02 KJG (조창민)-124.hwp

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1 Korean J Gastroenterol Vol. 73 No. 3, pissn eissn REVIEW ARTICLE 진행성췌장신경내분비종양치료의최신지견 조창민 1,2 경북대학교의과대학내과학교실 1, 칠곡경북대학교병원담도췌장암센터 2 Recent Updates in the Management of Advanced Pancreatic Neuroendocrine Tumors Chang Min Cho 1,2 Department of Internal Medicine, School of Medicine, Kyungpook National University 1 ; Center for Pancreatobiliary Tumors, Kyungpook National University Chilgok Hospital 2, Daegu, Korea Pancreatic neuroendocrine tumors (pnets) are rare neoplasms arising from the pancreatic islet of Langerhans and can be functioning or non-functioning based on the clinical symptoms caused by hormonal secretions. PNETs are the second most common tumor of the pancreas and represent 1-2% of all pancreatic neoplasms. The incidence of pnets appears to be rising and the prognosis seems to be improving, likely due to the improved treatment options. Recent updates of the World Health Organization classification and grading separate pnets into 2 broad categories according to the histopathologic criteria, including the Ki-67 proliferative index and mitotic counts: well-differentiated NET and poorly-differentiated neuroendocrine carcinoma (NEC). The classification also incorporates a new subcategory of well-differentiated high-grade NEC (grade 3) to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of the clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. The treatment of advanced or metastatic pnets may include surgical resection, liver-directed therapies, and/or systemic treatments. In unresectable patients, the goals of these therapies are to palliate the tumor-related symptoms and prolong the lifespan. Systemic therapy consists of the following broad modalities: somatostatin analogues, molecular targeted therapy, systemic chemotherapy, and peptide receptor radionuclide therapy. In conclusion, pnets are diagnosed increasingly throughout the world, usually with metastatic disease and requiring systemic therapy. Each patient should be evaluated thoroughly and discussed individually by a multidisciplinary and dedicated NET-expert team, which might consider all treatment options, including ongoing clinical trials before selecting the appropriate treatment sequence. (Korean J Gastroenterol 2019;73: ) Key Words: Pancreas; Neuroendocrine tumors; Therapy 서론 췌장신경내분비종양은랑게르한스소도 (islet of Langerhans) 에서기원한종양을의미하며, 종양에서분비하는호르몬이나펩타이드단백질에의하여발현되는증상의유무에따라기능성과비기능성종양으로구분할수있다. 췌장신경내분비종양은전체췌장암의약 1.3% 를차지하고, 그발생률은연간 10만 명당 1-3명정도이다 년부터 2009년까지국내신경내분비종양과관련한다기관연구에서췌장신경내분비종양은전체신경내분비종양에서약 8.7% 를차지하고, 매년그발생률은증가하고있는추세이다. 2 1,185명의췌장신경내분비종양환자를대상으로한통계자료에의하면진단당시 14% 에서는췌장에국한되고, 23% 에서는주위장기로침범을동반하며, 54% 에서는원격전이로나타난다고하였고, 병기에따른 5년 Received January 31, Revised February 7, Accepted February 14, 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 : 조창민, 41404, 대구시북구호국로 807, 칠곡경북대학교병원담도췌장암센터 Correspondence to: Chang Min Cho, Center for Pancreatobiliary Tumors, Kyungpook National University Chilgok Hospital, 807 Hokuk-ro, Buk-gu, Daegu 41404, Korea. Tel: , Fax: , cmcho@knu.ac.kr, ORCID: Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 73 No. 3, March

2 Cho CM. Management of Advanced pnets 125 생존율은각각 79%, 62%, 27% 로보고하고있다. 3 진단당시진행된병기를보이더라도예후는췌장선암에비하여양호한편이다. 최근다양한약제의개발로장기생존을보고하고있지만, 어떤약제를우선적으로사용해야하는지에대한명확한지침이제시된자료는매우제한적이다. 진행성췌장신경내분비종양에사용할수있는치료는소마토스타틴유사체, streptozocin을기반으로하는항암화학요법, 표적치료제등이있다. 4 또한펩타이드수용체를이용한표적방사선요법이제한적으로사용되고있다. 본고에서는신경내분비종양의병기분류와진행된췌장신경내분비종양의치료와관련된최신지견에대하여알아보고자한다. 본론 1. 신경내분비종양의최신분류세계보건기구 (World Health Organization, WHO) 는신경내분비종양을 10개의고배율시야당세포분열수 (mitoses), Ki-67 세포증식지수 (proliferation index) 그리고세포분화도를기준으로 grade 1 (G1), 2 (G2), 3 (G3) 로분류하였다. 2010년 WHO 분류에서세포분열수 2 미만과 Ki-67 분열지수 2% 이하를 G1으로, 세포분열수 2-20과 Ki-67분열지수 3-20% 사이를 G2로, 세포분열수 20 이상, Ki-67 분열지수 20% 이상을 G3 neuroendocrine carcinoma로구분하였다. 하지만 G2에해당하는세포분열수나 20% 이상의 Ki-67 분열지수를보이는신경내분비종양에서치료반응및생존율에차이를보여 G3에해당하는군을세분할필요성을제기하였다. 5 또한 G3에서 Ki-67 분열지수 55% 를기준으로분류하였을때, 항암에반응여부와생존율에차이를보여 G3 신경내분비종양에서이질적인군이존재할것이라고제안하고있다. 6 위와같은연구결과에따라 Ki-67 세포증식지수 20% 이상에서세포분화도에따라치료반응과예후에차이를보일것으로예측하여, 최근 2017년 WHO 분류에서는조직학적분류기준을이용하여 G3를고분화신경내분비종양과저분화신경내분비암으로구분하여명명하고있다 (Table 1). 7 향후이분류에따른예후및치료반응의타당성에대한대규모비교연구가필요할것으로생각된다. 앞에서언급한췌장신경내분비종양의 WHO grade 뿐만아니라예후및치료계획수립을반영하기위해서는 Tumor-Node-Metastasis (TNM) 병기분류체계를주로이용하는데, American Joint Committee on Cancer (AJCC) 와 European Neuroendocrine Tumor Society (ENETS) 에서제시하는병기를주로사용한다. 8,9 AJCC 7판에서는종양의크기를 2 cm를기준으로 T 병기를구분하여 2 cm와 4 cm를기준으로구분하는 ENETS와차이가있었으나, 최근개정된 AJCC 8판에서는 ENETS와동일한 TNM 병기기준을사용하고있다. 하지만 TNM stage에서 ENETS는 stage II와 III를세분화하여 IIA, IIB, IIIA, IIIB로분류하였으나, AJCC 8판에서는단순히 II와 III로구분하였다 (Table 2). 이러한다양한등급분류와 TNM 병기시스템은예후예측과치료방향결정에주요한변수로고려될수있지만, 현 Table 2. AJCC (8th ed) and ENETS Staging Systems for pnets AJCC ENETS T stage T1 Tumor limited to the pancreas, <2 cm T2 Tumor limited to the pancreas, 2-4 cm T3 Tumor limited to the pancreas, >4 cm invading the duodenum or bile duct T4 Tumor invading adjacent organs a or the wall of large vessels b N stage N0 No regional LN involvement N1 Regional LN involvement M stage M0 No distant metastasis M1 Distant metastasis Stage I T1, N0, M0 T1, N0, M0 II T2, N0, M0 T2,N0, M0 (IIA) T3, N0, M0 T3, N0, M0 (IIB) III T4, N0, M0 T4, N0, M0 (IIIA) Any T, N1, M0 Any T, N1, M0 (IIIB) IV Any T, any N, M1 Any T, any N, M1 AJCC, American Joint Committee on Cancer; ENETS, European Neuroendocrine Tumor Society; pnets, pancreatic neuroendocrine tumors; LN, lymph node. a Stomach, spleen, colon, adrenal gland; b Celiac axis or superior mesenteric artery. Table 1. WHO 2017 Nomenclature and Classification of Neuroendocrine Tumors Nomenclature Cell differentiation Grade Mitoses/10 HPF Ki-67 index NET, grade 1 Well-differentiated Low grade (G1) <2 <3% NET, grade 2 Well-differentiated Intermediate grade (G2) % NET, grade 3 Well-differentiated High grade (G3) >20 >20% NEC, grade 3 Poorly-differentiated High grade (G3) >20 >20% WHO, World Health Organization; HPF, high power field; NET, neuroendocrine tumor; NEC, neuroendocrine carcinoma. Vol. 73 No. 3, March 2019

3 126 조창민. 췌장신경내분비종양의치료 재까지추천되는일관된기준이없어실제임상진료및연구에제한점으로작용한다. 하지만국내 15개기관 153명의췌장신경내분비종양환자를대상으로한후향적연구에서 WHO 등급과 TNM 병기시스템모두의미있는예후인자로제시하였고, 무진행생존기간 (progression free survival) 은 WHO 등급보다 TNM 분류체계가더잘반영하고있었다. 10 최신분류에따른예후에대한향후추가적인연구가필요하다. 2. 소마토스타틴유사체 (somatostatin analogues) 소마토스타틴은위장관과뇌에분포하고있는곁분비세포 (paracrine cell) 에서분비되는신경펩타이드로, 5가지형태의소마토스타틴수용체 (somatostatin receptor) 에결합하여신경내분비세포에영향을끼쳐다양한호르몬분비를억제하는것으로알려져있다. 췌장신경내분비종양은소마토스타틴수용체의높은발현을특징으로하는데, 이중 2형이췌장신경내분비종양의 80% 에서발현하고있어, 소마토스타틴유사체를기능성신경내분비종양에서분비되는호르몬으로인한증상을조절하기위하여주로사용하였다. 또한신경전달물질로서면역조절역할을하며, 세포독성및세포증식억제작용을하고특별한조건하에서는세포사멸을유도하게된다. 이러한작용기전을바탕으로소마토스타틴유사체가수용체에결합하여여러가지기전을통하여종양에직접적으로증식억제효과를보이거나, 간접적으로신생혈관억제, 호르몬분비억제그리고면역조절을통하여종양을억제하게된다. 11 주로신경내분비종양의치료에사용되고있는유사체는 octreotide long acting release (LAR) 와 lanreotide가대표적이다. 12 Octreotide는소마토스타틴보다성장호르몬, 글루카곤및인슐린분비를더강력하게억제하는것으로알려진최초의소마토스타틴유사체로서, 1980년대부터단회투여제형으로 150 mcg을 1일 3회피하투여로사용되었으며, 당시에는기능성신경내분비종양환자의 88% 에서임상적개선을보여주었고, 5-10% 에서종양의크기감소, 50% 에서종양의안정화를보였다. 13 이후한달에한번근육주사가가능한 octreotide LAR가개발되어치료가더욱편리해졌다. 소마토스타틴유사체를종양억제에사용하게된계기는두가지연구에바탕을두고있다. Octreotide LAR를이용한 PROMID 연구는전이성신경내분비종양환자에서종양성장억제에대한전향적, 위약-대조군, 이중맹검무작위연구로서, 위약군에비하여종양진행에걸리는시간을의미있게연장시킨연구였다. 14 하지만이연구에서는전체생존율에는통계학적으로차이가없었으며, 췌장에침범한신경내분비종양은포함되어있지않아기능성췌장신경내분비종양이외에사용하기에는제한점이있다. 다른전향적무작위, 이중맹검, 위약대조연구인 CLARINET 연구는 lanreotide autogel을위장관및췌장에서기원한비기능성진행성신경내분비종양을대상으로하여, 위약군과비교하여무진행생존기간이통계적으로유의한연장을보여, 증상조절이잘되지않거나서서히자라는종양에서종양성장억제를위하여, 그리고다른전신치료전에사용이가능함을시사하였다. 15 소마토스타틴유사체의부작용으로는주사부위에통증이흔하며, 이외에위장관증상 ( 복통, 설사, 오심 ) 이대표적이나치료에제한되지는않는다. 비록소마토스타틴유사체가진행성신경내분비종양환자에서증상을완화시킬뿐만아니라종양의진행을억제하는것으로알려져있지만, 종양의퇴행은드물고생명연장에는제한이있어향후다른약제와병용혹은약제용량이나투여주기를조절하여치료효과를보는다양한연구결과가기대된다. 최근에는소마토스타틴수용체 1, 2, 3, 5에높은친화력을보이는 pasireotide (SOM230) 가소개되었는데, 주로 octreotide와 lanreotide의치료에불응하는말단비대증환자치료에사용하고있다. 최근이와관련한연구에카시노이드증후군환자에서 octreotide LAR와비교한 3상임상연구에서 pasireotide가증상조절및무진행생존율에개선을보였으나, 통계적으로차이를보이지는않았다. 16 향후이약제와관련한종양억제효과에대한추가연구가필요하다. 3. 표적치료제 Mammalian target of rapamycin은세포성장, 증식및생존과같은일부세포진행과정을조절하는 serine/threonine protein kinase로서신경내분비종양을포함한다양한암종에서비정상적으로과발현되어나타난다. Rapamycin 과그유사체가 mammalian target of rapamycin을억제하는기전을응용하여치료약제로이용되고있는데, everolimus가췌장신경내분비종양의증식을중단하고종양의성장억제목적으로주로사용되었다. 17 Octreotide 치료에불응하는진행성 G1/G2 신경내분비종양환자를대상으로한 3상전향적무작위이중맹검, 위약-대조군비교연구에서 everolimus를사용한환자에서의미있는무진행생존율의연장 (11개월 vs. 4.6개월 ) 을보여, 미국식약청사용승인을받게되었다. 18 이후다른연구를통하여췌장뿐만아니라위장관과폐에기원한신경내분비종양의치료에도사용하게되었다. 더욱이이약제를소마토스타틴유사체와병용하였을경우시너지효과가있을것으로생각되어일부에서는병용치료를권장하고있어, 향후병용치료에대한결과가기대된다. 19 Everolimus 약제의주요부작용으로는약 60% 에서구내염, 발진, 설사, 피로감, 체중감소, 고혈당, 상기도감염등이 The Korean Journal of Gastroenterology

4 Cho CM. Management of Advanced pnets 127 흔하며, 일부에서는약제감량이필요하여 19% 에서부작용으로인하여약제사용중단을경험하였다고한다. 19,20 국내다기관후향적연구에서 G1/G2 진행성비기능성췌장신경내분비종양환자 40명을대상으로 everolimus를사용하였을때무진행생존율중앙값은 20개월 ( 범위, 개월 ) 이었으며, 특히 G1에서예후가더양호한것으로나타났다 (not reached vs. 11 months, p=0.015). 21 과거 G1/G2 신경내분비종양에서만약제효과를기대하였으나, 최근에는 G3에해당하는고분화신경내분비종양에서치료효과를기대하는연구가발표되고있어이에대한적응증확대가기대된다. 22 내피혈관성장인자 (vascular endothelial growth factor) 및다른성장인자와관련된 tyrosine kinase 수용체의과발현으로인한비정상적혈관신생조절이신경내분비종양의성장과전이과정에관여한다는연구결과를바탕으로이러한수용체와경로를억제하는약물이새로운치료약제로보고되고있다. Sunitinib maleate (Sutent ; Pfizer Inc., New York, NY, USA) 는내피혈관성장인자수용체를포함하는여러가지 kinase를비가역적으로억제할수있는대표적인 tyrosine kinase 억제제로다양한고형종양에대하여종양억제와혈관신생억제효과가증명되었다 명의고분화췌장신경내분비종양환자를대상으로한다국적무작위이중맹검위약대조 3상임상시험에서무진행생존율의연장 (11.4개월 vs. 5.5개월 ) 을보였고, 다른연구에비하여특이점은전체생존율의의미있는개선을보였다. 약제관련부작용으로는설사, 오심, 구토및피로감이흔하였고, 고혈압, palmar-plantar erythrodysesthesia, 중성구감소증, 갑상선기 능저하증도드물지않게발생하였다. 이연구로진행성혹은전이성췌장신경내분비종양의치료제로인정을받았으나다른장기에발생한신경내분비종양의치료로는명확한근거가부족한실정이다. 그외다양한 tyrosine kinase 억제제를이용한임상연구가있었으나, 대부분 2상임상연구에서더이상진행되지않고있다 (Table 3). 18,23-30 향후이와관련된췌장신경내분비종양의치료에대한비교임상연구결과가필요하다. 표적치료제의사용은대부분 WHO 분류 G1/G2의종양에국한되어사용하였으나, 최근의분류에따라고분화 G3 신경내분비종양의치료에도가능성을보이는연구가소개되고있다. Ki-67 증식지수가 20-55% 인고분화 G3 췌장신경내분비종양 15명의환자에게 everolimus를사용한후향적연구에서무진행생존기간의중앙값은 6개월이었고, 전체생존중앙값은 28개월이었다. 22 이중 6명의환자는적어도 12개월동안종양의안정화를보였고, 초치료로 everolimus를사용한 4명의환자중 3명에서 12개월이상의지속적인종양의안정화를확인하였다. 이를바탕으로향후고분화 G3 종양환자에서표적치료제관련안정성과효과에대한연구가진행중으로그결과가기대된다. 4. 항암화학요법전신화학요법은진행성이나종양의범위가넓은 G3 췌장신경내분비종양에적응이된다. 주로 Ki-67 분열지수가높거나급속히진행하는질환또는타장기로전이가동반된경우, 다른치료에실패하거나소마토스타틴수용체에음성 Table 3. Molecular Target Agents in Pancreatic Neuroendocrine Tumorsa Authors (year) Phase Target agent Patients ORR (95% CI) Response parameter Months (95% CI) or rate (%) Duran et al. (2006) 24 II Temisirolimus % ( ) TTP 6.0 (3.7-not reached) Hobday et al. (2006) 25 II Gefitinib 39 2 PR and 1 MR in 31 patients 6-month PFS 31% Hobday et al. (2007) 26 II Sorafenib 43 4 PR and 9 MR in 41 patients 6-month PFS 60.9% Kulke et al. (2008) 27 II Sunitinib % ( ) TTP 7.7 ( ) Yao et al. (2008) 28 II Everolimus+octreotide 30 20% PFS 15 ( ) Yao et al. (2010) 29 II Everolimus and everolimus+octreotide LAR 115 and 45 Yao et al. (2011) 18 III Everolimus vs. placebo 191 vs % and 4.4% PFS 9.7 ( ) and 16.7 (11.1-not reached) 5% vs. 2% PFS 11 ( ) vs. 4.6 ( ) Raymond et al. (2011) 23 III Sunitinib vs. control 86 vs % vs. 0% PFS 11.4 ( ) Phan et al. (2015) 30 II Pazopanib+octreotide deposit % ( ) PFS 14.4 ( ) ORR, overall response rate; CI, confidence interval; TTP, time to progression; PR, partial response; MR, minor response; PFS, progression free survival; LAR, long acting release. Vol. 73 No. 3, March 2019

5 128 조창민. 췌장신경내분비종양의치료 인경우우선적으로사용이고려된다. 고전적으로알킬화제 (streptozocin, dacarbazine, temozolomide) 가사용되었는데, 고분화 G1/G2 신경내분비종양의치료에적응증이며, 단독혹은항대사제 (5-fluorouracil [5-FU], capecitabine) 와병용으로사용할수있다. Cisplatin 및 carboplatin과같은백금함유항암제는저분화신경내분비종양의치료에사용되어왔다. Streptozocin은진행성췌장신경내분비종양환자에서일찍이소개된약제이다. 진행된췌장신경내분비종양환자 105명에서 streptozocin+5-fu, streptozocin+doxorubicin 또는 chlorozotocin을이용한무작위연구에서, doxorubicin 과병용하였을경우 5-FU와병용하였을때보다약제에대한반응률 (69% vs. 45%, p=0.05) 과중앙생존율 (2.2 years vs. 1.4 years, p=0.004) 에서우수한것으로알려졌다. 31 하지만이연구에서객관적인반응평가에사용되는고형종양의반응평가 (response evaluation criteria in solid tumors) 를사용하지않아치료효과를비교하는데있어제한점이있다. 이후다른후향적연구에서전이성췌장신경내분비종양환자 84명을대상으로 streptozocin, 5-FU 및 doxorubicin으로치료한연구에서 39% (95% CI, 27-50%) 의치료반응률, 무진행생존기간의중앙값은 18개월, 2년무진행생존율은 41% (95% CI, 26-56%) 였고, 전체평균생존기간은 37개월, 2년전체생존율은 74% (95% CI, 61-87%) 였다. 32 대부분의환자에서오심, 구토가주요부작용으로나타나고, 약 40-50% 의환자는단백뇨, 신여과율감소및투석이필요한경우도발생하기때문에주의가필요하다. Dacarbazine은 diazomethane 매개알킬화작용을통하여 DNA에손상을주어항종양효과를나타내는데, 주로악성흑색종, 호지킨림프종, 육종등의치료에주로사용되었다. 췌장신경내분비종양에서는 5-FU, epirubicin, leucovorin 등의약제와병용하여주로사용하며, 대부분의연구에서 20-40% 의치료반응과중간생존율및무진행생존율을각각 51.9개월과 11-21개월을보였다. 33 약제의흔한독성으로는골수억제, 피부점막장애, 오심및구토등이발생할수있다. Temozolomide는 dacarbazin의경구유사제제로서 guanine의 O 6 부위 methylation을통하여 DNA mismatch를초래하여세포사멸을유도하는기전으로작용한다. 이를근간으로 O 6-methylguanine-DNA methyltransferase (MGMT) 효소의발현이미약한경우 temozolomide 치료효과를기대한다고하였으나, MGMT 효소의역할에대해서는논란이있다. 34 Temozolomide 단독사용외에다른약물과의병용요법관련연구가소개되고있는데, 단일요법으로는반응률 14%, 무진행생존율 7개월, 생존기간중앙값은 16개월로치료성적이좋지 않지만 temozolomide와 capecitabine 병용요법의치료가시너지효과를기대해사용되고있는데, 일부연구에서 60-70% 의방사선학적치료반응과 14-18개월의무진행생존율을보고하고있다 향후병용요법관련치료기준및치료반응의 biomarker로서 MGMT 효소의역할에대한추가적인연구결과가기대된다. 전신항암요법은주로진행된신경내분비종양의초치료로다양한약제가소개되었지만약제간의비교연구는부족하여, 향후적절한적응을바탕으로한최적의치료권고관련한대규모 3상연구가필요하다. 5. 펩타이드수용체방사핵치료 (peptide receptor radionuclide therapy, PRRT) PRRT의작용기전은신경내분비종양에서소마토스타틴수용체의과발현에근거를두고있다. Radiopeptide는신경내분비종양의표면수용체에결합하여작용함으로주변조직에거의영향을주지않고표적방사선치료를하게된다. 하지만대부분의연구에서 radiopeptide 단독으로사용하기보다는산도스타틴유사체를병용하여사용하고있다. 표적방사선치료를위하여가장많이사용되는방사선핵종에는이트륨 ( 90 Y), 루테튬 ( 177 Lu) 혹은인듐 ( 111 In) 으로서, 수용체의발현이클수록 PRRT의치료가효과적이므로이를예측하는데 octreotide 또는 gallium 검사가유용하다 Y-DOTATOC ( 90 Yttrium-labeled tetraazocyclo-dodecane tetraacetic acid modified Tyr3-octreotide) 를이용한단일기관의치료성적보고에서 1,109명진행성신경내분비종양환자를대상으로 378명 (34.1%) 이영상학적치료반응을보였고, 172명 (15.5%) 에서는생화학적치료반응, 329명 (29.7%) 에서임상적인개선을보였다. 40 부작용으로는백혈구감소증, 빈혈, 혈소판감소증등이있으며, 12.4% 에서는 grade 3 혹은 4의일시적인혈액학적이상소견을보였고, 드물게신장기능의일시적인혹은영구적인손상을초래하였다. 최근에는 177 Lu-DOTATATE를사용하는 PRRT가소개되고있는데, phase III NETTER-1 임상시험에서 octreotide LAR 사용후진행된진행성소마토스타틴수용체양성신경내분비종양환자에서 177 Lu-DOTATATE와고용량 octreotide LAR의효능및안전성을비교평가하였다. 41 이연구에서 PRRT군에서 octreodide LAR군에비하여의미있는종양반응평가 (18% vs. 3%) 를보였으며질병진행또는사망에대한위험을 79% 로감소시킬수있었다. PRRT 치료에효과가있을것으로예측되는인자로는소마토스타틴수용체를이용한영상검사에서발현이좋은경우와 68 Ga-DOTATOC PET-CT에서 standardized uptake value 16 이상인경우에해당하며, 그외췌장의신경내분비종양, 종양의진행범위가작은경우 (low tumor burden) 그리고양호한환자의전신 The Korean Journal of Gastroenterology

6 Cho CM. Management of Advanced pnets 129 상태이다. PRRT 관련부작용으로는치료직후혹은신기능보호를위하여아미노산을병용투여할경우오심및구토가발생할수있으며, 드물게 carcinoid crisis, 골수억제, 신장기능저하등이발생할수있다. 조절이되지않는당뇨병과고혈압이동반될경우신기능장애의위험성이높으므로주의할필요가있다. 골수이형성증후군과백혈병이 1-3% 환자에서발생할수있으며, 주로 70세이상고령의환자, 과거방사선및알킬화제항암치료병력이있을경우위험성이높은것으로알려져있다. 6. 간전이병변에대한직접적인치료법 (liver-directed therapies) 근치적절제가불가능한전이성신경내분비종양에서간에만전이가있을경우에는종양의절제술, 간이식과같은적극적인치료로장기간의증상조절, 삶의질향상및생존기간의연장을기대할수있다. 이를근거로췌장신경내분비종양은일차적으로원발종양을수술로제거하고, 국소적으로간전이가있는경우간동맥화학색전술, 고주파열소작치료 (radiofrequency ablation) 및냉동치료등의치료법을시도하여볼수있다. 42 원발종양을포함한 90% 이상종양의부피를제거하는 debulking 수술은증상을동반한기능성신경내분비종양의완화치료로적응이된다. 주로원발병소가절제가능하고간전이병변이두드러진경우와종양의성장속도가완만한경우에 debulking 수술이효과가있다. 후향적연구에서 88% 의환자에서증상의호전과 5년생존율은 60-70% 를보고하고있다. 43 간동맥색전술은수술적절제의적응증이되지않는간전이환자에서우선적으로고려되며, 이는종양의성장을늦추고증상완화에효과적이다. 간동맥화학색전술은 lipiodol과함께 doxorubicin 혹은 streptozocin이주로사용되는데, 치료에대한반응은 67% 로보고하고있다. 44 치료의부작용으로오심및구토 (50-70%), 복통 (50-60%), 발열 (30-60%) 등이발생할수있으나대부분경미하며, 드물게는간부전, 신부전출혈, 감염과같은심각한합병증도유발될수있다. 아직까지는간전이부위에대한치료법에대한비교연구가부족한상태로치료법을선택함에있어환자의상태및전이정도에따라적절한치료방법을선택하여야할것이다. 7. 국내약제사용현황건강보험심사평가원홈페이지에서제공하는암질환별사용약제및보험기준에의하면, 진행성췌장신경내분비성종양에사용할수있는항암약제는 1군항암제로인터페론알 파와전신항암제 (etoposide+cisplatin, doxorubicin, etoposide+cisplatin+ifosfamide, 5-FU) 가포함되며, 2군항암제로는산도스타틴유사체, everolimus, sunitinib이사용가능하다. Everolimus와 sunitinib은고분화 G1/G2 진행성췌장신경내분비종양에서보험적용이되며, 산도스타틴유사체중 lanreotide는보험적용이되나, octreotide LAR는췌장병변에서는카시노이드증후군이동반되었을경우증상개선목적으로사용이가능하다. Temozolomide는 capecitabine과병용하여사용이가능하나보험적용이되지않으며, everolimus와 octreotide LAR 병용요법은의학적근거부족으로사용이허용되지않고있다. 8. 기대되는치료연구들면역치료 (immune therapy) 는다양한암에서빠르게진화하는치료분야로, programmed death-ligand 1 (PD-L1) 이암세포에서발현되어면역세포에있는 PD-1 수용체에작용하며 T 세포가암세포를인지못하도록함으로써암세포가면역반응을회피하도록되어있다. PD-1이나 PD-L1에대한항체를사용할경우 T 세포의항암작용을활성화시켜치료에사용하려는시도가소개되고있다. 국내진행성신경내분비종양조직에서 PD-L1 발현에대한연구에서전이성신경내분비종양으로진단된 32명의환자중 7명 (21.9%) 에서양성소견을보여이와관련면역치료가도움이될것으로기대된다. 45 또한 WHO G3에서통계적으로 PD-L1 발현이높아 (p=0.008), 면역치료선택시치료반응관련예후인자를알아볼필요가있다. 면역치료는다양한암종의치료에획기적인치료제로최근급속히진화하는치료약제로소개되고있는데, 신경내분비종양의치료경험에대한증례보고가있어향후이와관련연구가기대된다. 46 당뇨병치료제의하나인 metformin은항암효과가있는것으로알려져있다. 47 최근연구에따르면 445명의진행성췌장신경내분비종양환자에대한후향적분석연구에서당뇨가동반되지않았을경우무진행생존이당뇨가동반되었을때보다유의하게길었으나 (32개월 vs. 15.1개월 ), 당뇨가동반된환자에서 metformin을사용할경우무진행생존이 44.2개월로당뇨가없는경우보다길었으며 (hazard ratio, 0.45; 95% CI, ; p< ), everolimus나산도스타틴유사체로치료를받은당뇨가동반된환자에서무진행생존이 20.8개월로좀더오래생존하였다 (hazard ratio, 0.49; 95% CI, ; p<0.0001). 현재이와관련 2상연구가진행중이며그결과가기대된다. Vol. 73 No. 3, March 2019

7 130 조창민. 췌장신경내분비종양의치료 결 론 췌장신경내분비종양은전세계적으로발병이증가하고있으며, 대부분에서수술적절제가불가능한진행성혹은전이성병기로진단되어적절한국소및전신치료가요구된다. 과거에비하여다양한치료방법및성적이보고되고있어생존율이향상되고있다. 치료를선택함에있어증상의유무, 종양의전이정도및범위, 환자의신체상태등을고려하여결정하여야한다. 각각의환자에서개별적인평가를통하여치료가이루어져야하며, 이는여러방면의전문가들이팀을형성하여적절한치료방법을선택할필요가있다. REFERENCES 1. Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Ann Surg Oncol 2007;14: Gastrointestinal Pathology Study Group of Korean Society of Pathologists, Cho MY, Kim JM, et al. Current trends of the incidence and pathological diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Korea : multicenter study. Cancer Res Treat 2012;44: Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26: Shah MH, Goldner WS, Halfdanarson TR, et al. 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