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Korean J Gastroenterol Vol. 66 No. 3, 154-158 http://dx.doi.org/10.4166/kjg.2015.66.3.154 pissn 1598-9992 eissn 2233-6869 REVIEW ARTICLE 내시경초음파를이용한췌장종양의국소치료 윤원재, 서동완 1 인제대학교의과대학서울백병원내과학교실, 울산대학교의과대학서울아산병원내과학교실 1 Endoscopic Ultrasound-guided Local Therapy of Pancreatic Tumors Won Jae Yoon and Dong Wan Seo 1 Department of Internal Medicine, Inje University Seoul Paik Hospital, Inje University College of Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine 1, Seoul, Korea The development of curvilinear EUS has enabled EUS-guided fine-needle aspiration of intra-abdominal mass lesions. With the introduction of interventional EUS, this technology has undergone several modifications in order to be applied to clinical medicine. One of the potential uses of interventional EUS is the EUS-guided local therapy of pancreatic tumors. Various treatment modalities such as fine-needle injection, radiofrequency ablation, photodynamic therapy, laser ablation, and brachytherapy have been tried under EUS guidance. Some of these modalities are being applied clinically. These methods for EUS-guided local therapy of pancreatic tumors will be reviewed in this article. (Korean J Gastroenterol 2015;66:154-158) Key Words: Endosonography; Therapeutics; Pancreas; Neoplasms 서 본 선형주사내시경초음파 (EUS) 의등장이후 EUS 유도하세침흡인술 (EUS-guided fine-needle aspiration) 이가능하게되었다. 이후이기술을응용하여 EUS를이용한췌장종양의국소치료에대한연구가이루어져왔다. 이치료법은 EUS를이용한실시간유도가가능하고, 불량한전신상태로인해수술을받을수없는환자들에게국소치료를가능하게하며, 수술에비해시술후이환율이낮고, 외래에서시술이가능하다는잠재력이있다. 1 1. EUS 유도하세침주입술 (EUS-guided fine-needle injection) 초음파유도하에에탄올을주입하여낭종을제거하는것은갑상선, 신장, 비장등의장기에서이미보고되었다. 2-4 EUS 유도하세침주입술 (EUS-guided fine-needle injection, EUS-FNI) 은동물실험을통해비교적안전하게이루어질수있음이확인되었다. 5-7 특히주입한에탄올의농도와괴사된췌장조직의단면적이비례관계가있음이보고되었다. 6 고형종양에대한 EUS-FNI는임상에서제한적으로적용되고있다. 적용예로는전이성간암, 8 위장관기질종양, 9 췌장의인슐린종, 10 비소세포성폐암의부신전이 11 등을들수있다. EUS-FNI가가장활발히적용되는질환은췌장낭종이다. 많게는전체췌장낭종의 60% 가신생물 (neoplasm) 이며 12 이 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2015. Korean Society of Gastroenterology. 교신저자 : 서동완, 05505, 서울시송파구올림픽로 43길 88, 울산대학교의과대학서울아산병원내과학교실 Correspondence to: Dong Wan Seo, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Tel: +82-2-3010-3190, Fax: +82-2-485-5782, E-mail: dwseoamc@amc.seoul.kr Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 66 No. 3, September 2015 www.kjg.or.kr

Yoon WJ and Seo DW. EUS-guided Local Therapy of Pancreatic Tumors 155 중많은비율이전암성또는암성병변이므로 13 이러한신생물성췌장낭종이의심되는경우에는가능한한수술적치료가이루어지고있다. 14 그러나신생물성췌장낭종중약 15-39% 는암성변화가극히드문장액낭성종양 (serous cystic neoplasm) 이다. 15 또한 Correa-Gallego 등 16 은수술을시행한무증상췌장낭종환자의경우수술전진단의정확도는 68% 였으며, 수술을시행한췌장낭종중 5% 는신생물이아닌췌장낭종이었음을보고하였다. 췌장절제술은그동안비약적으로발전해왔으나, 아직도췌십이지장절제술후사망률은 1.0-3.9% 정도로보고되며, 합병증중하나인췌장누공의발생률은 2.1-12.6% 정도로보고되고있다. 17-22 췌미부절제술의경우수술후사망률은 1% 미만이나수술후이환율은 20-30% 정도로보고된다. 23 따라서수술이불필요한췌장낭종환자에게수술이적용되는문제점을보완할수있는치료방법의필요가대두되었는데, 이러한방법으로 EUS 유도하췌장낭종에탄올세척술 (EUS-guided ethanol lavage, EUS-EL) 이소개되었다. EUS-EL은 2005년에 Gan 등 24 에의해처음보고되었다. 25명의환자를대상으로췌장낭종에대해 1회의 EUS-EL을시행한결과 8명에서췌장낭종이소실되었다. 이후췌장낭종에대한 EUS-EL과 EUS 유도하생리식염수세척술을비교한무작위대조시험에서 EUS-EL을시행한군이생리식염수세척술을시행한군에비해췌장낭종의크기가통계적으로유의하게감소하였다는보고가있었다. 25 DiMaio 등 26 은 1회의 EUS-EL을시행받은환자에비해 2회이상의 EUS-EL을시행받은췌장낭종환자군에서췌장낭종의크기감소효과및낭종이소실되는비율이유의하게증가함을보고하였다. 이후 EUS-EL 후추가적으로파클리탁셀 (paclitaxel) 을췌장낭종에주입하는치료법 (EUS-guided ethanol lavage with paclitaxel injection, EUS-ELPI) 이개발되었다. 최초의시도는 14명의췌장낭종환자를대상으로이루어졌다. 시술후평균 9개월간추적관찰하였을때 11명의환자에서췌장낭종이완전히소실되었으며 2명의환자에서는부분적으로소실되었다. 1명의환자에서는반응이없었다. 합병증으로는무증상고아밀라아제혈증이 6예, 췌장염이 1예, 복통이 1예였다. 27 EUS-ELPI에대한비교적대규모의연구결과가 2011년에발표되었다. Oh 등 28 은췌장낭종에대한 EUS-ELPI 후 12개월이상추적관찰한 47명의환자에대한보고를하였다. 29명의환자에서췌장낭종이완전히소실되었으며, 6명의환자에서낭종의부분소실이나타났다. 12명의환자에서는반응이없었다. 췌장낭종의반응이없었던 12명의환자중 4명이수술을받았는데, 낭종상피가소실된비율은각각 0%, 25%, 40%, 100% 였다. 시술관련합병증으로는균혈증이동반되지않은발열 1예, 2주간지속된복부불편감 1예, 추가적인합병 증이동반되지않은췌장염 1예, 낭액의낭종주위유출 1예, 비장정맥폐쇄 1예였다. 이외에도종양내주입이가능한파클리탁셀제형 (OncoGel; MacroMed Inc., Salt Lake City, UT, USA) 29,30 과이리노테칸 (irinotecan) 을함유한염주 (bead) 31 를 EUS 유도하에돼지췌장에주입한실험결과가보고되었다. 두제제모두비교적용이하고안전하게주입이가능하였으며, 특히 OncoGel의경우에는췌장조직내에서비교적장시간치료범위의농도를유지함이보고되었다. 30 2. EUS 유도하고주파열치료 (EUS-guided radiofrequency ablation) 500 khz 내외의고주파교류를조직에가하면세포내이온의교반 (agitation) 이일어나고이에의해열이발생하게된다. 이때발생하는열에의해세포사멸및조직의응고괴사 (coagulative necrosis) 가발생하게된다. 1 EUS 유도하고주파열치료 (EUS-guided radiofrequency ablation, EUS-RFA) 는이원리를이용한국소치료법이다. RFA는간세포암과고도이형성이동반된바레트식도 (Barrett esophagus) 등의치료에이용되고있다. 32-34 췌장암은예후가불량하며, 근치적절제를통해서만완치를기대할수있으나 20% 내외의환자만이근치적절제가가능한병기에서진단이된다. 35 그러나근치적절제가이루어진경우에도재발이나전이가많아서, 초기에진단하여절제를한경우에도 5년생존율은 30% 내외인것으로알려져있다. 36 또한기존항암제에대한반응도좋지않아서, 항암화학요법의개선에도불구하고진행성췌장암의예후는불량하다. 37 이러한배경에서, 기존의췌장암의치료와국소치료법을병합하려는시도가시행되어왔다. 동물모델을이용한최초의 EUS-RFA는 Goldberg 등 1 에의해보고되었다. EUS 유도하에 19 G 바늘전극을돼지췌장미부로진입시킨후전극의온도를 90±2 o C로 6분간유지한결과지름 1 cm 내외의응고괴사가발생하였다. 이후 Carrara 등 38 은전극내부가이산화탄소로냉각되는양극성 (bipolar) RFA 전극을개발하여돼지췌장에대해 EUS-RFA를시행하였다. 단극성 (monopolar) RFA 전극에비해양극성 RFA 전극은 RFA 효과가떨어지는경향이있는데, 이를보완하기위해냉각이되는양극성 RFA 전극을개발한것이다. 이전극을이용하여최대단면적 4,000 mm 2 정도의응고괴사가발생하였다. 이전극은이후돼지간과비장에대해서도실험이이루어졌으며비교적안전하게 RFA를시행할수있음이보고되었다. 39 EUS-RFA의넓이를더욱크게하고자 Varadarajulu 등 40 은우산살형태의 RFA 전극을개발하였다. 이전극은평소에 Vol. 66 No. 3, September 2015

156 윤원재, 서동완. 내시경초음파를이용한췌장종양의국소치료 는접혀있다가전극을전진시키면 6개의전극이우산처럼펴지게된다. 이전극을이용하여 EUS 유도하에돼지간을 RFA 하였을때최대지름 27 mm 정도의응고괴사가발생하였다. Kim 등 41 은전극내부가저온식염수로냉각되는 18 G 바늘전극을이용한 EUS-RFA 동물실험결과를발표하였다. 10 마리의돼지를대상으로 50 W의전력으로 5분간췌장에대해 EUS-RFA를실행한결과, 평균지름 23 mm 정도의응고괴사가발생하였다. 시술전후로혈액검사결과의급격한변화나동물의이상행동은발생하지않았다. 부검소견에서 RFA를시행한부위이외의췌장조직의괴사나췌관손상은관찰되지않았으며, 혈관손상, 인접장기손상등의소견또한관찰되지않았다. 3마리의돼지에서섬유화와유착이발견되었다. EUS-RFA는병변조직의응고괴사를유도할수있으나, 과도하게 RFA를시행하는경우췌장주변장기의손상이나췌장염이발생하는문제점이있을수있다. 돼지생체모델에서 EUS-RFA는비교적안전하게시행할수있는것으로보고되었으나, 일부합병증이보고되었다. 보고된합병증으로는위벽화상, 장막화상, 췌장염, 췌장과장관간의유착등이있다. 1,38,41 3. EUS 유도하광역동치료 (EUS-guided photodynamic therapy) 광민감제 (photosensitizer) 투여후적절한파장의빛을종양조직에가하면일중항산소 (singlet oxygen) 라는세포독성을지닌산소종류가발생한다. 광역동치료 (photodynamic therapy) 는이원리를이용한종양치료방법이다. 42 EUS 유도하광역동치료는아직동물실험단계에머물러있다. 광민감제를돼지에게투여한후 EUS 유도하에돼지췌장을세침으로천자하고이를통하여광섬유를진입시켜광역동치료를시행하는것이다. 지금까지최대지름 30 mm 정도의괴사를유도할수있는것으로보고되었다. 43,44 4. EUS 유도하레이저치료 (EUS-guided laser ablation) EUS 유도하광역동치료와유사한방법으로 Nd:YAG 레이저광섬유를돼지췌장으로진입시켜조직괴사를유도한실험이있다. 이방법을통하여최대면적 87 mm 2 정도의췌장조직괴사가발생하였다. 45 이방법을이용하여간미상엽에위치한간세포암의치료를시행한증례가보고된바있다. 46 5. EUS 유도하근접치료 (EUS-guided brachytherapy) 근접치료는방사성선원 (radioactive source) 을종양조직또는종양주변조직에직접삽입하여종양을치료하는방법이다. 동물실험을통해비교적안전하게 EUS 유도하에췌장 에방사성선원을삽입하는것이가능하다는것이보고되었다. 47 이후수술적절제가불가능한췌장암환자 15명을대상으로한 EUS 유도하근접치료의예비연구결과가발표되었다. 12명의환자가안정병변상태를유지하거나부분반응을보였다. 중앙생존기간은 10.6개월이었다. 합병증으로는 3명의환자에서췌장염이발생하였으며이중 2명은가성낭종이병발하였다. 또한 3명의환자에서 3도혈액학적독성이발생하였다. 48 결 EUS를이용한췌장종양의국소치료는아직초기단계에있다. 동물실험을통하여여러가지방법이시험되고있으나실제적인치료방법의확립및임상적용까지는추가적인연구가필요하다. 효과적인치료방법의개발만큼중요한것은바로적절한적응증을찾는것이다. 췌장낭종에대해서는 EUS-FNI가비교적널리적용되고있으나, 췌장의고형종양에대해서는아직활발한연구가이루어지지않고있으며, 증례보고수준의단계에머물러있다. 그러나췌장접근의용이성을고려한다면, EUS를이용한췌장종양의국소치료는계속발전할것으로생각한다. REFERENCES 1. Goldberg SN, Mallery S, Gazelle GS, Brugge WR. EUS-guided radiofrequency ablation in the pancreas: results in a porcine model. Gastrointest Endosc 1999;50:392-401. 2. Bennedbaek FN, Hegedüs L. Treatment of recurrent thyroid cysts with ethanol: a randomized double-blind controlled trial. J Clin Endocrinol Metab 2003;88:5773-5777. 3. Skolarikos A, Laguna MP, de la Rosette JJ. Conservative and radiological management of simple renal cysts: a comprehensive review. BJU Int 2012;110:170-178. 4. Völk M, Rogler G, Strotzer M, Lock G, Manke C, Feuerbach S. Post-traumatic pseudocyst of the spleen: sclerotherapy with ethanol. Cardiovasc Intervent Radiol 1999;22:246-248. 5. Aslanian H, Salem RR, Marginean C, Robert M, Lee JH, Topazian M. EUS-guided ethanol injection of normal porcine pancreas: a pilot study. Gastrointest Endosc 2005;62:723-727. 6. Matthes K, Mino-Kenudson M, Sahani DV, Holalkere N, Brugge WR. Concentration-dependent ablation of pancreatic tissue by EUS-guided ethanol injection. Gastrointest Endosc 2007;65: 272-277. 7. Giday SA, Magno P, Gabrielson KL, et al. The utility of contrast-enhanced endoscopic ultrasound in monitoring ethanol-induced pancreatic tissue ablation: a pilot study in a porcine model. Endoscopy 2007;39:525-529. 8. Barclay RL, Perez-Miranda M, Giovannini M. EUS-guided treat- The Korean Journal of Gastroenterology

Yoon WJ and Seo DW. EUS-guided Local Therapy of Pancreatic Tumors 157 ment of a solid hepatic metastasis. Gastrointest Endosc 2002; 55:266-270. 9. Günter E, Lingenfelser T, Eitelbach F, Müller H, Ell C. EUS-guided ethanol injection for treatment of a GI stromal tumor. Gastrointest Endosc 2003;57:113-115. 10. Jürgensen C, Schuppan D, Neser F, Ernstberger J, Junghans U, Stölzel U. EUS-guided alcohol ablation of an insulinoma. Gastrointest Endosc 2006;63:1059-1062. 11. Artifon EL, Lucon AM, Sakai P, et al. EUS-guided alcohol ablation of left adrenal metastasis from non-small-cell lung carcinoma. Gastrointest Endosc 2007;66:1201-1205. 12. Basturk O, Coban I, Adsay NV. Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications. Arch Pathol Lab Med 2009;133:423-438. 13. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. 4th ed. Lyon: IARC, 2010. 14. Kent TS, Vollmer CM, Callery MP. Intraductal papillary mucinous neoplasm and the pancreatic incidentaloma. World J Gastrointest Surg 2010;2:319-323. 15. Yoon WJ, Brugge WR. Pancreatic cystic neoplasms: diagnosis and management. Gastroenterol Clin North Am 2012;41:103-118. 16. Correa-Gallego C, Ferrone CR, Thayer SP, Wargo JA, Warshaw AL, Fernández-del Castillo C. Incidental pancreatic cysts: do we really know what we are watching? Pancreatology 2010;10:144-150. 17. Balcom JH, Rattner DW, Warshaw AL, Chang Y, Fernández-del Castillo C. Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001;136:391-398. 18. Mullen JT, Lee JH, Gomez HF, et al. Pancreaticoduodenectomy after placement of endobiliary metal stents. J Gastrointest Surg 2005;9:1094-1104; discussion 1104-1105. 19. Kazanjian KK, Hines OJ, Eibl G, Reber HA. Management of pancreatic fistulas after pancreaticoduodenectomy: results in 437 consecutive patients. Arch Surg 2005;140:849-854; discussion 854-856. 20. Büchler MW, Friess H, Wagner M, Kulli C, Wagener V, Z'Graggen K. Pancreatic fistula after pancreatic head resection. Br J Surg 2000;87:883-889. 21. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567-579. 22. Schmidt CM, Powell ES, Yiannoutsos CT, et al. Pancreaticoduodenectomy: a 20-year experience in 516 patients. Arch Surg 2004;139:718-725; discussion 725-727. 23. Crippa S, Partelli S, Falconi M. Extent of surgical resections for intraductal papillary mucinous neoplasms. World J Gastrointest Surg 2010;2:347-351. 24. Gan SI, Thompson CC, Lauwers GY, Bounds BC, Brugge WR. Ethanol lavage of pancreatic cystic lesions: initial pilot study. Gastrointest Endosc 2005;61:746-752. 25. DeWitt J, McGreevy K, Schmidt CM, Brugge WR. EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest Endosc 2009;70: 710-723. 26. DiMaio CJ, DeWitt JM, Brugge WR. Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions. Pancreas 2011;40:664-668. 27. Oh HC, Seo DW, Lee TY, et al. New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection. Gastrointest Endosc 2008;67:636-642. 28. Oh HC, Seo DW, Song TJ, et al. Endoscopic ultrasonographyguided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts. Gastroenterology 2011;140:172-179. 29. Linghu E, Matthes K, Mino-Kenudson M, Brugge WR. Feasibility of endoscopic ultrasound-guided OncoGel (ReGel/paclitaxel) injection into the pancreas in pigs. Endoscopy 2005;37:1140-1142. 30. Matthes K, Mino-Kenudson M, Sahani DV, et al. EUS-guided injection of paclitaxel (OncoGel) provides therapeutic drug concentrations in the porcine pancreas (with video). Gastrointest Endosc 2007;65:448-453. 31. Karaca C, Cizginer S, Konuk Y, et al. Feasibility of EUS-guided injection of irinotecan-loaded microspheres into the swine pancreas. Gastrointest Endosc 2011;73:603-606. 32. Sutherland LM, Williams JA, Padbury RT, Gotley DC, Stokes B, Maddern GJ. Radiofrequency ablation of liver tumors: a systematic review. Arch Surg 2006;141:181-190. 33. Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 2009;49:453-459. 34. Spechler SJ, Sharma P, Souza RF, et al. American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology 2011;140: 1084-1091. 35. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004;363:1049-1057. 36. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database. Cancer 2007;110:738-744. 37. Michl P, Gress TM. Current concepts and novel targets in advanced pancreatic cancer. Gut 2013;62:317-326. 38. Carrara S, Arcidiacono PG, Albarello L, et al. Endoscopic ultrasound-guided application of a new hybrid cryotherm probe in porcine pancreas: a preliminary study. Endoscopy 2008;40: 321-326. 39. Carrara S, Arcidiacono PG, Albarello L, et al. Endoscopic ultrasound-guided application of a new internally gas-cooled radiofrequency ablation probe in the liver and spleen of an animal model: a preliminary study. Endoscopy 2008;40:759-763. 40. Varadarajulu S, Jhala NC, Drelichman ER. EUS-guided radiofrequency ablation with a prototype electrode array system in an animal model (with video). Gastrointest Endosc 2009;70:372-376. 41. Kim HJ, Seo DW, Hassanuddin A, et al. EUS-guided radiofrequency ablation of the porcine pancreas. Gastrointest Endosc 2012;76:1039-1043. 42. Agostinis P, Berg K, Cengel KA, et al. Photodynamic therapy of cancer: an update. CA Cancer J Clin 2011;61:250-281. 43. Chan HH, Nishioka NS, Mino M, et al. EUS-guided photodynamic Vol. 66 No. 3, September 2015

158 윤원재, 서동완. 내시경초음파를이용한췌장종양의국소치료 therapy of the pancreas: a pilot study. Gastrointest Endosc 2004;59:95-99. 44. Yusuf TE, Matthes K, Brugge WR. EUS-guided photodynamic therapy with verteporfin for ablation of normal pancreatic tissue: a pilot study in a porcine model (with video). Gastrointest Endosc 2008;67:957-961. 45. Di Matteo F, Martino M, Rea R, et al. EUS-guided Nd:YAG laser ablation of normal pancreatic tissue: a pilot study in a pig model. Gastrointest Endosc 2010;72:358-363. 46. Di Matteo F, Grasso R, Pacella CM, et al. EUS-guided Nd:YAG laser ablation of a hepatocellular carcinoma in the caudate lobe. Gastrointest Endosc 2011;73:632-636. 47. Sun S, Qingjie L, Qiyong G, Mengchun W, Bo Q, Hong X. EUS-guided interstitial brachytherapy of the pancreas: a feasibility study. Gastrointest Endosc 2005;62:775-779. 48. Sun S, Xu H, Xin J, Liu J, Guo Q, Li S. Endoscopic ultrasound- guided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy 2006;38:399-403. The Korean Journal of Gastroenterology