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1 Extending EXTENDING Role of ROLE Radiation OF RADIATION Therapy in THERAPY HCC Treatment IN HCC TREATMENT Indication of Radiation Therapy in Hepatocellular Carcinoma Treatment: Hepatologist s Perspectives 김강모 울산대학교의과대학서울아산병원내과 Kang Mo Kim Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Because of the technical improvement of radiation therapy (RT) for hepatocellular carcinoma (HCC), experiences of RT in the treatment of HCC are rapidly increasing. RT has a potential role particularly for locally confined viable HCC unsuitable for, or refractory to, other locoregional therapies. However, RT is generally not considered as a standard option in HCC consensus national guidelines, because of the lack of level 1 evidence. In daily practice of Korea where HCC is quite prevelant, external beam RT has been widely performed as a combination treatment with other locoregional or systemic treatment and the tentative indication is 1) HCC with gross vascular invasion, 2) salvage treatment for intrahepatic HCC, 3) curativeintent treatment in metastatic HCC, and 4) palliative treatment for symptomatic metastasis. In the near future, the role of RT in the treatment of HCC will be more and more important and RT needs to be considered as a treatment option in patients unsuitable for other local therapies in the daily practice. Future prospective studies and close collaboration of radiation oncologist and hepatologist is warranted for the refinement of adequate indication, potential benefit compared with other treatment and optimal combination strategy with RT. 서론 간세포암은서양에비해만성 B형간염의만연지역인우리나라에특히흔해서 2009년한국암등록사업의발표에따르면남성에서전체발생암의 4위, 여성에서 6위를차지하고있다. 간세포암은다른암에비해기저질환이있는장기에발생하여재발이흔하고, 진행된이후에나증상이발생하여늦게진단되는경우가많아서전통적으로예후가좋지않은암이었다. 하지만최근에는암발생위험군에대한선별검사로비교적초기에발견하는경우가늘어나고있으며간이식을포함하는수술적치료와경동맥화학색전술 (transarterial chemoembolization; TACE) 등치료기술의발전, 항바이러스제의사용을포함하는간기능보전법의개발에힘입어치료예후가아주좋아지고있다. 간세포암의표준치료법으로현재사용되는것으로는간절제술, 간이식술, 고주파열치료 (radiofrequency ablation; RFA), 알코올주입술 (percutaneous ethanol injection; PEI) 등의근치적치료법과 TACE 같은고식적치료법이있는데상기한국소치료가불가능하거나실패한경우에는전신약물요법으로서 sorafenib이사용되고있다. 1 이외에아직국내에서널리사용되지는않지만 drug eluting bead- TACE(DEB-TACE), 경동맥방사선색전술 (transarterial radioembolization; TARE), 간동맥주입화학요법 (hepatic artery infusion chemotherapy; HAIC), 양성자치료 (proton beam therapy), 세포독성화학요법 (cytotoxic chemotherapy) 등이각센터의경험에따라시도되고있으며일부좋은결과를발표하고있으나아직표준치료법으로널리받아들여지기에는각치료의적응증, 다른치료법과비교한효능및부작용등에대한자료가더필요한실정이다. 상기한간세포암에대한여러치료법에더해서체외방사선치료 (external beam radiation therapy; EBRT) 는 582 The Liver Week 2014

2 최근 10년사이에비약적으로발전한분야로서간세포암주변의정상조직에대한방사선조사를최소화하고간세포암에보다높은방사선량을조사하는기술이발전함에따라간세포암의치료에적극활용되고있으며우리나라에서특히활발히시행되어서대한간암연구회와국립암센터가발표한 2009년간세포암종진료가이드라인에방사선치료가간세포암의표준치료법의하나로포함되어있다. 2 하지만간세포암은다발성으로나타나는경우가대부분이므로 EBRT가 RFA나 TACE 등과같은다른국소치료법에비교하여전체간세포암의치료에있어서더뛰어나다는결론을내릴수는없고다른치료법과의병합치료를시도하는경우어떤적응증에적합한지에대한통일된의견도아직없다. 또한간세포암의크기나위치에따라방사선조사시부작용이차이날수있어서해당간세포암이방사선치료에적합한지, 적합하다면방사선량이나방사선조사스케쥴을어떻게할지등도센터마다달라서치료를표준화하기에는아직자료가부족하다. 본연제에서이러한질문에적합한근거를대거나답을할수는없으나간세포암에대한방사선치료를가장활발히하는센터에근무하는 내과의 의입장에서방사선치료의경험과그적응증에대한제언을하고자하는바이다. 그리고본연제에서언급하는방사선치료는 TARE를제외하고 EBRT에국한하고자한다. 본론 1. 방사선치료가간세포암에효과적이라는증거 방사선치료가간세포암의국소치료에효과적이라는대규모전향적연구는없으나소규모 phase 2 연구와후향적연구에서 conformal RT는약 70-80% 의 1 year local control rate를보고하고있다. 3-5 우리나라에서의보고도이와비슷하여 hypofractionated conformal RT에의해약 67% 의 overall response rate(complete response+partial response) 와 % 의 local control rate를보고하고있으나후향적연구라는단점이있고분석된환자의간세포암크기가 5-6 cm 미만이라는특징이있다. 6,7 Conformal RT에대한연구에서 Child B 간기능을가진환자에서는 radiation induced liver disease(rild) 가많이발생한다는보고가있어서 8 어느간기능까지, 그리고어느정도크기의간세포암까지 conformal RT가안전하게시행될수있는지에대해서는추가연구가필요하다. 5-6 cm 미만의간세포암에대한 stereotactic body RT(SBRT) 의결과는여러소규모후향적연구와전향적연구가발표되어있는데약 70% 의 objective response rate를보이며크기가 2cm 보다작은경우에는 100% 의 local control rate를보이는보고도있어서국소치료의효과는아주좋은것을알수있다 하지만역시 Child B 간기능을가진환자에서는 RILD가유의하게증가한다는보고가있으므로 12 이러한환자에서는적용에주의를요하며추가연구가필요하다. 간문맥침범을동반하는간세포암은대부분간절제술이나간이식이불가능하고 TACE 역시간기능부전의우려로인해치료가용이하지않다. 이러한경우 sorafenib이사용될수있으나 sorafenib에의한효과도낮은 overall response rate(3.3% partial response in AP trial) 로인해만족스럽지않아서새로운치료법이필요한실정이었다. 13 이에이러한환자를대상으로 TACE 혹은 HAIC와간문맥에국한된방사선치료를병합하여비교적좋은결과를보이는여러후향적연구결과가발표되었는데 명을대상으로장기간예후를조사한연구에따르면간문맥을침범한간세포암환자에서반복적인 TACE와간문맥침범에대한방사선치료 (21-60 Gy in 2- to 5-Gy fraction) 를시행한경우 madian survival 이 10.6 개월에달하였고간문맥침범간세포암이방사선치료에반응이있었던경우가그렇지않은경우에비해유의하게 median survival이길었다 (19.4 개월 vs. 7.0 개월 ). 17 현재간문맥침범간세포암환자를대상으로 TACE + SBRT 병합치료와 sorafenib 단독요법을비교하는전향적연구가진행중이므로그결과를기다려보아야겠다. 간문맥이외에간정맥이나대정맥을직접침범하는간세포암의경우에도 TACE 와더불어국소적인방사선치료를병합하였을때비교적좋은반응률및생존율을보고하는후향적연구가있다. 18,19 The Liver Week

3 10 cm 이상의거대간세포암에대한방사선치료는 RILD에대한우려로인해시행에제한이따르는데최근국내후향적연구의결과를보면 TACE 혹은 HAIC에더해서간세포암에대한 EBRT를추가한경우생존률이증가한다고보고하고있다.20 하지만그대상환자수가적고후향적연구이므로추후다른연구가더필요하다. 마지막으로간세포암에의한복부림프절전이, 뼈전이, 뇌전이, 척추전이가있을경우에도방사선치료가증상의호전과생존기간연장에효과적이라는보고가있으므로 증상이있거나증상을일으킬것으로예견되는전이성병변에대해서도 sorafenib 치료에더해서방사선치료를고려해볼수있겠다. 2. 간세포암의치료에있어서방사선치료의적응증 : 내과의의관점으로 1) 육안적인혈관침범 ( 간문맥, 간정맥및대정맥 ) 을동반하는간세포암이러한환자에서기존의치료는수술적절제가가능한극히일부환자에서는수술을시도하지만, 그외의대부분의환자에서는 TACE가가능한지확인후 palliative TACE를시행하고 TACE가어려운경우에는 sorafenib이표준치료법으로제안되었다. 최근에는전술한바와같은여러임상경험에의해서 TACE가가능한환자에서는첫번째와두번째 TACE 사이에혈관침범한간세포암에국한하여 EBRT를시도하는방법이본저자의센터에서는널리사용되고있다. 이러한접근법은간문맥분지나간정맥을침범의경우에는적용하기가수월하나주간문맥을침범하는경우에는 TACE 자체가간기능부전의위험성을가지므로시도하기가쉽지않고후향적연구에서의생존율도주간문맥침범의경우는많이낮아지는것을볼수있다. 따라서주간동맥침범간세포암에서 TACE + RT confined to gross vascular invasion을시도하는경우에는 TACE 에서 gelfoam embolization을제외하고 transarterial chemolipiodolization(tacl) 을시도하거나 HAIC로대체하는방법을사용해볼수있을것으로생각된다. 이러한접근법에서는환자의간기능및전신상태가아주중요하며간세포암자체의크기도고려하여 TACE, TACL 혹은 HAIC 등을결정하여야하며간문맥침범의정도나간외전이의유무가 RT의 contraindication이되지는않는다. 다만간외전이가동반된경우에는 sorafenib의단독혹은병합사용을항상고려하여야한다. 2) 간내간세포암에대한구제요법 (salvage treatment for intrahepatic HCC) 반복적인 TACE 에반응하지않고지속적으로 viable HCC가있는경우국소적인구제요법으로방사선치료가시도될수있다. 이러한경우에는방사선치료의대상이되는간세포암이외의간내혹은전이간세포암이다른치료법에의해조절이된다는것을전제로하여야하는데다른다발성간세포암이조절되지않는경우특정간세포암만을방사선으로치료하는것이환자의생존율향상에큰의미가없을것으로생각되기때문이다. 또한이때에는대상간세포암의크기와위치에따라 SBRT를시도할것인지혹은 conformal RT를시도할것인지결정하여야하는데본저자의센터에서는이를위해모든경우에대해방사선종양학과전문의와긴밀히상의하여환자마다개별화된치료를시도하고있다. 방사선으로치료가가능한간세포암의최대직경에대해서는아직 consensus가없는데대상간세포암의크기가커질수록조사가능한방사선량이작아질수있어서그효과도줄어들것으로생각이된다. 이에대해서는더많은연구와경험이필요하다. 3) 전이성간세포암에대한근치적목적치료 (curative-intent treatment in metastatic HCC) 간내간세포암이 TACE, RFA, 간절제술등에의해잘조절되는환자에서 3개미만의폐전이나림프절전이가있는경우이를대상으로근치적목적의방사선치료를계획하기도하는데특히폐전이의경우에는 SBRT를시도하여아주좋은결과를얻는경우를많이경험한다. 이러한접근법의전제조건은간내간세포암이잘조절되고있어야하며모든전이부위가치료계획에포함되어야한다. 또한다른부위에서의재발위험성이 584 The Liver Week 2014

4 상존한다는점을알고있어야하며항상 sorafenib 의사용에대해고려하고있어야한다. 치료계획과방사선량 등에대해방사선종양학과전문의와긴밀히상의하여야하는것은당연하다. 4) 증상완화를위한고식적치료 (palliative treatment) 간세포암의전이에의해증상이나타나거나향후심각한합병증을유발할수있는부위의경우선행적으로고식적방사선치료를시행한다. 이는전통적인방사선치료의적응증으로뼈전이나림프절전이에의한통증조절, 대퇴골이나척추전이에서의골절예방, 상대정맥증후군의치료및예방등을들수있다. 이러한치료를계획할때에는간세포암의상태나환자의간기능을통해환자의잔여생존기간을고려하게되는데, 환자의잔여생존기간동안상기한증상이나합병증이나타날지, 또한치료를해서얻게되는증상의완화혹은예방이라는이득이치료의부작용에의한손실보다더큰지등을고려해서결정하여야한다. 결론 간세포암에대한방사선치료는최근비약적으로발전하여간세포암치료의한축을담당하고있다. 하지만간세포암은대부분다발성으로발생하고재발이많아서그치료자체가여러치료법의병합요법이많이이용되는데이러한여러치료법중어떠한경우에국소적인방사선치료를적절히조합할지에대해서는아직 consensus가이루어져있지않으며이러한 consensus를위한임상연구를계획하기에도어려운점이많다. 현재는전통적인증상완화를위한고식적치료이외에육안적인혈관침범에대한병합요법, TACE에불응하는간내간세포암에대한구제요법, 일부전이성간세포암에대한근치적목적의치료등에체외방사선치료가많이사용되고있으며향후경험이축적된다면더다양한적응증에방사선치료가사용될것으로기대된다. 이러한치료법의발전을위해다학제간긴밀한협의가필요함을다시한번강조하는바이다. References 1. Llovet JM,Brú C,Bruix J.Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis1999;19: Korean Liver Cancer Study Group and National Cancer Center, Korea.Practice guidelines for management of hepatocellular carcinoma Korean J Hepatol2009;15: Klein J,Dawson LA. Hepatocellular carcinoma radiation therapy: review of evidence and future opportunities. Int J Radiat Oncol Biol Phys2013;87: Ben-Josef E, Normolle D, Ensminger WD, Walker S,Tatro D,Ten Haken RK,et al. Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 2005;23: Mornex F, Girard N, Beziat C, Kubas A,Khodri M,Trepo C, et al. Feasibility and efficacy of high-dose threedimensional-conformal radiotherapy in cirrhotic patients with small-size hepatocellular carcinoma non-eligible for curative therapies--mature results of the French Phase II RTF-1 trial. Int J Radiat Oncol Biol Phys 2006;66: Park JH,Yoon SM,Lim YS,Kim SY,Shim JH,Kim KM,etal.Two-week schedule of hypofractionated radiotherapy as a local salvage treatment for small hepatocellular carcinoma. J Gastroenterol Hepatol2013;28: Bae SH,Park HC,Lim do H,Lee JA,Gwak GY,Choi MS,etal. Salvage treatment with hypofractionated radiotherapy in patients with recurrent small hepatocellular carcinoma. Int J Radiat Oncol Biol Phys2012;82:e603-e Liang SX, Zhu XD, Lu HJ, Pan CY, Li FX, Huang QF, et al. Hypofractionated three-dimensional conformal radiation therapy for primary liver carcinoma. Cancer 2005;103: Blomgren H, Lax I, Näslund I, Svanström R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol 1995;34: Price TR, Perkins SM, Sandrasegaran K, Henderson MA,Maluccio MA,Zook JE, et al. Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma. Cancer 2012;118: The Liver Week

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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