DOI: 10.3857/jkstro.2011.29.1.11 직장암의수술전항암화학방사선치료후병리학및임상적효과분석 가톨릭대학교의과대학서울성모병원방사선종양학교실 *, 종양내과학교실, 대항병원외과, 병리과 송진호 * ㆍ장홍석 * ㆍ김연실 * ㆍ정수미 * ㆍ손석현 * ㆍ강진형 ㆍ육의곤 ㆍ이두석 ㆍ이숙희 ㆍ윤세철 * 목적 : 수술전항함화학방사선치료는국소진행된직장암에서표준치료로알려져있다. 이연구는동시항암화학방사선치료를받은국소진행된직장암환자의생존율및병기하향률에영향을미치는인자들을분석하였다. 대상및방법 : 2004 년 3 월부터 2008 년 8 월까지수술전항암화학방사선치료를받은국소진행된직장암환자 33 명을대상으로하였다. 모든환자는전골반방사선조사를시행하였으며, 28 명 (84.8%) 은동시적소조사야추가방사선치료, 5 명 (15.2%) 은조사영역축소방사선치료를실시하였다. 총방사선량은 50.4 Gy 이었으며, 5-fluorouracil 를동시투여하였다. 추적관찰기간은중앙값 24.2 개월 (9.8 64.7 개월 ) 이었다. 결과 : 33 명중 31 명 (93.9%) 에서수술이시행되었으며, 24 명 (72.7%) 은항문괄약근보존술, 7 명 (21.2%) 은복회음부절제술이시행되었다. 3 년생존율과무병생존율은각각 78.8%, 63.4% 이었다. 무병생존율에영향을미치는인자로수술후병리학적소견이중요하였다. 병리학적 N 병기 (p=0.001), 절제면침윤여부 (p=0.029) 및분화도 (p=0.030) 가통계학적으로의미있게영향을미치는인자였다. 종양크기 (p=0.081), 림프혈관과신경주위침윤여부 (p=0.073) 모두영향을미치는인자로서의경향성을보였다. 한편, 수술전임상소견으로는임상적 T 병기만이유의한결과를보였다 (p=0.018). 병리학적완전관해율은 9.1% 였으며, T 병기하향률은 30.3%, N 병기하향률은 72.7% 로나타났다. 단변량분석에서항암화학방사선치료후수술까지의기간및임상적 T 병기가의미있는병기하향의예측인자로분석되었다 (p=0.029, 0.027). 치료전 carcinoembryonic antigen 수치는예측인자의경향성을보였다 (p=0.068). 결론 : 국소진행된직장암환자의생존율은임상적병기보다수술후병리학적소견에더의존되었다. 그러므로수술전항암화학방사선치료로병기하향을얻는것이의미가있으며, 수술까지의기간, 임상적 T 병기가이러한병기하향을예측하는인자였음을알수있었다. 핵심용어 : 직장암, 수술전항암화학방사선치료, 동시적소조사야추가방사선치료 서 대장직장암은국내에서남녀전체암발생중위암에이어 2위를차지하고있으며, 세계적으로도 4번째로흔한종양으로매년 80만명의새로운환자들이전세계에서발생하는것으로알려져있다. 1,2) 그중직장암은전체대장직장암의 1/3을차지한다. 1) 국소진행된직장암의치료에서 Sauer 등 3) 은수술전과수술후항암화학방사선치료를비 이논문은 2010 년 12 월 7 일접수하여 2011 년 1 월 13 일채택되었음. 책임저자 : 윤세철, 가톨릭대학교의과대학서울성모병원방사선종양학교실 Tel: 02)2258-1501, Fax: 02)2258-1532 E-mail: scyoon@catholic.ac.kr 이논문의일부는 2009 년대한방사선종양학회추계학술대회에서발표하였음. 론 교한대규모무작위전향적연구를시행하여수술전항암화학방사선치료가수술후치료에비해국소종양제어율및항문괄약근보존율을높이고생존율에는차이가없었음을보고하였다. 그이후로국소진행된직장암에서수술전항암화학방사선치료는한표준치료로인정되고있다. 4 6) 이러한치료의성적을결정하는인자로항암화학방사선치료후의병기하향률과병리학적관해정도등종양의반응이중요한것으로알려져있으며, 7 9) 새로운방사선치료및항암제의도입으로이러한성적을개선시키고자하는수많은노력들이진행되고있다. 10 13) 또한, 이러한항암화학방사선치료후종양의반응을예측할수있는임상적인자들을찾으려는연구들도진행되고있다. 14 16) 이연구는본과에서직장암으로진단되어치료받은환자중수술전항암화학방사선치료를시행한환자를대상으로생존율및병기하향률을분석하고치료결과에영향 - 11 -
Table 1. Patient and Tumor Characteristics Characteristics No. (%) Gender Male Female Age (yr) Range (median) Clinical T stage T2 T3 T4 Clinical N stage N0 N1 N2 Histology Adenocarcinoma Mucinous adenocarcinoma Differentiation Well differentiated Moderate to poorly differentiated Unknown Distance from anal verge (cm) 3 <3 Tumor size (cm) 5 <5 Pre-treatment CEA* (ng/ml) 3.0 <3.0 *carcinoembryogenic antigen. 을미치는예후인자를분석하고자하였다. 대상및방법 1. 대상환자및치료전평가 27 (81.8) 6 (18.2) 36 72 (54) 1 (3.0) 29 (87.9) 3 (9.1) 2 (6.1) 16 (48.5) 15 (45.5) 30 (90.9) 3 (9.1) 10 (30.3) 11 (33.3) 12 (36.4) 24 (72.7) 9 (27.3) 13 (39.5) 20 (60.6) 16 (48.5) 17 (51.5) 2004년 3월부터 2008년 8월까지, 가톨릭대학교서울성모병원방사선종양학과에서직장암으로수술전항암화학방사선치료를시행하였던총 33명의환자를대상으로후향적분석을시행하였다. 모든환자는원격전이가없는조직학적으로확진된국소진행된직장암환자였으며, 종양의위치는항문피부선 (anal verge) 에서 12 cm 이내의환자만을대상으로하였다. 모든환자는수술전동시항암화학방사선치료를시행받았다 (Table 1). 또한, 모든환자에서진단시직장수지검사를포함한이학적검사, carcinoembryogenic antigen (CEA) 를포함한혈액검사, 직장내시경, 골반자기공명영상을시행하였고, 필요시골반전산화단층촬영및경직장초음파검사, 양전자단층촬영등을시행하였다. 병기는 American Joint Commission on Cancer (AJCC) 2002년의병기를이용하여정하였다. 2. 방사선치료방사선치료는골반고정장치를사용하여엎드린자세로 3차원입체조형치료를위해전산화단층모의치료 (CT simulation) 를시행하였다. 육안적종양체적 (GTV) 은직장의원발종양과임상적으로전이가의심되는 CT 혹은 MRI에서 1 cm 크기이상의림프절을포함하였고, 임상표적체적 (CTV) 은 GTV와직장주위림프절, 천골전방및내장골림프절을포함하여정의하였다. 계획용표적체적 (PTV) 은임상표적체적에서 1.5 cm 여유를포함하여정의하였다. 대부분의환자에서전골반방사선조사영역은위쪽으로는 5번요추체하연, 아래쪽으로는육안적종양체적에서 3 cm 여유를두었고, 4문조사 (box technique) 방법을사용하였다. 종양부위의추가조사영역은육안적종양체적을포함하여모든방향으로 2 cm 여유를두어, 역시 4문조사방법을사용하였고, 두가지방사선요법을사용하였다. 대한방사선종양학임상연구회프로토콜 04-01 (Korean Radiation Oncology Group, KROG 04-01) 에의한동시적소조사야추가요법 (small field concomitant boost technique) 으로 10) 치료를시행한환자는전체환자중 28명 (84.8%) 이었다. 전골반강에일일분할선량 1.8 Gy씩 24회, 총 43.2 Gy 를조사하고, 이의후반부 12회는육안적종양체적에만분할선량 0.6 Gy씩총 7.2 Gy를동시적으로추가조사하여결국육안적종양체적에는 50.4 Gy/24회, 임상표적체적에는 43.2 Gy/24회를조사하였다. 나머지 5명 (15.2%) 은전골반강에역시일일분할선량 1.8 Gy씩 25회, 총 45 Gy를조사하고, 조사영역축소요법 (cone down technique) 으로연이어서 3회에걸쳐육안적종양체적에만일일 1.8 Gy씩총 5.4 Gy를추가조사하여, 육안적종양체적에는 50.4 Gy/28회, 임상표적체적에는 45.0 Gy/25회를조사하였다. 3. 항암화학요법및수술치료항암화학요법은 5-fluorouracil (5-FU; 400 500 mg/m 2 / day) 와 leucovorin (20 mg/m 2 /day) 을사용하였으며, 24명 (72.7%) 은방사선치료제1주및 5주째에 5일동안일시 (bolus) 에투여하는방법을, 9명 (27.3%) 은방사선치료전기간동안에지속적으로투여하는방법을이용하였다. 수술은환자의거부로시행하지못한 2명을제외하고모든환자에서근치적목적으로시행되었으며, 항암화학방사선치료종료후 4 8주사이에시행하려하였으나, 실제로 - 12 -
송진호외 9 인 : 직장암의수술전항암화학방사선치료의효과 Table 2. Treatment Characteristics Characteristics No. (%) RT* method Concomitant boost Cone down RT duration (day) 35 <35 Interval between CCRT and surgery (wk) 8 <8 Chemotherapy method Bolus LF Protracted 5-FU Infusion Adjuvant chemotherapy LF FOLFOX Oral 5-FU only No adjuvant chemotherapy Unknown Surgery Refuse LAR LATA** APR 28 (84.8) 5 (15.2) 13 (39.4) 20 (60.6) 18 (54.5) 13 (39.4) 24 (72.7) 9 (27.3) 21 (63.6) 2 (6.1) 5 (15.2) 1 (3.0) 4 (12.1) 2 (6.1) 21 (63.7) 3 (9.1) 7 (21.2) *radiotherapy, concurrent chemoradiotherapy, leucovorin fluorouracil, fluorouracil, oxaliplatin fluorouracil leucovorin, low anterior resection, **laparoscopic abdominal transanal procto-sigmodectomy and coloanal anastomosis, abdominoperineal resection. 8주이내에수술이시행된경우는 16명 (48.5%) 에불과하였으며, 수술까지기간의중앙값은 8.3주 ( 범위, 4.1 44.0주 ) 이었다. 21명 (63.7%) 은저위전방절제술, 3명 (9.1%) 은복강경을이용한항문괄약근보존술중하나인복강경경복경항문직장에스결장절제술및결장항문문합술 (laparoscopic abdominal transanal procto-sigmodectomy and coloanal anastomosis, LATA), 7명은복회음부절제술을시행하였다. 수술후항암화학요법은수술 3 6주경과후에병리학적소견및환자상태에따라투여여부를달리하였으며, 투여된항암제종류와용량이다양하였다. 28명 (84.8%) 이수술후항암화학요법을시행받았다 (Table 2). 4. 추적관찰및통계학적분석 추적관찰은수술후 2년간적어도매 6개월마다문진과이학적검사, 종양표지자검사, 혈액검사, 흉부 X-선검사, 복부골반전산화단층촬영을시행하였으며필요시양전자단층촬영, 대장내시경등을시행하였다. 종양의크기는수술전자기공명영상을사용하여종양의길이를측정하였으며, T 및 N 병기하향률은수술전자기공명영상과수술 후조직학적소견을비교하여산출하였다. 생존율과무병생존율은조직학적으로진단된일로부터산출하였으며, Kaplan-Meier 방법을사용하였다. 단변량분석은 log-rank test, 다변량분석은 Cox 비례위험모델을사용하였다. 범주형변수간상관관계분석은 chi-square 검사또는 Fisher s exact 검사로분석하였다. 이러한통계학적분석에는 SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 결과 1. 환자의특성대상환자의연령은 36 72세 ( 중앙값, 54세 ) 였고, 남자환자들이대다수였다 ( 남 : 여 =27 : 6). 원발종양의위치는 24 명 (72.7%) 에서항문피부선에서 3 cm 상부에있었으며, 수술전종양의크기는 13명 (39.4%) 에서 5 cm 이상이었다. 임상적병기 ct3는 29명 (87.9%) 이었으며, ct4는 3명 (9.1%) 이었다. 임상적병기 ct2환자 1명도포함되었는데, CT와 MRI 모두에서 cn1 소견을보였다. N 병기는각각 cn0 2명 (6.1%), cn1 16명 (48.5%), cn2 15명 (45.5%) 이었다. 대상환자모두선암이었으며, 이중 3명 (9.1%) 은점액성선암이었다. 조직학적분화도는 21명 (63.6%) 에서확인되었고그중고분화선암이 10명 (30.3%) 이었다. 치료시작전 CEA수치는평균 10.5 ng/ml ( 범위, 0.5 15.4 ng/ml) 이었으며, 16명 (48.5%) 은 3 ng/ml 이상이었다 (Table 1). 2. 치료방법의특성방사선치료의총기간은중앙값 33일 ( 범위, 31 58일 ) 이었다. 전골반방사선조사와동시적소조사야추가방사선치료 (KROG04-01) 를시행한 28명의치료기간은 32일로전골반방사선조사와조사영역축소방사선치료를시행한 5명의 41일보다의미있게짧았다 (p=0.005). 수술적치료는총 23명 (69.7%) 의환자에서항문괄약근보존술을시행할수있었다. 복회음부절제술을시행받은 7 명 (21.2%) 의원발종양위치는항문피부선에서평균 3 cm 였으며, 항문괄약근보존술을시행할수있었던환자의평균 4.5 cm에비해더낮았으나, 원발종양의크기는항문보존수술에통계학적으로의미있는영향을주지는않았다 (Table 1, 2). 3. 생존율과재발률추적관찰기간 ( 범위, 9.8 64.7개월 ; 중앙값, 24.2개월 ) 동안에재발은총 9명 (27.3%) 에서발생하였다. 7명은골반내국소림프절 (lcogoregional) 에재발하였고, 그중한명은간 - 13 -
Fig. 1. The overall survival curve of all patients. The 3 years overall survival rate was 78.8%. Fig. 2. The disease free survival curve of all patients. The 3 years disease free survival rate was 63.4%. 의원격전이를동반하였다. 두명은국소림프절전이없이원격전이로만재발하였는데, 한명은폐에다른한명은대동맥주위림프절에재발하였다. 전체환자의 3년생존율및무병생존율은각각 78.8%, 63.4% 이었다 (Fig. 1, 2). 무병생존율에영향을미치는예후인자를수술전과수술후인자로나누어서분석할때, 수술전인자로는임상적 T 병기만이무병생존율에영향을미쳤으나 (p=0.018) 수술후인자는병리학적 N 병기 (p= 0.001), 절제면침윤여부 (p=0.029), 종양분화도 (p=0.030) 가의미있는인자였다. 또한, 종양크기 (p=0.081) 및혈관과신경주위침윤여부 (p=0.073) 는영향을미치는인자로서의경향 (marginal significance) 을보였다. 그러나방사선치료방법에따른차이는없었다 (p=0.343) (Table 3). 4. 병기하향률과종양반응수술후병리학적완전관해율은 9.1% (3/33) 이었다. T 병기하향률과 N 병기하향률은각각 30.3% (10/33), 72.7% (24/33) 이었다. 이러한병기하향률에영향을미치는인자를각각분석한결과, 완전관해율에영향을미치는의미있는인자는없었다. 치료전 CEA 수치만이 3.0 ng/ml를기준으로완전관해율에영향을미치는경향을보여주었다 (p= 0.068). T 병기하향에는임상적 T 병기 (p=0.027) 와항암화학방사선치료종료후수술까지의기간 (p=0.029) 이의미있는영향을보였는데, 그기간이 8주이상인경우 T병기하향률이하락하였다. N 병기하향률을예측할수있는인자는찾지못하였다. 이러한모든종양의반응에방사선치료혹은항암치료의방법은영향을주지못하였다 (Table 4). 고안및결론국소진행된직장암은수십년동안많은치료방법의발전이있었다. 근치적절제술을시행하더라도 5년생존율이 50% 이하였으며, 국소재발률도높은편이었다. 따라서수술전, 후에다양한보조요법을추가하는연구들이진행되었다. 17,18) 수술전방사선치료는수술후요법에비해산소공급이좋은상태에서방사선조사가되므로방사선생물학적으로효율성이높고, 병기를하향시켜절제율을높이며, 수술후골반내에소장이고정되는경우가적어소장에대한부작용이적은장점이있어유럽에서많이이용되어왔다. 19 22) 수술전총 25 Gy의소분할조사방사선치료를시행한군과수술단독군을비교한 Swedish study에서국소재발률은 27% 에서 11% 로감소되고, 5년생존율은 48% 에서 58% 로증가하였다. 19) Stockholm II trial에서도수술전소분할방사선치료를시행한군에서국소재발률이절반이상감소하였고, 수술전방사선치료와함께근치적절제술을받은환자군은생존율도함께증가하였다. 20) Camma 등 21) 이시행한메타분석에서도수술전방사선치료가수술단독에비해국소재발과생존율에서의미있게좋은결과를보여주었다. 이후에는수술전보조요법으로방사선치료단독이아닌동시적항암화학방사선치료를시행하여더높은국소제어율과생존율을얻고자하는연구들이진행되었다. 3,4,22,23) EORTC 22921 연구에서는국소재발률은 9% 와 17%, 완전관해율은 14% 와 5% 로항암병용군이더좋은결과를보고하였다. 4,23) FFCD 9203 연구에서도수술전방사선요법에항암화학요법을더하는것이급성독성은증가하였지만, 국 - 14 -
Table 3. Prognostic Factors Affecting 3-yr Disease Free Survival (DFS) 송진호외 9 인 : 직장암의수술전항암화학방사선치료의효과 Variables DFS (%) p-value Variables DFS (%) p-value Age (yr) 60 <60 Pre T stage T3 T4 Pre N stage N0 or N1 N2 Distance from anal verge (cm) 3 <3 Tumor size (preoperative, cm) 5 <5 Pre-treatment CEA* level (ng/ml) 3.0 <3.0 RT method Concomitant boost Cone down RT duration (day) 35 <35 68.6 61.8 67.8 33.3 83.3 40.2 73.3 44.4 33.0 73.6 62.9 63.4 61.1 100.0 69.2 61.9 0.407 0.018 0.073 0.251 0.279 0.545 0.343 0.618 Post T stage T2 T3 or T4 Post N stage N0 N1 or N2 Histologic grade (post-operative) Well Moderate to Margin involvement Yes No Tumor size (post-operative, cm) 5 <5 Lymphovascular or perineural invasion Yes No Adjuvant chemotherapy LF or FOLFOX Oral 5-FU Interval between CCRT and surgery (wk) 8 <8 100.0 60.7 85.7 28.1 85.7 62.7 27.8 73.9 0.0 77.4 31.1 82.0 66.1 66.7 64.6 90.9 0.105 0.001 0.030 0.029 0.081 0.073 0.506 0.376 *carcinoembryogenic antigen, radiotherapy, leucovorin fluorouracil, oxaliplatin fluorouracil leucovorin, fluorouracil, concurrent chemoradiotherapy. Table 4. Predictors of Tumor Response (Represented in p-value) Variables Pathologic complete response T down staging N down staging Age <60 yr Sex, male Differentiation, well Location 3 cm, anal verge Length 5 cm Pretreatment CEA* 3.0 ng/ml Post CCRT CEA 3.0 ng/ml Pre T stage Pre N stage RT method RT duration 35 days CCRT to surgery period 8 wk 0.488 0.881 0.156 0.121 0.068 0.259 0.551 0.098 0.422 0.558 0.717 0.591 0.713 0.880 0.439 0.278 0.027 0.709 0.296 0.373 0.029 0.173 0.483 0.822 0.241 0.415 0.666 0.635 0.639 0.889 0.880 *carcinoembryogenic antigen, concurrent chemoradiotherapy, radiotherapy. 소재발률 8.1% 와 16.5%, 완전관해율 14.6% 와 2.7% 로각각우월한결과를보여주었다. 22) 이러한수술전동시적항암화학방사선요법은수술후동일요법과비교했을때에도독성은비교적적으면서높은항문괄약근보존율과국소제어율을보인다는연구들이발표되면서, 표준치료로권고되고있다. 3 6) 이러한치료방법의발전으로국소진행된직장암에서수술전항암화학방사선치료의치료성적은 5년생존율이대략 65 76%, 5년무병생존율은 56 74% 로향상되었고, 3,4,9,16,22 24) 본원의연구에서는추적관찰기간이짧아 5 년생존율은구할수없었지만, 3년생존율과무병생존율이각각 78.8%, 63.4% 로향후추적기간이길어질경우비 - 15 -
슷한결과가예상된다. 이러한치료성적을좌우하는중요한인자들로치료후의병리학적소견이중요함은잘알려져있다. Chan 등 25) 은 128명의동시항암화학방사선치료후수술을시행한직장암환자에서병리학적 TNM병기, 병리학적 T 병기와 N 병기, 림프혈관침범및신경주위침윤여부가생존율에영향을미치며, 그중병리학적 TNM 병기가가장중요한예후인자라하였다. Capirci 등 26) 은 566명의완전관해가이루어진환자들을추적관찰한결과, 국소림프절재발률을 1.6%, 5년생존율과무병생존율을각각 90%, 85% 로보고하였다. 본연구에서도재발및생존율에영향을미치는인자로항암화학방사선치료전의임상적병기보다는수술후의병리학적소견이중요함을알수있었다. 특히수술후병리학적 N 병기 (p=0.001), 절제면침윤여부 (p=0.029), 종양분화도 (p=0.030) 가의미있는인자였으며, 종양크기 (p=0.081), 림프혈관신경침윤여부 (p=0.073) 등도영향을미치는인자로서의경향성을보였다. 이들중병리학적 N 병기, 절제면침윤여부, 종양크기, 림프혈관신경침윤여부등은항암화학방사선치료후종양의반응성이더좋아진다면개선할수있는소견들이다. 따라서종양의반응을향상시키기위한연구와종양반응을예측할수있는인자들을밝히려는시도가중요하다고본다. 종양의반응을향상시키기위해방사선치료나항암화학요법의개선을위한연구들이진행되고있다. 10,24,27 29) 방사선치료의방법에대한연구로 Lyon R96-02 trial에서는항암제를병용하지는않았지만, 39 Gy/13회외부방사선치료만시행한군과 39 Gy/13회외부방사선치료후관내접촉 X-선을이용한근접치료를시행하여추가방사선치료 (85 Gy/3회 ) 를시행한군을비교하여, 향상된종양반응과항문보존율을보고하기도하였다. 24) Berger 등 28) 은수술전방사선선량이 44 Gy 이상인경우병기하향률이높다고보고하기도하였다. Mohiuddin 등 29) 은완전관해율을높이기위해서는 55 Gy 이상의방사선을조사해야한다고보고하였다. 본연구에서대다수의환자가치료되었던방법인동시적소조사야추가방사선요법 (KROG 04-01) 에서는 T 병기하향률은 41.7%, N 병기하향률은 85.2% 로기존문헌들에비해우월한성적을보여주지는못하였다. 10) 본연구에서도두군의환자수가불균등하여한계점은있지만, 동시적소조사야추가방사선치료총 50.4 Gy를시행한환자와조사영역축소방사선요법총 50.4 Gy를시행한환자간의임상적결과의차이는없었다. 이는소조사야추가방사선요법이총치료기간을단축시키고, BED는 α/β=10 기준으로 2 Gy 가량증가시키지만, 임상적결과에영향을줄 정도의차이는아니었다고생각된다. 수술전동시적항암화학방사선요법시종양반응을향상시키기위하여항암화학요법을강화하는연구들은더욱다양하게진행되고있다. NCCTG 86-47-51연구에서는 5-FU 투여는일시 (bolus) 에투여하는방법보다는지속적 (protracted) 으로투여하는방법이더좋은결과를얻을수있다고보고하였다. 27) 반면, Intergroup 0144 연구에서는두방법간에재발기간과생존율에서차이가없다고하였다. 30) 본연구에서도일시투여와지속적투여두그룹간의의미있는차이는발견하지못하였다. Lee 등 13) 은 5-FU를방사선치료첫주 3일에만급속정주하는경우 ( 비적정군 ), 방사선치료제 1주및 5주째 3일동안급속정주하는경우 ( 적정군 ) 보다수술시항문보존률이더낮은경향성이있음을보고하였다. 5-FU와경구용항암제인 capecitabine을비교한무작위배정 3상임상연구는아직없으나, 대부분대등한혹은 capecitabine 군에서좀더높은완전관해율을보고하고있다. 31,32) 반면, 5-FU혹은 capecitabine에 cisplatin 혹은 oxaliplatin을더하여항암효과를강화시키는연구들은대부분약간의향상된종양반응률을보여주기는했지만독성이증가하여아직은그사용에있어주의가필요하다. 33 35) 종양반응률을향상시키기위한연구와더불어반응률을미리예측할수있는임상적인자들을찾으려는노력들도활발하다. Das 등 14) 은수술전병용요법을시행한결과완전관해율은 19% 로, 종양의둘레범위가 60% 이상인경우완전관해율이낮으며, 종양위치가항문피부선으로부터 5 cm 이상인경우병기하향률이낮다고보고하였다. Lee와 Lee 15) 는종양의둘레범위와종양의길이, 방사선량, 방사선치료기간을종양반응의예측인자로보고하였고, Yoon 등 36) 은치료전헤모글로빈수치, 임상적림프절전이와 CEA 수치를예측인자로보았다. 본연구에서는치료전 CEA 수치가 3.0 ng/ml를기준으로완전관해율을예측해볼수있는경향성을보여주었다 (p=0.068). 반면, T 병기하향에는 8주를기준으로항암화학방사선치료종료후수술까지의기간이의미있는예측인자였다 (p=0.029). 이러한임상적인자들외에도생물학적표지자 (biologic marker) 를예측인자로보고하기도한다. Epidermal growth factor receptor 37) 와 Cyclooxygenase-2 38) 의발현은종양반응을떨어뜨린다고하였다. 본연구에서는매우적은일부의환자에서만생물학적표지자검사가시행되어있어이에대한연구는시행하지못하였다. 결론적으로이번연구를통하여국소진행된직장암에서수술전항암화학방사선치료및수술의성적은주로수술후병리학적결과에의해결정되며, 따라서종양의반 - 16 -
송진호외 9 인 : 직장암의수술전항암화학방사선치료의효과 응을극대화하여최대한병기하향을높이는것이중요함을알수있었다. 치료전임상 T 병기, 항암화학방사선치료종료후수술까지의기간이종양반응을예측해볼수있는인자였으며, 치료전 CEA 수치도예측인자로서의경향성을보여주었다. 소조사야추가방사선요법은통상사용되는조사영역축소방사선요법과대등한임상적결과를보여줌을알수있었다. 참고문헌 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96 2. National Cancer Information Center. Cancer statistics, 2007. Goyang: National Cancer Information Center; [cited 2011 Jan 30]. Available from: http://www.cancer.go.kr/cms/statics/ incidence 3. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740 4. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results-eortc 22921. J Clin Oncol 2005;23:5620-5627 5. National Comprehensive Cancer Network. Clinical practice guidelines in oncology V. 2. 2009: Rectal cancer. 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Preoperative chemoradiotherapy with concomitant small field boost irradiation for locally advanced rectal cancer: a multi-institutional phase II study (KROG 04-01). Dis Colon Rectum 2006;49:1684-1691 11. Saif MW, Hashmi S, Zelterman D, Almhanna K, Kim R. Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer: a retrospective review. Int J Colorectal Dis 2008;23:139-145 12. De Paoli A, Chiara S, Luppi G, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol 2006;17:246-251 13. Lee J, Kang HC, Chie EK, et al. Effect of suboptimal chemotherapy on preoperative chemoradiation in rectal Cancer. J Korean Soc Ther Radiol Oncol 2009;27:78-83 14. Das P, Skibber JM, Rodriguez-Bigas MA, et al. Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer 2007;109:1750-1755 15. Lee J, Lee KJ. Clinical factors predicting the pathologic tumor response after preoperative concurrent chemoradiotherapy for rectal cancer. J Korean Soc Ther Radiol Oncol 2008;26:213-221 16. Choi SG, Kim SS, Bae HS. Results of preoperative concurrent chemoradiotherapy for locally advanced rectal cancer. J Korean Soc Ther Radiol Oncol 2007;25:34-42 17. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988;80:21-29 18. Wolmark N, Wieand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388-396 19. Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336:980-987 20. Martling A, Holm T, Johansson H, Rutqvist LE, Cedermark B; Stockholm Colorectal Cancer Study Group. The Stockholm II trial on preoperative radiotherapy in rectal carcinoma: long-term follow-up of a population-based study. Cancer 2001;92:896-902 21. Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000;284:1008-1015 22. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24:4620-4625 23. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114-1123 24. Gerard JP, Chapet O, Nemoz C, et al. Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96-02 randomized trial. J Clin Oncol 2004;22:2404-2409 25. 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of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypcr patients. Int J Radiat Oncol Biol Phys 2008;72:99-107 27. O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-507 28. Berger C, de Muret A, Garaud P, et al. Preoperative radiotherapy (RT) for rectal cancer: predictive factors of tumor downstaging and residual tumor cell density (RTCD): prognostic implications. Int J Radiat Oncol Biol Phys 1997;37:619-627 29. Mohiuddin M, Regine WF, John WJ, et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys 2000;46:883-888 30. Smalley SR, Benedetti JK, Williamson SK, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006;24:3542-3547 31. Crane CH, Sargent DJ. Substitution of oral fluoropyrimidines for infusional fluorouracil with radiotherapy: how much data do we need? J Clin Oncol 2004;22:2978-2981 32. Saif MW, Hashmi S, Zelterman D, Almhanna K, Kim R. Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer: a retrospective review. Int J Colorectal Dis 2008;23:139-145 33. Gerard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010;28:1638-1644 34. Mehta VK, Cho C, Ford JM, et al. Phase II trial of preoperative 3D conformal radiotherapy, protracted venous infusion 5-fluorouracil, and weekly CPT-11, followed by surgery for ultrasound-staged T3 rectal cancer. Int J Radiat Oncol Biol Phys 2003;55:132-137 35. Glynne-Jones R, Sebag-Montefiore D, Maughan TS, Falk SJ, McDonald AC. A phase I dose escalation study of continuous oral capecitabine in combination with oxaliplatin and pelvic radiation (XELOX-RT) in patients with locally advanced rectal cancer. Ann Oncol 2006;17:50-56 36. Yoon SM, Kim DY, Kim TH, et al. Clinical parameters predicting pathologic tumor response after preoperative chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 2007;69:1167-1172 37. Kim JS, Kim JM, Li S, et al. Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 2006;66: 195-200 38. Smith FM, Reynolds JV, Kay EW, et al. COX-2 overexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy. Int J Radiat Oncol Biol Phys 2006;64:466-472 - 18 -
송진호외 9 인 : 직장암의수술전항암화학방사선치료의효과 Abstract The Pathological and Clinical Effects of Preoperative Chemoradiation in Rectal Cancer Jin-Ho Song, M.D.*, Hong-Seok Jang, M.D.*, Yeon-Sil Kim, M.D.*, Su-Mi Chung, M.D.*, Seok-Hyun Son, M.D.*, Jin-Hyeong Kang, M.D., Eui-Gon Youk, M.D., Doo-Seok Lee, M.D., Suk-Hi Lee, M.D. and Sei-Chul Yoon, M.D.* Departments of * Radiation Oncology and Medical Onocology, Seoul St. Mary s Hospital, The Catholic University of Korea School of Medicine, Departments of Colorectal Surgery and Clinical Pathology, Daehang Hospital, Seoul, Korea Purpose: To evaluate the pathological and clinical effects of preoperative chemoradiation (CCRT) in cases of locally advanced rectal cancer and to determine the predictive factors for tumor downstaging. Materials and Methods: From March 2004 to August 2008, 33 patients with locally advanced rectal cancer were treated with preoperative CCRT. Twenty-eight patients (84.8%) were treated using a concomitant boost technique while five (15.2%) patients were treated using a cone down boost technique. All patients received 50.4 Gy of irradiation and concurrent chemotherapy with 5-fluorouracil. The median follow-up duration was 24.2 months (range, 9.8 to 64.7 months). Results: Thirty-one (93.9%) patients underwent surgery. Twenty-four patients (72.7%) underwent anal sphincter-preserving surgery. The 3-year disease free survival (DFS) and overall survival rates were 63.4% and 78.8%, respectively. Post-operative factors were more important for DFS. Pathologic N stage, margin status, and pathologic differentiation were significant prognostic factors (p=0.001, 0.029, 0.030). Tumor size and lymphovascular invasion were also associated with marginal significance (p=0.081, 0.073). However, only pre-treatment T stage was a significant pre-operative factor (p=0.018). The complete pathological response rate was 9.1%. T-downstaging was observed in ten (30.3%) patients, whereas N-downstaging was found in 24 (72.7%) patients. Pre-treatment T stage and the interval between CCRT and operation were the predictive factors for downstaging in a univariate analysis (p=0.029, 0.027). Pre-treatment carcinoembryogenic antigen was also associated with marginal significance (p=0.068). Conclusion: The survival of rectal cancer patients can be better determined based on post-operative findings. Therefore, pre-operative CCRT for downstaging of the tumor seems to be important. Pre-treatment T stage and the interval between CCRT and operation can be used to predict downstaging. Key Words: Rectal cancer, Preoperative concurrent chemoradiation, Concomitant boost technique - 19 -