Extending EXTENDING Role of ROLE Radiation OF RADIATION Therapy in THERAPY HCC Treatment IN HCC TREATMENT Radiation Induced Hepatic and Gastrointestinal Side Effects 계철승가톨릭대학교인천성모병원방사선종양학과 Chul-Seung Kay Department of Radiation Oncology, Incheon St, Mary Hospital, College of Medicine, The Catholic University of Korea, Korea At present, the role of radiotherapy in hepatocellular carcinoma is gradually expanding from palliation to cure because the accurate delivery of tumorcidal high dose of radiation to the intrahepatic tumor without increasing spillage dose to nearby normal liver or gastrointestinal organ. However, normal tissue complications such as radiation induced liver disease and radiation induced gastric/duodenal ulcer are still a kind of problems to be solved. We will discuss the strategy to minimize radiation induced side effect of liver and gastrointestinal organ in present article. Key words: Hepatocellular carcinoma, Radiotherapy, Side effect 최근간암환자에서방사선치료의역할이증가되는이유는종양에대한정확한방사선조사가가능하고동시에주변조직에조사되는방사선량을줄일수있는기술적발전에힘입은바크지만여전히주변정상조직이조사되는저선량의방사선에노출되거나, 종양과의경계부위에있는정상조직이고선량의방사선에조사되는현상은방사선치료를시행하는경우에는피할수없다. 특히방사선으로인한간과위장관부작용은간암환자에서방사선치료를시행하는데선량제한독성으로취급되며, 현재까지는특별한치료법이없기때문에치료보다는예방이우선되어야한다. 본논문에서는간암환자에서방사선치료를시행하는경우에방사선으로인한간과위장관의부작용을예방하는방법들에대하여논의하고자한다. 1. 방사선치료와관련된간부작용 1.1 방사선간부작용의평가 간암환자에서방사선치료로인한간부작용을평가하기위해서는방사선치료전후의간기능에대한비교평가가매우중요하며, 그와동시에기저질환혹은동반간질환의악화여부와감별하는것이반드시필요하다. 1 596 The Liver Week 2014
1.1.1 Common Terminology Criteria for Acute Event (CTCAE) version 4.0 1 2 3 4 5 ALT (SGPT) >ULN- 3.0xULN Asymptomatic with ALT>3.0-5.0xULN; the appearance or worsening of symptoms* with >3.0xULN >5.0-20.0xULN; >5xULN for 2weeks >20.0xULN - AST (SGOT) >ULN- 3.0xULN Asymptomatic with ALT>3.0-5.0xULN; the appearance or worsening of symptoms* with >3.0xULN >5.0-20.0xULN; >5.0xULN for 2weeks >20.0xULN - ALK GGT >ULN- 2.5xULN >ULN- 2.5xULN >2.5-5.0xULN >5.0-20.0xULN >20.0xULN >2.5-5.0xULN >5.0-20.0xULN >20.0xULN * fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia 1.1.2 RTOG (Radiation therapeutic Oncology Group) toxicity criteria Liver 1 2 3 4 Mild lassitude; nausea; dyspepsia; slightly abnormal liver function Moderate lassitude; some abnormal liver function test; normal serum albumin Disabling hepatic insufficiency; liver function tests grossly abnormal; low albumin; edema or ascite Necrosis/hepatic coma or encephalopahty 급성부작용에대한기준은없고, 만성부작용에대한기준만있으며, 기준에대한정의가명확하지않으므로요즘은잘사용하지않는다. 1.1.3 Child Pugh classification 1 point 2 points 3 points Bilirubin (total) < 2mg/dl 2-3mg/dl >3mg/dl Serum albumin > 3.5g/dl 2.8-3.5g/dl <2.8g/dl INR 1.7 1.7 2.2 > 2.2 Acsites none Controlled with medication refractory Hepatic encephalopathy none Mild to moderate symptoms; limiting instrumental ADL Severe symptoms; limiting self care ADL; urgent intervention INR: international normalized ratio A, 5-6 pints; B, 7-9 points; C, 10 points or higher 간기능의평가에가장많이쓰이는방법으로방사선치료전후의간기능을비교하여방사선치료로인한간부작용을평가할수있으며, 최근에많이사용되고있다. 임상적으로방사선치료후간기능이상으로인하여 2점이상증가될경우에는환자의생존기간이짧아진다는보고도있다. 2 The Liver Week 2014 597
1.1.4 MELD (model for end stage liver disease) score 최초간이식을기다리는간경화환자의예측사망률평가를위하여개발되었으며, 혈청 bilirubin, creatinine, INR에따른점수의합으로 3개월예측사망률을추정하는데이용되고있고, 6-40점의범위에서점수에따른 3개월예측사망률은다음과같다. score 3 months mortality 40 or more 100% 30 39 83% 20-29 76% 10-19 27% 10 or less 6% 1.1.5 Classic radiation induced liver disease (RILD) 일반적으로방사선치료종료후 4개월이내에나타나며, 피로, 체중증가, 간비대혹은비황달성복수로인한복부둘레증가그리고 alkaline phosphatase 가정상치의두배이상증가되는소견등이나타난다. 병리학적소견으로는간소엽중심정맥의폐쇄및이차성간세포괴사등이나타나며, 치료방법이매우제한되어있어결국은간부전및사망으로이어진다. 3 이에비하여 non-classic RILD는기저질환으로만성간질환이동반되어있는경우방사선치료후 1주일내지 3개월이지나면서나타나는간기능저하를말하는것으로 classic RILD의기준에는부합하지않는경우를총칭하여말한다. 4-6 방사선치료후발생하는간부작용특히 non classic RILD는만성간질환이동반되어있기때문에간경화등의기저질환이악화되는경우 (52%) 7 그리고만성간염이동반되어있는경우바이러스의재증식등과감별을필요로한다. 8 1.2 선량체적관계 간경화가없는경우수술후전체간의 20-25% 정도를남길수있다면, 수술을시행해도무방하다는사실은이미널리알려져있으며, 9 이러한사실은간암에대한부분적방사선치료시고선량의방사선치료가가능하다는이론적인근거가되고있다. 그러나간기능저하가동반된간질환이있는환자의경우에는 RILD 발생의위험군으로간주되어야한다. 1.2.1 전간방사선치료 (whole liver radiotherapy) Ingold등에의하면 35Gy/3-4주의전간방사선치료를시행한경우 classic RILD가전체환자의 44% 에서발생하였으며, 10 Emami등은일일분할크기 2Gy로전간방사선치료를시행한경우 TD 5/5 가 30 Gy라고보고하였다. 11 RTOG 84-05연구에서는 1.5Gy bid로전간방사선치료를 27-30Gy시행한경우와 33Gy를시행한경우를비교했을때 RILD의발생은각각 0% 와 9.8% 였다. 12 1.2.2 부분적간방사선치료를시행한경우방사선치료와관련된간부작용에대한자료를아래표에요약하여제시하였다. 598 The Liver Week 2014
Study group n Dx Baseline CPscore Fraction size Crude % RILD MLD in pts RILD(+/-) End point Factors Michigan 13,14 203 PLC LMC 203A 1.5Gy bid 9.4% 37Gy/30Gy Classic MLD Taipei 15 89 HCC Shanghai 4,16 109 PLC 68A 21B 93A 16B 1.8-3.0Gy 19% 23Gy/19Gy Classic HBV, LC 4-6Gy 15.6% 24.9Gy/19.9Gy Classic (LFT abn 24.5%) LC Guangdong 15 94 HCC 43A 51B 4-8Gy 17%(16/94) 4 fatal Ns Classic LC Yeonsei 17 158 HCC 117A 41B 1.8Gy 7% Ns Classic (LFT abn 38%) Dose NCC 5 105 HCC 85A 20B 2.0Gy 12.3% 25.4Gy/19.1Gy CTCAE (liver enzyme) Gr 3 V30>60% CP score, Child Pugh score; RILD, radiation induced liver disease; MLD, mean liver dose; LFT,liver function test; PLC, primary liver cancer; LMC, liver metastatic cancer; HCC, hepatocellular carcinoma 1.2.3 방사선치료후의간부작용과관련된인자로는환자의치료전간기능이불량한경우, HBV 보균자, 경동맥화학색전술을시행한경우, 간문맥종양혈전이있는경우, 종양의병기가높은경우, 남성인경우와 CLIP score가높은경우등이있으며, 이러한경우방사선간부작용의발생률이높은것으로보고되고있다. 1.2.4 정위절제방사선치료 (SABR, Stereotactic Ablative Body Radiotherapy) 정위절제방사선치료혹은정위체부방사선치료 (SBRT, stereotactic body radiotherapy) 는고선량의방사선을종양부위에짧은기간내에선택적으로정확하게조사하는방법이다. 그러나이러한방사선치료법은방사선치료후간부작용이발생할확률이더높아지므로, 이러한부작용을예방하기위한노력이매우중요하다. 정위절제방사선치료후발생한간부작용에대한보고들을아래표에요약제시하였다. No of pts Prescription dose RILD Mendez-Romero et al 18 8 HCC 7 LMC 37.5Gy/3fx(<4cm) 25Gy/5fx or 30Gy/10fx 2RILD 1 death (CP B) Hoyer et al 19 44 LMC 45Gy/3fx 1 hepatic failure death (V 60% > 10Gy, MLD 14.4Gy) Tse et al 20 41 PLC Median 36Gy (24-54gy)/6fx 17% CP A B (MLD 17.5Gy, 5.2~25.2Gy) Lee et al 21 68 LMC 28-60Gy/6fx 95% CI serious toxicity (0-5.3%) in MLD 16.9Gy Son et al 22 36 HCC 30-39Gy/3fx 3% classic RILD 11% CP progression (V 18 < 800ml) HCC, hepatocellular carcinoma; LMC, liver metastases; PLC, primary liver cancer; RILD, radiation induced liver disease The Liver Week 2014 599
1.2.5 선량체적관계 부분적간방사선치료시방사선치료후간부작용의위험성을 5% 이하로제한하기위하여서는 선량체적관계를아래와같이제한하는것이필요하다. 23 Liver metaststases Primary liver cancer MNLD, mean normal liver dose Palliative radiotherapy 30 Gy, in 2 Gy per fraction 21 Gy in 7 fractions 28 Gy, in 2 Gy per fraction 21 Gy in 7 fractions Therapeutic radiotherapy MNLD (liver minus GTV) < 32 Gy in 2 Gy fraction MNLD (liver minus GTV) < 28 Gy in 2 fraction 정위절제방사선치료시방사선치료후나타나는간부작용의위험성을 5% 이하로제한하기위하여서는선량체적관계를아래와같이제한하는것이필요하다. 23 Mean liver dose comment Liver metastases Primary liver cancer CP, child pugh class < 15 Gy in 3 fractions < 20 Gy in 6 fractions < 13 Gy in 3 fractions < 18 Gy in 6 fractions < 6 Gy, CP class B in 4-6Gy per fraction (for classic or non classic RILD) critical volume model based 700ml of normal liver receives 15 Gy in 3 to 5 fractions 1.3 방사선관련간부작용의치료 Warfarin 을이용한항응고요법을포함한보존적치료가주로시행되고있으며, 최근에는 glutathione, selenium/ vitamine E 혹은 fibrinolytic agent인 defibritide등도사용할수있으나임상적효과에대한보고는아직없다. 24 그러므로방사선관련간부작용은예방이더욱중요하며, 간부작용을예방하기위해서는간기능과종양의크기를고려한선량체적권고기준등을준수하여야한다. 2. 방사선치료와관련된상부위장관부작용 2.1 방사선치료시상부위장관의방사선견딤선량 (TD 5/5 ) 은전체상부위장관이방사선범위에포함되는경우에는분할크기 2 Gy인경우 45-50 Gy이며, 전체상부위장관의 2/3가포함될경우에는 50-55 Gy이다. 그리고, 1/3이하로포함되는경우에는 55-60 Gy이지만상부위장관이불가피하게방사선범위에포함되는암인췌장암이나담도암의경우에는항암제와방사선치료를병용하게되는데, 이경우항암제가방사선민감제로작용하게되어서방사선으로인한위장관부작용의빈도가높아질수있으며, 이와관련된보고자료는자료는아래와같다. 600 The Liver Week 2014
Patients Technique of Radiotherapy chemotherapy Grade > 3 (%) Dose constraints Huang et al 25 46 Pancreas ca 3DCRT/IMRT 2.0-2.8Gy/fx gemcitabine 37% V35<20% Milano et al 26 25 Pancreas/biliary ca IMRT 1.8Gy/fx 5FU continuous 20%(acute) - Nakamura et al 27 40 Pancreas ca 3DCRT 2.0Gy/fx gemcitabine 20% V50<33cm 3 (stoduo) Kelly et al 28 106 Pancreas ca 3DCRT/IMRT 1.8-2.0Gy/fx 5FU+xeloda/ gemcitabine 7.5% V55?1cm 3 3DCRT, 3 dimensional conformal radiotherapy; IMRT, intensity modulated radiotherapy; Vn, volume percentage of organ receiving n Gy or more; stoduo, stomach plus duodenum 그러나간경화가동반되거나, 간문맥압이항진이동반되어있는간암의경우에는위혹은십이지장궤양이자주동반되어있으므로, 기저질환이방사선치료후에더악화되지않도록하기위해서는매우주의를기울여야한다. 2.2 간암의방사선치료시에는상부위장관부작용에관한보도들에관하여살펴보면췌장암이나담도암등과는달리방사선치료시분할크기및총방사선조사량이기관별로매우상이하기때문에방사선견딤선량에대한기준이기관마다다르게보고되고있는현실이다. 아래표는이와관련된보고자료들을요약정리한것이다. No of patients Technique of radiotherapy Child Pugh class GI toxicity Dose constraint Chon et al 29 123 3DCRT A 113 (91.9%) B 10 (8.1%) 52.8% 14.6% (>gr 3) - (LC presensce) Kim et al 30 73 3DCRT 3Gy/fx;30-54Gy 12.3% (>gr 3) V35 < 5% Yoon et al 31 90 3DCRT 2.0-5.0Gy/fx;30-50Gy A 78(87%) B 12(13%) 30% (> gr 3) Sto V25<6.3% Duo V35<5.4% Hata et al 32 19 Proton 3.0-5.0Gy/fx;50-84Gy C 3/19 (r I) 3DCRT, 3 dimensional conformal radiotherapy; LC, liver cirrhosis; gr, grade; Vn, volume percentage of organ receiving n Gy or more; sto, stomach; duo, duodenum 2.2.1 간암의정위절제방사선치료에서는일일분할크기가크고총방사선량이높기때문에간암혹은간주변의위장관에고선량의방사선이조사되어위장관부작용의빈도및정도가증가할가능성이높아지기때문에세심한주의가필요하다. 이와관련된보고는주로국내의학자들에의해서보고되었는데, 그결과를요약하면아래표와같다. The Liver Week 2014 601
Patients Technique of radiotherapy Child Pugh class GI toxicity > gr. 3 Dose constraints Bae et al 33 17 Live malignancy Kang et al 34 50 HCC SABR 33-60Gy/3fx SABR 42-60Gy/3fx - A5 32 A6 9 B7 6 SABR, stereotactic ablative radiotherapy; HCC, hepatocellular carcinoma; GDU, gastroduodenal ulcer 5% 10% Dmax<35Gy Dmax<38Gy 10.7% Preexisting GDU 2.2.2 간암에서정위절제방사선치료시위장관부작용은기존의위십이지장궤양유뮤에따라서그발생및정도가영향을받을수있다고보고되고있다. 그러나위십이지장궤양의유무에따른위십이지장의방사선량제한치에대한명확한결과는없다. 대한방사선종양학회방사사선수술분과에서는간암의정위절제방사선치료시에위십이지장궤양유무에따라선량제한치를다르게하여간암의정위절제방사선치료를시행하는 2상임상연구 (KROG, Korean Radiation Oncology Group 12-02) 를진행중에있다. References 1. Yamasaki SA, Marn CS, Francis IR, Robertson JM, Lawrence TS. High dose localized radiation therapy for treatment of hepatic malignant tumors: CT findings and their relation to radiation hepatitis. Am J Roentgenol 1995;165:79-84 2. Son SH, Jang HS, Jo IY, Choi BO, Jang JW, Yoon SK et al. Significance of an increase in the Child-Pugh score after radiotherapy in patients with unresectable hepatocellular carcinoma. Radiat Oncol 2014;9:101 3. Lawrence TS, Roberson JM, Anscher MS, Jirtle RL, Ensminger WD, Fajardo LF. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995;31:1237-1248 4. Xu ZY, Liang SX, Zhu J, Zhu XD, Zhao JD, Lu HJ et al. Prediction of radiation induced liver disease by Lyman normal tissue complication probability model in three dimensional conformal radiation therapy for primary liver carcinoma. Int J Radiat Oncol Biol Phys 2006;65:189-195 5. Kim TH, Kim DY, Park JW, Kim SH, Choi JI, Kim HB et al. Dose-volumetric parameters predicting radiation induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three dimensional conformal radiotherapy. Int j Radiat Oncol Biol Phys 2007;67:225-231 6. Cheng JC, Wu JK, Huang CM, Liu HS, Huang DY, Cheng SH et al. Radiation induced liver disease after three dimensional conformal radiotherapy for patients with hepatocellular carcinoma: Dosimetric analysis and implication. Int J Radiat Oncol Biol Phys 2002;54:156-162 7. Liovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al. Sorafenib in advanced hepatocellular carcinoma. N Eng J Med 2008;359:378-390 8. Kim JH, Park JW, Kim TH, Koh DW, Lee WJ, Kim CM. Hepatitis B virus reactivation after three dimensional conformal radiotherapy in patients with hepatitix B virus related hepatocellular carcinoma. Int J Radiat Onol Biol Phys 2007;69:813-819 9. Penna C, Nordlinger B: Coloerectal metastasis (liver and lung). Surg Clin North Am 2002;82:1075-1090 10. Ingold JA, Reed GB, Kaplan HS, Bagshaw MA. Radiation Hepatitis. Am J Roentgenol Radium Ther Nucl Med 1965;93:200-208 11. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE et al. Tolerance of normal tissue to therapeutic irradiation, Int J Radiat Oncol Biol Phys 1991;21:109-122 12. Russell AH, Clyde C, Wasserman TH, Turner SS, Rotman M. Accelerated hyperfractionated hepatic irradiation in the management of patients with liver metastases: Result of the RTOG dose escalating protocol. Int J Radiat Oncol Biol Pyhs 1993;27:117-123 13. Dawson LA, Normolle D, Batler JM, McGinn CJ, Lawrence TS, Ten Haken RK. Analysis of radiation induced liver disease using the Lyman NTCP model. Int J Radiat Oncol Biol Phys 2002;53:810-821 602 The Liver Week 2014
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