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1 대한내과학회지 : 제 89 권제 5 호 종설 (Review) 진행성방광암의항암화학요법 가천대학교길병원혈액종양내과 심선진 Systemic Treatment for Metastatic Bladder Cancer Sun Jin Sym Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea Metastatic bladder cancer is generally incurable, with a median survival of 14 to 15 months under a modern chemotherapy regimen. Cisplatin-based chemotherapy, including the combination regimens methotrexate-vinblastine-doxorubicin-cisplatin and gemcitabine-cisplatin, are the standard first-line therapy. Despite response rates of 40% to 60% achieved, most patients cancers progress after about 8 months. Second-line single agents have only marginal efficacy after cisplatin-based treatment failure, with objective response rates of 5% to 20% and a median progression-free survival of only 3 to 4 months. Moreover, there is little evidence that second-line systemic treatment can substantially improve overall survival or quality of life. Agents targeting growth, survival, and proliferation pathways have been added to cytotoxic therapy with limited added benefits to date. Drugs that modulate the host immune response to cancer-associated antigens, including immunologic checkpoint blockade by antibodies against programmed cell death protein-1 or its ligands, appear promising, and multiple new therapeutic approaches are being pursued. In addition, the receptor tyrosine kinase/ras pathway and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin pathway represent potential therapeutic targets for advanced disease, and novel agents are in development. (Korean J Med 2015;89: ) Keywords: Urinary bladder cancer; Drug therapy; Metastasis 서론전이성요로상피방광암은항암치료에매우감수성을보이는종양으로알려져있으며, 전신항암화학요법이가장최적의치료방법으로간주되고있다. 하지만 cisplatin을근간으로하는일차항암화학요법에실패할경우이차치료약제의선택은매우제한되어있고, 5년생존율이불과 5% 정도로 보고되고있다. 지난십여년동안, 비뇨기암종중신세포암및전립선암은많은연구가진행되었고이를통해괄목할만한치료성적의향상을보인반면, 진행성방광암의치료는상대적으로여전히답보상태에놓여있다. 수술전선행항암화학요법은근육층을침범한방광암 (muscle-invasive bladder cancer, MIBC) 의표준치료의하나로간주되고있다. 수술전 methotrexate-vinblastine-doxorubicin과 cisplatin 복합요법 (MVAC) Correspondence to Sun Jin Sym, M.D., Ph.D. Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Hospital, 21 Namdong-daero 774 beon-gil, Namdong-gu, Incheon 21565, Korea Tel: , Fax: , Shim.SeonJin@mayo.edu Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 89, No. 5, 을이용한선행항암화학요법은선행항암화학요법없이수술단독으로치료한환자군에비해서생존율향상의결과를보여주었다 [1]. 이러한수술전선행항암화학요법은최근들어다양한종류의항암제가시도되고있으며, 전이성방광암의치료에있어 MVAC 와비교시동등한생존율을보이면서부작용이덜한 gemcitabine-cisplatin (GC) 복합요법이최근들어수술전선행항암화학요법으로많이사용되고있다 [2,3]. 전이성방광암의경우, MVAC와 GC 요법의경우비슷한생존율 (15개월 vs. 14개월 ) 을보이며, 무진행생존율에있어서도두치료법사이에차이가관찰되지않는다 [3,4]. 이러한 MVAC 요법의치료효과에도불구하고많은환자가항암치료와관련된부작용을경험하게된다. 이를개선하기위한다양한노력들이있었고, 이중하나가용량-강화 (Dose-Intensified) MVAC 요법이다. 용량- 강화 MVAC 의경우표준항암화학치료의하나인 MVAC와비교시부작용이적었으며, 비록의미있는생존율의차이는관찰하지못했으나, 용량- 강화 MVAC 요법군에서생존율이더우월한경향을보여주었다 [5]. GC 요법에 paclitaxel 을추가하는요법의경우오히려부작용의증가만초래하며, 생존율향상은보여주지못했다 [6]. 현재까지 MVAC, dose-dense MVAC 그리고 GC 요법이 cisplatin 사용이가능한 ( 신기능이좋은 ) 진행성또는전이성방광암환자의표준항암화학요법이다. 최근들어방광암발병기전에대한생리학적, 유전학적연구의발전에의해방광암에대한이해가증가하고, 이를통한새로운치료방법들이시도되고있다. Receptor tyrosin kinase (RTK)/Ras pathway, phosphatidylinositol 3-hydroxy kinase (PI3K)/Protein kinase B (AKT)/mammalian target of rapamycin (mtor) pathway 그리고 cell-cycle checkpoints pathway의변형들이방광암발생전 high-grade dysplasia 단계에서부터관찰되고있고이러한변형된경로를표적으로하는치료가활발하게연구되고있다 [7]. 또한대부분의 MIBC 에서 epigenetic pathway의이상이있는것으로알려지고있으며, 다양한 chromatin remodeling genes의유전적변화가관찰되고있어, 이들을표적으로하는치료법또한활발하게연구되고있다 [8]. 이번고찰을통해진행성방광암의최적의항암화학치료및현재연구되고있는표적치료와면역치료에대해알아보고자하며, 진행되고있는임상연구에대해서도살펴보고자한다. 일차및이차항암화학요법선행항암화학요법은 MIBC 의표준치료의하나로사용되고있다. 국소림프절전이를보이는진행성방광암의경우도최근들어항암화학요법시행후좋은반응을보인환자에서근치적목적의수술을시도하는경우좋은치료성적을기대해볼수있다. Cisplatin은진행성또는전이성방광암의치료에있어근간이되는항암제이다. 약 50-70% 의종양반응률을보이며중앙생존값도약 13개월정도로보고되고있다. 400명의절제불가능한방광암환자를대상으로일차치료로 MVAC와 GC 항암화학요법을비교한 3상연구에서, MVAC 복합요법이 GC 복합요법과비교시장기생존율및무진행생존율에있어차이를보이지않았다 ( 위험도 1.04, 95% 신뢰구간 ; p = 0.75). 하지만부작용면에서 GC 복합요법이 MVAC 요법보다의미있게부작용이낮아서, GC 복합요법이진행성또는전이성방광암의일차항암화학요법으로더선호되고있다 [3]. 고전적인 MVAC 요법이치료효과는우수하나부작용에대한우려로, 이를개선하기위한새로운연구의시도가진행되었는데, 그중하나가용량- 강화 MVAC 요법이다. 용량-강화 MVAC 요법은매 2주간격으로 G-CSF를투여하는방법으로, 용량-강화 MVAC 요법이 MVAC보다더우수한완전관해율을보였으며, 종양반응이더지속적으로유지되었다. 부작용면에서도더개선된결과를보였다 [9]. 7년장기추적관찰후발표된연구에서용량- 강화 MVAC 요법이기존의 MVAC 요법에비해질병진행과사망률도낮추는것으로보고되었다 [6]. 하지만이러한 MVAC, 용량- 강화 MVAC 그리고 GC 요법이진행성또는전이성방광암치료에매우효과적이나, 실제임상현장에서고령, 전신수행능력의불량, 신기능저하 ( 크레아티닌청소율 < 50 ml/min) 등으로인해, 이러한복합항암화학요법이적합한지않는환자가많은경우발생한다. 이러한경우 cisplatin을같은백금화합물중하나인 carboplatin으로변경하는치료를고려해볼수있다. Cisplatin 을사용하기적합하지않은진행성또는전이성방광암환자의일차치료로 gemcitabine-carboplatin 2제복합요법과 methotrexate-vinblastin-carboplatin 3제복합요법을비교하는임상연구에서두항암화학요법사이에중앙생존값이 9개월정도로비슷한치료효과를보였으며, gemcitabine-carboplatin 2 제복합요법이 3제요법보다부작용면에서더개선된결과를보여주었다 [10]. Cisplatin을대신하여 carboplatin을사용한

3 - Sun Jin Sym. Bladder cancer chemotherapy - 여러연구에서도비슷한연구결과를보여주고있다 [11,12]. Paclitaxel과 carboplatin 복합요법과 MVAC 복합요법을비교하는소규모 3상임상연구에서는 paclitaxel과 carboplatin 복합요법에서치료성적이더낮은결과를보여주었다. 하지만이연구는환자모집지연문제등으로인해조기종료되었으며, 두군간의통계적인차이를알아보기에는연구설계에논란이있다 [13]. 일차치료로 paclitaxel 을 GC 요법에추가하는방법도생존율향상을보여주지못했다. Paclitaxel-GC 요법에서의종양반응률이 55.5% 로 GC 단독군의 43.6% 보다높게관찰되었으나, 이러한 paclitaxel-gc 요법의우월한종양반응률의차이가생존율의향상으로는이어지지는않았다 [6]. 하지만이연구에서요로상피세포암의원발부위에따라생존율차이를다시분석해보았을때원발부위가방광인환자군에서 GC 복합요법에 paclitaxel를추가하는경우생존율이더우월하게관찰되었다 (11.5 months vs months; 위험도 0.80; 95% 신뢰구간 ; p = 0.03). 백금화학물을근간으로일차항암화학치료에 pemetrexed를추가하는소규모 2상연구결과에따르면 pemetrexed와 cisplatin 복합요법의종양반응률이 66.7% 로기존의치료결과와비교시매우높게관찰되었고, 이는향후일차항암화학치료로 pemetrexed 와 cisplatin 복합요법에대한대규모임상연구가필요하다하겠다 [14]. 진행성또는전이성방광암의이차항암화학치료로 pemetrexed 및 taxanes 계열의약제 (paclitaxel, docetaxel) 등다양한약제들에대한소규모 2상임상연구가진행되었으나, 대부분백금에저항성을보이는방광암환자에서반응률이 20% 이내로매우제한된치료효과만을보이고있다 [15-17]. 이차항암화학요법으로 pemetrexed 단독치료에대한소규모 2상연구결과, 종양반응률은 % 로보고되었으나, 대규모후향적연구에서는 pemetrexed 단독요법의반응률이 7% 정도로관찰되었다 [18]. Paclitaxel 단독치료는약 10% 정도의종양반응률이관찰되어방광암에서이차항암화학요법으로효과가크지않는것으로보고되었으나 [16], albumin-bound paclitaxel 의경우 27.7% 의종양반응률이관찰되었다 [19]. 기타약제로는 gemcitabine, ifosfamide 그리고 oxaliplatin 등이단독치료로연구되었으나, 매우제한된치료효과를보였다 [20-22]. 최근새로운 microtubule 억제제인 vinflunine이 platinum에저항을보이는진행성또는전이성요로상피세포암의이차항암화학치료제로유럽에서승인이되었다. Vinflunine과최적의지지치료를비교하는대규모 3상연구에서 vinflunine 으로치료받은환자군에서최적의지지치료를받는환자군에비해, 사망의위험이 23% 감소되는소견을보였다 (p = 0.04) [23]. 또다른약제로유방암에서 microtubule modulator 로승인받은 erlibulin이있는데, erlibulin은약물의대사체가신장을통해배설되지않아신기능저하로인해 cisplatin을사용할수없는방광암환자에서고려해볼수있다. 이전의치료받지않은환자들을포함한 (72.5% 환자가이전치료로보조항암화학치료나선행항암화학치료를시행받음 ) 2상임상연구에서 38% 의반응률을관찰하였다. 이러한고무적인치료성적으로인해, 현재방광암일차치료로 erlibulin과 GC 복합요법 (NCT ) 의연구가진행되고있으며일차치료에저항성을보이는환자들을대상으로 erlibulin 단독치료에대한 (NCT ) 연구가진행중이다. 표적치료및면역치료상피세포성장인자수용체 (EGFR), HER2/neu (ERBB2) 그리고섬유아세포성장인자수용체 3 (FGFR-3) 등을포함한 RTK/Ras 경로가요로상피암의발생과질병의진행에관련되어있음이알려지고, 또한 PI3K/AKT/mTOR 경로의변화가요로상피암에서흔히관찰되는등이들경로를표적으로하는다양한치료법들이연구되고있다. 혈관내피성장인자 (VEGF) 를통한종양내신생혈관생성이요로상피암발생과관련있음이알려져있고, 종양및혈청내 VEGF 상승이진행성요로상피암의나쁜예후와관련됨이보고되었다. EGFR Family 를표적으로하는치료 EGFR의과발현은요로상피암의나쁜예후인자로알려져있다 [24]. EGFR 을표적으로하는여러약제에대한연구가있었으나, 환자의치료성적을향상시키지는못했다. 대표적인 EGFR 억제제인 gefitinib을일차항암화학치료로 GC 복합요법에병합한연구에서종양반응이나생존율향상의결과를보이지못했다 [25]. 또한 EGFR의과발현환자를대상으로한 gefitinib 단독치료에관한연구에서도치료효과를보여주지못했다 [26]. EGFR 단클론항체인 cetuximab 의경우에도 GC 복합요법에추가시오히려부작용만증가시키고, 예후의향상은관찰할수없었다 [27]. 요로상피암에서 HER2/neu 의과발현및증폭은 8-81% 에서관찰되고있다. HER2/neu의과발현은공격적인질병진행

4 - 대한내과학회지 : 제 89 권제 5 호통권제 663 호 경과를보이는것으로알려져있다 [28]. 또한 HER2/neu 의증폭은원발부위보다전이병소에서더흔히관찰되는것으로알려져있다 [29]. HER2/neu와 EGFR을동시에억제하는 tyrosine kinsse inhibitor인 lapatinib은이차항암화학치료를받는전이성요로상피암환자를대상으로한연구에서비록의미있는치료효과를보여주지는못하였지만 EGFR 과 HER2/neu 의과발현을보이는일부환자에서치료효과의향상을관찰할수있었다 [30]. 이러한연구결과를근거로현재 EGFR과 HER2/ neu가과발현된환자를대상으로이차항암화학요법으로 lapatinib과 docetaxel 병합치료가진행되고있으며 (NCT ), HER2/neu 또는 EGFR 과발현환자들을대상으로일차항암화학요법에종양반응을보이거나안정화소견이관찰될때 lapatinib 유지요법에대한임상연구 (NCT ) 도진행중이다. HER2/neu 수용체에대한단클론항체인 trastzumab 을 HER2/neu 가과발현된환자를대상으로 gemcitabine, carboplatin 그리고 paclitaxel 복합요법에추가한 2상연구에서, 17% 의환자가임상적이득을얻을수있었으며 (5명의완전관해, 26명의부분반응 ), 이는 HER2/new 가과발현된일부특정환자군에서이를표적으로하는치료가치료효과를증대시킬수있음을시사해준다고할수있다 [31]. FGFR3 을표적으로하는치료 FGFR3 의유전적변이는 low-grade non-mibc 에서흔히관찰되는소견이고, 일부진행성요로상피암환자에서도관찰되고있다 [32]. 이러한소견은 FGFR3 유전적변이를표적으로하는치료제가진행성방광암치료에효과적일수있음을시사한다. 하지만최근 VEGF 수용체와 FGFR 수용체를모두억제하는 dovitinib에대한 2상연구에서 FGFR3 유전자변이가있는환자군에서도의미있는치료효과의상승을보여주지못했다 [33]. 최근요로상피암에서 FGFR 활성에대한새로운기전이알려졌는데, 염색체재조합으로인한융합유전자가발생되고이로인한 FGFR kinase 활성이지속되는것으로밝혀졌다 [34]. 이러한융합유전자는 FGFR3 억제제에매우효과적으로억제가되는것으로알려져있어, 염색체재조합으로인한융합유전자가있는환자들을대상으로한연구의진행이필요하겠다. 신생혈관을표적으로하는치료-VEGF VEFG 및 VEGF 수용체의과발현은더나쁜임상경과를 보이며질병진행과관련있음이알려져있다 [35]. VEGF를포함한다양한 tyrosine kinsase 억제제인 sunitinib과 sorafenib 이진행성또는전이성방광암에서연구되었다 [36-38]. Cisplatin 사용에적합하지않는전이성요로상피암환자의일차항암화학치료로 sunitinib 50 mg/d를 4주복용후, 2주휴약하는일정으로진행된 2상연구에서 58% 의환자에서임상적이득이관찰되었고, 중앙생존값은 8.1개월이었다 [36]. Sunitinib 37.5 mg/d을휴약기없이지속복용하는또다른용법의 2상연구에서도비슷한치료결과를보여주었다 [37]. 하지만두연구모두 sunitinib의효과를보기위한초기연구가설을만족시키지는못했다. 또다른다양한 tyrosin kinse을억제하는 (VEGF receptor, PDGFR, and c-kit) pazopanib 을재발성또는저항성요로상피암단독치료에관한 2상연구에서 17% 의종양반응을관찰할수있었다 [39]. 혈관생성억제제에대해소규모임상결과들을종합해볼때, 일부진행성방광암환자에서이들약제의단독치료가특정환자에서치료효과를보일수있음을시사해준다. 기존의표준일차항암화학치료에이들신생혈관억제제를추가한복합요법에대한치료효과는아직까지명확하게밝혀지지않았다. Cisplatin을사용하기부적합한환자를대상으로 bevecizumab 과 gemcitabine-carboplatin 복합요법에대한 2상연구결과, 49% 의종양반응및 13.9개월의중앙생존값을보고하였고 [40], 이러한결과는기존보고된 gemcitabine-carboplatin 치료의중앙생존값 10.3개월보다생존율이더향상된결과이다. 비슷한연구로 gemcitabine-cisplatin 복합요법에 bevacizumab을추가했을때중앙생존값이 19.1개월로이는 gemcitabine-cisplatin 복합요법의기존 14개월의중앙생존값보다의미있게향상된결과이다 [41]. 진행성또는전이성요로상피암에서 bevacizumab 의고무적인연구결과를바탕으로현재 bevacizumab 과 GC 복합요법에대한다기관 3상임상연구가진행중이다 (NCT ). c-met proto-oncogen은방광암발암과정에관련되어있음이알려져있고, 활성화된 MET은 VEGF를활성화하여신생혈관생성과종양의성장을촉진시킨다. 또한소변과혈청에서 MET의증가는종양의나쁜임상진행과관련됨이알려져있다. VEGFR 2와 MET 경로를억제하는 cabozantinib 에대한재발성또는전이성요로상피암환자를대상으로진행된 2상연구의초기결과를보면, 48% 의환자에서임상적이득 (37% 안정화반응, 11% 부분반응 ) 이관찰됨을보고하였다, MET 억제제인 cabozantinib 임상연구의최종결과가기다려진다

5 - 심선진. 방광암항암치료 - PI3K/AKT/mTOR 경로를표적으로하는치료 PI3K/AKT/mTOR 경로가비침습성및침습성방광암모든진행단계에서발암성변화를보인다고잘알려져있다. mtor 억제제인 everolimus 에대한 2개의 2상임상연구의결과가발표되었는데 27% 의종양반응률을보고하였다 [42,43]. GC 복합요법에 everolimus 를추가한연구 (NCT ) 와 cisplatin 에사용이부적합한환자를대상으로 everolimus-paclitaxel 복합요법과 everolimus 단독치료를비교하는 3상연구 (NCT ) 가현재진행중이다. 면역반응조절치료 Non-MIBC 에서 bacillus Calmette-Guerin을이용한면역치료는표준치료중하나이다. 하지만 MIBC 와전이성방광암에서면역치료에대한연구는이제초기단계라할수있다. 면역관용에관여하는 T-cell 경로의변형은다양한암종에서관찰되고있으며, cytotoxic T-lymphocyte antigen-4 (CTLA-4) 와 programmed cell death protein-1 (PD-1) 또는관련된리간드 (PD-1/L1) 을차단하는치료는여러암종에서고무적인치료결과를보이고있고, 종양면역치료의패러다임을바꾸고있다. 이는기존의종양백신및재조합싸이토카인에의한면역반응의증가와는달리, 암세포에대한기존면역반응의억제를풀어암세포에대한면역반응을활성화하는것을요점으로하고있다. 요로상피암의선행항암화학요법에관한 anti-cytotoxic T lymphocyte antigen 4 (CTLA4) antibody인 ipilimumab 에대한 pilot 연구에서일부놀랄만한항종양효과를관찰할수있었다. 이연구에서 CTLA4 차단을통해종양조직내 CD4 + ICOS hi T-cell을증가소견을관찰할수있었고, 이러한소견이생존율향상의지표가될수있음을보여주었다 [44]. 이전항암화학치료에실패한 PD-L1 양성방광암환자에서 PD-L1 억제제에초기임상연구결과에의하면 20 명중 10명에서종양반응이관찰됨을보고하였다. 결론전이성방광암환자의생존율은매우불량하다. 백금화합물근간의항암화학치료가표준치료이다. 최근유럽에서이차항암화학요법으로 vinflunine이최근허가를받고사용중이나, 일차항암화학요법에저항을보이거나, 질병진행시이차항암치료에대한치료성적은아직기대에미치지 못하며, 이차항암화학치료가생존율을향상시킨다는증거는아직없다. 다양한표적을대상으로하는표적치료제와항암화학요법을병합하는치료는많은연구가진행중이나아직까지이들치료가효과적이라는임상적인근거는미약하다. 표적치료의성공을위해서는특정대상에대한표적의발굴이치료성패에매우중요하다. 초기면역반응조절제의임상연구결과들은진행성방광암에서도면역반응조절치료의역할이매우중요해질것으로생각된다. 중심단어 : 방광암 ; 약물치료 ; 전이 REFERENCES 1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349: Dash A, Pettus JA 4th, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer 2008;113: von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;18: von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23: Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006;42: Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study J Clin Oncol 2012; 30: Iyer G, Al-Ahmadie H, Schultz N, et al. Prevalence and cooccurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol 2013;31: Gui Y, Guo G, Huang Y, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet 2011;43:

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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