대한내과학회지 : 제 79 권제 6 호 2010 특집 (Special Review) - 간문부담관암의최신지견 간문부담관암의최근치료성적 경희대학교의학전문대학원소화기내과학교실 동석호 Current treatment outcome of hilar cholangiocarcinoma Seok Ho Dong, M.D., Ph.D. Department of Gastroenterology and Hepatology, Kyung Hee University School of Medicine, Seoul, Korea Cholangiocarcinoma (CC) is one of the most lethal cancers defying long-term control of disease. Hilar cholangiocarcinoma (Klatskin tumor) which occur at the confluence of right and left hepatic ducts are getting special attention for these tumors due to difficult management. Surgical treatment of hilar cholangiocarcinoma remains difficult and most of patients are diagnosed when unresectable. The 5-year survival rate after curative resection was 20~40% with median survival of 12~16 months. In those patients with unresectable hilar CC, liver failure and recurrent sepsis secondary to biliary obstruction occupy substantial proportion of cause of death. For most of these patients endoscopic or percutaneous biliary drainage provides effective palliation. Palliative chemotherapy and radiation therapy either alone or in combination have been relatively ineffective for unresectable cholangiocarcinoma. A photodynamic therapy is an emerging palliative treatment that seems to provide pain relief, improve biliary patency and increase survival. In addition to these options, newly developed target therapies are promising, but still experimental treatment. Liver transplantation in combination with neoadjuvant chemoradiation therapy seems to be an option for a highly selected group of patients. The development of new therapeutic options and multimodal promising combinations of the palliative therapeutic options is expected to improve the health-related quality of life and prolong the overall survival. (Korean J Med 79:623-629, 2010) Key Words: Hilar cholangiocarcinoma; Surgery; Palliation; Outcome 서론간문부담관암은좌우담관의합류부에서 2 cm 이내에서발생하는암으로 Klatskin 종양으로불리기도한다. Klatskin 은간문부에발생한선암 13증례를 1965년에처음으로보고하면서, 성장속도가느리고, 원격전이가드물며, 종양의크기가작다는특성을보고하였다 1). 그러나간문부담관암은해부학적으로복잡한부위에서발생하기때문에실제로는수술이어려운경우가많으며대부분간부전이나담관염등으로사망하게되는예후가매우불량한암이다. 간문부담관암의유일한근치적치료법은수술적완전절 제술이다. 그러나진단당시수술적완전절제가불가능하거나고령의환자에서전신상태가좋지못한이유등으로제한된환자에서만수술이가능하다. 완전절제를위한광범위절제술의경우사망률과합병증은점차적으로감소하고있으나, 이와같은적극적인수술에도불구하고 5년생존율은 20~40% 정도이다 2). 수술적절제가불가능한담관암의주요사망원인은담관폐쇄로인한패혈증이나간부전이므로담관배액술을반드시시행해야한다. 내시경적혹은경피적담관배액술은수술적담도우회술에비하여합병증발생이나사망률이낮고배액술의치료성적은유사하여수술적절제가불가능한경우에 - 623 -
- The Korean Journal of Medicine: Vol. 79, No. 6, 2010 - 일차적인치료로시행되고있다 3,4). 간문부담관암에서수술이불가능하여담관배액술만시행한경우국내외의보고에의하면평균생존기간은 4~6개월정도이다 5-7). 절제불가능한담관암에대한방사선치료나항암화학요법의효과는아직까지확실하지않은실정이며, 수술후보조화학요법및방사선치료는불완전절제된경우에한하여효과가일부인정되고있다. 광역학치료는담관배액기간및삶의질향상과함께생존기간의연장까지도기대되는치료로서현재절제불가능한담관암의보조치료방법으로선택할수있다. 최근에표적치료제들이화학요법이나방사선치료와병합하여담관암에서시도되고있다. 표적치료제효과에대하여좋은결과의보고도있으나실제로생존율향상등의치료효과에대해서는향후좀더많은연구가필요한실정이다. 수술적절제술담관암의완치를기대할수있는유일한치료법은수술적인완전절제로서잔존하는암이없도록근치적절제술 (RO resection) 만이담관암을완치시킬수있다. 이를위해서는대부분의환자에서간절제를동반한적극적인수술이추천되고있으며실제로간합병절제술, 광범위림프절절제, 혈관절제술등의적극적인외과적수술이시행되면서절제율및치료성적의향상이보고되고있다 8-11). 환자가수술적치료에적합한지여부를평가하기위해서는수술전에환자를철저히조사해야한다. 환자의전신상 태가수술에적합한지, 어떠한전이성병변도없는지, 암완전제거 (RO 절제 ) 의가능성등을면밀히평가해야한다. 만약이중어느하나라도부적합한경우에는수술적치료보다는보존적인치료를시행해야한다. 담관암의절제가능성을판별하기위해서는종양의담관내침윤및간침윤정도, 중요혈관침범, 간엽의위축, 전이성병변등이중요한판별인자이다 12,13). 불필요한수술을방지하기위해서는가능한모든임상적, 영상의학적진단방법을총동원하여위와같은인자들을면밀히조사해야한다. 그러나간문부담관암의경우수술전절제가능성을정확히판정하기는매우어렵다. 영상의학적진단술의발전에도불구하고수술전절제가가능할것으로보였던환자중약 16~25% 에서는수술당시절제불가로판정되기도한다 14,15). 절제가능성의판정과함께환자의전신상태와간절제시잔존간기능의평가등이수술결정및수술방법의선택에있어서매우중요하다. 간문부담관암에서광범위간절제술을시행하는경우수술로인한사망률은 5~15% 정도이며, 주요사망원인은간절제로인한간부전과관련되어있다 16,17). 간문부담관암의수술적절제술후전체적인 5년생존율은 20~40% 이며, 근치적절제 (RO 절제 ) 의경우 5년생존율은 30~50% 정도로보고되고있다 ( 표 1) 2). 국내연구에서도수술적절제를시행한환자 259명중근치적절제율은 71.8% 였고, 근치적절제군의 5년생존율은 29% 로외국과유사한수술성적을보고하였다 18). 국내의다른기관에서간문부담관암 711명을대상으로한생존율조사에서도수술적절제가시행된 268명에서 5년생존율은 21% 였으나, 비절제군 443명에서는 0.4% 로수술적절제만이장 Table 1. Survival rates after surgical resection of hilar cholangiocarcinoma 2) Author (yr) Resections (n) Liver resection (%) RO resection (%) Overall 5-year survival (%) RO 5-year survival (%) Hasegawa et al [213], 2007 49 92 78 40 50 DeOliveira et al [67], 2007 173 20 19 10 30 Dinant et al [214], 2006 99 38 31 27 33 Hemming et al [205], 2005 53 98 80 35 45 Rea et al [208], 2004 46 100 80 26 30 Kawasaki et al [182], 2003 * 79 96 68 NR 40 Kawarada [215], 2002 87 75 64 26 NR Jarnagin et al [166], 2001 80 78 78 37 NR Tabata et al [216], 2000 75 71 60 23 40 Kosuge et al [217], 1999 65 88 52 35 52 Miyazaki et al [218], 1998 76 86 71 26 40 * Five-year survival for patients with R1 resection is 6%. RO, complete resection; NR, not reported. - 624 -
- Seok Ho Dong. Current treatment outcome of hilar cholangiocarcinoma - 추천하기어렵다. 현재간이식은특화된센터에서매우신중한환자선택후시행할것을권고하고있다. p<0.001 수술후보조치료 (Adjuvant therapy) Figure 1. Survival curve according to resection in Klatskin tumor 19). 기생존을기대할수있었다 ( 그림 1) 19). 이중근치적절제군 (RO 절제 ) 141명의 5년생존율은 28%, 절제연에종양침범이남아있는불완전절제군 54명의 5년생존율은 10% 로의미있는차이를보였다. 따라서환자의전신상태및잔존간상태를고려하여종양이남지않도록근치적절제의범위를결정하는것이수술후사망률을낮추면서장기생존을높이는방법으로추천하고있다. 간이식 간문부담관암의치료방법으로간이식은기존의절제술에비하여근치적절제가능성이높을뿐만아니라, 중요혈관의암침윤과관계없이수술을시행할수있는장점이있다. 그러나간문부담관암의간이식치료성적은 5년생존율 20~30% 정도로기존의수술방법에비하여우월하지않은것으로보고되고있다 20,21). 간이식으로좋은치료성적을보고한 Mayo clinic에서는간이식전에항암제와방사선치료를선행보조치료시행후복강내전이및림프절전이가없는담관암에서간이식을시행하여 5년생존율 71% 를보고하였다 22). 이는절제술의 5년생존율 20~40% 에비교하여볼때획기적인생존율의향상을보인것이다. 그러나간이식대상환자가대부분일차성경화성담도염환자에서발생한담관암이었고, 림프절전이가없는초기병변에국한된것으로이결과만으로간이식이절제술을대체할수있는우월한수술로인정하기는어렵다. 국내에서는간공여자가부족하고간문부담관암에서간이식은높은암재발률과함께전체적으로치료성적이좋지않기때문에절제술보다좋은치료로 수술후보조화학요법 (adjuvant chemotherapy) 은생존기간의연장효과가없는것으로보고되고있다 23,24). 다기관무작위비교연구에서도수술후 mitomycin C와 5-FU의병합투여군이수술단독군 (RO 절제 ) 에비하여생존율향상효과가없는것으로판명되었다 25). 최근담관암치료에효과가인정되고있는 gemcitabine의경우, 광범위절제술후경구항암제 S-1과같이투여한군의 5년생존율은 57% 로수술만시행한군의 23% 에비하여생존율향상에도움이됨을시사하였다 26). 그러나화학요법군의환자수가 18명으로너무적었고, 후향적분석이므로향후무작위비교연구를통해서그결과를확인하여야할것이다. 수술후방사선치료는근치적절제가시행된경우에는환자의생존기간향상에도움이되지않는다 27,28). 그러나절제연에암세포가남아있는불완전절제 (R1 resection) 가된경우에방사선치료는생존율향상에도움이될수있다 29,30). 절제연에서암세포잔존이증명된 R1 절제군환자들에서방사선치료를시행한군의 5년생존율은 34% 로서방사선치료를시행하지않은군의 14% 에비하여의미있는생존율향상을보였다 31). 항암제를투여하면서방사선을조사하게되면방사선치료효과를증강할수있다. 5-fluorouracil (5-FU) 는방사선치료시방사선민감물질 (radiosensitizer) 로가장널리사용되는항암제이다. 담관암으로수술한환자 84명중방사선치료와함께 5-FU를투여한군에서생존율향상이보고되었다 32). 그러나담관암에서이러한화학요법과방사선의병합치료효과는간문부담관암보다는주로원위부담관암에서생존율향상의효과가있는것으로보고되고있다 33-36). 고식적치료 (Palliative treatment) 간문부담관암의 50~90% 에서는진단당시에절제가불가능한상태이므로고식적치료법으로담관배액술, 방사선치료, 항암화학요법및표적치료, 광역학치료등을시행할수있다. 담관배액술담관폐쇄로인한담도염을방지하고간부전으로진행을 - 625 -
- 대한내과학회지 : 제 79 권제 6 호통권제 604 호 2010 - 막기위해서는우선적으로담관배액술을반드시시행해야한다. 담도- 공장문합술, 간- 공장문합술등의수술적배액술은효과적이기는하지만수술로인한사망 (6~12%) 과합병증 (17~51%) 이발생하는문제가있다 13). 비수술적배액술로는내시경담관배액관삽입술, 경피경간담관배액술등이있으며, 수술적배액술에비하여사망률과합병증이적고, 담관배액효과는수술과비슷하다 3,4). 내시경담관배액관삽입술은비침습적이며합병증이적고배액효과가좋은치료법으로절제불가능한담관암에서일차적으로시행되고있다. 수술적절제가불가능하여담관배액술만시행한간문부담관암의평균생존기간은 4~6개월정도로보고되고있다 5-7). 항암화학요법 (Palliative chemotherapy) 수술적절제불가능한담관암환자에서질병의진행을막고생존연장을위해서항암화학요법 (palliative chemotherapy) 을시행할수있다. 그러나확실히생존율을향상시킬수있는표준화학요법은현재까지정해져있지않다. 담관암에서초기에사용되었던 5-FU 단독투여의반응율은 10% 에불과하였다. 이후 5-FU와함께 leucovorin, interferon-alpha, cisplatin, oxaliplatin 등여러가지항암제의병합투여가시도되었으며, 반응률은 25~55%, 중앙생존율은 6~12개월정도로보고되었다 37-40). Capecitabine과 cisplatin 병합요법의제 2상임상연구에서는반응률 41%, 중앙생존기간 12개월을보고하였다 41). 그러나이들연구의대부분이소규모후향적연구였으며, 대상환자의균질성문제, 무작위비교연구의미흡등으로생존율향상효과에대한결과는그해석에있어서신중을기해야할것이다. 현재담관암에서가장효과적인항암제로인정되고있는 gemcitabine의경우단독투여로반응율은약 30%, 중앙생존기간은 10개월정도이다 42). Cisplatin, capecitabine, oxaliplatin 등과병합투여시반응률은 36% 까지, 중앙생존기간은 10~15 개월로보고되고있다 42-45). 진행된담관암을대상으로 1985 년부터 2006년까지보고된항암치료결과들을분석한논문에서도 gemcitabine과 platinum 제재 (cisplatin, oxaliplatin) 의병합요법이가장효과적인치료법으로권장하고있다 46). 방사선치료 (Radiation therapy) 담관암에서방사선치료는통증경감, 담관개통유지, 생존기간향상등의효과가있는것으로알려져있다 47,48). 방사 선치료방법으로는외부방사선치료 (external beam radiation) 와관내근접방사선치료 (intraluminal brachytherapy) 두가지가있으며, 단독혹은두가지방사선치료를병행하여사용할수있다. 외부방사선조사량을올릴경우주변장기에방사선으로인한합병증을유발하게된다. 방사선조사량을줄이면서종양주변의일정한부위에만높은방사선을조사할수있는방법이관내근접방사선치료이다. 방사선 source (iridium-192 seeds) 를장착한도관을경피적, 혹은내시경적방법으로담관암부위에위치해서국소부위에만집중적으로방사선을조사한다 49-52). 두가지방사선치료를병행하는경우중앙생존기간은 9~14개월로보고되고있다. 그러나방사선치료로인한위십이지장염, 입원기간의연장, 담도염등의문제를발생할수있으므로방사선치료가도움이될수있는환자를잘선택하여적절히시행해야한다. 표적치료 (Target therapy) 종양의성장을억제하는다양한표적치료제가개발되어종양치료에도입되고있다. 종양이성장하기위해서는영양공급이필수적이며, VEGF (vascular endothelial growth factor) 및그수용체는혈관형성의중요한인자로알려져있다. 실제로 VEGF의발현정도는암의진행, 전이와연관되어환자의생존기간및예후에영향을미치게된다. Anti-VEGF monoclonal antibody로잘알려진표적치료제인 bevacizumab 의경우종양혈관생성을억제하는역할을하며, gemcitabine 및 oxaliplatin과함께담도암에투여하여부분반응률 45%, 중앙생존기간 13.2개월의치료성적이보고되었다 53). 이외에도수많은표적치료제들이개발되고있으며임상시험중에있다. 이들중일부에서는뚜렷한치료효과를보이고있지만 54), 최상의치료효과를얻기위해서는향후다른표적치료제와병합투여, 항암화학요법이나방사선과의병용치료등에대한연구가필요할것이다. 광역학치료 (Photodynamic therapy) 광역학치료란광민감제 (photosensitizer) 를암환자에게주사하면주로암세포에선택적으로축적되고여기에특정파장의빛 ( 레이저 ) 을쏘여주면광민감제가활성화되어암세포가괴사되는치료법으로암조직이괴사되는깊이는 4~6 mm 정도이다. 수술이불가능한담관암환자에서광역학치료는환자삶의질, 담관배액및생존율을향상시킨다고보고되었 - 626 -
- 동석호. 간문부담관암의최근치료성적 - 다 55,56. 무작위비교연구에서도내시경담관배액술과광역학치료를같이시행한환자는담관배액술만시행한환자에비해서중앙생존기간 493일대 98일로서생존기간의현격한차이를보였고, 이러한중간분석의결과에따라서이연구는더이상진행하지못하고종료되었다 57). 근치적절제술이불가능한환자에서수술전에광역학치료를시행하였더니근치적완전절제가가능하였다는보고는광역학치료가암을축소시키는 downstaging의방법으로쓰일수있음을시사하고있다 58). 결 간문부담관암은수술이어렵고, 수술적절제후에도 5년생존율이 20~40% 정도로예후가좋지않은악성질환이다. 그러나적극적인외과적절제술, 기타보존적인치료의발달로보다정확한진단하에근치적수술이가능해지면서수술로인한합병증, 사망률은감소하고생존율은증가하고있다. 수술이불가능한경우에는비침습적인배액술, 항암화학요법이나방사선치료, 표적치료, 광역학치료등의적극적인보존적치료로삶의질향상및생존기간을연장할수있게되었다. 이를위해서는소화기내과, 외과, 영상의학과, 종양학및방사선치료의사가유기적인협력을통한다양한진단적, 치료적접근이반드시선행되어야할것이다. 론 중심단어 : 간문부담관암, 수술, 고식적치료, 예후 REFERENCES 1) Klatskin G. Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis: an unusual tumor with distinctive clinical and pathological features. Am J Med 38:241-256, 1965 2) Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol 15:4240-4262, 2009 3) Smith AC, Dowsett JF, Russell RC, Hatfield AR, Cotton PB. Randomised trial of endoscopic stenting versus surgical bypass in malignant low bileduct obstruction. Lancet 344:1655-1660, 1994 4) Lai EC, Chu KM, Lo CY, Fan ST, Lo CM, Wong J. Choice of palliation for malignant hilar biliary obstruction. Am J Surg 163: 208-212, 1992 5) Chang WH, Kortan P, Haber GB. Outcome in patients with bifurcation tumors who undergo unilateral versus bilateral hepatic duct drainage. Gastrointest Endosc 47: 354-362, 1998 6) Devière J, Baize M, de Toeuf J, Cremer M. Long-term follow-up of patients with hilar malignant Stricture treated by endoscopic internal biliary drainage. Gastrointest Endosc 34:95-101, 1988 7) Park J, Kim MH, Kim KP, Park do H, Moon SH, Song TJ, Eum J, Lee SS, Seo DW, Lee SK. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver 3:298-305, 2009 8) Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi M. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 230: 663-671, 1999 9) Kondo S, Hirano S, Ambo Y, Tanaka E, Okushiba S, Morikawa T, Katoh H. Forty consecutive resections of hilar cholangiocarcinoma with no postoperative mortality and no positive ductal margins: results of a prospeilar cstudy. Ann Surg 240:95-101, 2004 10) Ebata T, Nagino M, Kamiya J, Uesaka K, Nagasaka T, Nimura Y. Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 238: 720-727, 2003 11) Zervos EE, Osborne D, Goldin SB, Villadolid DV, Thometz DP, Durkin A, Carey LC, Rosemurgy AS. Stage does not predict survival after resection of hilar cholangiocarcinomas promoting an aggressive operative approach. Am J Surg 190:810-815, 2005 12) Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BS J, Youssef BA M, Klimstra D, Blumgart LH. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234:507-517, 2001 13) Anderson CD, Pinson CW, Berlin J, Chari RS. Diagnosis and treatment of cholangiocarcinoma. Oncologist 9:43-57, 2004 14) Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, Piantadosi S, Hruban RH, Lillemoe KD, Yeo CJ, Cameron JL. Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 224:463-473; discussion 473-475, 1996 15) Forsmo HM, Horn A, Viste A, Hoem D, Ovrebo K. Survival and an overview of decision-making in patients with cholangiocarcinoma. Hepatobiliary Pancreat Dis Int 7:412-417, 2008 16) Todoroki T, Kawamoto T, Koike N, Takahashi H, Yoshida S, Kashiwagi H, Takada Y, Otsuka M, Fukao K. Radical resection of hilar bile duct carcinoma and predictors of survival. Br J Surg 87:306-313, 2000 17) Rea DJ, Munoz-Juarez M, Farnell MB, Donohue JH, Que FG, Crownhart B, Larson D, Nagorney DM. Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients. Arch Surg 139:514-523, 2004 18) Song GW, Lee SG, Lee YJ, Park KM, Hwang S, Kim KH, Ahn CS, Moon DB, Ha TY, Ryu JH, Park JI, Lee HJ. Analysis of survival predictors after surgical resection of hilar cholangiocarcinoma (HCCC) in a single institute with large volume. Korean J Hepatobiliary Pancreat Surg 11:32-39, 2007-627 -
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