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1 DOI: /jkstro 국소전립선암의영구적근접치료 : 조기결과 차의과학대학교분당차병원방사선종양학교실 박혜리ㆍ장세경ㆍ김자영ㆍ이보미ㆍ고승영ㆍ김성준ㆍ신현수 목적 : 국소전립선암의영구적근접치료후단기간추적관찰동안의생화학적재발률과부작용의정도및이에영향을미치는인자들에대해알아보고자하였다. 대상및방법 : 27 년 4 월부터 28 년 12 월까지영구적근접치료를시행받은환자는 67 예이었다. 추적관찰이중단된환자 5 명, 이전에방사선치료를받았던환자 2 명을제외한 6 예중근치적으로외부방사선치료를병용한 16 예, 구제요법으로외부방사선치료를병용한 1 예를제외한 43 예를대상으로종양표지인자의변화와부작용의발생여부를조사하였다. T1-T2a, Gleason score 6 점이하, prostate specific antigen (PSA) 1 ng/ml 미만의조건을모두충족시킬경우를저위험군으로정의하였으며, T2b-T2c, Gleason score 7 점, PSA 1 2 ng/ml 중한가지이상의조건을충족시키는경우를중간위험군으로정의하였고, T3a 이상, Gleason score 8 1 점, PSA>2 ng/ml 중한가지이상의조건을충족시키는경우를고위험군으로정의하였다. 저위험군은 18 명이었고, 중간위험군은 19 명, 고위험군은 6 명이었다. 처방선량은 145 Gy 이었다. 결과 : 저위험군과중간위험군에서각각 1 예씩 PSA 가 2 ng/ml 이상증가하여생화학적재발로진단받았으며 (4.7%), 생화학적재발률에영향을미치는통계적으로유의한인자는없었다. 급성요로계부작용의경우 Radiation Therapy Oncology Group (RTOG) grade 1 과 2 가각각 4 예, 3 예있었으며, grade 2 이상의급성직장부작용은없었고 grade 1 인경우가 5 예있었다. 만성요로계부작용은 RTOG grade 1, 2, 3 이각각 1 예, 4 예, 1 예에서나타났으며, RTOG grade 1, 2 의만성직장부작용이각각 5 예, 1 예에서나타났고직장요도간장루가생긴 grade 4 인경우가 3 예있었다. 부작용의발생에통계적으로유의한영향을미치는요인은급성직장염의경우전체직장에서최고선량이조사되는직장.1 cc 에들어가는최소선량 (p=.41), 전체직장중처방선량의 15% 이상이들어가는부피 (p=.38), 치료부위에포함된직장중 1% 선량이들어가는부피 (p=.47) 및비율 (p=.19) 이있었으며, 급성요로계부작용의경우 seed 개수 (p=.28) 가유의한영향을미쳤다. 만성요로계부작용에유의한영향을미치는인자는없었으며, 만성직장염의경우전체직장의 1% 처방선량이들어가는부피의비율 (p=.11), 치료범위직장에서 1% 처방선량이들어가는부피 (p=.23) 및최고선량이조사되는직장.1 cc 에들어가는최소선량 (p=.49) 이유의하게나타났다. 결론 : 국소전립선암환자에서영구적근접치료는저위험군환자뿐아니라중간위험군이나고위험군환자에게도선택적으로적용가능한치료방법이라고생각되며, 직장부작용을감소시키기위한노력이필요하다고생각된다. 핵심용어 : 전립선암, 근접방사선치료 서 국소전립선암의치료에는수술, 외부방사선치료, 호르몬치료, 영구적근접치료등이사용되고있다. 근치적전립선절제술이국소전립선암의기본적인치료로사용되어 이논문은 211 년 4 월 1 일접수하여 211 년 5 월 23 일채택되었음. 책임저자 : 신현수, 분당차병원방사선종양학과 Tel: 31) , Fax: 31) shin29@chamc.co.kr 론 져왔으나, 외부방사선치료및영구적근접치료결과의추적관찰에서방사선치료는근치적전립선절제술과대등한국소제어율및생존율을보이고있다. 1 5) 근치적전립선절제술의경우요실금의발생률과성기능장애율이가장높으나소화기계부작용이적다고보고되고있다. 외부방사선치료의경우는근치적전립선절제술을시행한경우보다배뇨기능장애는낮게보고되고있으나, 근치적전립선절제술에비하여방광충만감이나배뇨시불편감의발생률이높게보고되고있으며소화기계부작용의발생비율이높다고보고되고있다. 영구적근접

2 치료는성기능보존율이가장높으며병원내원횟수및재원일수를감소시킬수있고일상생활로빠른복귀가가능하다는장점을가지고있다. 6) 그러나배뇨시불편감의비율또한가장높다고보고되고있다. 2,7) 본연구는국소전립선암의영구적근접치료후단기간추적관찰기간동안의생화학적재발률과부작용및이에영향을미치는인자들에대해알아보고자하였다. Table 1. Patient Characteristics Mean age (yr) Range Mean follow-up (mo) Range T stage T1c T2a T2b T2c Gleason Score PSA* (ng/ml) <1 1 2 >2 Duration of HT (median days) Range 18 >18 Start before brachytherapy Start after brachytherapy 대상및방법 27년 4월부터 28년 12월까지영구적근접치료를시행받은 67예중추적관찰이중단된 5예, 이전에외부방사선치료를시행받은 2예를제외한 6예중근치적으로외부방사선치료를병용한 16예, 구제요법으로외부방사선치료를병용한 1예를제외한 43예를대상으로전립선특이항원 (prostate specific antigen, PSA) 의변화와요로계및직장부작용의정도및이에영향을미치는인자에대하여조사하였다. 대상환자들은조직검사에서전립선암으로확진받았으며, CT 또는 MRI에서정낭침윤이나임파선및 Group 1 (n=18) , Group 2 (n=19) , *prostate-specific antigen, hormone therapy. 2 Group 3 (n=6) 원격전이소견이없는환자군으로정하였다. 고위험군환자의경우고위험군의조건을한가지만충족시키거나장기간치료를받기힘든경우외부방사선치료를배제하고근접치료단독으로치료를시행하였다. 중간위험군및고위험군환자는근접치료전또는후에호르몬치료를시행받았으며, 저위험군환자중에서도전립선부피가 2 ml 이상인경우호르몬치료를시행받았다. American Joint Committee on Cancer (AJCC) 7판의병기 I 은 18명, IIA는 8명, IIB는 17명이었으며, T1c는 9명, T2a는 18명, T2b는 4명, T2c는 12명이었다. 본연구에서는 T1-T2a, Gleason score 6점이하, PSA 1 ng/ml 미만의조건을모두충족시킬경우를저위험군 (group 1) 으로정의하였으며, T2b-T2c, Gleason score 7점, PSA 1 2 ng/ml 중한가지이상의조건을충족시키는경우를중간위험군 (group 2) 으로정의하였고, T3a 이상, Gleason score 8 1 점, PSA>2 ng/ml 중한가지이상의조건을충족시키는경우를고위험군 (group 3) 으로정의하였다. 저위험군은 18 명이었고, 중간위험군은 19명, 고위험군은 6명이었다 (Table 1). American Association of Physicists in Medicine Task Group 43에따라전립선임상표적체적에 145 Gy를처방하였다. Mick Applicator (Mick Radio-Nuclear Instruments, Mount Vernon, WA, USA) 를사용하여경직장초음파와 C-arm 유도하에 Best Medical (Springfield, VA, USA) 의 iodine 125 ( 125 I) seed를삽입하였다. 수술실에서경직장초음파를이용하여 5 mm 간격으로전립선이미지를획득하였으며, 초음파이미지에전립선을그려서임상표적체적을정하고이에적절한선량분포를얻기위해필요한 seed 삽입위치와개수를정하기위한전계획을시행하였다. 전계획을바탕으로 seed 삽입을진행하였으며시술중실시간으로 Strata Suite Volume Plan (Rosses Medical Systems, Columbia, MD, USA) 을이용하여등선량곡선과선량체적히스토그람을확인하면서 seed 삽입위치와개수를수정, 보완하였다 (Fig. 1A). Seed 삽입이종료된후방광경검사를통해요도나방광내에 seed가존재하는지여부를확인하였다. Seed 삽입후 1개월후부터부작용을조사하였고, 3개월에서 5 개월간격으로 PSA를추적관찰하였다. 사용된 seed의개수는평균 15개 (79 147) 이었고, seed 의강도는평균.338 mci ( ) 이었으며사용된 needle의개수는평균 3.33개 (19 49) 이었다. Seed 삽입후 1개월가량경과후골반 CT를시행하였고, Strata Suite CT Plan (Rosses Medical Systems Columbia, MD, USA) 프로그램을이용하여 CT 영상에전립선과직장을그린후 (Fig

3 박혜리외 6 인 : 국소전립선암의영구적근접치료 : 조기결과 1B) 삽입된 seed 위치및강도를지정하여임상표적체적과손상위험장기의선량체적히스토그람을알아보았다. 임상표적체적은 CT 영상에서확인되는전립선체적을확장시키지않고사용하였으며, 직장부피는 S자결장이끝나는부위부터직장항문경계부까지외벽을그려서계산한부피와 Crook 등 8) 이손상위험장기의규정과선량측정에관한 American Brachytherapy Society Consensus Statement 에서권고한내용을바탕으로 seed가있는부위에한정하여외벽과내벽을그려서계산한직장벽의부피두가지에대하여선량체적히스토그람을각각분석하였다. 조영증강및도뇨관삽입을하지않은 CT 영상에서요도를정확히구분하기어려우므로요도선량에대한분석은시행하지않았다. 모든환자가호르몬치료를시행받았으며근접치료전에시작한사람이 37명, 영구적근접치료후시작한사람이 6명이었다. 호르몬치료기간이 6개월미만인환자는 4 명, 6개월이상인환자는 3명이었다 (Table 1). 근접치료시행후호르몬치료를한달이상지속한경우는 14명이었고최장기간이 7개월이었다. 방사선치료후생화학적재발의기준으로 Radiation Therapy Oncology Group (RTOG)-American Society for Therapeutic Radiology and Oncology (ASTRO) Phoenix Consensus Conference 9) 에서는외부방사선치료후최저 PSA 값에서 2이상증가한것으로정하였으며 Kuban 등 1) 은 2,693명의근 접치료를시행받은환자를대상으로연구하였을때외부방사선치료와같이최저 PSA 값에서 2 ng/ml 이상증가한것을생화학적재발의기준으로삼는것이추적관찰중치료실패를가장잘반영하였다고보고하였다. 이를바탕으로본연구에서도최저 PSA 값에서 2 ng/ml 이상증가한것을생화학적재발의기준으로정하였다. 또한 PSA 반등 (bounce) 은치료후 PSA가최소값으로감소한후에.1 ng/ml 이상증가하였다가추가적인치료없이추후시행한검사에서감소한경우로정하였다. 생화학적재발률과직장및요로계부작용에영향을미치는요인에대해 SPSS ver. 19. (SPSS Inc., Chicago, IL, USA) 을사용하여독립표본 T 검정및분산분석, 교차분석을시행하였다. 결과근접치료후 1개월에비조영증강골반 CT를시행하여전립선선량분포를분석한결과평균 D 9 ( 전립선의 9% 부피에조사되는최소선량 ) 은 Gy ( ), 평균 D 1 은 Gy ( ), 평균 V 9 ( 처방선량의 9% 이상이조사되는전립선의부피의비율 ) 은 99.7% (96.6 1), 평균 V 1 은 99.2% (94.4 1), 평균 V 15 은 92.4% (69.8 1), 평균 V 2 은 78.1% ( ) 이었다 (Table 2). Fig. 1. Isodose curve of permanent brachytherapy. (A) Intraoperative transrectal ultrasound (TRUS) based plan. Isodose curve acquired from intraoperative TRUS based plan. (B) Postoperative computed tomography based plan. Isodose curve acquired from postoperative CT based postplan. Dots represent the location of seed. R2 represents rectal wall confined in the irradiated level

4 추적관찰중에.1 이상 PSA 반등이있었던환자는 2 명이었고, PSA가 2 ng/ml 이상증가하여생화학적재발로판정한경우는 2예였으며, 저위험군과중간위험군에서각각 1예씩있었고원격전이가나타난경우는없었다 (Table 3). PSA 증가까지기간은각각 22개월, 29개월이었으며 1 예는영상검사에서재발부위가발견되지않았고, 1예는자기공명영상에서폐쇄공임파선및대퇴부임파선이커진소견이관찰되었으나양전자방출단층촬영술상에서는 18 F fluorodeoxyglucose (FDG) 섭취증가소견은없었다. 임파선크기증가가있었던환자는호르몬치료를추가시행하였으나 PSA가증가된상태로추적관찰중이며, 재발부위가발견되지않았던환자는호르몬치료와전립선고주파열치료를시행한후 PSA가감소하고있다. 생화학적재발과연관된인자를분석하였을때통계적으로유의한인자는없었으며전립선선량분포와 PSA, Gleason score, 위험군, 병기등은모두유의한영향을미치지못하였다. RTOG grade 1의급성직장부작용을나타낸사람이 5명 ( 저위험군 1명, 중간위험군 3명, 고위험군 1명 ) 으로배변시통증이나배변횟수증가등의증상이있었으며 RTOG grade 2 이상의급성직장부작용이나타난경우는없었다. RTOG grade 1의만성직장부작용이 5명 ( 저위험군 4명, 중 Table 2. Postimplant CT based Dosimetry of Prostate CT based dosimetry Mean Minimum Maximum Minimum dose (Gy) Maximum dose (Gy) D9 (Gy)* D1 (Gy) V9 (%) V1 (%) V15 (%) V2 (%) , , *minimal dose in the 9% of prostate volume, percentage of volume receiving at least 9% of the prescribed dose. 간위험군 1명 ) 에서있었고설사나간헐적출혈등 RTOG grade 2의만성직장부작용을나타낸사람이 1명 ( 저위험군 2명, 중간위험군 7명, 고위험군 1명 ) 이있었다. RTOG grade 4의만성직장부작용으로직장요도간누공이생긴경우가 3명 ( 중간위험군 2명, 고위험군 1명 ) 이었다 (Table 4). 누공이생긴첫번째경우는근접치료 2개월후시행한골반강 CT에서직장요도간또는직장과전립선간누공이의심되어시행한직장내시경결과항문연상방 5 cm 부위에 3 cm 가량의궤양및 seed가발견되었고누공이있었으며직장경으로흡착시소변이유출되는것이확인되었다. 메살라진좌약및포비돈요오드좌약을사용하며보존적치료를 1개월가량시행후재시행한 S자결장경검사상궤양은호전양상을보였으나, 누공은잔존상태였으며신선혈이뭍어나는혈관확장이있었다. 좌약을유지하며스테로이드관장을시행하는등보존적치료를 3개월가량더유지하며시행한 S자결장경검사상누공크기가감소하였으며, 근접치료시행 27개월경과후시행한방광경검사상누공이관찰되지않았고, 28개월경과후시행한 S 자결장경검사에서도누공및출혈소견이없었으며궤양이호전된양상이관찰되고있었다. 누공이발생한두번째경우는근접치료 2개월후시행한골반강 CT에서직장에활동성출혈이의심되어시행한 S자결장경검사결과직장과전립선사이의누공이발견되었다. 첫번째환자와동일한보존적치료를시행하던중배뇨시항문으로소변이나오는증상이있어, 근접치료후 25개월째시행한 S자결장경검사상직장점막궤양크기가증가하였으며누공잔존소견보여도뇨관을삽입하고보존적치료를지속하며추적관찰하고있다. 누공이발생한세번째경우는근접치료시행 8개월후 RTOG grade 2의직장출혈이있어 S자결장경적지혈술및아르곤플라스마응고소작술을시행받았으며 S자결장경검사추적관찰중직장궤양소견이지속적으로관찰되다 Table 3. Biochemical Outcome of Permanent Brachytherapy PSA* bounce PSA recurrence (increase >2 ng/ml from nadir) Group 1 Group 2 Group 3 *prostate-specific antigen. Rate (%) 2/43 (46.5) 2/43 (4.7) 1/18 (5.6) 1/19 (5.3) /6 () Table 4. Acute and Chronic Side Effects of Permanent Brachytherapy RTOG* grade Urinary tract 4 3 Acute Rectum 5 *Radiation Therapy Oncology Group. Urinary tract Chronic Rectum

5 박혜리외 6 인 : 국소전립선암의영구적근접치료 : 조기결과 Table 5. Postimplant CT Based Dosimetry of Rectum Entire rectal dosimetry Involved rectal dosimetry Mean Minimum Maximum Mean Minimum Maximum D 2cc (Gy)* D.1cc (Gy) V 1 (cc) V 1 (%) V 15 (cc) V 15 (%) Dmax (Gy) *Minimal dose in the most irradiated 2 cc volume of the rectum, absolute rectal volume receiving at least 1% of the prescribed dose, percentage of rectal volume receiving at least 1% of the prescribed dose. 가, 근접치료후 19개월째시행한 S자결장경검사상궤양및누공이발견되었다. 근접치료시행 21개월째결장조루술을시행하였으며근접치료 23개월후시행한 S자결장경검사상육아조직이관찰되었으며보존적치료를지속하고있다. 근접치료 1개월후시행한 CT로직장선량분포를분석한결과전체직장에서평균 D 2cc ( 최고선량이조사되는직장부피 2 cc에들어가는최소선량, Gy) 는 Gy ( ), 평균 D.1cc 는 Gy ( ), 평균 V 1 ( 처방선량의 1% 이상이조사되는직장의부피및비율 ) 은 3.5 cc ( 8.6), 7.% ( 18.7), 평균 V 15 은 1.1 cc ( 3.1), 2.3% ( 8.5) 이었으며평균 Dmax (Gy) 는 Gy ( ) 이었다. 치료부위에포함된직장벽의선량분포를분석하였을때평균 D 2cc 는 Gy ( ), 평균 D.1cc 는 Gy ( ), 평균 V 1 은 2.1 cc ( 4.6), 13.9% ( 31.8), 평균 V 15 은.8 cc ( 2.3), 5.4% ( 15.5) 이었다 (Table 5). 전체직장의 D O.1cc (p=.41) 및 V 15 (cc) (p=.38), 치료부위에포함된직장의 V 1 (cc) (p=.47) 및 V 1 (%) (p=.19) 이급성직장부작용에대한 RTOG grade에통계적으로유의한영향을미치는요인이었다 (Table 6). 전체직장의 D.1cc 는 grade 에서평균 Gy, grade 1에서평균 Gy 이었으며, V 15 (cc) 는 grade 에서평균 1.3 cc 이었으며 grade 1에서평균 1.7 cc이었다. 치료부위에포함된직장의 V 1 (cc) 및 V 1 (%) 는 grade 에서평균 2.3 cc, 평균 13.1%, grade 1에서평균 3.2 cc, 평균 21.32% 이었다 (Table 7). 만성직장부작용의경우에는 RTOG grade 1을환자군 1, RTOG grade 2 3을환자군 2, RTOG grade 4를환자군 3으로정하여분산분석을시행하였을때전체직장의 V 1 (%) (p=.11), 치료범위에포함된직장의 D.1cc Table 6. Univariate Analysis of the Parameters for Acute and Chronic GI Complication Vablialbes Prostate volume (cc) Seed no. Whole rectum D 2cc* (Gy) D.1cc (Gy) V 1 (cc) V 1 (%) V 15 (cc) V 15 (%) Dmax (Gy) Involved rectum D 2cc (Gy) D.1cc (Gy) V 1 (cc) V 1 (%) V 15 (cc) V 15 (%) Acute complication Chronic complication p-value *Minimal dose in the most irradiated 2 cc volume of the prostate, absolute rectal volume receiving at least 1% of the prescribed dose, percentage of rectal volume receiving at least 1% of the prescribed dose. (p=.49) 및 V 1 (cc) (p=.23) 이통계적으로유의하게나타났다 (Table 6). 전체직장의 V 1 (%) 은각각평균 5.95, 9.31, 1.62% 이었으며, 치료범위에포함된직장의 D.1cc 및 V 1 (cc) 는각각평균 273.1, 3.6, Gy, 평균 1.93, 2.55, 2.9 cc이었다 (Table 7). RTOG grade 1의급성요로계부작용이나타난경우는 4명 ( 저위험군 18명, 중간위험군 16명, 고위험군 6명 ) 이었으며가장빈번하게나타난증상으로는빈뇨, 배뇨통, 급박뇨, 야간뇨등이었고 RTOG grade 1의만성요로계부작용이나타난경우는저위험군에서 1명있었다. RTOG grade

6 Table 7. Rectal Dosimetry According to Radiation Therapy Oncology Group (RTOG) Grade for Rectal Complication RTOG grade Whole rectum (mean) D 2cc* (Gy) D.1cc (Gy) V 1 (ml) V 1 (%) V 15 (cc) V 15 (%) Dmax (Gy) Involved rectum (mean) D 2cc (Gy) D.1cc (Gy) V 1 (cc) V 1 (%) V 15 (cc) V 15 (%) Acute Chronic complication complication *Minimal dose in the most irradiated 2 ml volume of the rectum, absolute rectal volume receiving at least 1% of the prescribed dose, percentage of rectal volume receiving at least 1% of the prescribed dose. 의급성및만성요로계부작용은각각 3명 ( 중간위험군 ), 4 명 ( 저위험군 1명, 중간위험군 1명, 고위험군 2명 ) 에서있었다. RTOG grade 3의만성요로계부작용은중간위험군 1 명에서있었으며 RTOG grade 4의요로계부작용은없었다 (Table 4). 평균 22.3개월후에요로계증상및직장염이호전되었으며 (6 39개월) 36명에서증상호전을보였고, 요로계자극증상이있을경우알파차단제나항콜린제등의약물로보존적치료를하였으나약물에의한호전양상은명확히관찰되지않았다. 시술전국제전립선증상점수표 (international prostate symptom score, IPSS) 를시행한환자는 12명이었고, 이환자군에서 IPSS 점수와요로계부작용의정도는연관성이발견되지않았다. 급성요로계부작용의 RTOG grade 에영향을미치는요인을분석하였을때 seed 개수 (p=.28) 가유의한영향이있었으며, 전립선부피, 시술전전립선비대증의유무, 시술전호르몬치료여부등이모두유의한차이를나타내지않았다. RTOG grade 1인환자군의평균 seed 개수는 14개, RTOG grade 2인환자군의평균 seed 개수는 123개였다. 만성요로계부작용의 RTOG grade에영향을미치는통계적으로유의한요인은없었다 (Table 8). Table 8. Univariate Analysis of the Parameters for Urologic Complication Variables Dmax* of bladder (Gy) Prostate volume (cc) Seed no. Needle no. NAH BPH Acute p-value Chronic *Maximum dose, neoadjuvant hormone therapy, benign prostate hypertrophy. 고안및결론 본연구는최소 2년의단기추적관찰기간동안영구적근접치료의성적에대해알아보고자하였다. National Comprehensive Cancer Network (NCCN) 권고안에서는저위험군환자에서는방사선치료단독 ( 외부방사선치료단독또는근접치료단독 ) 또는수술단독요법을권고하고있으며, 중간위험군환자에서는수술단독, 또는외부방사선치료를기본으로호르몬치료나근접치료를선택적으로시행할것을권고하고있다. 고위험군환자에서는수술단독또는외부방사선치료와장기간호르몬치료를병행하는것, 외부방사선치료와근접치료를병행하고단기호르몬치료의선택적시행, 또는호르몬치료단독을권고하고있다. 또한외부방사선치료후재발하였을경우전립선적출술, 저온수술, 근접치료등을시행할것을권고하고있다. 그러나 Potters 등 11) 은 T2c 이하인모든위험군의환자를대상으로근접치료후생화학적재발과관련된인자를조사한연구에서 D 9 으로대표되는삽입의적절성이가장중요한인자라고보고하였으며, 호르몬치료나외부방사선치료의추가가재발률에영향을미치지않았다고보고하였다. Blasko 등 12) 은근접치료단독군과외부방사선치료병용군에서생화학적조절률을비교한연구에서저위험군의기준을 T1-T2, Gleason score 2 6점, PSA 1 ng/ml 이하의기준을모두충족시키는경우로정의하였으며, T3, Gleason score 7 1점, PSA>1 ng/ml 중한가지인자를충족시키는경우를중간위험군, 두가지이상충족시키는경우를고위험군으로정의하였다. 중앙값 58개월의추적관찰기간의생화학적조절률은근접치료단독군과외부방사선치료병용군에서저위험군은각각 94%, 87% 이었으며중간위험군에서는 84%, 85%, 고위험군에서는 54%, 62% 로유

7 박혜리외 6 인 : 국소전립선암의영구적근접치료 : 조기결과 의한차이가없었다고보고하였다. Lee 등 13) 이근접치료단독으로치료한환자들을대상으로시행한연구에서는 PSA 1 2 ng/ml, Gleason score 7, T2b 중한가지조건을충족시킬때를중간위험군, 두가지이상의조건을충족시킬경우와 PSA>2 ng/ml, Gleason score 8 1점, T2c-T3을한가지이상충족시킬때를고위험군으로정의하였다. 호르몬치료를시행받은환자에서 D 9 이 14 Gy 이상일경우 4년간생화학적조절율은중간위험군에서 94%, 고위험군에서 77% 로보고하였으며, 호르몬치료를시행받지않은중간위험군및고위험군환자에서 5년간생화학적조절률은 D 9 이 14 Gy 이상일경우 81%, 14 Gy 이하인경우 38% 로보고하였다. Dosoretz 등 14) 은 73세이상의환자군에서는근접치료단독군보다호르몬치료병행군에서사망률이더높았다고보고하고있다. 반면 D Amico 등 15) 은고위험군환자를대상으로근접치료를단독시행하였을경우와근접치료에호르몬치료나외부방사선치료중한가지또는두가지모두를병행하였을경우에서의사망률을비교한연구에서세가지치료방법을모두사용한경우근접치료단독치료에비해유의한사망률의감소를가지고왔다고보고하였으며, Hoffman 등 16) 도고령의고위험군환자에서근접치료단독군보다근접치료, 외부방사선치료, 호르몬치료를모두병행한환자군의사망률이유의하게낮았다고보고하였다. 국소전립선암의적절한치료방법에대해서는환자의상태나연구에따라다양한결과들이보고되고있으며, 중간위험군과고위험군환자에서근접치료단독치료의역할은아직명확하게밝혀지지않았다. 17) 본원에서는저위험군환자뿐아니라중간위험군과고위험군환자중에서도외부방사선치료를거부하거나고위험군의조건중한가지만을충족시키는경우근접치료와호르몬치료를병행하였으며단기간추적관찰결과 4.7% 의낮은생화학적재발률을보였다. 그러나현재최소추적관찰기간이 2년에불과하므로추후장기추적관찰이필요하다고생각한다. 미국근접치료협회 (American Brachytherapy Society, ABS) 의근접치료선량에대한권고안에서는근접치료후시행한선량측정에서 D 9 이처방선량이상이되는것을적절한삽입을판단하는척도로제시하고있으며, 18) 근접치료후시행한 CT로측정한 D 9<14 Gy일때 PSA 제어율은 68% 이며 D 9 14 Gy일경우 92% 이라고보고하였다. 19) Chauveinc 등 2) 은 45명의환자를대상으로조사하였을때시술중초음파로측정한 D 9 이 175 Gy 이상, V 1 이 99.95% 이상인경우시술후 CT로선량측정을하였을때 선량분포의적절성이보장되었다고보고하였다. Salembier 등 21) 은 ESTRO/EAU/EORTC 권고안의보충안에서전립선에서각방향으로 3 mm 확장하여계획용표적체적을정한후이부피에대해선량분포를 V 15 5%, V 1 95%, D 9> 1% 의기준을맞추도록권고하고있다. 또한직장선량은 D 2cc<145 Gy, D.1cc (-Dmax)<2 Gy로권고하고있다. 본연구에서는전립선에서부피확장을하지않고선량을측정하였으며, 평균 D 9 은 Gy, 평균 V 1 은 99.2%, 평균 V 15 은 92.4% 으로 V 1 을제외하고기존보고들의권고에비해다소높은선량분포를보였다. 전립선근접치료로인한직장염에대한보고들을살펴보면 RTOG grade 2의후기직장합병증은 %, RTOG grade 3, 4의직장합병증은 <1 8% 로보고되고있다. 22) 그리고직장누공의발생률은초기에발표된보고들에서는 <1% 에서 7% 이었으며평균발생률은 2.6% 로보고되었으나최근에는 1% 의발생률이보고되고있다. 22) Wallner 등 23) 은전립선근접치료의조기결과보고에서직장궤양의발생률에대하여 1% 가량이라고보고하였으나, 근접치료경험이누적된후발표한연구에서는 1% 로감소한발생률을보고하였다. 24) Kleinberg 등 25) 은무증상의직장출혈또는궤양이 47% 에서발생하였으며삽입후 1, 2개월내에배변습관이나양상변화가 25% 에서관찰되었다고보고하였다. 직장부작용이나타나는선량및부피에관한연구들에서 Snyder 등 26) 은처방선량을받는직장벽의부피가 1.3 cm 3 이하일경우 5년내에 grade 2의직장염이생길확률은 5% 미만이며, 1.3 cm 3 이상일경우 18% 이라고보고하였으며, Waterman과 Dicker 27) 는 1 Gy 이상을받는직장표면면적의비율이근접치료후 Grade 2 후기부작용의예측인자라고보고하였다. 또한 1, 15, 2 Gy를대략 3%, 2%, 1% 의직장표면에받을경우 5% 이하의후기부작용을보인다고보고하였으며, 직장최대선량이 15, 2, 25 Gy일때직장염가능성은.4%, 1.2%, 4.7% 라고보고하였다. Albert 등 28) 은 1 Gy 이상을받는직장부피가아르곤플라즈마응고소작술을필요로하는직장출혈의예측인자라고보고하였으며 1 Gy 이상을받는직장부피가 8 cc 이하일경우지혈술이필요한환자는없었으며그이상일경우 3년추적관찰결과 2% 에서필요로하였다고보고하였다. Han과 Wallner 29) 는 9명의방사선직장염환자와 18명의직장염이없는환자군의 1% 처방선량을받는직장의부피를비교한연구에서직장염환자군에서는 2.5 cm 3, 대조군에서는.6 cm 3 이었다고보고하였

8 다 (p<.8). 본연구에서는 43명중 3명의환자에서직장누공이발생하여 7% 의발생률을보였으며, RTOG grade 2의만성직장염이 1명 (23.3%) 에서발생하여최근연구들에비해다소높은발생률을보였다. 또한 RTOG grade 2의만성직장염이발생한환자군의전체직장의 V 1 은평균 9.31%, 4.4 cc, V 15 은평균 3.16%, 1.33 cc이었고 RTOG grade 4의직장염이발생한환자군의전체직장의 V 1 은평균 1.62%, 5. cc, V 15 은평균 3.67%, 1.76 cc로부작용의발생이적었던연구들에비해고선량을받은부피가크게나타났다. 방사선직장염의가능성은직장벽에들어가는선량및부피의증가와연관되어있으므로 8,22) 치료계획시에주변장기선량분포를고려하여선량증가로인한주변장기부작용가능성의증가와국소제어율간에균형을맞추어야할것으로생각된다. 본원에서근접치료시술시전계획을세우는과정에서손상위험장기의선량분포에대한검증을시행하는과정을시행하지않고전립선의선량만을확인하였으나, 경직장초음파영상을바탕으로직장선량을예측하여 seed 삽입위치와개수를조절하는과정이추가되어야할것으로판단된다 (Fig. 2). Fig. 2. Preplan showing change of rectal dose by modification of seed location (A) Intraoperative transrectal ultrasound (TRUS) based preplan. Preplan considered coverage of planning target volume only. (B) Dose volume histogram (DVH). DVH shows high rectal dose. (C) Modified intraoperative TRUS based preplan. Preplan considered rectal dose and coverage of planning target volume. (D) DVH of modified plan. DVH shows reduced rectal dose and similar coverage of target volume. Dots represent the location of seeds

9 박혜리외 6 인 : 국소전립선암의영구적근접치료 : 조기결과 또한 Crook 등 8) 은전립선근접치료후직장선량의보고방법에대한합의는아직이루어지지않았으며, 근접치료에서는등선량곡선의급격한감소 (rapid fall-off) 가나타나기때문에직장내용물을포함한전체직장의선량체적히스토그람과직장벽의선량체적히스토그람은큰차이를보이지않을것으로생각되나직장벽을기준으로하는것이실제직장을가장정확하게반영한다고보고하였다. 본연구에서는전체직장과직장벽의선량체적히스토그람및직장염과의관계를각각알아보았다. 전체직장을대상으로측정하였을때 D.1cc (p=.41) 및 V 15 (cc) (p=.38) 이급성직장부작용의 RTOG grade에통계적으로유의한연관이있었으며, V 1 (%) (p=.11) 가만성직장부작용의 RTOG grade에통계적으로유의한관련이있었다. 치료부위에포함된직장벽을대상으로측정하였을때 V 1 (cc) (p=.47) 및 V 1 (%) (p=.19) 가급성직장부작용의 RTOG grade에통계적으로유의한연관이있었으며, D.1cc (p=.49) 및 V 1 (cc) (p=.23) 이만성직장부작용의 RTOG grade에통계적으로유의하게나타났다. 그러나 D 2cc, D.1cc, V 1 (cc), V 1 (%), V 15 (cc), V 15 (%) 에대하여전체직장및치료범위에포함된직장벽을대상으로측정한값을비교하였을때, V 1 (cc) (p=.), V 1 (%) (p=.), V 15 (%) (p=.) 에서만유의한차이가있었다. 직장부작용에영향을미치는지표는전체직장을대상으로측정할때와직장벽을대상으로측정할때차이가있었다. 그러나통계적으로직장부작용에유의한영향을보였던모든지표에서, 직장을그리는방법에따라서유의한차이가발견되지않았으므로직장을그리는방법에따라직장부작용을예측하기위한적절한지표가달라진다고판단하기는어려울것으로생각된다. 또한유의한지표의개수도전체직장으로측정하였을경우에 3가지, 직장벽으로측정하였을경우에 4가지로직장을그리는방법에따라큰차이가발견되지않았다. 근접치료시직장선량을보고하기위하여직장을그리는적합한방법및직장부작용과유의한관련이있는지표를결정하기위해서는많은수의환자를대상으로한추가적인연구가필요할것으로생각된다. 근접치료의요로계부작용에관한보고들을살펴보면 Smith 등 6) 은방광목의최대선량이요로계부작용과관계가있다고보고하고있으며, Crook 등 3) 은전립선의크기와근접치료전호르몬제사용이급성요폐색과연관이있다고보고하고있다. Merrick 등 31) 은예방적알파차단제사용이요로계부작용을줄이는효과가있다고보고하였다. Merrick 등 32) 은또한외부방사선치료를추가하는것이저 위험군과중간위험군환자에서는이익이없으며, 혈뇨의발생및후기요정체를증가시키고, 발기부전및대장기능을저하시킨다고보고하였다. 본연구에서는방광목의최대선량, 전립선크기, 근접치료전호르몬제사용여부모두요로계부작용의정도에유의한차이를보이지않았으며사용된 seed 개수가급성요로계부작용의정도와연관성을보였다. 반면 Pinkawa 등 33) 은 seed 강도가.65 mci 이하인경우와삽입된 seed의개수가많은경우선량이고루분포하여요로계부작용이감소하였다고보고하였다. Masucci 등 34) 은평균.44±.163 mci와.61±.178 mci의 seed를사용하였을때 seed 강도가높을경우요로계부작용이더많았다고보고하였다. 그외에 Lee 등 35) 은사용된 needle의개수가 33개이상인경우요폐색이오히려증가한다고보고하였다. 기존에보고된연구에서는본연구에서의 seed 강도보다높은강도의 seed를사용하였기때문에낮은강도에서도 seed의개수와강도의차이가요로계부작용에영향을미치는지에대해서는보다많은수의환자를대상으로부작용의양상을조사하여야할필요가있을것으로생각되며이결과가도출되어야근접치료에적합한 seed의강도와개수를정할수있을것으로생각된다. 본연구에서는모든환자가호르몬치료를시행하였다. 외부방사선치료와호르몬치료를병용하였을때생화학적재발률이감소한다고보고되고있으며, 36) 국소진행된전립선암에서외부방사선치료와호르몬치료를병용할경우생화학적재발률이 1% 감소하였다고보고되었다. 37) 그러나 Potters 등 38) 은후향적대응쌍분석에서모든위험군에서근접치료와호르몬치료의병용이근접치료단독과비교하여생화학적재발률에영향을미치지못하였다고보고하였다. 반면에 Merrick 등 32) 은근접치료단독과외부방사선치료병용으로치료받은환자의비율이각각 92.6% 와 7.4% 로구성된고위험군에서호르몬치료가생화학적재발률에유의한연관이있었다고보고하였다. 호르몬치료의추가가근접치료의생화학적조절률에미치는영향에대해서는연구에따라다양한결과들이보고되고있으며, 본연구결과에호르몬치료의추가가영향을주었는지의여부를판단하기위해서는호르몬치료기간및방법에따라많은수의환자군을대상으로한추가적인연구가있어야할것으로생각된다. 본연구는최소추적관찰기간이 2년으로단기간의치료성적이지만 95.3% 의높은생화학적조절률을보였다. 장기간추적관찰을통해치료성적을검증할필요가있으나국소전립선암환자에서근접치료는저위험군환자뿐만

10 아니라중간위험군및고위험군환자에서도선택적으로적용가능한치료방법이라고판단되며환자의신체상태나삶의질에영향을미치는요인들에대한환자의가중치에따라치료방법이결정되어야할것으로생각된다. 또한직장부작용을감소시키기위한노력이병행되어야할것으로생각된다. 참고문헌 1. Marcus DM, Jani AB, Godette K, Rossi PJ. A review of low-dose-rate prostate brachytherapy: techniques and outcomes. J Natl Med Assoc 21;12: Henderson A, Laing RW, Langley SE. Quality of life following treatment for early prostate cancer: does low dose rate (LDR) brachytherapy offer a better outcome? A review. Eur Urol 24;45: Taira AV, Merrick GS, Galbreath RW, Wallner KE, Butler WM. Natural history of clinically staged low- and intermediate-risk prostate cancer treated with monotherapeutic permanent interstitial brachytherapy. Int J Radiat Oncol Biol Phys 21;76: Taira AV, Merrick GS, Butler WM, et al. Long-term outcome for clinically localized prostate cancer treated with permanent interstitial brachytherapy. Int J Radiat Oncol Biol Phys 211;79: Kupelian PA, Elshaikh M, Reddy CA, Zippe C, Klein EA. Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy. J Clin Oncol 22;2: Smith RP, Jones HA, Beriwal S, Gokhale A, Benoit R. Predictors of Urinary Morbidity in Cs-131 Prostate Brachytherapy Implants. Int J Radiat Oncol Biol Phys Sep 3 [Epub]. DOI:1.116/j.ijrobp Ferrer M, Suárez JF, Guedea F, et al. Health-related quality of life 2 years after treatment with radical prostatectomy, prostate brachytherapy, or external beam radiotherapy in patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 28;72: Crook JM, Potters L, Stock RG, Zelefsky MJ. Critical organ dosimetry in permanent seed prostate brachytherapy: defining the organs at risk. Brachytherapy 25;4: Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 26;65: Kuban DA, Levy LB, Potters L, et al. Comparison of biochemical failure definitions for permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 26;65: Potters L, Huang D, Calugaru E, Fearn P, Lee L, Kattan MW. Importance of implant dosimetry for patients undergoing prostate brachytherapy. Urology 23;62: Blasko JC, Grimm PD, Sylsvester JE, Cavanagh W. The role of external beam radiotherapy with I-125/Pd-13 brachytherapy for prostate carcinoma. Radiother Oncol 2;57: Lee LN, Stock RG, Stone NN. Role of hormonal therapy in the management of intermediate- to high-risk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Biol Phys 22;52: Dosoretz AM, Chen MH, Salenius SA, et al. Mortality in men with localized prostate cancer treated with brachytherapy with or without neoadjuvant hormone therapy. Cancer 21; 116: D'Amico AV, Moran BJ, Braccioforte MH, et al. Risk of death from prostate cancer after brachytherapy alone or with radiation, androgen suppression therapy, or both in men with high-risk disease. J Clin Oncol 29;27: Hoffman KE, Chen MH, Moran BJ, et al. Prostate cancer-specific mortality and the extent of therapy in healthy elderly men with high-risk prostate cancer. Cancer 21;116: Expert Panel on Radiation Oncology-Prostate, Frank SJ, Arterbery VE, et al. American College of Radiology appropriateness criteria permanent source brachytherapy for prostate cancer. Brachytherapy Apr 16 [Epub]. DOI: 1.116/j.brachy Nag S, Beyer D, Friedland J, Grimm P, Nath R. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44: Nag S, Bice W, DeWyngaert K, Prestidge B, Stock R, Yu Y. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2;46: Chauveinc L, Flam T, Solignac S, et al. Prostate cancer brachytherapy: is real-time ultrasound-based dosimetry predictive of subsequent CT-based dose distribution calculation? A study of 45 patients by the Institut Curie/Hospital Cochin (Paris) Group. Int J Radiat Oncol Biol Phys 24;59: Salembier C, Lavagnini P, Nickers P, et al. Tumour and target volumes in permanent prostate brachytherapy: a supplement to the ESTRO/EAU/EORTC recommendations on prostate brachytherapy. Radiother Oncol 27;83: Phan J, Swanson DA, Levy LB, Kudchadker RJ, Bruno TL, Frank SJ. Late rectal complications after prostate brachytherapy for localized prostate cancer: incidence and management. Cancer 29;115: Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996;14: Willins J, Wallner K. CT-based dosimetry for transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1997;39: Kleinberg L, Wallner K, Roy J, et al. Treatment-related - 8 -

11 박혜리외 6 인 : 국소전립선암의영구적근접치료 : 조기결과 symptoms during the first year following transperineal 125I prostate implantation. Int J Radiat Oncol Biol Phys 1994;28: Snyder KM, Stock RG, Hong SM, Lo YC, Stone NN. Defining the risk of developing grade 2 proctitis following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 21;5: Waterman FM, Dicker AP. Probability of late rectal morbidity in 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys 23;55: Albert M, Song JS, Schultz D, et al. Defining the rectal dose constraint for permanent radioactive seed implantation of the prostate. Urol Oncol 28;26: Han BH, Wallner KE. Dosimetric and radiographic correlates to prostate brachytherapy-related rectal complications. Int J Cancer 21;96: Crook J, McLean M, Catton C, Yeung I, Tsihlias J, Pintilie M. Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation. Int J Radiat Oncol Biol Phys 22;52: Merrick GS, Butler WM, Wallner KE, Lief JH, Galbreath RW. Prophylactic versus therapeutic alpha-blockers after permanent prostate brachytherapy. Urology 22;6: Merrick GS, Butler WM, Wallner KE, et al. Impact of supplemental external beam radiotherapy and/or androgen deprivation therapy on biochemical outcome after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 25; 61: Pinkawa M, Fischedick K, Piroth MD, et al. Healthrelated quality of life after permanent interstitial brachytherapy for prostate cancer: correlation with postimplant CT scan parameters. Strahlenther Onkol 26;182: Masucci GL, Donath D, Tetreault-Laflamme A, et al. Comparison between high and low source activity seeds for I-125 permanent seed prostate brachytherapy. Int J Radiat Oncol Biol Phys 21;78: Lee N, Wuu CS, Brody R, et al. Factors predicting for postimplantation urinary retention after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2;48: Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 26;(4):CD Bria E, Cuppone F, Giannarelli D, et al. Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer? Meta-analysis of randomized trials. Cancer 29;115: Potters L, Torre T, Ashley R, Leibel S. Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2;18:

12 Abstract Permanent Brachytherapy of Localized Prostate Cancer: Preliminary Results Hyeli Park, M.D., Sei Kyung Chang, M.D., Jayoung Kim, M.D., Bo Mi Lee, M.D., Seong Young Ko, B.S., Sung Joon Kim, M.S., and Hyun Soo Shin, M.D. Department of Radiation Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea Purpose: To evaluate the biochemical control rate and the rate of side effects after performing permanent brachytherapy of localized prostate cancer. Materials and Methods: 67 patients with localized prostate cancer were treated with brachytherapy between April 27 and December 28. Of these, 43 patients who were followed up and did not receive external radiotherapy were evaluated for the change in prostate specific antigen (PSA) level and the occurrence of side effects. In total, 18 patients were classified as low risk, 19 patients as intermediate risk, and 6 patients as high risk. The prescription dose was 145 Gy. Results: A PSA increase greater than 2 ng/ml occurred in 2 patients (4.7%). Radiation Therapy Oncology Group (RTOG) grade 1 and 2 acute urologic complications (UC) occurred in 4 and 3 patients, respectively. Further, 5 patients had RTOG grade 1 acute rectal complication (RC). The numbers of RTOG grade 1, 2, and 3 chronic UC were 1, 4, and 1, respectively. The numbers of RTOG grade 1, 2, and 4 chronic RC were 5, 1, and 3, respectively. The statistically significant risk factors (RF) of acute RC were the minimal dose in the most irradiated.1 cc volume (D.1CC, p=.41) and absolute volume receiving 15% of the prescribed dose (V 15cc, p=.38) in the entire rectum (ER). The percentage (V 1%, p=.19) and absolute volume (V 1cc, p=.47) in the involved rectum (IR) were also statistically significant. The RF of chronic RC were V 1% (p=.11) in the ER and the D.1cc (p=.49), V 1cc (p=.23) in the IR. The number of used seeds were related with acute UC (p=.28). Conclusion: Permanent brachytherpy of localized prostate cancer showed a favorable short term biochemical control rate. As such, selective intermediate and high risk patients can be managed with permanent brachytherapy. The effort to reduce rectal complication is also necessary. Key Words: Prostate neoplasms, Brachytherapy

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