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172 pissn 1598-9992 eissn 2233-6869 REVIEW ARTICLE 담도암의항암치료 우상명 국립암센터간담췌암연구과, 간암센터, 국제암대학원대학교 Chemotherapy for Biliary Tract Cancer Sang Myung Woo Liver and Pancreatobiliary Branch, Research

biliary tract or the biliary drainage system, including the intra- and extra-hepatic bile ducts as well as the gallbladder.

1 Korean J Gastroenterol Vol. 69 No. 3, pissn eissn REVIEW ARTICLE 담도암의항암치료 우상명 국립암센터간담췌암연구과, 간암센터, 국제암대학원대학교 Chemotherapy for Biliary Tract Cancer Sang Myung Woo Liver and Pancreatobiliary Branch, Research Institute, Center for Liver Cancer, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea The term of biliary tract cancer (BTC) refers to all tumors that arise from the biliary tract or the biliary drainage system, including the intra- and extra-hepatic bile ducts as well as the gallbladder. BTCs are aggressive tumors with limited treatment options and poor overall survival. Currently, surgery remains to be the only potentially curative treatment, and most patients develop recurrence. For advanced tumors, only limited effective treatment modalities exist today. Gemcitabine plus cisplatin is considered as a standard option for advanced biliary cancer. A randomized phase III trial (ABC-02 trial) showed superiority of gemcitabine plus cisplatin over gemcitabine alone. In that study, they showed that after a median follow-up of 8.2 months, the median overall survival was 8.1 months in the gemcitabine-only group and 11.7 months in the gemcitabine plus cisplatin group (p<0.001). However, while this is a definite advancement, a 3-month survival extension among patients with BTC is modest at best. Moreover, this regimen has not been compared head-to-head with other gemcitabine based combinations. Gemcitabine monotherapy, 5-fluorouracil plus leucovorin, and single-agent capecitabine are all reasonable options for patients with a borderline performance status. Recent advancements have provided new insight into the genomic landscape of BTCs, and thus, it remains unclear whether combined treatment with molecular targeted agents or other cytotoxic chemotherapeutic agents may also be effective against advanced BTC. (Korean J Gastroenterol 2017;69: ) Key Words: Cholangiocarcinoma; Chemotherapy 서론 담도암 (biliary tract cancer) 은답즙이배출되는경로인담관, 담낭에발생하는악성종양을통칭한다. 한국중앙암등록본부자료에의하면담낭암을포함한담도암은 2013년에 5,283건이발생하여전체암발생의 9위를차지하고있다. 다른대부분의고형성종양과마찬가지로담도암에서도근치적절제술만이완치를기대할수있는유일한치료법이나대부분의담도암환자는수술이불가능한상태에서발견되며, 설령 근치적수술을하더라도잦은국소재발과원격전이로장기생존을기대하기어렵다. 이로인해효과적인전신화학요법은담도암의치료에서매우중요하며, 최근적용이점차적으로확대되고있다. 절제가불가능한진행성담도암에서전신항암요법이효과적인담도배액을포함한최적의보존적치료 (best supportive care) 에비해생존기간을연장하는효과가있다는것은 2개의무작위대조연구에근거를두고있다. 총 93명의진행성췌장암과담도암환자를대상으로 5-FU 투여와최적의보존적치 Received February 17, Revised February 23, Accepted February 26, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 우상명, 10408, 고양시일산동구일산로 323, 국립암센터간담췌암연구과, 간암센터, 국제암대학원대학교 Correspondence to: Sang Myung Woo, Liver and Pancreatobiliary Branch, Research Institute, Center for Liver Cancer, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea. Tel: , Fax: , wsm@ncc.re.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 69 No. 3, March

2 Woo SM. Chemotherapy for Biliary Tract Cancer 173 료를비교한연구에서 5-FU 치료군에서생존기간연장과삶의질향상을보였다. 37명의담도암환자중 5-FU 치료군의중앙생존기간이 6개월로보존적치료군의 2.5개월에비해뚜렷하게우월하였으나, 대상환자숫자가적어통계적유의성에는도달하지못하였다. 1 진행성담낭암 81명을대상으로한무작위대조연구에서는 gemcitabine과 oxaliplatin (GEMOX) 복합화학요법치료군의중앙생존기간이 9.5개월이었고, 보존적치료군의 4.5개월과 5-FU/folinic acid 치료군의 4.6개월에비교하여통계적으로유의하게향상되었다. 2 현재 gemcitabine과 cisplatin (GP) 병합요법이 gemcitabine 단독요법에비해효과적이라는 3상연구결과를근거로현재 GP 병합요법을진행성담도암의 1차항암치료로우선적으로사용하고있으나생존기간연장효과는만족할만한수준에이르지못하고있다. 본종설에서는담도암의항암치료를수술후항암화학요법, 고식적목적의항암치료, 표적치료제순으로나누고, 최신지견을중심으로정리하였다. 본론 1. 수술후항암화학요법근치적절제술만이완치를기대할수있는유일한치료법이나수술후잦은국소재발과원격전이로장기생존을기대하기어렵다. 담도암의 5년생존율은약 10% 에머물러있는상황이다. 3,4 따라서치료성적을향상시키기위해서는수술후항암화학요법이필요하나대부분의연구들이후향적연구로일치된결과를보여주지못하였다. 5 미국 National Comprehensive Cancer Network의가이드라인에서는이러한후향적연구들에대한종합적인분석을바탕으로환자의전신상태에따라 5-fluorouracil 또는 gemcitabine을이용한항암치료, 임상시험등록또는보존적치료를추천한다. 6 통합분석 (pooled analysis) 결과에서는림프절전이혹은수술절단면종양침범양성인환자에서수술후항암화학요법이임상적이점이있는것으로나타났다. 6 최근 gemcitabine, oxaliplatin, 혹은 capecitabine을이용한전향적임상연구의결과들이발표되었다. 국내에서진행된 2상연구에서는 72명의담도암환자를대상으로수술후 gemcitabine 항암치료를 6개월동안시행 하였다. 7 2년무재발생존율이 43% (95% CI, 33 57%) 이며, 가장흔한 3도이상의부작용은호중구감소증이었으며 56% 의환자에서발생하였다. GEMOX 병합요법을수술후항암화학요법으로시행한 3상무작위대조연구 (PRODIGE 12-ACCORD 18 trial) 는프랑스 33개병원에서 196명의담도암환자를대상으로진행되었다. 8 GEMOX를투여한환자군의경우무재발생존기간의중앙값은 30.4개월이었고대조군의경우 22.0개월이었다. GEMOX 치료군과대조군의 4년무재발생존율은각각 39.3% 와 33.2% 였으나양군간통계적으로의미있는차이가없었다. 현재까지담도암환자에서수술후항암화학요법은근거가부족한상태이기때문에재발위험성과환자전신상태를고려한개별화된접근이필요하다. Human equilibrative transporter 1 (hent1) 과 cytidine deaminase (CDA) 등 gemcitabine의 transport와대사에관여하는단백질의발현이 gemcitabine 기반항암요법의치료반응예측마커로제시되고있으나, 9 전향적인임상연구가필요하다. 또한 capecitabine 을사용한 3상무작위대조연구가완료된상태로그결과를기대한다 (ClinicalTrials.gov identifier: NCT ). 2. 고식적항암화학요법어떠한약물이나약물의조합이담도암에가장효과적인가에대해서는분명하지않다. 그러나, GP 병합요법이 gemcitabine 단독요법에비해효과적이라는연구결과를근거로현재 GP 병합요법을진행성담도암의 1차치료로우선적으로추천한다 (Table 1). 2010년발표된무작위대조연구 (ABC-02 trial) 10 에서국소진행되거나전이된담도암환자 410명 ( 담도암 [cholangiocarcinoma] 242명, 담낭암 148명, 바터팽대부암 20 명 ) 이 cisplatin (25 mg/m 2 ) 과 gemcitabine (1,000 mg/m 2 ) 을 1, 8일째 21일간격으로정주하는복합항암요법군과 gemcitabine 단독사용군 (1,000 mg/m 2 days 1, 8, 15, every 28 days) 으로무작위배정되었다. GP 병합요법군의중앙생존기간과중앙무진행생존기간은각각 11.7개월과 8.0개월로, gemcitabine 단독사용군의 8.1개월과 5.0개월과비교하여통계적으로의미있게향상되었다. 이외임상연구들은대부분소수의환자들만을대상으로한 Table 1. First-line Chemotherapy Options for Patients with Unresectable or Metastatic Biliary Tract Cancer First-line treatment Median survival (months) Good performance status Gemcitabine plus cisplatin 10 (preferred) 11.7 Gemcitabine plus oxaliplatin Poor performance status Gemcitabine Capecitaine (cholangiocarcinoma) 9.9 (gallbladder cancer) 5-FU plus lecovorin Vol. 69 No. 3, March 2017

3 174 우상명. 담도암의항암치료 2상임상시험이거나후향적연구이다. 또한간내담도암과간외담도암및담낭암, 바터팽대부암이다른비율로혼재되어있다. 이종양들은유사한위치에서발생하지만, 독특한자연경과및화학요법에대한반응을나타낸다. 213명의진행성담도암환자를대상으로한국내연구를살펴보면간내담도암, 전이성질환, 간전이, ECOG performance state, 그리고혈청알칼라인포스포타제상승이다변량분석에서의미있는예후인자였다. 11 따라서담도암임상연구의결과를해석할때이러한변수들을고려해야한다. GP 병합요법의연구결과는분명히담도암항암치료에있어서의미있는진전이라할수있으나 3개월의생존기간연장이라는효과는여전히만족스럽지않다. 또한 capecitabine, oxaliplatin 등과같은타약제와의병합요법과직접비교하는전향적인연구가없어서 GP 병합요법을표준치료로인정하기어렵다. 특히 gemcitabine과 capecitabine 병합요법은여러 2상연구들에서 25% 안팎의비교적높은반응률을보여우수한항암효과를기대할수있다 또한 GEMOX 병합요법도 15-41% 의반응률과 개월의중앙생존기간을보였으며, capecitabine과 oxaliplatin의병합요법도 23% 의반응률과 12.8개월의중앙생존기간을보고하였다. 21 전신상태가좋지않은환자의경우 capecitabine이나 gemcitabine 단독요법, 혹은 5-FU과 lecovorin 병합요법을 1차치료로고려할수있다. 5-FU 단독혹은복합항암요법에대한연구들은 0-34% 의반응률과 2-12개월의중앙생존기간을보고하였다. 5-FU을정주하거나 lecovorin을병합한연구들이비교적높은반응률을보고하였으나생존기간이연장되는지는명확하지않다 Capecitabine은경구투여가가능한 5-FU 전구체로서 5-FU 정주를대신할수있다는장점이있다. 25 Cisplatin과의병합한연구들에서 17-41% 의반응률과 개월의중앙생존기간을보고하였다 최근에개발된 5-FU 경구용제제인 S1과 cisplatin을병합한국내연구 30 에서 51명의담도암환자를대상으로 30% 의반응률과 8.7개월의중앙생존기간을보였으며, gemcitabine과의병합요법에서는반응률이 34.3% 였고중앙생존기간은 11.6개월로나타났다. 31 GP 병합요법에실패한환자에서 5-FU 기반항암요법을 2 차치료로사용하고있으나근거는매우부족하다. 321명담도암환자를대상으로후향적분석을시행한국내연구 32 에서반응률은 3% 에불과하였으며, 중앙무진행생존기간과중앙생존기간은각각 1.9개월 (95% confidence interval [CI], ) 과 6.5개월 (95% CI, ) 이었다. Cisplatin과의병용요법을사용한경우반응률이향상되었으나 ( 각각 8%, 1%), 생존기간의차이는없었다. Oxaliplatin과 5-FU 단기정주및 leucovorin (FOLFOX) 병용요법도 2차요법으로고려할수있으며, 37명환자를대상으로한 2상연구에서반응률은 22% 로보고되었다. 33 현재 FOLFOX 항암요법을 2차항암요법으로적용한 3상무작위대조연구가 162명환자참여를목표로진행하고있다 (ClinicalTrials.gov identifier: NCT ). 3. 표적치료담도암에서종양유전학적지식은깊어지고있으며이를바탕으로표적치료제를이용한임상시험들이지속적으로진행되고있다. Vascular endothelial growth factor를표적으로한 bevacizumab과 epidermal growth factor receptor (EGFR) 억제제인 erlotinib을병합한다기관 2상연구에서반응률은 12%, 중앙생존기간은 10개월로나타났다. 34 발진이가장흔한 3도독성이었다. 이러한표적치료제만의조합요법이효과가있는지알기위해서는세포독성항암제와비교하는무작위대조연구가필요하나, 매우높은약제비용이한계이다. Bevacizumab을 GEMOX요법과병용한 2상연구는 41% 의반응률과 14.2개월의중앙생존기간을보고하였다. 35 EGFR에대한단클론항체인 cetuximab과 panitumumab 을기존세포독성항암요법과병합하는것이효과적인지명확하지않다. Cetuximab의경우 GEMOX요법과병합한연구 36 에서 63% 의반응률과함께 30% 의환자에서근치적절제술을시행할수있었다는고무적인성적을보고하였다. 그러나 150 명환자를대상으로진행한 2상무작위대조연구에서는중앙무진행생존기간이 cetuximab을병합한군에서 6.1개월, 병합하지않은환자군에서 5.5개월이었으며, 병합한군에서중앙생존기간이연장되지않았다 ( 각각 11개월, 12.4개월 ). 37 KRAS 정상형 (wild type) 담도암환자 89명을대상으로 panitumumab 을 GEMOX요법과병합한 2상무작위대조연구에서도무진행생존기간이연장되지않았다. 38 Erlotinib의경우 GEMOX요법과병합한무작위대조연구가국내에서대규모로진행되었다. 268명환자를대상으로연구가진행되었다. 반응률은 erlotinib과 GEMOX 병합군에서높았으나 ( 각각 30%, 16%), 일차목표인무진행생존기간은의미있게연장되지않았다 ( 중앙무진행생존기간각각 5.8개월, 4.2개월 ). EGFR 돌연변이유무등을포함한담도암의분자생물학적분류에따른개별화된치료전략이필요하다. 최근 DNA sequencing 기술의발달로 isocitrate dehydrogenase (IDH) 1, IDH2, fibroblast growth factor receptor 2 (FGFR2), mismatch repair protein 및 ERBB2 변이를담도암에서확인하였고, 이러한돌연변이의빈도는종양발생위치즉간내담도암, 간외담도암, 담낭암에따라다르다. 현재 IDH1 억제제 39 와 FGFR 억제제 40 가각각변이가있는담도암환자에만적용하는임상연구들이진행되고있으며, 유망한결과를보고하였다. 또한 mismatch repair protein 결 The Korean Journal of Gastroenterology

4 Woo SM. Chemotherapy for Biliary Tract Cancer 175 함이있는담도암에대해 immune checkpoint 억제제인 pembrolizumab를사용하는연구가진행되고있다. 41 결 론 현재담도암에서항암치료의효과는만족스럽지않으나 1차요법으로 GP 항암요법을추천한다. Cisplatin으로인한신독성이우려되는경우 GEMOX요법이대안이될수있다. 전신상태가좋지않은환자의경우 capecitabine이나 gemcitabine 단독요법, 5-FU과 lecovorin 병합요법을 1차항암치료로고려할수있다. 현재돌연변이유무에따른개별화된치료전략이임상시험중에있으며특히 IDH1와 FGFR 억제 제의연구결과를기대할수있다. 현재까지담도암환자에서 수술후항암화학요법은근거가부족한상태로재발위험성과 환자전신상태를고려한개별화된접근이필요하다. REFERENCES 1. Glimelius B, Hoffman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7: Sharma A, Dwary AD, Mohanti BK, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol 2010;28: Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383: Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013;145: Howell M, Valle JW. 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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy