J Clin Cancer Res. 2007;1(Suppl. 1):1-4 Session 1 경항문적절제술후 T2 로진단된직장암의치료 연세대학교의과대학외과학교실 이강영 서 론 직장암의치료는다른고형암에서와같이근치적절제를포함한다병합치료방법이적용된다. 직장암의근치적절제술은원발암의절제연을확보한광범위절제와직장간막의절제 (Total or subtotal mesorectal excision) 를포함하는영역림프절곽청술을원칙으로한다 (1,2). 직장암의수술은직장고유근막 (rectal proper fascia) 에손상을주지않고골반내신경을보존하며진행되어야하며수술자의숙련도가직장암환자의합병증뿐아니라생존율에영향을미치는것이보고되어있다 (3,4). 직장암수술은술기의어려움뿐아니라수술후배변과관련된기능장애등으로인하여수술후에많은환자들이불편을호소하기도한다. 또한항문연에가깝게위치한암의경우에는과거보다그시행빈도는많이감소하였지만항문괄약근을포함해서절제하고영구적인장루를조성해야하는복회음절제술을시행하여야한다. 이러한이유로직장암수술을계획할때는암의근치적치료뿐아니라환자의삶의질또한고려되어야한다. 경항문적절제술은항문을통하여직장의원발암을절제하는술기로항문괄약근을보전할수있고수술뒤합병증의빈도도낮은것으로보고되고있다. 하지만직장암에서경항문적절제술은영역림프절절제술을하지않고원발암만절제하는술기이므로근치적절제술과비교하여높은국소재발률및치료실패로인하여조기직장암의치료나환자의전신상태등으로인하여근치적절제술이불가능한환자에서제한적으로적용되고있다. 조기직장암에서경항문적절제술의종양학적안전성에대한결과는시술초기근치적절제술에비교하여견줄만한것으로보고되었었으나 (5,6) 근래에많은보고에서이술기후치료실패율이유의하게높은것으로보고되며제한된적응증을가지고이술기를적용해야한다고보고되고있다. 이에경항문적절제술후 T2병기로진단된암의경우치료에대하여고찰해보고자한다. 경항문적절제술후 T2 병기암은무엇이문제인가? 경항문적절제술은직장벽의원발암을제거하는술기로전직장층을안전절제연을확보하며절제하지만림프절곽청을할수없는술기이다. 따라서림프절전이가동반된직장암에서경항문적절제술만을시행한다면잔존암으로인하여치료에실패하게된다. 이러한이유로근치적치료를계획하는경 S1
J Clin Cancer Res. 2007;1(Suppl. 1) 우경항문적절제술은조기암에서제한적으로시행되며절제된조직에대하여도림프절전이가능성을예측하기위하여세밀한조직병리검사가요구된다. 조직병리검사상심부점막하층 (SM3) 이상의암침윤 (7,8), 분화도가나쁜경우 (G3 이상 )(9,10), 혈관또는림프관침윤등이림프절전이의위험요인으로보고되고있으며 (11,12) 특히침윤깊이가깊어짐에따라림프절전이의가능성은현저히증가된다. 즉, T1암에서는 10 15% 의림프절전이가보고되고있지만 T2의경우 17 22%, T3의경우 49 66% 로보고되고있다 (9,13,14). 따라서경항문적절제술후 T2 병기로진단된직장암은높은국소재발률및치료실패로인하여추가치료가요구된다. 경항문적절제술후 T2 병기로진단된직장암환자에가능한치료는? 1. 근치적절제술로의전환경항문적절제술을시행한후 T2 병기로진단된경우근치적절제술을시행할수있다. T2병기진단즉시영역림프절곽청을포함하는근치적절제를하는경우에는보다정확한병기의진단과함께국소재발을최소화할수있는반면수술후배변장애등의불편을초래하거나영구적인장루조성의가능성이있다. 과거에비하여항문연에서가까운직장암의경우에도항문보존술식의빈도는많이증가되었지만장루조성의빈도또한수술자의술기에의존적이다. 2. 수술후항암방사선치료직장암의경항문적절제후 T2 병기로진단된경우높은국소재발률을줄이기위하여항암방사선치료가시도되고있다. Chakravarti 등은 T2 병기암에서경항문적절제술만을시행한경우에비교하여항암방사선치료가추가된경우에국소재발률을감소시키고생존율을증가시킨다고보고하였다 (15). 다른보고들에서도 T2 병기암에서경항문적절제술만으로치료한경우국소재발률은 30 50% 의국소재발률이항암방사선치료를추가한경우 11 25% 로감소된다고하여 T2 병기암에서항암방사선치료가치료결과를호전시키는것으로보고되었다 (16,17). T2 직장암을경항문적절제술과항암방사선치료로치료한경우와근치적절제를시행한경우를비교하면국소재발률은 19 40% vs. 9 10%, 생존율은 63 95% vs. 81 96% 로유의하게근치적절제술이치료효과가우월하였다 (18-20). 최근의보고에의하면 T1 병기에서조차도경항문적절제술이근치적절제술에비하여 3배이상국소재발률이높다고하여 T1 직장암에서도보다근치적인치료방법은광범위근치적절제술이라고하였다 (21). 경항문적절제술후재발암에대한치료 직장암의경항문적절제술에의한결과들은근치적절제술과비교하여국소재발률이높음에도불구하고경항문적절제술후재발의대부분은근치적절제술후와는달리대부분국소재발이어서재발이진단되어도재발암에대한근치적절제술이가능하다고생각되어졌다. 하지만, 최근국소절제술의재발암에대한치료결과들을살펴보면비록대부분의재발이국소영역재발이라고하더라도진단시에근치적절제술을시행한때보다치료성적이좋지않음을보고하여국소절제를계획할때그환자선택에신중하여야함을강조하고있다 (22,23). S2
이강영 : 경항문적절제술후 T2 로진단된직장암의치료 결 론 직장암치료에서기능보전과환자의삶의질에관한문제는종양학적안전성의확보와균형을유지하는것이무엇보다도중요하다. T2병기의직장암은국소절제술만을시행하는경우높은재발률과이에따른치료실패의고위험군이며이에항암방사선치료를추가하여도근치적절제술을시행한경우보다치료성적이좋지않은것으로보고되고있다. 따라서종양학적안전성의확보를위하여국소절제후 T2 병기로진단된경우는이에대한치료로근치적절제술을우선적으로고려하는것이좋은치료방침이될것으로생각된다. 참고문헌 1. Heald RJ, Moran BJ, Ryall RD Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997 Arch Surg 133:894-899, 1988 2. Enker WE, Thaler HT, Cranor ML Total mesorectla excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181;335-346, 1995 3. Phillips RK, Hittinger R, Blesovsky L, Fry JS, Fielding LP. Local recurrence following 'curative' surgery for large bowel cancer. Br J Surg 71:12-6, 1984. 4. Harmon JW, Tang DG, Gordon TA, Bowman HM, Choti MA, Kaufman HS, et al: Hospital volume can serve as a surrogate for surgeon volume for achieving excellent outcomes in colorectal resection. Ann Surg 230:404-11, 1999 5. Read DR, Sokil S, Ruiz-Salas G: Transanal local excision of rectal cancer. Int J Colorectal Dis 10:73-6, 1995. 6. Bailey HR, Huval WV, Max E, Smith KW, Butts DR, Zamora LF: Local excision of carcinoma of the rectum for cure. Surgery 111:555-61, 1992. 7. Kikuchi R, Takano M, Takagi K, Fujimoto N, Nozaki R, Fujiyoshi T, et al: Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 38:1286-95, 1995. 8. Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR: Risk of lymph node metastasis in T1 carcinoma of the colon and rectum. Dis Colon Rectum 45:200-6, 2002. 9. Ricciardi R, Madoff RD, Rothenberger DA, Baxter NN: Population-based analyses of lymph node metastases in colorectal cancer. Clin Gastroenterol Hepatol 4:1522-7, 2006. 10. Goldstein NS, Hart J: Histologic features associated with lymph node metastasis in stage T1 and superficial T2 rectal adenocarcinomas in abdominoperineal resection specimens. Identifying a subset of patients for whom treatment with adjuvant therapy or completion abdominoperineal resection should be considered after local excision. Am J Clin Pathol 111:51-8, 1999. 11. Ueno H, Mochizuki H, Shinto E, Hashiguchi Y, Hase K, Talbot IC: Histologic indices in biopsy specimens for estimating the probability of extended local spread in patients with rectal carcinoma. Cancer 94:2882-91, 2002. 12. Brodsky JT, Richard GK, Cohen AM, Minsky BD: Variables correlated with the risk of lymph node metastasis in early rectal cancer. Cancer 69:322-6, 1992. 13. Fang WL, Chang SC, Lin JK, Wang HS, Yang SH, Jiang JK, et al: Metastatic potential in T1 and T2 colorectal cancer. Hepatogastroenterology 52:1688-91, 2005. 14. Sitzler PJ, Seow-Choen F, Ho YH, Leong AP: Lymph node involvement and tumor depth in rectal cancers: an analysis of 805 patients. Dis Colon Rectum 40:1472-6, 1997. S3
J Clin Cancer Res. 2007;1(Suppl. 1) 15. Chakravarti A, Compton CC, Shellito PC, Wood WC, Landry J, Machuta SR, et al: Long-term follow-up of patients with rectal cancer managed by local excision with and without adjuvant irradiation. Ann Surg 230:49-54, 1999 16. Paty PB, Nash GM, Baron P, Zakowski M, Minsky BD, Blumberg D, et al: Long-term results of local excision for rectal cancer. Ann Surg 236:522-29, 2002 17. Taylor RH, Hay JH, Larsson SN: Transanal local excision of selected low rectal cancers. Am J Surg 175:360-3, 1998. 18. Lee W, Lee D, Choi S, Chun H: Transanal endoscopic microsurgery and radical surgery for T1 and T2 rectal cancer. Surg Endosc 17:1283-7, 2003 19. Mellgren A, Sirivongs P, Rothenberger DA, Madoff RD, Garcia-Aguilar J: Is local excision adequate therapy for early rectal cancer? Dis Colon Rectum 43:1064-71, 2000 20. Balani A, Turoldo A, Braini A, Scaramucci M, Roseano M, Leggeri A: Local excision for rectal cancer. J Surg Oncol 74:158-62, 2000 21. Bentrem DJ, Okabe S, Wong WD, Guillem JG, Weiser MR, Temple LK, et al: T1 adenocarcinoma of the rectum: transanal excision or radical surgery? Ann Surg 242:472-7, 2005 22. Friel CM, Cromwell JW, Marra C, Madoff RD, Rothenberger DA, Garcia-Aguilar J: Salvage radical surgery after failed local excision for early rectal cancer. Dis Colon Rectum 45:875-9, 2002 23. Baron PL, Enker WE, Zakowski MF, Urmacher C: Immediate vs. salvage resection after local treatment for early rectal cancer. Dis Colon Rectum 38:177-81, 1995 S4
J Clin Cancer Res. 2007;1(Suppl. 1):5-9 Session 1 Role of Radiotherapy for T3N0 Rectal Cancer (T3N0 직장암에서의방사선치료의역할 ) Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Jong Hoon Kim, M.D., Ph.D. 서 론 대장과직장은연속적인위치에있는장기임에도불구하고악성종양의발생시그치료에있어서는상이한점이많은기관들이다. 대장및직장의암은수술적으로완전절제를시행하는것이가장중요한치료요소임은누구도부정하기어려우울것이나, 직장암의경우는병리학적으로 AJCC T3 이상이거나임파절전이가확인되는경우수술전또는수술후에방사선치료를시행하는것이표준적인치료로서널리시행되고있으며, 그이유는해부학적인특성에서찾아볼수있다. 직장의경우상부 1/3 을제외하면 serosa가덮여있지않아근육층을통과한암세포가직장주위지방층으로쉽게침투하며, 수술로병변을절제함에있어골반내종양이기에복강내종양인대장암만큼여유있는절제연을확보하기가쉽지않고외과의사의수술시야가상대적으로좋지못하다. 그러나골반이라는제한된공간에위치하기에복막전이와같은위험요인이적으며따라서국소치료인방사선치료가골반내재발의위험을줄일수있다는점이다. 즉수술후암세포의국소잔류가능성은대장암에비하여더높지만그것이제한된공간에한정되어있기때문에수술후국소보조치료인방사선치료가역할을할수있는것이다. 이러한해부학적가설은여러전향적 3상임상연구들을통하여방사선치료의국소재발억제효과가증명됨에따라현재방사선치료는표준적인보조치료로서사용되고있다. 1990년도 National Institutes of Health (NIH) consensus conference에서는 T3N0 환자군에서도보조방사선치료를항암제와함께시행할것을권고하였고, 2007년의미국 National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology에서도임상병기 T3N0의경우수술전방사선치료와항암제의병용또는수술후병기가 pt3n0로확인된경우수술후방사선치료를권고하고있다 (1,2). 이러한권고안들은과거시행되었던전향적임상연구들의결과를토대로하고있지만, 1990년도의 NIH consensus statement는근거가된연구들이병기 T3N0에대한구체적인구분이없었기에일반적으로 T3 이상이거나림프절전이가확인된경우를모두포함하여권고한것이며, NCCN의권고안도그근거는 category 2B (There is nonuniform NCCN consensus (but no major disagreement), based on lower-level evidence including clinical experience, that the recommendation is appropriate.) 에해당되는경우이므로 T3N0 직장암에서방사선치료를반드시시행해야하는치료로주장하기에는어려움이있다고하겠다. 또한 1980년대중반이후 Heald 등이전장간막절제술 (TME, total mesorectal excision) 이우수한국소제 S5
J Clin Cancer Res. 2007;1(Suppl. 1) 어효과가있음을보고하면서 TME는새로운표준수술방법으로자리매김하게되었다 (3). Heald 등은 1986년도 Lancet에발표한수술결과에서 Dukes' stage B의경우 5년무병생존율 87% 의매우뛰어난성적을발표하였고, 연이어 MacFarlene등은 Dukes' stage B-C의 TME 시행후 5년국소재발률이 5% 로서 NCCTG의성적인수술단독시행시의 25%, 수술과방사선치료병용시의 13.5% 의국소재발률에비하여월등한결과를얻었음을보고하였다 (4). 물론이러한연구결과가전향적 3상임상연구의결과가아니며연구자에따라포함된환자의선정기준이다를수있기에직접적인치료효과를비교하기는어렵지만전통적인수술후의성적과비교하여매우우수한것임은분명하다. 이론적으로 TME는재발의위험부위인동시에방사선치료의주요목표인 perirectal adipose tissue를 mesorectum에싸인채로제거하기에암세포의 CRM (circumferential resection margin) 침범빈도를낮추고국소재발을획기적으로줄일수있는수술방법이며, 따라서국소재발률이상대적으로낮은 T3N0 직장암의경우보조방사선치료의효과가미미할수도있다. 실제일부연구자들은직장의상부에발생한종양이면서 serosa 층을미세하게침범한경우는국소재발의위험도가낮아특별한위험요소가있지않는한방사선치료를권장하지않는경우들도있다. 따라서 NIH나 NCCN의권고안과같이 pt3n0 직장암에서일률적인방사선치료의권고보다는개별연구들의결과들을통하여방사선치료가필요한환자군을구분하고이러한환자에서방사선치료효과가있는지를밝혀나가는것이합리적일것이다. 이에본원고에서는 T3N0 직장암에있어국소재발의고위험군선별과방사선치료의효과에대하여살펴보고자한다. 수술후 pt3n0 의국소재발과방사선치료 Gunderson 등은직장암의전통적수술후방사선치료와항암제의효과에대한전향적 3상임상연구들 (NCCTG 79-47-51, NCCTG 86-47-51, US Gastrointestinal Intergroup 0114, NSABP R01, R02) 의결과를종합하여각병기에따른재발양상과생존율등을보고하였는데, T3N0의경우 75% 의 5년생존율과 65% 의 5년무병생존율을보여중간위험군 (intermediate risk group) 으로분류된바있다 (5). 총 664명환자에서의재발양상은 9% 의국소재발률과 20% 의전이율을보인것으로보고하였으며국소재발률을보면수술만시행했던환자군은 14%, 방사선치료와항암제를병용한군에서는 5-10% 의재발률을나타냄으로써 T3N0의병기에서보조방사선치료가항암제와병용시국소재발률을감소시킬가능성은보여주었으나통계적유의성에대한언급이없어단정하기는어려운상태이다. 따라서국소재발의고위험군을선별하여방사선치료를고려하는것이현재로서는가장합리적인치료일것으로생각된다. 종양의위치즉하부에위치할수록국소재발이많음은주지의사실이며그외현재까지알려진중에서는 CRM(circumferential resection margin) 이가장대표적인국소재발의위험요소이다 (6-8). 네덜란드 TME trial의연구에서는 LAR환자의 13.5%, APR환자의 28.8% 에서 CRM 양성이었으며항문연 5 cm 이하의 low rectal cancer의 25.9%, 10 cm 이상의 upper rectal cancer에서는 16.5% 에서양성을나타낸것으로관찰되었다. 또한 CRM 양성여부뿐아니라 CRM의폭이짧을수록국소재발과원격전이의빈도가높아짐도함께보고되었다 (6). 재발위험요소분석연구에따르면 APR을시행받은 low rectal cancer의경우다변량분석에서 CRM 양성이음성에비하여국소재발의 hazard ratio (HR) 가 4.89 (95% CI, 2.67-8.94, P<0.001), 생존율의경우 HR이 3.03 (95% CI, 2.23-4.13, P<0.001) 로나타나 TME를시행하는환자에서도 CRM은매우중요한국소재발의위험요소인것으로나타났다 (7). 이러한 CRM의양성여부는 N-stage와더불어생존율에영향을미치는가장중요한독립적인인자임이밝혀졌다 (8). S6
Jong Hoon Kim: Role of Radiotherapy for T3N0 Rectal Cancer Marijnen 등은 CRM의폭에따라수술전방사선치료에의해국소재발에차이가있는가를비교분석하였는데 CRM이 1.1 2 mm (14.9% 대 0%, P=0.02), 2 mm 이상 (5.8% 대 0.9%, P<0.0001) 등으로구분되었을때모두방사선치료가국소재발을유효하게감소시켰고, CRM이 0 1 mm 이내인경우에는 16.4% 대 9.3% 로서 (P=0.08) 통계적유의성에는도달하지못하였으나국소재발이감소하는경향을보여주었다 (9). 이것은수술전방사선치료를시행하지않고수술을먼저시행하여완전절제가되어 CRM 음성인경우라하더라도 CRM 인접조직에서의국소재발이방사선치료에의해감소될수있음을의미하는것으로해석할수있겠다. 수술전 ct3n0 의방사선치료 최근수술전방사선치료가보편화되면서위에언급된병리학적위험요소를수술전에찾아내는것은쉽지않은상황이지만영상진단기술의발전으로병리학적소견을수술전에예측하는것이점차가능해지고있다. 현재널리사용되고있는내시경적초음파 (endorectal ultrasound, EUS) 의경우시술자에따른정확도의차이는있으나일반적인정확도에관한 Marusch 등의연구에의하면 422명의수술전 EUS와병리소견을비교한연구결과에서전체적인병기의일치도 (accuracy) 가 63.3% 였던것으로보고하였고 pt3 병변의경우 74.8% 에서 EUS 병기와조직학적병기가일치하는것으로보고한바있다 (10). 최근주목을받고있는 phase array MR의경우 pt3-4 병변에서 EUS보다더우수한결과를보여전체 T-병기의정확도는 65 78% 이지만 pt3-4병기에서는정확도가더높은것으로알려져있다. 영국의 MERCURY study group의보고에의하면종양의직장벽침윤깊이를측정한결과병리조직학적소견과 MRI의소견과의차이가 +/- 0.5 mm로 MRI가매우정확히종양의침윤정도를예측할수있다는결과를보여주었다 (11). 일부연구자들은 MRI와 CRM에대한 metaanalysis를통하여 MRI가 CRM을수술전에예측하는데유용하며직장주위림프절전이를진단하는것은 EUS와비교시대등한결과를보이는것으로결론지은바있지만최근주목받고있는 USPIO (ultra small particles of iron oxide) 를이용한 MRI의경우림프절진단에도유용한것으로보고되고있다 (12,13). 이러한영상진단뿐아니라치료전이학적검사상의위험요소들도재발이위험성이높은환자들을찾아내는데도움을주고있다. Myerson 등은수술전방사선치료를받은후국소재발에대한위험인자를분석한결과, 항문연 5 cm 이내에위치했거나, 직장수지검사상병변이고정되어있거나움직임이제한된경우 (fixed or tethered), 직장을둘러싸는병변 (circumferential lesion), 내강 1 cm 이하로좁아진병변 (lumen less than 1 cm) 등의 4 요소를국소재발의고위험요소로발표한바있고이중위험요소가 3개이상인경우국소제어율이 74% 에그치는것으로보고하였다 (14). 따라서위와같은요소가 3개이상있다면수술전방사선치료를고려하는것이타당할것으로생각된다. 그러나아직까지수술전방사선치료가 CRM 의양성빈도및폭을줄여준다는전향적비교연구결과는없다. Dutch TME trial에서는수술전방사선치료를시행하더라도 CRM의폭이감소하지않았는데이는이연구의방사선치료방법이종양의축소효과를기대하기힘든단기간의저분할방사선치료이고방사선치료후수술까지의기간도 1주내외로짧았던까닭에종양의반응이나타날만한충분한시간적여유가없었음을고려한다면당연한결과라하겠다 (15,16). 그러나전통적인다분할방사선치료를시행한독일의 CAO 연구에서는수술전방사선치료를받은환자군에서병기가감소됨이확인되었기에간접적증거로서전통적다분할방사선치료가 CRM 양성을줄여줄수있을것으로기대할수있겠다 (17). 또한전술한바와같이 CRM의폭에 S7
J Clin Cancer Res. 2007;1(Suppl. 1) 따라서도방사선치료는국소재발의억제효과가있으며 CRM양성인경우에도억제효과의가능성을보여준바있기에수술전방사선치료는 ct3n0 직장암에서도국소억제효과가있었던것으로생각된다. TME를시행하는환자에서수술전방사선치료의효과를비교한 3상연구는아직까지 Dutch TME trial 연구가유일하다 (16). 이들은 TME 수술전방사선치료가어떠한영향을미치는가를연구한논문에서 stage II의경우방사선치료를시행하지않고 TME만시행한환자군의국소재발이 1.0%, 방사선치료를시행한군은 5.7% 로서 (P=0.01) stage II 병기에있어수술전방사선치료를시행하는것이 TME 에비하여월등히국소재발을줄일수있다는점을보고하였다. 또한국소재발의예후인자에대한단변량분석에서성별과상관없이방사선치료가유효하며, 병변의위치에따라서는항문연 5 cm 이하, 5 10 cm 의경우모두방사선치료가의미있게국소재발을줄인반면항문연 10 cm 이상의병변인경우에는 1.3% 대 3.8% 로서 (P=0.17) 차이가없는것으로나타났다. 수술의방법에따라서도 low anterior resection이나 abdominoperineal resection에관계없이모두방사선치료가국소재발에유효함을보여주었다. 이상의결과를종합하면 ct3n0 직장암으로서직장상부 1/3에발생하였고 MRI상 CRM 음성으로나타나수술로완전절제가가능할것으로예상된다면수술전방사선치료없이수술을시행한후병리조직소견상위험요소가없다면관찰만해도좋을것으로생각된다. 그러나직장의하부 2/3에발생하였거나상부 1/3이라도 MRI상 CRM 양성의소견을보인다면수술전방사선치료를시행하는것이타당해보인다. 참고문헌 1. National Institutes of Health Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer. J Am med Assoc 264:1444-1450, 1990 2. National Comprehensive Cancer Network: NCCN clinical practice guidelines in oncology. http://www.nccn.org/ professionals/physician_gls/pdf/rectal.pdf 3. Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1:1479-1482, 1986 4. MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer. Lancet 341:457-460, 1993 5. Gunderson LL. Sargent DJ, Tepper JE, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22:1785-1796, 2004 6. Nagtegaal ID, Marijnen CAM, Kranenbarg KE, et al: Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: Not one but two mm is the limit. Am J Surg Pathol 26:350-357, 2002 7. den Dulk M, Marijnen CA, Putter H, Rutten HJ, et al: Risk factors for adverse outcome in patients with rectal cancer treated with an abdominoperineal resection in the total mesorectal excision trial. Ann Surg 246:83-90, 2007 8. Gosens MJ, van Krieken JH, Marijnen CA, Kranenbarg EM, et al: Improvement of staging by combining tumor and treatment parameters: the value for prognostication in rectal cancer. Clin Gastroenterol Hepatol 5:997-1003, 2007 9. Marijnen CAM, Nagtegaal ID, Kapitejin E, et al: Radiotherapy does not compensate for positive resection margins in rectal cancer patients: Report of a multicenter randomized trial. Int J Radiat Oncolo Biol Phys 55:1311-1320, 2003 S8
Jong Hoon Kim: Role of Radiotherapy for T3N0 Rectal Cancer 10. Marusch F, Koch A, Schmidt U, et al: Routine use of transrectal ultrasound in rectal carcinoma: results of a prospective multicenter study. Endoscopy. 34:385-390, 2002 11. MERCURY Study Group: Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology. 243:132139, 2007 12. Lahaye MJ, Engelen SM, Nelemans PJ, Beets GL, et al: Imaging for predicting the risk factors--the circumferential resection margin and nodal disease of local recurrence in rectal cancer: a meta-analysis. Semin Ultrasound CT MR. 26:259268, 2005 13. Koh DM, Brown G, Temple L, et al: Rectal cancer: mesorectal lymph nodes at MR imaging with USPIO versus histopathologic findings-initial observations. Radiology 231:91-99, 2004 14. Myerson RJ, Valentini V, Birnbaum, et al: Pretreatment clinical findings predict outcome for patients receiving preoperative radiation for rectal cancer. Int J Radiat Oncolo Biol Phys 50: 665-674, 2001 15. Marijnen CAM, Nagtegaal ID, Kranenbarg EK, et al: No downstaging after short-term preoperative radiotherapy in rectal cancer patients. J Clin Oncol 19:1976-1984, 2001 16. Kapiteijn E, Marijnen CAM, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. New Eng J Med 345:638-646,2001 17. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 S9
J Clin Cancer Res. 2007;1(Suppl. 1):10-18 Session 1 Adjuvant Chemotherapeutic Regimen in Elderly Colon Cancer Patients in Practical Field Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Bundang, Korea Jee Hyun Kim, M.D., Ph.D. 서 론 2002년한국중앙암등록사업연례보고서에의하면대장암은한국에서남녀공히발생율 4위를기록하고있으며이중 50% 에가까운환자들이 65세이상의노인이다 (1). 미국의경우대장암환자의 75% 가 65세이상의노인으로, 대장암은노인의질환이라해도과언이아니다 (2). 그러나, 대부분의보조항암화학요법에대한연구들이노인을제외하고이루어져노인환자들을대상으로한적절한진료지침이없는실정이다. 본논문에서는현재까지노인들을대상으로한대장암보조항암화학요법의효과와독성에대한문헌을고찰하고, 노인암환자의치료를결정할때고려해야할필수적인요소들을점검하여, 실제로진료실에서노인대장암환자들을대상으로보조항암화학요법을결정할때도움이되고자한다. 결장암보조항암화학요법 1. 3기결장암에서의보조항암화학요법 1) 5-FU 5-FU는 1970년대부터결장암의보조항암화학요법에도입되기시작하여여러대규모 III상임상연구를통하여수술단독에비하여 3기결장암환자에서전체생존율을증가시킴이입증되었다. 1990년미국의 National Cancer Institute consensus conference에서는 5-FU를근간으로한보조항암화학요법을 3기결장암에서추천하였고 (3), 이후여러임상연구결과들을바탕으로 3기결장암환자에서보조항암화학요법으로 5-FU와 leucovorin 복합요법을 6개월간시행하는것이표준요법으로자리잡았다 (4). 2) Oxaliplatin Oxaliplatin은 diaminocyclohexane platinum compound로대장암세포주를대상으로 5-FU와상승효과를지닌다. 전이성대장암환자에서 5-FU/leucovorin과병용하였을때효과를보임이보고된후, 보조항암화학요법으로서의유용성을검증하기위한대규모 3상임상시험이진행되었다. Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) 연구에 S10
Jee Hyun Kim: Adjuvant Chemotherapeutic Regimen in Elderly Colon Cancer Patients in Practical Field 서는 2기결장암환자 40%, 3기결장암환자 60% 로구성된총 2246명의환자를무작위배정하여 6개월간 LV5FU2 또는여기에 oxalipaltin을추가한 FOLFOX4 요법으로치료한후 3년무병생존율을비교하였는데, FOLFOX 4 치료군에서유의하게 3년무병생존율 (78.2% vs 72.9%: HR 0.77, P=0.002) 이증가하였음을보고하였다 (5). 2007년 6년간의중앙추적관찰기간후최종보고된전체생존율은 75.8% 대 78.5%, HR 0.85 (0.71 1.01) 로통계적유의성을보이지못하였으나 3기의환자에서는 68.3% 대 72.9% (HR 0.80 [0.66-0.98]) 으로 FOLFOX4 군에서더높았다. 2기환자에서는생존율이양군에서모두 86.8% 로동일하였다. 단, 2기결장암환자중고위험군 (T4, bowel obstruction, tumor perforation, poorly differentiated histology, venous invasion, or less than 10 examined lymph nodes) 에있어서 3년무병생존율은 5.0% 의차이를보이며 FOLFOX 4 요법이더우월하였다 (6). NSABP C-07 연구에서는 2,407명의 2기 (29%) 와 3기 (71%) 결장암환자들을무작위배정하여 5-FU와 leucovorin을매주급속정주하는 Rosewell Park 방법의 5-FU/LV 요법과같의방법의 5-FU/LV 요법에 oxaliplatin 85 mg/m 2 를 8주주기중첫 1, 3, 5주에주사하는 FLOX 요법을비교하였는데, 3년무병생존율에서 71.8% 대 76.1% (HR 0.80, P<0.004) 로 MOSAIC 연구에서와거의유사한정도의차이를보이며 FLOX 요법이우월함을보여주었다 (7). 3) Capecitabine Capecitabine은 5-FU의경구전구약물로 thymidylate phosphorylase에의하여종양세포에서선택적으로 5-FU로변환되도록설계되었다. X-ACT 연구에서 1,987명의 3기결장암환자를대상으로경구 capecitabine과 Mayo Clinic 방법의 5-FU/LV을각각 24주간투여하는치료법을비교하였다. 이연구는적어도무병생존율이 capecitabine 군에서열등하지않음을증명하는 non-inferiority trial로진행되었는데, 3년무병생존율이 64.2% 대 60.6% 로 capecitabine 경구요법이적어도 5-FU/LV 요법과동등함을증명하였으며 (p<0.001), 무재발생존기간에서는 capecitabine 군이우월하였다 (HR 0.86 [0.74 0.99], p=0.04). 또한 capecitabine 군에서 3,4도의독성이적게보고되었다 (P<0.001)(8). 4) UFT-E UFT-E는 tegafur를 dihydropyrimidine dehydrogenase (DPD) 의억제제인 uracil 과같이투여하여 5-FU가장점막에서불규칙적으로흡수되는것을방지하여 tegafur의경구생체이용률을높이고자개발되었다. UFT와 leucovorin은전이성대장암에서직접주입 FL 과유사한효능과독성을보임이보고된바있다. NSABP C-06 연구에서는 2기 (47%) 와 3기 (53%) 의결장암환자 1,608명을대상으로 UFT-E/LV 요법과 FL 요법을비교하여동등한무병생존율 (HR=1.004 [95% CI, 0.847 to 1.190]) 과전체생존율 (HR=1.014 [95% CI, 0.825 to 1.246] 을보였으며유사한독성을보였다 (9). 5) Irinotecan (CPT-11) 전이성대장암에서 Irinotecan 복합요법이 5-FU/LV 요법에비해우월한생존기간을보여표준요법의하나로자리잡은것과는대조적으로, 현재까지 irinotecan 복합요법이 3기결장암환자에서 5-FU/LV에비하여 3년생존율의유의한향상을가져온다는증거가없다. FOLFIRI 요법과 LV5FU2를비교한 PETACC 연구에서 3년무병생존율은 62.9% 대 59.9% (HR 0.89, P=0.107) 로유의한차이가없었고 (10), 급속정주법의 FU/LV를사용한 IFL 요법과 FU/LV를비교한 C89803에서는무병생존율, 중앙생존율은차이가없으면서 IFL 군에서치료기간중의사망률이높아 (2.8% vs 1.0%, P=0.008), IFL요법을결장암의보조항암화학요법으로사용하지않을것을권고하였다 (11). 이들연구의결과로부터어떤요법이전이성대장암에서우월한효과를보인다고하여독립된임상시험의결과없이보조요법에서적용해 S11
J Clin Cancer Res. 2007;1(Suppl. 1) 서는안된다는교훈을얻을수있겠다. 2. 2 기결장암에서의보조항암화학요법 현재까지시행된대부분의결장암보조항암화학요법에관한연구는 2기와 3기환자를모두포함하여시행되어, 2기환자단독을대상으로생존율을입증하기에는부족한환자수가배정되었으며, 현재까지단하나의연구도 2기환자만을대상으로시행하여보조항암화학요법이수술단독군에비하여전체생존기간을증가시킴을보고한바가없다. Gill S 등이 7개의연구를모아서보고한 pooled analysis에서도 1,440명의 2기결장암환자들의 5년전체생존율은수술단독군이 80%, 5-FU 포함보조항암화학요법군 81% 로차이를보이지못함을보고하였다 (12). 단, NSABP C01-04 연구의후향적분석과 QUASAR 연구에서는 2기환자에서도 3기환자와유사한정도의생존율의증가를보임을보고하여 2 기환자에서도보조항암화학요법을시행하는것의이론적근거를제공하고있다 (13,14). American Society of Clinical Oncology (ASCO) 에서는 2기결장암환자에서일률적으로보조항암화학요법을시행하는것은추천하지않고있으며, 보조항암화학요법을시행하여생존율이증가한다하더라도그절대적차이는매우미미하며 (5% 미만 ), 이를모두설명한후동의하는환자에게는선별적으로시행할수도있다고하였다 (15). 2기의결장암환자중에서고위험군 (T4, bowel obstruction, tumor perforation, poorly differentiated histology, venous invasion, less than 10 examined lymph nodes) 의경우에는보조항암화학요법이생존율향상에도움이될것으로기대되는바이나, 이환자군을대상으로한독립적임상시험은시행된바가없으며, 따라서역시일률적인보조항암화학요법을추천하기는어렵다. 단, ECOG INT-0035 연구등일부임상시험의 subgroup analysis에서고위험 2기결장암환자에서 5-FU를근간으로한보조항암화학요법을시행한군에서무병생존율이좀더높았음을보고한바있다 (16). MOSAIC 연구에서는고위험군을대상으로시행한 subgroup analysis에서 3년무병생존율은 80.4% 대 85.4% 로 FOLFOX 4 군에서더 높았다 (6). 노인결장암보조항암화학요법의성적 1. 5-FU 근간요법노인암환자만을대상으로시행된독립적연구는거의없고, 임상연구에포함된 65세이상의환자들을대상으로후향적으로분석한 pooled anaylsis에서는공통적으로노인에서도젊은환자와유사한생존율의향상을보임을보고하였다. Sargent 등은 3,351명의환자를대상으로했던 7개의임상시험의결과를모아서연령대별로효과와독성을분석하였는데, 보조화학요법을받은치료군의 5년생존율은 71% 로, 대조군의 64% 에비하여약 24% 의상대적생존율증가를보고하였다 (HR=0.76; 95% CI 0,68-0.85, P<0.001)(17). 70세이상연령대의 5년생존율또한유사한정도의차이를보여치료군이 69%, 대조군이 62% 였으며, 독성또한 70세이상과이하의연령대에서유사하였다. 5-FU와 levamisole 치료를받은 70세이상환자에서만 leukopenia의빈도가더높았다. 일반인구집단을대상으로 SEER- Medicare database를이용하여분석한연구에서도 5-FU를근간으로한보조화학요법을받은 65세이상의 3기결장암환자들에서 34% 의상대적사망률감소를보고하여, 적어도항암화학요법을받을수있는노인환자에서는젊은환자와유사한생존율의상승을기대할수있는증거를제시하였다 (18). 반 S12
Jee Hyun Kim: Adjuvant Chemotherapeutic Regimen in Elderly Colon Cancer Patients in Practical Field 면, 항암화학요법의독성은고령이라하여반드시증가하지는않음을보고하고있어, 3기의결장암환자에있어 5-FU 보조항암화학요법은젊은환자와유사한생존율증가를가져오며, 독성을특별히증가시키지는않는다고정리할수있겠다. 2. Oxaliplatin Goldberg 등이 FOLFOX4 항암요법을시행한 (MOSAIC연구포함 ) 임상연구에등록된환자들을 70세미만과 70세이상으로나누어분석하였을때에도, 재발율과반응율등효과는각연령대에서유사하였고, 3도이상의혈액학적독성발생은 70세이상에서더높았으나, 투여된항암제의 dose intensity, 3도이상의부작용, 60일미만의사망률은양군에서유사하였다 (19). 다만, MOSAIC 연구는대상환자군이 75세미만으로한정되어있었고, 임상연구에포함될수있는환자들은수행능력이양호하고장기기능이정상인선별된집단임을고려할때, 이러한임상연구의결과를그대로진료실에적용하기에는주의가필요하다. 노인암환자의항암요법에서고려할사항 1. 기대여명통계청에서작성한생명표에의하면 2005년현재 70세노인의기대여명은남성 12.4년, 여성 15.7년, 75세의경우 9.4, 11.9년, 80세의경우도남녀각각 7.0년, 8.7년의기대여명을가지고있다 (20). 대장암의재발의 80% 가수술후 3년이내에일어나며거의대부분의재발이 5년이내에일어나는것을감안하면 (21), 기대여명이 5년이상인노인환자들을대상으로보조화학요법을시행하는것이추천된다. 기대여명은환자가가지고있는동반질환과기능상태, 노인질환증후군 (geriatric syndrome) 등에따라달라질수있으므로, 노인암환자에게항암화학요법을시행할때에는이환자가암으로인하여사망할것인지 (die of cancer), 아니면다른질환으로사망할가능성이더높은지 (die with cancer) 충분히고려해야한다. 2. 동반질환 (Comorbidity) 노인환자의기대여명과예후를예측함에있어동반질환의유무와개수, 중증도등은매우중요하다. Yancik 등은 NCI-SEER database를이용한 population study에서대장암환자에서연령과동반질환이조기사망률에미치는영향을평가하였는데, 연령이증가할수록동반질환의개수가증가하며중증도도높아짐을보고하였고, 동반질환은조기사망을예측할수있는독립적예측인자였다 (P= 0.0007). 특히, 동반질환이 5 6개, 7 14개인노인의경우사망률이각각 1.44배, 1.85배높았다 (22). 조기유방암환자를대상으로한연구에서도 3개이상의동반질환유무가병기와독립적인생존율예측인자로작용하며, 동반질환의개수가증가할수록유방암으로사망할확률보다다른질환으로사망할확률이높아져서동반질환이각각 0, 1, 2, 3개이상일때사망원인의비율 ( 유방암 / 다른질환 ) 은각각 4.1, 1.7, 0.8, 0.3 이었다 (23). 또한당뇨병이있는대장암환자는없는환자에비하여통계적으로유의하게낮은 5년무병생존율 (48% 대 56%; P<0.0001) 과전체생존율 (57% 대 66%; P<0.0001) 을보인바있고, 이는다른대장암의예후인자를보정하여도독립적인사망과재발의위험인자로작용하였다 (24). S13
J Clin Cancer Res. 2007;1(Suppl. 1) 3. 노인포괄평가 (Comprehensive geriatric assessment) 노화의과정은여러장기의기능적 reserve가감소하여외부혹은내부환경으로부터의스트레스에대응하여항상성을유지할수있는능력이점차감퇴되는현상 (homeostenosis) 으로요약할수있다. 이는지극히개인적인과정으로연대기적나이가생물학적나이를반영하지못하여, 같은연령의노인이라하더라도동반질환이없거나잘조절되며기능적으로도움이필요없는 fit elderly' 의경우표준용량의항암화학요법을잘견딜수있고, 젊은환자와비교하여유사한효과를얻을수있으나여러동반질환이있고기본적인생활에도주변의도움을받아야하는 frail elderly' 의경우항암화학요법의독성이증가하고회복을하지못할가능성이높다. 따라서, 노인의치료방침을결정할때에는이노인이노화의 spectrum에서어느선상에있는지, 즉 fit, vulnerable, frail elderly인지를구별하는것이매우중요하며, 일반적으로 frail elderly는보조화학요법의대상이되지않는다 (Table 1). 노인환자를평가할때에는단순한수행능력 (performance status) 로는부족하여, 노인환자의예후를예측할수있는, 동반질환과기능평가를포함하는포괄적인평가도구가필요하다. 노인포괄평가 Table 1. 노쇠노인 (Frail elderly) 의정의 Frail elderly 85 세 Geriatric syndrome 3 serious comorbidities Impaired ADL Table 2. 노인포괄평가항목 Physical status Functional Status ADL (activity of daily living) Bathing, dressing, toileting, continence, transferring, feeding IADL (instrumental activity of daily living) Telephone, transportation, shopping, taking medications, financial, meal preparing, clothes washing, housework and laundry Comoribidity Charlson comorbidity index, Cumulative Illness Rating Scale-Geriatrics (CIRS-G) Mental status MMSE (mini-mental status examination) Emotional status Geriatric depression scale Nutritional status Multi-nutritional assessment, body mass index, body weight Polypharmacy Drug compliance, interaction Geriatric syndrome Delirium, dementia, depression, more than three falls in a month, incontinence, spontaneous bone fracture, neglect and abuse, failure to thrive Social environmental Family involvement, caregiver, economics, Risk of fall, sanitary conditions S14
Jee Hyun Kim: Adjuvant Chemotherapeutic Regimen in Elderly Colon Cancer Patients in Practical Field (Comprehensive geriatric assessment) 는노인의다양한문제를찾아내고기술하여적절한관리계획을수립함으로써궁극적으로노인환자의문제를해결하기위하여시행하는포괄적평가로서, 노인의기능상태, 동반질환, 인지기능, 정신적상태, 사회적지지기반, 영양상태, 복용약제등을다분야의전문가들이함께시행하는도구이다 (25). International Society of Geriatric Oncology (SIOG) 의 task force에서도노인암환자의문제목록을발견하고기능을개선하여궁극적으로생존율을높이기위하여노인포괄평가를시행할것을권고하였고 (26), 여기에포함되는요소는 Table 2에정리된바와같다. 4. 약제독성 각항암화학요법은고유의독성 profile을지니므로, 노인암환자를대상으로약제를선택할때에는노화에따른생리적변화와약제별독성 profile을충분히고려하여야한다 (Table 3). 1) 5-FU 정맥주입요법 위에서열거된연구들에서 70세이상의노인에서 5-FU의독성이 70세미만의환자들과유사함을보인바있으나, 특히전신상태가좋지않은노인들에서는설사, 구내염, 구역, 구토의부작용의빈도가높고, 이는특히노인여성에서더높음이알려져있다 (27). 5-FU의독성이주입방법과 schedule에의하여달라지며, 일반적으로급속주입법의 5-FU에서특히혈액학적독성이높다. 노인의경우탈수에대한구갈반응이느려젊은환자에비해같은정도의설사에도탈수가더심하게올수있으며, 탈수로인하여심근경색이나뇌졸중등의합병증이발생할위험이증가할수있음을유념하여야한다. 2) Capecitabine Capecitabine의약력학은신장기능이정상인한연령에의해영향을받지않는다. 5-FU 정맥주입요법에비하여골수독성은적고수족증후군이주된독성이다. Capecitabine의독성은 Ccr 30 50 ml/min 의신장기능장애가있는환자들에서증가함이보고되어있고, 노인들에서는근육량의감소로인하여정상혈중크레아티닌농도에도 creatinine clearance가감소할수있으므로, CCr을계산하여이에따라 capecitabine의용량을조절함이바람직하다. SIOG에서는 Ccr 60 ml/min 이상에서는 1,250 mg/m 2 1일 2 회, 30 60 ml/min에서는 950 mg/m 2 1일 2회요법을권고하였고, CCr 30 ml/min 미만일경우 capecitabine은사용하지않을것을권고하였다 (28). 3) Oxaliplatin Oxaliplatin 역시 30 50% 가신장으로배설되는약물이나 GFR이 20 ml/min이상으로유지되는경우라 Table 3. Toxicity profile of adjuvant chemotherapy INT 0089(30) MOSAIC(5) X-ACT(8) CALGB 89803(11) NSABP C06(9) NSABP C07(7) Adverse Mayo Rosewell Mayo Rosewell Rosewell Rosewell Capeci- Event Clinic Park LV5FU2 FOLFOX4 Clinic Park IFL Park UFT-E/LV Park FLOX tabine FL FL FL FL FL FL Diarrhea 21 30 6.6 10.8 13 11 35 31 28.5 29.4 32.2 38 Stomatitis 18 1 2.2 2.7 14 2 - - 0.5 1.3 - - Hand-foot syndrome - - - - <1 17 - - 0.2 0.7 - - Neutropenia 24 4 4.7 41.1 26 2 5 43 1.3 1.3 - - Neutropenia with fever or infection - - 0.2 1.8 3 0.3 - - 1.3 0.6 1.0 2.2 Nausea/vomiting - - 1.8/1.4 5.1/5.8 3 3 11/7 13/10 7.4/6.7 7.1/4.3 11/8.4 0/0.7 Any 56 41 - - - - - - 37.8 38.2 - - Mortality 0.5 0.8 0.5 0.5 0.4 0.3 1.0 2.8 1.2 0.8 1.0 1.2 S15
J Clin Cancer Res. 2007;1(Suppl. 1) 면독성이특별히증가하지않음이보고되었다 (29). FOLFOX4 요법의독성과성적을 70세를기준으로연령별로분석한 pooled analysis에서, 70세이상에서유의하게 3도이상의 neutropenia와 thrombocytopenia의빈도가높았으나그외의비혈액학적독성이나감염등의독성은유의하게증가되지않았다 (19). 위의연구에서는 70세이상의노인들도유사한독성과치료기간, 치료용량을보여연령이 FOLFOX4 요법을받는것에제한요소로작용하지않음을보였다. 결 론 위의자료를바탕으로, 임상시험에참여할수있을만한 fit elderly에게는젊은환자와동일한치료방침을적용할수있음을알수있다. 3기결장암환자를대상으로 FOLFOX요법을권유할수있고, FU/leucovorin, capecitabine도사용될수있겠다. 2기결장암의경우현재여러연구결과를바탕으로생존율을증가시킨다는증거가없으며있다하더라도미미하므로일률적으로권고하지않는것이추천된다. Fit elderly에속하지못하는 (vulnerable) 3기결장암환자나고위험군 2기의결장암환자들이치료방침을정하기어려운 group으로이 group에서는노인포괄평가등을통하여적절한 intervention을시행하면서항암화학요법을시행할수있을것으로사료되며, 치료여부와항암제의선택은환자개개인의기능상태, 동반질환및각화학요법의독성을고려하여충분한 informed consent하에시행되어야할것이다. 참고문헌 1. 보건복지부한국중앙암등록본부한국중앙암등록사업연례보고서 (2002.1~2002.12). 2003 2. Yancik R and Ries LA. Aging and Cancer in America. Demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 14:17-23, 2000 3. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 264:1444-1450, 1990 4. Macdonald JS. Adjuvant therapy of colon cancer. CA Cancer J clin 49:202-219, 1999 5. Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, and Topham C. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 6. de Gramont A, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, and Bonetti A. Oxaliplatin/5FU/LV in adjuvant colon cancer: updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years. Proc Am Soc Clin Oncol 2007 7. Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, and Petrelli J. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25:2198-2204, 2007 8. Twelves C, Wong A, Nowacki MP, Abt M, Burris III H, Carrato A, and Cassidy J. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696-2704, 2005 9. Lembersky BC, Wieand HS, Petrelli NJ, O'Connell Mj, Colangelo LH, Smith RE, and Seay TE. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 24:2059-2064, 2006 10. Van Cutsem E, Labianca R, Hossfeld D, Bodoky G, Roth A, Aranda E, and Nordlinger B. Randomized phase S16
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J Clin Cancer Res. 2007;1(Suppl. 1):19-25 Session 1 Postoperative Follow-up Strategies in Colorectal Cancer Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea Kyung Hae Jung, M.D. ABSTRACT PURPOSE: To review and summarize the available evidence and experts opinions concerning the benefits of intensive follow-up of curatively resected colorectal cancer patients. METHODS: Guidelines of several oncology societies, which were based on results of several meta-analyses of randomized controlled trials that compared low-intensity and high-intensity follow-up programs of colorectal cancer, are summarized. RECOMMENDATIONS: History and physical examination should be performed every 3 to 6 months for the first 3 years, every 6 to 12 months during next 2 years, and subsequently at the discretion of the physician; carcinoembryonic antigen every 3 to 6 months for at least 3 years if the patient is a candidate for surgery or systemic therapy. Liver imaging including abdominal CT or ultrasound is recommended every 6 12 months for 3 years. There are controversies in using chest X-rays or chest CT. Colonoscopy should be done in 1 year and if normal, then the interval before the next subsequent examination should be 3 years, and then 5 years. Associated adenoma findings or hereditary syndromes may indicate shorter interval. CBCs, and liver function tests are not recommended, and molecular or cellular markers should not influence the surveillance strategy. Key words: Colorectal cancer, surveillance, CEA, CT scan, colonoscopy 서 론 대장암환자의약 2/3가수술과보조요법으로근치가가능한상태로진단되지만, 이들중 30 40% 가재발하며, 수술후첫 2, 3년사이에대부분의재발이발생한다 (1). 원발암치료를끝낸환자에서이후의관심은치료로인한합병증을평가하고, 간, 폐, 또는복부나골반강내에국한되어근치적치 This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (0412-CR01-0704-0001). S19
J Clin Cancer Res. 2007;1(Suppl. 1) 료가가능한상태의재발한암을발견하거나, 이시성 (metachronous) 의다른대장암을조기에발견하며, 환자를안심시키는것이다. 그러나, 근치적치료를마친환자의추적과감시 (surveillance) 중어떤검진을얼마나자주하고, 얼마동안하는것이환자의장기결과를향상시키는가에대해서는이견이있다. 방 법 최근좀더집중추적과감시를하는것이환자생존에득이된다는전향적연구들 (2-4) 과덜집중적인감시를하는군과집중감시를시행한군들을비교한무작위배정연구들 (2,3,5-8) 을메타분석한연구결과들이발표되었다 (9-12). 이결과들과이에근거하여각전문가집단이모여도출한각학회들의진료지침, 즉 2005년미임상암학회 (American Society of Clinical Oncology, ASCO) 의진료지침 (13), 2007년국립포괄적암망 (National Comprehensive Cancer Network, NCCN) 의진료지침 (14), 2005년유럽종양학회 (European Society of Medical Oncology, ESMO)(15,16) 의진료지침등을근거로작성하였다 (Table 1). 진료권고안 전이성대장암환자의일부에서전이또는재발병소를절제함으로써완치를시킬수있다는것이알려지면서다양한감시전략과검사의유용성에대한연구가시행되었다. ASCO는최근발표된우수한 3개 (9-11) 의메타분석을조사한결과, 집중감시를한경우모든사망의위험을 20 30% 감소시킬수있었고, 절대적인사망률의차이는 7% 였다고보고하였다 (13). 덜집중적인감시를하는군에비해집중감시를하는경우, 두군간에재발률의차이는없었지만더조기에재발을발견할수있었고, 재발또는전이병소의절제가능성이높았다 (2). 또한 carcinoembryonic antigen (CEA) 와간영상검사를시행한경우좋은결과를얻을수있었다. 1. 병력청취와이학적검사주기적방문의빈도, 기간및이점에대한체계적인연구결과는없지만, 이방문을통해재발의위험도를평가하고, 재발증상을묻거나, 증상이없이재발한병변을찾고, 유전자검사나간절제와같은수술적처치에대한상담, 및향후검사에대한계획을조율할수있다. 개개환자의재발위험, 즉 5년무병생존기간은 http://www.mayoclinic.com/calcs에서산출해볼수있다. 결장암의재발중 80% 가수술후첫 3년내에발생하므로 (17), 첫 3년간은매 3 6개월마다, 그후는덜자주방문하는것을권고하고있다. 직장암의경우 5년이후에도재발의위험이계속되므로 (18,19) 더오랜기간추적검사가필요할수있다. ASCO 진료지침은수술후첫 3년동안은매 3 6개월마다, 4,5년째는매 6개월마다의사를방문하여야하며, 이후기간은의사의판단에따르도록권고하고있고, 결장암의 ESMO 진료지침은첫 3년간은매 3 6개월마다, 4, 5년째는 6 12개월마다방문하도록권고하고있다. 그러나직장암의경우는근거가부족하다고하여, ESMO에서는첫 2년간 6개월마다방문하는것외에지침을세우고있지않다. 그러나 NCCN은첫 2년간은매 3 6개월마다, 이후총 5년간은매 6개월마다진료를받도록권고하고있고, CCO는첫 3년간은최소 6개월마다, 이후총 5년간은매년받도록권고하고있다. S20
Kyung Hae Jung: Postoperative Follow-up Strategies in Colorectal Cancer Table 1. Recommendations for follow-up of patients with curatively resected colorectal cancer ASCO(13) NCCN v.1.2008(23) CCO(9) ESMO, colon cancer(15) ESMO, rectal cancer(16) History & physical examination Every 3-6 months for first 3 years, then every 6 months during years 4 & 5 Every 3-6 months for 2 years, then every 6 months for a total of 5 years At least every 6 Every 3-6 months Every 6 months months for 3 years and then for 3 years and every 6-12 months for 2 years yearly for at least year 4 & 5 5 years in patients for stage IIB & III and fit for treatment CEA CBC, Liver function test, & FOB Every 3 months in patients with stage II or III for at least 3 years if candidate for surgery or systemic therapy Every 3-6 months for 2 years, then every 6 months for a total of 5 years for T2 or greater lesions if candidate for aggressive surgery At least every 6 months for 3 years and then yearly for at least 5 years in patients for stage IIB & III and fit for treatment Every 3-6 months for 3 years and every 6-12 months year 4 & 5 if initially elevated Not recommended - - Restricted to patients with suspicious symptoms - - Abdominal CT/ ultrasound of liver Annual CT for 3 years if candidate for curative-intent surgery Annual CT for 3 years for patients at high risk of recurrence Ultrasonography at least every 6 months for 3 years and then yearly for at least 5 years in patients for stage IIB & III and fit for treatment Ultrasonography every 6 months for 3 years and then annually for years 4 & 5 - Chest CT Annually for 3 years if candidate for curative-intent surgery Pelvis CT Annually for 3 years if candidate for curative-intent surgery in rectal cancer Annually for 3 years for patients at high risk of recurrence Annually for 3 years for patients at high risk of recurrence - - - - - - Chest X-ray Not recommended - At least every 6 months for 3 years and then yearly for at least 5 years in patients for stage IIB & III and fit for treatment Low sensitive, but can be considered every year for 5 years - S21
J Clin Cancer Res. 2007;1(Suppl. 1) Table 1. Continued. ASCO(13) NCCN v.1.2008(23) CCO(9) ESMO, colon cancer(15) ESMO, rectal cancer(16) Colonoscopy Pre- or perioperative documentation of cancer or polyp-free colon At 3 years and then, if normal, once every 5 years thereafter if high-risk genetic syndromes, consider guideline by the AGA(21) Within 1 year of resection (or 3-6 months if not performed preoperatively due to obstructing lesion), if abnormal, repeat in 1 year, if no advanced adenoma, repeat in 3 years, then every 5 years Postoperatively if not yet done if polyps are present, repeat yearly as long as polyps are found if no polyps, repeat in 3 to 5 years At 1 year and thereafter every 3 years to look for metachronous adenomas or cancers Every 5 years Procto (sigmoido)scopy Every 6 months for 5 years if not received pelvic radiation in rectal cancer Every 6 months for 5 years for patients status post low anterior resection (Rectal cancer) Every 6 months for 2 years for distal sigmoid colon cancer Every 6 months for 2 years PET scan - Not routinely recommended - - - Abbreviations: ASCO, American Society of Clinical Oncology; CT, computed tomography; NCCN, National Comprehensive Cancer Network; CCO, Cancer Care Ontario; ESMO, European Society of Medical Oncology; CEA, carcinoembryonic antigen; FOB, fecal occult blood test; CT, computed tomography; PET, positron emission tomography 2. 실험실검사 ASCO는혈청 carcinoembryonic antigen (CEA) 를 2기와 3기환자에서최소 3년동안은 3개월마다시행하되, 5-FU를근간으로하는보조치료로인해 CEA치가올라갈수있으므로보조요법을끝내고집중감시를시작하도록권고하고있다. ESMO는결장암환자에서처음진단시 CEA가상승된경우, 첫 3년간은매 3 6개월마다, 이후 2년간은매 6 12개월마다검사하도록권고하고있으나, 직장암에서는정기적인 CEA 측정을권장하고있지않다. NCCN에서도 T2 이상의병기를갖고적극적인수술의대상이되는경우, 첫 2년간은매 3 6개월마다, 이후총 5년간은매 6개월마다 CEA를검사하도록권하고있다. 다른혈액검사 ( 일반혈액검사, 간기능검사 ) 나대변잠혈검사를주기적으로측정하는것은모두추천되지않으며, 의심되는증상이있는환자에국한하여시행할것을모든진료지침에서추천하고있다. 3. 영상검사 2005년 ASCO 진료지침중 2000년진료지침에비해가장달라진점은컴퓨터단층촬영부분이다. S22
Kyung Hae Jung: Postoperative Follow-up Strategies in Colorectal Cancer 3개의메타분석에서모두컴퓨터단층촬영또는간영상검사가생존향상에도움이된다고보고하였고, 특히간영상검사를했던환자에서사망률을 25% 감소시킬수있었다. 따라서 ESMO의직장암진료지침을제외한모든진료지침이복부컴퓨터단층촬영또는간초음파검사를주기적으로시행할것을권장하고있다. ASCO와 NCCN은재발위험이높고근치목적의수술이적합한환자는첫 3년간매년복부와흉부컴퓨터단층촬영을하도록권하고있으며, 직장암환자, 특히방사선치료를받지않았던환자는골반컴퓨터단층촬영도함께고려하도록추천하고있다. 흉부컴퓨터단층촬영에대한증거는적지만, 절제가능한폐전이의대부분이복부단층촬영보다는흉부단층촬영에서많이발견되고 (20), 폐전이에서는 CEA의상승이잘관찰되지않고, 직장암에서는간만큼폐전이가흔하며절제가능하므로, 추적검사에포함시켰다. 그러나 CCO와 ESMO는복부컴퓨터단층촬영대신간초음파검사를첫 3년간매 6개월마다시행하고, 이후 2년내지 5년간매년시행하도록권고하고있지만, 흉부나골반컴퓨터단층촬영은권장하고있지않다. ASCO는흉부 X선검사를시행하지말도록권고하고있으나, CCO는첫 3년간은매 6개월마다, 이후 5년간은매년시행할수있다고하고있고, ESMO도민감도가떨어지는검사이지만 5년간매년시행을고려할수있다고하고있다. 4. 내시경검사 모든대장암환자는수술전또는수술직전이나직후에다른암이나용종이없는가를확인하기위해대장내시경술을받아야한다. ASCO는 2003년발표된미국위장병학학회 (American Gastroenterology Associatioin, AGA) 의권고 (21) 에따라수술후 3년째대장내시경술을시행하고, 정상이면이후매 5년마다시행하도록권고하고있다. 그러나, NCCN이나 ESMO에서는 2006년발표된 American Cancer Society와 US Multi-Society Task Force On Colorectal Cancer의지침 (22) 에따라수술후첫 1년째대장내시경술을시행한후용종등의이상이있는경우에는이후매년반복하고, 이상이없는경우는 3 5 년후검사를반복하도록권고하고있다. 유연구불결장경술은직장암환자, 특히골반방사선조사를받지않은환자에서매 6개월마다최소 2년에서 5년간시행하도록권고하고있다. 5. 검사실검사에의한예후또는예측인자 ASCO는현재까지전향적임상연구결과가나오기까지는분자또는세포학적표지자를감시전략수립에사용하지말도록권고하고있다. 결 론 진료지침에따라대상환자의범위가달라지지만, 재발의위험이높으면서 (2기와 3기 ) 재발하였더라도수술과같은적극적인치료의대상이되는환자는재발의집중감시를하는것이권장되며, 정기적인병력청취와이학적검진, CEA, 간영상검사, 및대장내시경술과같은검사를받도록권고하고있다. 그러나, 같은 2기나 3기의환자라할지라도병기아형, 검사된림프절개수, 분화도, 림프관 / 혈관침범과같은병리학적소견이나분자생물학적표지자에따라재발의위험이다르므로이를전향적으 S23
J Clin Cancer Res. 2007;1(Suppl. 1) 로평가하고이에따른감시체계를평가하는전향적임상시험이필요하다. 참고문헌 1. Bohm B, Schwenk W, Hucke HP, Stock W: Does methodic long-term follow-up affect survival after curative resection of colorectal carcinoma? Dis Colon Rectum 36:280-6, 1993 2. Pietra N, Sarli L, Costi R, Ouchemi C, Grattarola M, Peracchia A: Role of follow-up in management of local recurrences of colorectal cancer: a prospective, randomized study. Dis Colon Rectum 41:1127-33, 1998 3. Secco GB, Fardelli R, Gianquinto D, Bonfante P, Baldi E, Ravera G, et al: Efficacy and cost of risk-adapted follow-up in patients after colorectal cancer surgery: a prospective, randomized and controlled trial. Eur J Surg Oncol 28:418-23, 2002 4. Rodriguez-Moranta F, Salo J, Arcusa A, Boadas J, Pinol V, Bessa X, et al: Postoperative surveillance in patients with colorectal cancer who have undergone curative resection: a prospective, multicenter, randomized, controlled trial. J Clin Oncol 24:386-93, 2006 5. Schoemaker D, Black R, Giles L, Toouli J: Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 114:7-14, 1998 6. Kjeldsen BJ, Kronborg O, Fenger C, Jorgensen OD: A prospective randomized study of follow-up after radical surgery for colorectal cancer. Br J Surg 84:666-9, 1997 7. Ohlsson B, Breland U, Ekberg H, Graffner H, Tranberg KG: Follow-up after curative surgery for colorectal carcinoma. Randomized comparison with no follow-up. Dis Colon Rectum 38:619-26, 1995 8. Makela JT, Laitinen SO, Kairaluoma MI: Five-year follow-up after radical surgery for colorectal cancer. Results of a prospective randomized trial. Arch Surg 130:1062-7, 1995 9. Figueredo A, Rumble RB, Maroun J, Earle CC, Cummings B, McLeod R, et al: Follow-up of patients with curatively resected colorectal cancer: a practice guideline. BMC Cancer 3:26, 2003 10. Renehan AG, Egger M, Saunders MP, O'Dwyer ST: Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. Bmj 324:813, 2002 11. Jeffery GM, Hickey BE, Hider P: Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev CD002200, 2002 12. Jeffery M, Hickey BE, Hider PN: Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev CD002200, 2007 13. Desch CE, Benson AB, 3rd, Somerfield MR, Flynn PJ, Krause C, Loprinzi CL, et al: Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 23:8512-9, 2005 14. Engstrom PF BA, et al: NCCN colon cancer clinical practice guidelines in oncology. 2008 [cited; Available from: http://www.nccn.org 15. Van Cutsem EJ, Kataja VV: ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer. Ann Oncol 16:i16-7, 2005(Suppl 1) 16. Tveit KM, Kataja VV: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of rectal cancer. Ann Oncol 16:i20-1, 2005(Suppl 1) 17. Sargent DJ, Wieand HS, Haller DG, Gray R, Benedetti JK, Buyse M, et al: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-70, 2005 18. Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB, Cummings B, et al: Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114. J Clin Oncol S24
Kyung Hae Jung: Postoperative Follow-up Strategies in Colorectal Cancer 20:1744-50, 2002 19. Guillem JG, Chessin DB, Cohen AM, Shia J, Mazumdar M, Enker W, et al: Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg 241:829-36; discussion 836-8, 2005 20. Chau I, Allen MJ, Cunningham D, Norman AR, Brown G, Ford HE, et al: The value of routine serum carcino-embryonic antigen measurement and computed tomography in the surveillance of patients after adjuvant chemotherapy for colorectal cancer. J Clin Oncol 22:1420-9, 2004 21. Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucci J, et al: Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology 124:544-60, 2003 22. Rex DK, Kahi CJ, Levin B, Smith RA, Bond JH, Brooks D, et al: Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer. CA Cancer J Clin 56:160-7; quiz 185-6, 2006 23. Engstrom PF BA, et al: NCCN colon cancer clinical practice guidelines in oncology. 2007 [cited; Available from: http://www.nccn.org S25
J Clin Cancer Res. 2007;1(Suppl. 1):26-29 Session 2 대장직장암의근치적수술후나타난대동맥주변림프절단독재발의치료 관동대학교의과대학외과학교실 박재균 Abstract Isolated paraaortic lymph node recurrence (IPLR) is a rare type of recurrence after curative surgery for colorectal carcinoma and there is no previous literature specifically addressing this type of recurrence. Although clinical features and outcome of the patients with IPLR are not been well defined, IPLR is well characterized in cervical cancer. IPLR in cervical cancer is known to occur in about 2% of patients and can be succesfully treated with concurrent chemoradiation therapy. In colorectal cancer, some authors has been categorized IPLR as a retroperitoneal recurrence, which is a type of locoregional recurrence. The curative resection rate in IPLR is very low, and than poor prognosis. However, the group of patients with curative resection has been demonstrated considerable survival time than those non-operative and/or incomplete resection group. Recently some authors has been reported aggressive resection of the IPLR with improvement of survival. And also the developments of new biologic agents and improvement of radiation therapy has improved the survival of patients with metastatic colorectal cancer. Thus, despite IPLR after curative surgery for colorectal carcinoma is a very rare type of recurrence and found to be associated with poor prognosis, in cautiously selected cases, better survival might be expected through potentially curative resection of IPLR. Key words: paraaortic lymph-node recurrence, locoregional recurrence, colorectal cancer 서 론 대장직장암은국내에서 4번째로흔한암환자사망률의원인이며, 근치적인절제유무가환자의생존율과재발의방지에매우중요한예후인자이다. 대장직장암으로근치적절제술을시행받은환자들중 20 40% 는재발을경험하게된다 (1). 그중국소재발은 5 10%, 전신재발은 15 30% 를차지하는것으로보고되고있지만대동맥주변림프절의단독재발은매우드문형태로써이에해당되는환자들의임상적특징및예후에관해서는거의알려진바가없다. 대장직장암의수술후후복막재발 (retroperitoneal recurrence) 및국소적인재발 (locoregional recurrence) 의범주에분류한저자들이있지만대동맥주 S26
박재균 : 대장직장암의근치적수술후나타난대동맥주변림프절단독재발의치료 변의단독재발로보기는힘들다 (2-4). 본종설에서는대장및직장암의근치적절제술후발생한후복막의재발, 국소적인재발등으로이전에발표된논문및 Min 등 (5) 이 2007년춘계대장항문학회에서 " 대장직장암의근치적수술후나타난대동맥주변림프절단독재발 " 에대하여구연발표한데이터를비교분석하고, 대동맥주변림프절단독전이가발견된환자들의임상적특징및이들의예후에관여하는인자들을비교해보고자한다. 본 론 대장직장암의근치적절제술후발생하는후복막의재발은매우드문형태의재발양상으로써예후가매우불량한것으로보고되고있다. 대동맥주변림프절의단독재발 (IPLR: isolated paraaortic lymphnode recurrence) 은대장직장암의근치적수술후복강및전신의다른부위에재발의징후가없이대동맥주위의림프절에재발된경우로주로원발암의근치적절제술후외래에서시행하는추적검사중혈청 CEA의증가와복부전산화단층촬영 (CT) 으로진단이된다 (5). 조직검사는진단의가장정확한방법이지만수술이불가능한상태에서는조직검사가시행되지는않는다. IPLR은자궁경부암의경우에약 2% 정도의발병률을보이고, 항암방사선치료로써치료가가능한것으로보고되고있다 (6,7). 외과의경우에는후복막재발로발표된논문이있으나그곳에는 IPLR 외에종양의침윤혹은수술후잔존암에서발생한경우도포함되기때문에 IPLR의예후를유출하기에는무리가있다 (4). Min 등 (5) 이실행한검사에서는 IPLR의발병률이 1.3% 로조사되었지만 3차병원의특성상재발환자들이전원될수있기때문에실제발병률은그보다낮을것으로생각된다. IPLR의예후가불량할것이라고예상할수있는데 Shibata 등 (4) 은후복막재발후약 15개월의생존율을보고하였고, 재발후근치적절제를시행한경우에는약 40 44개월의생존율을보고하여, 다른국소적인재발의생존율과비슷한결과를보고하였다 (1-3,8). Min 등 (5) 은원발암의수술후 IPLR이발생한경우평균생존율이 17개월이었고, 근치적절제가가능했던환자의생존율이 34개월이었다고보고하였다. 위의결과로 IPLR의경우에원발암의수술후발생한다른국소적인재발과비교하여예후가차이가없을것으로생각된다. 대장직장암의수술후재발이발생한경우여러가지인자들이환자의예후에영향을미치는것으로보고된다. Bowne 등 (8) 은대장암의수술후국소적인재발이발생한 100명의환자에서복막의전이, 림프절전이, 2군데이상의병소, 혈청 CEA 5μg/ml 이상등이근치적절제술에영향을미치는불량한예후인자라고보고하였고, Shibata 등 (4) 은원발암수술후 2년이상의무병기간, 재발병소의근치적절제유무, 종양의크기 5 cm 이하등이생존율에영향을미치는예후인자라고보고하였다. 또한전이림프절의위치가중요한예후인자인데, 신장동맥의상부에위치한병소는주위에복강동맥 (celiac artery), 상장간막동맥 (superior mesenteric artery), 총담관 (common bile duct) 및췌장 (pancreas) 등의장기들과밀접한관계가있기때문에근치적절제술이어려운경우가많다 (4,5). 그에반하여하부에위치한림프절은하장간막동맥 (inferior mesenteric artery) 의결찰및잔존결장의절제가가능하기때문에근치적절제가더용이하다고생각된다. 그럼에도불구하고 IPLR의근치적절제율이매우낮은데이는질환의특성상복부대동맥, 신장, 요관 (ureter) 등후복막장기에직접적인침범이많고, 이러한경우에외과의사들이적극적인절제를시도하지않는것도원인일것이라고생각된다. Min 등 (5) 은총 38명의환자중 6명 (15.7%) 의환자에서절제를시행했는데그중 4명이신장동맥하부에위치한림프절이었으며, 2예에서좌측신장, 소장및결장등의다장기절제 (en block resection) 를시행하였다. 근래에 Hashimoto 등 (9) 이복부대 S27