. 28 이러한병합요법은근치적치료에서뿐만아니라완화적치료에서도유의하게생존율을증가시킴이밝혀졌다. 29,30 큰간세포암에서색전술이시행되면종양의구조가붕괴되고종양간의격막이파열되어, 후에경피적에탄올주입술로알코올이주입될때큰종양에서도쉽고고르게에탄올이확산될수있는원리이다. 31 또한고주파절제술과경피적에탄올주입술을복합적으로사용하는치료의효용성도여러차례연구되어왔다. 32,33 경피적에탄올주입술자체가비교적제한적인활용도를가지고있고어느정도재발에취약하기때문에, 다양한간세포암의치료에서는이처럼단독요법뿐아니라다른치료방침과의병합을항상염두에두어야하며, 이때의부작용및합병증을줄이는방향으로연구가진행되어야할것이다. 물론이모든치료는, 수치화되고정형화된적응증에의존하기보다는환자의상태, 기능및질병의특성등여러요인에따라적절히시행되어야할것이다. 참고문헌 1. El-Serag, H. B. Hepatocellular carcinoma: an epidemiologic view. Journal of clinical gastroenterology 35, S72-78 (2002). 2. Llovet, J. M., Burroughs, A.,Bruix, J. Hepatocellular carcinoma. Lancet 362, 1907-1917, doi:10.1016/s0140-6736(03)14964-1 (2003). 3. Livraghi, T. Role of percutaneous ethanol injection in the treatment of hepatocellular carcinoma. Digestive diseases 19, 292-300, doi:50696 (2001). 4. Lai, E. C., Fan, S. T., Lo, C. M., Chu, K. M., Liu, C. L.,Wong, J. Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Annals of surgery 221, 291-298 (1995). 5. Bismuth, H., Chiche, L., Adam, R., Castaing, D., Diamond, T.,Dennison, A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Annals of surgery 218, 145-151 (1993). 6. Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. The Liver Cancer Study Group of Japan. Cancer 74, 2772-2780 (1994). 7. Colombo, M., de Franchis, R., Del Ninno, E., Sangiovanni, A., De Fazio, C., Tommasini, M. et al. Hepatocellular carcinoma in Italian patients with cirrhosis. The New England journal of medicine 325, 675-680, doi:10.1056/nejm199109053251002 (1991). 8. Lencioni, R., Cioni, D., Crocetti, L.,Bartolozzi, C. Percutaneous ablation of hepatocellular carcinoma: state-of-the-art. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 10, S91-97, doi:10.1002/lt.20043 (2004). 9. Livraghi, T., Festi, D., Monti, F., Salmi, A.,Vettori, C. US-guided percutaneous alcohol injection of small hepatic 66

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