J Korean Med Assoc 2015 March; 58(3): Table 1. Fluoropyrimidine and platinum combination chemotherapy for patients with advanced gastric cance

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1 Focused Issue of This Month J Korean Med Assoc 2015 March; 58(3): pissn / eissn 전이성위암의치료 김태용 오도연 방영주 서울대학교의과대학서울대학교병원내과 Treatment for unresectable gastric cancer Tae-Yong Kim, MD Do-Youn Oh, MD Yung-Jue Bang, MD Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea Systemic chemotherapy is the cornerstone of treatment for patients with advanced gastric cancer. The combination of fluoropyrimidine and platinum is the most widely used first-line treatment worldwide. In patients with HER2- positive gastric cancer, the combination of trastuzumab (an anti-her2 monoclonal antibody) and chemotherapy is the standard-of-care. Second-line chemotherapy can also prolong patients survival after progression; treatment options include cytotoxic chemotherapy (paclitaxel, docetaxel or irinotecan) and/or ramucirumab (an anti-vegfr2 monoclonal antibody). A number of new targeted-agents are currently being studied, and more personalized approaches will be realized in the near future. Key words: Stomach neoplasms; Neoplasm metastasis; Drug therapy 서론 위암은전세계적으로 5 번째로흔한종양이며, 3 번째 의암사망원인으로매년 951,000명의환자가발생하고, 723,000명이위암으로사망한다 [1]. 국내에서는 1년에약 32,000명의새로운환자가발생하여 2번째로흔한종양이며, 폐암및간암에이어 3번째의암사망원인이다 [2]. 서양에서위암은진단당시진행된병기가많아예후가불량하여 5년생존율이 20-30% 내외에불과하다 [3,4]. 이에비하여우리나라나일본에서는국가조기검진의시행으로조기위암의발견이많아지면서 5년생존율이향상되어 60-70% 에이르고있다 [2,3]. Received: January 18, 2015 Accepted: February 1, 2015 Corresponding author: Yung-Jue Bang bangyj@snu.ac.kr Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 전이성위암또는수술후재발한위암환자에서는항암화학요법이주된치료가된다. 지난 30여년간전이성위암에대한항암화학요법은상당히발전되어과거에비해생존기간이뚜렷하게개선되었지만아직도전이성위암환자의전체생존기간은 12개월을약간넘는수준에불과한실정이다 [5]. 최근 trastuzumab 및 ramucirumab 등표적치료제가위암치료에도입이되면서위암환자의생존기간이연장되고있으며새로운표적치료제를이용한임상연구가매우활발히진행되고있다. 본종설에서는전이성위암에서의항암요법의현황에대해살펴보고앞으로의발전전망을논하고자한다. 1 차항암요법 1. 세포독성항암제전이성위암에서치료의근간은항암화학요법이다. 항암화학요법이전이성위암환자의생명을연장하고삶의질을향상시키는지에대해서는더이상의이론은없는상태이다 전이성위암의치료 209

2 J Korean Med Assoc 2015 March; 58(3): Table 1. Fluoropyrimidine and platinum combination chemotherapy for patients with advanced gastric cancer Regimen Objective response (%) PFS OS Kim et al. [7] FP NS FAM FU Ohtsu et al. [8] 5-FU for 5-FU vs. FP FP for 5-FU vs. UFT+M UFT+M Webb et al. [10] FAMTX EFP Vanhoefer et al. [9] Eto+FL for Eto+FL vs. FP FAMTX PFS, progression-free survival; OS, overall survival; F, fluorouracil ; P, cisplatin; A, doxorubicin; M, mitomycin C; NS, not significant; 5-FU, 5-fluorouracil; MTX, methotrexate; E, epirubicin; Eto, etoposide; L, leucovorin. Table 2. Phase III trials of new generation chemotherapeutic agents in patients with advanced gastric cancer 5-FU vs. capecitabine ML17032 [15] No. of patients Treatment Objective response(%) PFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.28 to 0.52) [4]. 전이성위암환자에서는 fluoropyrimidine계항암제 (5-fluorouracil [5-FU], capecitabine, TS-1), anthracycline계 (epirubicin, doxorubicin), platinum계 (cisplatin, oxaliplatin), taxane계 (docetaxel, paclitaxel) 및 topoisomerase I 억제제 (irinotecan) 등이널리사용되고있다. 이들약제들을병용하여치료하는복합치료와단독치료를비교한메타분석에서는단독치료에비해복합치료군에서향상된종 양반응률 (35% vs. 18%) 및유의한생존기간의연장 (HR, 0.83; 95% CI, 0.74 to P-value for OS 0.93) 을보여주어환자의전신상태가괜찮다면우선적으로복합항암화학요법을고려해야한다 [6]. 우리나라에서는일찍이 Kim 등 [7] 이 5-FU와 cisplatin 복합요법 (5-fluorouracil+cisplatin [FP] 요법 ) 을 5-FU 단독과 5-FU, doxorubicin, mitomycin-c 등과비교하여종양반응률이 FAMTX, 0.77 for FP vs. FAMTX 나, 무진행생존기간 (progression-free survival, PFS) 이우월함을보고하였다. 이연구에서환자들의전체생존기간이통계적으로유의한만큼연장되지는 HR for OS 않았지만, FP요법은우리나라를비롯한 여러나라에서가장널리사용되는치료의하나가되었다 년대에다른나라에서시행된 3상임상시험은 Table 1 과같으며, 거의유사한결과를보여주 ( ) 었다 [7-10]. 2000년대들어서면서 5-FU의새로 ( ) 운경구용약제 (capecitabine 및 TS-1), oxaliplatin, taxane계항암제그리고 irinotecan 등이위암의치료에시험되었다. Table 2에보는것처럼 capecitabine 또는 TS-1은 5-FU와비슷한효과를보여주었으며, oxaliplatin 도 cisplatin과동등한결과를나타내었다 [11-15]. Capecitabine 및 TS-1은경구로편리하게투여할수있으며, oxaliplatin은신기능보전을위한별도의보조치료가필요없다는점에서환자에게투여의편익을제공할수있다. 한편, 5-FU/leucovorin/irinotecan 또는 TS-1/irinotecan 등 cisplatin을포함하지않은요법도시도되었는데, Table 3에서나타난바와같이 cisplatin 포함복합항암화학요법과비슷한임상적효과를보여주었다 [16-18]. 전이성위암환자의생존기간을더연장시키기위하여 5-FU/ OS 160 XP FP ( ) REAL-2 [14] 494 EPX, EOX ( ) a) ( ) 508 EPF, EOF FU vs. S-1 FLAGS [11] 527 TS-1/P T5-FU/P JCOG FU [13] 234 TS Cisplatin vs. oxaliplatin AIO [12] 112 FLO FLP ( ) REAL-2 [14] 489 EOF, EOX ( ) a) ( ) 513 EPF, EPX PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; 5-FU, 5-fluorouracil; X, capecitabine; P, cisplatin; F, fluorouracil; E, epirubicin; O, oxaliplatin; L, leucovorin. a) HR. 210 대한의사협회지

3 Kim TY Oh DY Bang YJ Treatment for unresectable gastric cancer Table 3. Phase III trials for non-platinum based-chemotherapy in patients with advanced gastric cancer Guimbaud et al. [17] Dank et al. [16] Narahara et al. [18] Phase Treatment No. of patients Objective response (%) PFS platinum에 docetaxel을추가한 docetaxel/5-fu/cisplatin 요법이시행되었는데비록전체생존기간은향상시켰지만 (9.2개월 vs. 8.6개월 ; HR, 1.29; 95% CI, 1.0 to 1.6; P=0.02), grade III/IV의과립구감소증과발열또는설사가각각약 30% 의환자에서관찰되어, 이연구에서사용된용량으로는별로사용되고않고있다 [19]. 유럽에서는 epirubicin 을추가한 epirubicin/cisplatin/5-fu요법이널리사용되어왔으나, 최근연구에서 epirubicin/cisplatin/cape-citabine 요법이 5-FU/leucovorin/irinotecan요법에비해효과는비슷하지만, 부작용이더많은것으로나타났다 [17]. 따라서 3제요법은과도한독성등을고려할때 2제요법보다더낫다고할수없으며임상현장에서의적용에는신중을기해야할것이다. 2. 표적치료제 : HER2 targeted agents HER2는 human epidermal growth factor receptor (HER family) 의한종류로세포막관통단백질이며, HER2의과발현또는유전자증폭은비정상적인세포내신호전달을초래하여세포증식및생존에관여하는것으로알려져있고, 위암에서의 HER2 과발현빈도는연구자마다차이는있지만 10% 전후로보고되고있다 [20,21]. HER2 양성은면역조직화학염색에서강양성 (3+) 이거나또는중등도양성 (2+) 이면서 fluorescence in situ hybridization 양성으로정의한다. 이러한 HER2를표적으로하는약제에는 HER2 수용체를차단하는단클론항체인 trastuzumab, pertuzumab 등이있고, 저분자물질로 tyrosine kinase 억제제인 HR for OS lapatinib이있다. ToGA 연구에서는 HER2 양성진행 ( ) 성위암환자 594명을대상으로항암화 P=0.95 학요법 (5-FU/cisplatin 또는 capecitabine/cisplatin) 군과항암화학요법에 ( ) P=0.53 trastuzumab을병용한군을비교하였는데 trastuzumab 병용군에서생존기간의연장 (13.8개월 vs. 11.1개월, P=0.0046) 은물론, 반응률개선과 PFS의연장을보여주었다 [22]. 이러한차이는면역조직화학염색에서강양성 (3+) 을보이거나또는중등도양성 (2+) 이면서 fluorescence in situ hybridization 양성인환자에서더뚜렷한차이를보여주었다 (16.0개월 vs. 11.8개월, P=0.036). ToGA 연구결과를바탕으로 HER2 양성위암에서 1차치료로 trastuzumab 병합항암화학요법이표준치료가되었다. HER2 및 epidermal growth factor receptor (EGFR) 의 tyrosine kinase 억제제인 lapatinib은 HER2 양성위암세포주에서 trastuzumab보다우월한항암효과를보여주었기에 lapatinib도 HER2 양성전이성위암에서시험되었다 [23]. LOGiC 연구는 1차치료로서 HER2 양성위암환자를대상으로 XELOX 항암제군과항암제와 lapatinib 병용군을비교하였는데생존기간에서양치료군간에유의한차이는관찰되지않았다 (10.5개월 vs. 12.2개월, P=0.35) [24]. TyTAN 연구에서는 2차치료로서 HER2 양성위암환자를 paclitaxel군과 paclitaxel과 lapatinib 병용군으로나누어비교분석하였는데 lapatinib 병용군에서유의한생존기간의연장은보여주지못하였다 (8.9개월 vs. 11.0개월, P=0.1044). OS III ECX FOLFIRI III IF a) CF a) 8.7 III IS b) S b) 10.5 P=0.233 PFS, progression-free surv ival; OS, overall survival; HR, hazard ratio; CI, confidence interval; E, epirubicin; C, cisplatin; X, capecitabine; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; I, irinotecan; F, fluorouracil; S, TS-1. a) Time to progression; b) Time to treatment failure. 3. 기타표적치료제 Vascular epidermal growth factor (VEGF) 및 VEGF receptor (VEGFR) 는혈관신생에관여하는인자로위암발생에중요한인자중하나로알려져있다. Bevacizumab은 VEGF-A에대한인간단클론항체로 AVAGAST 연구는 1차항암요법으로 fluoropyrimidine/cisplatin 화학요법과화학 전이성위암의치료 211

4 J Korean Med Assoc 2015 March; 58(3): Table 4. Summary of phase III trials for 2nd-line chemotherapy in patients with advanced gastric cancer after the failure of 1st-line chemotherapy 2 차항암요법 Kang et al. [31] COUGAR-02 [30] Treatment Irinotecan or docetaxel No. of patients PFS OS HR for OS 133 NA ( ) P=0.007 BSC 66 NA 3.8 Docetaxel a) BSC 84 NA 3.6 ( ) P=0.01 AIO [32] Irinotecan BSC 19 NA 2.4 ( ) P=0.012 PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; NA, not available; BSC, best supportive care. a) Week. 요법에 bevacizumab을병용한요법을비교한제3상연구이다 [25]. 이연구에서 bevacizumab 과의병용요법은 PFS는연장시켰으나연구의 1차목표였던전체생존기간은연장시키지못하였다 (12.1개월 vs. 10.1개월, P=0.1002). EGFR (HER1) 는암의성장, 분열및증식에관여하며, 위암에서 EGFR 발현이증가된경우불량한예후를보이는것으로알려져있다 [26,27]. Cetuximab 및 panitumumab 은대표적인 EGFR 표적단클론항체이다. 전이성위암에서도화학요법에 cetuximab또는 panitumumab을병용한 EXPAND 연구와 REAL-3 연구가시행되었는데, 두연구모두생존기간의연장을보여주는데실패하였다 [28,29]. 전이성위암에서 1차항암화학요법이생존기간을연장시키나, 아직까지 1차항암화학요법의종양반응률은 35-50%, PFS는 4-6개월에불과하다 [6,11-15]. 따라서 1차항암화학요법에불응하거나실패한경우 2차항암화학요법을고려할수있으며, 최근 2차항암요법에대한몇몇제3상연구결과들이발표되었다 (Table 4) [30-32]. 국내에서는 irinotecan 또는 docetaxel과최선의지지요법을비교한 3상연구가있으며, COUGAR-02는 docetaxel을그리고 AIO 연구는 irinotecan을최선의지지요법과비교한 3상연구이다. 상기 3개의연구모두에서 2차항암화 HR for OS 학요법은최선의지지요 OS P-value 법에비하여의미있는생존기간의연장을보여 주었으며, 메타분석에서 ( ) P=0.017 도 2차항암화학요법을 시행하는경우통계적으 ( ) P=0.047 로유의한사망위험도의감소가관찰되었다 (HR, 195 a) 0.71 ( ) 0.64; 95% CI, 0.52 to P< ; P<0.0001) [33]. 따라서 1차치료에불응하거나실패한전이성위암에서 2차항암화학요법은환자의전신상태를고려하여표준치료로써시행된다. 그러나 2차항암화학요법으로어떤약제가더우월한지에대해서는아직까지명확한결론이나지않은상태이며, 환자의전신상태, 이전치료력등을종합적으로고려하여 2차항암화학요법약제를선택하는것이필요하다. Ramucirumab은 VEGFR-2에결합하는인간 IgG1 단클론항체로수용체매개신호전달체계를억제하는것으로알려져있으며, 1차치료에실패한전이성위암환자를대상으로 ramucirumab을이용한 2개의임상연구결과가최근발표되었다 [34,35]. REGARD 연구는이전에 platinum- Table 5. The results of phase III trials for chemotherapy incorporating vascular epidermal growth factor receptor targetedagents in patients with advanced gastric cancer Treatment Objective response rate (%) PFS HR for PFS P-value Ramucirumab RAINBOW [35] Paclitaxel+ramucirumab Paclitaxel+placebo ( ) P< REGARD Ramucirumab [34] Placebo ( ) 3.8 P< Apatinib Qin S Apatinib a) 0.44 [36] ( ) Placebo 0 53 a) P< a) PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival. a) Day. 212 대한의사협회지

5 Kim TY Oh DY Bang YJ Treatment for unresectable gastric cancer 또는 fluoropyrimidine-포함항암화학요법에실패한전이성위암환자를대상으로시행되었으며, ramucirumab 은위약에비하여의미있는생존기간의연장을보여주었다 (Table 5) [34-36]. 다른부작용은양치료군간에차이는없었으나고혈압은 ramucirumab 투여군에서더흔하게관찰되었다. Ramucirumab은 1차항암화학요법실패 상으로 C-MET, PI3K, FGFR 및 immune checkpoint 등과연관된여러새로운표적치료제에대한임상연구가활발히진행되고있으므로이들연구결과가임상현장에적용될경우향후환자들의생존과삶의질을향상시키며, 더나아가환자개개인의분자적, 유전적특성에맞는치료를할수있을것으로전망된다. 후 2 차단계에서사용하여생존기간을연장시킨첫번째표 적치료제로그의의가있다. RAINBOW 연구는 1차항암화학요법이실패한전이성위암환자를대상으로 paclitaxel 과 ramucirumab의병합요법을 paclitaxel 단독과비교한제3상연구이며, 이연구에서 ramucirumab 병합군은위약군에비해의미있는생존기간의연장이관찰되었다 (Table 5) [34-36]. 위의두가지연구에서 ramucirumab은단독 찾아보기말 : 위암 ; 전이 ; 항암화학요법 ORCID Tae-Yong Kim, Do-Youn Oh, Yung-Jue Bang, 요법또는 paclitaxel 과의병합치료로효과가있음이밝혀졌 으며, 향후임상현장에도입되어사용될것으로기대된다. Apatinib은저분자 tyrosine kinase 억제제로 VEGFR-2 를표적으로하며, 이전에 2차이상의항암화학요법을시행받았던환자를대상으로 apatinib 단독과위약을비교한제 3상연구에서 apatinib은위약에비하여의미있는생존기간의연장을보여주었다 [36]. 결론 전이성위암에서 1차항암화학요법은생존기간을연장시키고삶의질을향상시키므로환자의전신상태가양호하다면표준요법으로시행되어야하며, 국내에서는 fluoropyrimidine과 platinum의병합요법이가장흔하게사용된다. 또한 1차치료에실패한위암환자에서 2차항암화학요법은표준치료이며, 환자의전신상태에따라그시행을적극적으로고려해야한다. HER2 양성위암에서 trastuzumab 포함복합항암화학요법을시행해야하며, 진행성위암으로진단시먼저 HER2 과발현여부를확인하는것이매우중요하다. 최근혈관신생성장인자와관련된 ramucirumab의항암효과에대한임상결과가보고되었으며, 조만간임상현장에적용가능할것으로기대가되고있다. 현재진행성위암환자를대 REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN Int J Cancer 2015;136:E359-E Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in Cancer Res Treat 2014;46: Park JY, von Karsa L, Herrero R. Prevention strategies for gastric cancer: a global perspective. Clin Endosc 2014;47: Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006;24: Bang YJ. Advances in the management of HER2-positive advanced gastric and gastroesophageal junction cancer. J Clin Gastroenterol 2012;46: Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;(3):CD Kim NK, Park YS, Heo DS, Suh C, Kim SY, Park KC, Kang YK, Shin DB, Kim HT, Kim HJ. A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer 1993;71: Ohtsu A, Shimada Y, Shirao K, Boku N, Hyodo I, Saito H, Yamamichi N, Miyata Y, Ikeda N, Yamamoto S, Fukuda H, Yoshida S; Japan Clinical Oncology Group (JCOG9205). Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group (JCOG9205). J Clin Oncol 2003;21: 전이성위암의치료 213

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<30312EC6AFC1FD30312DB6F3BCB1BFB52E687770> 대한내과학회지 : 제 77 권제 1 호 2009 특집 (Special Review) - 진행성악성종양별맞춤항암요법의최신지견 위암의맞춤항암요법의최신지견 연세대학교의과대학내과학교실 정희철 라선영 Recent advance in tailored treatment of gastric cancer Hei-Cheul Jeung, M.D. and Sun Young Rha,