근치적절제술을시행받은바터팽대부 (Ampulla of Vater) 암환자의예후인자 연세대학교대학원의학과정문재
근치적절제술을시행받은바터팽대부 (Ampulla of Vater) 암환자의예후인자 지도교수박승우 이논문을석사학위논문으로제출함 2008 년 6월 연세대학교대학원의학과정문재
정문재의석사학위논문을인준함 심사위원 인 심사위원 인 심사위원 인 연세대학교대학원 2008 년 6월
감사의글 본논문이완성되기까지깊은애정과자상한지도로이끌어주신박승우교수님께진심으로감사드립니다. 선생님의도움으로의학을생각하고표현하는기술을배울수있었습니다. 또한제연구의부족한점을냉철하게지적해주시고방향을잡아주신권오헌교수님과김경식교수님께도지면을빌어감사의말씀을드립니다. 아울러여러가지조언을아끼지않으셨던방승민교수님과김희만선생님께도감사의말씀을드리며, 이논문을완성하는과정에서격려로써도움을준강원석, 김덕환, 이진하선생님께도감사드립니다. 언제나저에대한사랑으로가득한아내가있었기에이논문을완성할수있었습니다. 마지막으로항상안타까운마음으로제앞길을염려하고걱정하시는부모님께고개숙여감사드리며이작은논문을바칩니다. 저자씀
차례 국문요약 1 Ⅰ. 서론 4 II. 대상및방법 7 1. 연구대상 7 2. 연구방법 9 3. 통계및분석 12 III. 결과 13 1. 연구대상자의임상적특징 13 2. 생존기간에영향을미치는인자 17 가. 생존기간에영향을미치는인자에대한단변량분석 17 나. 생존기간에영향을미치는인자에대한다변량분석 20 3. 국소재발에영향을미치는인자 21 가. 국소재발에영향을미치는인자에대한단변량분석 21 나. 국소재발에영향을미치는인자에대한다변량분석 24 4. 원격재발이영향을미치는인자 25 가. 원격재발에영향을미치는인자에대한단변량분석 25 나. 원격재발에영향을미치는인자에대한다변량분석 29 5. 치료군에따른생존기간의차이 30 가. 치료군에따른위험인자의분포 30
나. 고위험군에서치료군에따른생존기간의차이 31 6. 치료군에따른재발율의차이 32 가. 고위험군에서치료군에따른국소재발율의차이 32 나. 고위험군에서치료군에따른원격재발율의차이 33 IV. 고찰 34 V. 결론 39 참고문헌 41 영문요약 46
그림차례 Fig. 1. Selection process of patient population 8 Fig. 2. Kaplan-Meier curves estimating overall survival stratified by presence or absence of lymph node 18 Fig. 3. Kaplan-Meier curves estimating overall survival stratified by TNM stage 18 Fig. 4. Kaplan-Meier curves estimating cumulative local recurrence rate stratified by presence or absence of lymph node 21 Fig. 5. Kaplan-Meier curves estimating cumulative local recurrence rate stratified by T stage 22 Fig. 6. Kaplan-Meier curves estimating cumulative local recurrence rate stratified by TNM stage 22
Fig. 7. Kaplan-Meier curves estimating cumulative distal recurrence rate stratified by Histologic grade 25 Fig. 8. Kaplan-Meier curves estimating cumulative distant recurrence rate stratified by lymph node 26 Fig. 9. Kaplan-Meier curves estimating cumulative distant recurrence rate stratified by T stage 26 Fig. 10. Kaplan-Meier curves estimating cumulative distant recurrence rate stratified by TNM stage 27
표차례 Table 1. Patients characteristics 15 Table 2. Characteristics comparison of three treatment groups 16 Table 3. Univariate analysis of overall survival: outcomes by risk factor stratification 19 Table 4. Multivariate analysis of overall survival: outcomes by risk factor stratification 20 Table 5. Univariate analysis of local recurrence: outcomes by risk factor stratification 23 Table 6. Multivariate analysis of local recurrence: outcomes by risk factor stratification 24 Table 7. Univariate analysis of distant recurrence: outcomes by risk factor stratification 28
Table 8. Multivariate analysis of distant recurrence: outcomes by risk factor stratification 29 Table 9. Distribution of adverse risk factors between treatment groups 30 Table 10. Distribution of adverse risk factors between adjuvant therapy modality 30 Table 11. Effect of adjuvant therapy on overall survival, stratified by negative prognostic categories 31 Table 12. Effect of adjuvant therapy modality on overall survival stratified by negative prognostic categories 31 Table 13. Effect of adjuvant therapy on local recurrence, stratified by negative prognostic
categories 32 Table 14. Effect of adjuvant therapy modality on local recurrence, stratified by negative prognostic categories 32 Table 15. Effect of adjuvant therapy on distant recurrence, stratified by negative prognostic categories 33 Table 16. Effect of adjuvant therapy modality on distant recurrence, stratified by negative prognostic categories 33
국문요약 근치적절제술을시행받은바터팽대부 (Ampulla of Vater) 암환자의예후인자 바터팽대부암은팽대부주위암의약 6%~20% 을차지하고있으며, 췌장암이나담도계암에비해예후가좋고, 절제가능한경우가많은것으로알려져있다. 팽대부주위암중췌장암의경우근치적절제술과보조항암화학요법이생존율을증가시킨다는사실이과거전향적대조군연구를통하여입증되어왔지만, 바터팽대부암에서는보조항암화학요법이나보조동시화학방사선요법같은수술후보조항암요법의역할이알려져있지않다. 따라서본연구는근치적절제술을시행받은바터팽대부암환자들을대상으로생존기간, 국소재발, 원격재발등의예후를예측할수있는수술전예후인자들과근치적절제술후보조항암요법이생존기간을향상시키거나, 국소재발, 원격재발을감소시키는데에기여하는지를조사하였다. 본연구는 1987년 1월부터 2007년 8월까지연세대학교 1
세브란스병원에서바터팽대부암으로진단받고근치적절제술을시행받은총 137명의환자들의진료기록부를후향적으로조사하였다. 이중수술후 2개월이내에사망한 5명은제외하였다. 16명의환자가수술후보조항암화학요법을, 9명의환자가수술후보조동시항암방사선요법을받았다. 중앙추적기간은 38.4개월 ( 범위 ; 2-237개월 ) 이었다. 대상환자들의중앙생존기간은 43.1개월 (3-237개월 ) 이었으며 2년, 5년생존율은각각 79.7%, 60.4% 이었다. 단변량분석결과생존기간의감소를예측하게하는예후인자는수술전국소림프절전이여부, TNM 병기였고, 다변량분석결과국소림프절전이여부만이생존기간의감소를예측하게하는예후인자였다 (HR 2.8, p=0.015). 국소림프절전이를보이는고위험군에서의생존기간을분석한결과, 치료군 ( 수술군, 보조항암화학요법군, 보조동시화학방사선요법군 ) 간생존기간의차이는없었다. 결론적으로바터팽대부암환자에서근치적절제술후불량한예후를예측하게하는위험인자는수술전국소림프절전이이며. 고위험군환자에서근치적절제술후 2
보조항암요법은생존기간을증가시킨다는것을입증하지 못하였다. ---------------------------------------------- 핵심되는말 : 바터팽대부암, 근치적절제술, 예후인자 보조항암화학요법, 보조동시화학방사선요법, 생존기간, 국소재발, 원격재발 3
근치적절제술을시행받은바터팽대부 (Ampulla of Vater) 암환자의예후인자 < 지도교수박승우 > 연세대학교대학원의학과 정문재 Ⅰ. 서론 바터팽대부암은팽대부주위암의 6%~20% 을차지한다. 팽대부주위암의 60%~65% 을차지하는췌장두부암에이어두번째로높은빈도이다 1-3. 팽대부암은췌장암이나담도계암에비해예후가좋고, 절제가능한경우가많은것으로알려져있다. 보고자에따라다르지만진단당시절제가능한경우가 80% 내외이고 4, 5, 근치적절제술을시행받은경우 5년생존율이 30%~68% 정도로조사되고있다 6-11. 지금까지췌십이지장절제술이바터팽대부암뿐만 4 아니라 4
췌장암에있어서근치적치료법으로생각되어지고있다. 1970년대후반에서 1980년대초반에걸쳐이루어진 GITSG study(the Gastrointestinal Tumor Study Group) 결과췌장암환자에서근치적절제술만을시행받은환자군과비교하여근치적절제술을시행받은후보조동시화학방사선요법 (adjuvant concurrent chemoradiotherapy) 을받은환자에서 2년생존율이증가되는것을관찰할수있었다. 하지만이후에이루어진 EORTC study(the European Organization for Research and Treatment of Cancer) 에서는보조동시화학방사선요법이생존기간, 2년생존율을증가시키는데기여하지못한다는결과를얻었다. 췌장암에서수술후보조항암요법에대한전략이확립되지않은상태에서 ESPAC-1 trial(the European Study Group for Pancreatic Cancer) 이시행되었다. 이연구에서 238 명의보조항암화학요법을시행받은췌장암환자가근치적절제술을받고보조항암화학요법을시행받지않은 235 명의췌장암환자와비교하여유의한생존율의증가를보였다 12, 13. 368명의췌장암환자를대상으로한 CONKO- 001(Charité Onkologie) 연구에서도근치적절제술후보조항암화학요법 (Gemcitabine) 을시행받은환자군에서그렇지않은환자군에비해근치적절제술후재발의시기를늦출수있다는결과를보였다 14. 한편 125명의바터팽대부암환자를대상으로한후향적연구에서국소림프절전이를보이는고위험 5
환자군에서보조동시화학방사선요법이생존기간의향상을가져올수있다는보고를하였다 6. 하지만바터팽대부암환자에있어서생존기간이나재발율에대한확립된예후인자나치료원칙이없는상태이다. 이연구의목적은바터팽대부암환자의생존기간과누적재발률에영향을미치는예후인자들을조사해보고, 아울러바터팽대부암환자의생존기간과누적재발율에대한보조항암요법의역할에대해알아보려고한다. 6
Ⅱ. 대상및방법 1. 연구대상 본연구는 1987 년 1 월부터 2007 년 8 월까지연세대학교세브란스병원에서바터팽대부암으로진단받고근치적절제술을시행받은환자들을대상으로하였다. 바터팽대부암은팽대부나유두부에서기시한암으로정의하였고, 조직학적소견은샘암종으로국한하였다. 환자군중간경화, 말기신장병등예후와관련된동반질환이있거나기타장기에악성종양이동반된경우는대상 환자군에서제외하였다. 수술후 2 개월이내에사망한환자가 5 명이었는데, 수술후사망환자들은보조항암요법의대상자가 되지못하고, 수술군의생존기간을낮추게되어다른군과의 불균형을방지하기위해연구대상에서제외하였다 (Fig. 1). 7
AOV cancer (N=172) Non-resectable cases (N=18) Curative resection (N=154) Adenocarcinoma (N=150) Cases other than adenocarcinoma on pathology (N=4) N=137 Total of 132 patients included Comorbidity (cancer, LC, ESRD) (N=13) Patients died within 2months after operation (N=5) Fig. 1. Selection process of patient population (AOV: Ampulla of Vater, LC: Liver cirrhosis, ESRD: End stage renal disease) 8
2. 연구방법 가. 바터팽대부암 : 팽대부 (ampulla) 혹은유두부 (papilla) 혹은두부위를모두침범한경우로정의하였고, 췌장두부암이나총담관암은제외하였다. 팽대부주위십이지장과팽대부를함께침범한경우에는그원발장소를정확히구분할수없을경우에도팽대부침범이확인되면바터팽대부암으로포함시켰다. 진단은수술후절제된검체의병리학적소견을기준으로하였다. 나. 수술 : 132명의환자중 5명의환자에서경십이지장유두부절제술을시행하였으며, Whipple 술식이 51명, 유두보존췌두부십이지장절제술이 76명이었다. 수술후모든환자에서절제연에암침윤이없는것을확인하였다. 다. 근치적절제 : 수술후절제된검체의절제면에서현미경적으로악성종양의침범이없음이증명되고, 수술부위와다른장기에남아있는종양이없을때로정의하였다. 라. 결과측정 (1) 생존기간은진단일로부터계산하였다 (2) 국소재발과원격재발은컴퓨터단층촬영, 복부초음파등의방사선학적검사소견을기준으로하였다. (3) 국소재발은절제연또는주변림프절에서의재발로 9
정의하였다. (4) 원격재발은 국소 재발 부위를 넘어선 부위의 재발로 정하였다. 마. 치료군 (1) 수술군 (Surgery only group): 수술후보조항암요법을시행 받지않은치료군 (2) 보조항암화학요법군 (Adjuvant Chemotherapy group): 수술 후보조항암화학요법을시행받은치료군 (3) 보조동시화학방사선요법군 (Adjuvant concurrent chemoradiotherapy group): 수술 후 보조동시항암방사선요법을시행받은치료군 바. 예후인자 : 성별, 진단당시연령, 종양의크기, 췌장침범여부, 종양의육안적소견, TNM(Tumor node metastasis) 병기, 국소 림프절 전이 여부, 조직학적 분화도를 바터팽대부암의 예후인자로써 예상하여 조사하였다. TNM 병기는 AJCC(American Joint Committee on Cancer) cancer staging manual, 6 th edition을따랐다. 사. 사망일 : 환자들의사망일및생존여부는통계청자료와병력 기록지의내용을, 마지막추적일은병력기록지의내용을 기준으로하였다. 10
아. 본연구를위한자료중종양의크기, 췌장의침범여부, 국소 림프절전이여부, 조직학적분화도는병리보고서를, 종양의 육안적소견은수술기록지및병리보고서를근거로하였다. 11
3. 통계및분석 모든자료의통계처리는개인용컴퓨터통계프로그램 SPSS Window release Ver. 11.0 을이용하여수행하였으며, p-value 가 0.05 미만인경우통계학적으로유의한차이가있는것으로간주하였다. 생존기간, 생존곡선등의생존자료분석을위하여 Kaplan-Meier 방법을이용하였다. 생존기간과재발율에영향을미치는예후인자를조사하기위한단변량검사는 Log-rank testing 을, 다변량검사는 Cox regression model 을사용하여수행하였다. 통계학적으로유의한예후인자를확인한후, 고위험군에서치료군간생존기간, 누적국소재발율, 누적원격재발율을조사하기위해 Log-rank testing 을이용하였다. 예후인자의치료군간분포는 Fisher s Exact Test 를사용하여 비교하였다. Hazard ratio 를추정하기위하여 Cox regression model 을이용하였다. 12
Ⅲ. 결과 1. 연구대상자의임상적특징 본연구기간동안연세대학교세브란스병원에서바터팽대부암으로진단받고근치적절제술을시행받은환자중포함기준과제외기준을만족하는연구의대상자는총 132명이었다. 이중남자가 74명 (56.1%) 이었고, 여자가 58명 (43.9%) 이었다. 중앙연령은 58.0( 범위 ; 28-78) 세이었고, 평균종양크기는 2.2cm(±1.16cm) 이었다. 16명의환자에서보조항암화학요법을, 9명의환자에서보조동시화학방사선요법을시행받았으며, 107명의환자는수술후보조항암요법을시행받지않았다. AJCC cancer staging manual, 6 th edition 에따른 TNM 병기별환자분포는각각 Ⅰa 16명 (12.1%), Ⅰb 45명 (34.1%), Ⅱa 25명 (19.0%), Ⅱb 43명 (32.6%), Ⅲ 3명 (2.3%) 이었다. 종양의육안적소견에따라궤양이동반된경우가 39명 (31.2%), 궤양을형성하지않은경우가 86명 (68.8%) 이었다 (Table 1,2). 수술후 2개월이내에사망한환자가 5명이었으며, 문합부췌관의누출로인한사망, 수술후심근경색으로인한사망, 간동맥파열에따른간기능부전에의한사망, 장출혈에의한사망이각각 1명씩이었다. 나머지한명은수술후 2개월후에사망하였고퇴원후내원하지않아사인을 13
확인할수없었다. 이들은모두연구대상에서제외되었다. 평균추적기간은 63.2개월이었으며최장추적기간은 237개월이었다. 분석당시총 56명의환자가사망한상태였다. 모든환자들을대상으로수술전전산화단층촬영검사, 자기공명영상검사, 내시경적초음파검사, 내시경적역행성담췌관조영술검사중적어도하나이상의검사를통해수술전병기를예측하였다. 보조항암화학요법을시행받은환자중 Fluorouracil(5-FU) 을기본으로한항암제조합이 11명, Gemcitabine을기본으로한항암제조합이 5명이었으며, 보조동시화학방사선요법을시행받은환자중 Fluorouracil(5-FU) 을기본으로한항암제조합이 8명, Gemcitabine을기본으로한항암제조합이 1명이었다. 보조동시화학방사선요법군에서중앙총방사선량은 50.4Gy( 범위 ; 45.2-54.0Gy) 였다. 보조항암요법을받은환자들에서백혈구감소증및혈소판감소증, 빈혈등항암화학요법과관련된 Grade 3 이상의혈액학적독성 (toxicity) 은 6명 (24%) 에서관찰되었다. 오심, 구토는 56%, 설사는 28%, 구내염은 8.0%, 혈액학적독성은 36% 의환자에서 Grade 1,2의독성을보였다. 14
Table 1. Patients characteristics (n=132) Characteristics Value Age at diagnosis, y 58.0(28-78) 1 Men 74(56.1%) Primary treatment Surgery only 107(81.1%) Surgery + Adjuvant chemotherapy 16(12.1%) Surgery + Adjuvant CCRTx 2 9(6.8%) Tumor size, cm 2.2(±1.16) TNM stage 16(12.1%) Ⅰb 45(34.1%) Ⅱa 25(19.0%) Ⅱb 43(32.6%) Ⅲ 3(2.3%) Pathologic stage, primary tumor T1 16(13.1%) T2 61(46.2%) T3 52(39.4%) T4 3(2.3%) Pathologic stage, lymph node N0 87(65.9%) N1 45(34.1%) Histologic grade 3 Grade 1 and 2 108(86.4%) Grade 3 and 4 17(13.6%) Not reported 7(4.6%) Ulceration Non-ulcer formation 86(68.8%) Ulcer formation 39(31.2%) Not reported 7(4.6%) 1 Median(range) 2 Concurrent chemoradiotherapy 3 Histologic grade: 1.well differentiated 2.moderate differentiated 3.poor differentiated 4.Undifferentiated 15
Table 2. Characteristics comparison of three treatment groups Value Surgery only CTx 1 CCRTx 2 p- Characteristics (n=107) (n=16) (n=9) value Age 57.22 56.68 55.17 0.850 Men 59(55%) 11(68.8%) 4(44.4%) 0.497 Tumor size 2.06 2.93 3.29 0.000 TNM stage 0.000 58(54.2%) 2(12.5%) 1(11.1%) Ⅱ 48(44.9%) 14(87.5%) 6(66.7%) Ⅲ 1(9.3%) 0(0%) 2(22.2%) primary tumor 0.006 T1 15(14.0%) 1(6.3%) 0(0%) T2 53(49.5%) 6(37.5%) 2(22.2%) T3 38(35.5%) 9(56.3%) 5(55.6%) T4 1(0.9%) 0(0%) 2(22.2%) lymph node 0.000 N0 79(73.8%) 4(25%) 4(44.4%) N1 28(26.2%) 12(75%) 5(55.6%) HG 3 0.071 Grade 1 40(37.4%) 6(37.5%) 2(22.2%) Grade 2 51(47.7%) 6(37.5%) 3(33.3%) Grade 3 11(10.3%) 3(18.8%) 2(22.2%) Grade 4 0(0%) 0(0%) 1(11.1%) Ulceration 0.000 Non-ulcer 87(81.3%) 6(37.5%) 2(22.2%) Ulcer 24(22.4%) 8(50%) 7(77.8) 1 Surgery + Adjuvant chemotherapy 2 Surgery + Adjuvant concurrent chemoradiotherapy 3 Histologic grade: 1.well differentiated 2.moderate differentiated 3.poor differentiated 4.Undifferentiated 16
2. 생존기간 (Overall survival) 에영향을미치는인자 가. 생존기간에영향을미치는인자에대한단변량분석대상환자의중앙생존기간은 43.1개월 ( 범위 ; 3-237개월 ) 이었으며 2년, 5년생존율은각각 79.7%, 60.4% 이었다. 생존기간에영향을미치는인자에대한단변량분석을시행한결과, 림프절전이여부 (Fig. 2), TNM 병기 (Fig. 3) 가의미있는인자였다 (Table 3). 17
Fig. 2. Kaplan-Meier curves estimating overall survival stratified by presence or absence of lymph node (HR 4.075; 95% CI 2.370-7.006; p=0.000). Fig. 3. Kaplan-Meier curves estimating overall survival stratified by TNM stage (HR 3.199; 95% CI 1.741-5.878; p=0.000). 18
Table 3. Univariate analysis of overall survival: outcomes by risk factor stratification Cumulative survival (%) Factor Patients 2y 5y HR p-value Age 1 1.0 0.073 Size 1.2 0.075 Sex 0.416 Male 74 80.3 64.1 1.0 Female 58 76.0 53.9 1.2 HG 2 0.198 1/2 107 81.0 62.7 1.0 3/4 17 59.8 44.1 3 1.6 LN 4 0.000 Negative 87 87.3 72.6 1.0 positive 45 61.0 35.6 4.1 Ulceration 5 0.604 Non-ulcer 86 80.2 60.6 1.0 Ulcer 39 75.9 60.2 1.2 T stage 0.055 T1/T2 77 81.1 70.7 1.0 T3/T4 55 74.9 45.2 1.7 TNM stage 0.000 Ⅰ 61 90.5 77.3 1.0 Ⅱ/Ⅲ 6 71 68.6 45.6 3.2 1 Age at diagnosis 2 Histologic grade: 1.well differentiated 2.moderate differentiated 3.poor differentiated 4.Undifferentiated 3 마지막사망확인 45.2개월임. 당시누적생존율을표기 4 Lymph node, 수술전국소림프절전이 5 Gross morphology 6 stageⅢ에해당하는환자가 3명으로적어 stageⅡ/Ⅲ군과 stageⅠ군을비교함 19
나. 생존기간에영향을미치는인자에대한다변량분석단변량분석결과에서의미있었던인자와기존연구결과에서의미있었던인자인육안적소견등을포함하여다변량분석을시행한결과림프절전이여부가생존기간에영향을미치는의미있는예후인자임을알수있었다 (Table 4). Table 4. Multivariate analysis of overall survival: outcomes by risk factor stratification Overall survival Factor HR P value Age at diagnosis 1.0 0.153 Positive lymph node 2.7 0.016 T3/T4 0.8 0.770 Stage Ⅱ/Ⅲ 1.9 0.236 20
3. 국소재발에영향을미치는인자 가. 국소재발에영향을미치는인자에대한단변량분석 2년, 5년누적국소재발율은각각 13.0%, 21.4% 이었다. 국소재발에영향을미치는인자에대해단변량분석을시행한결과, 림프절전이여부 (Fig. 4), T 병기 (Fig. 5), TNM 병기 (Fig. 6) 가의미있는인자였다 (Table 5). Fig. 4. Kaplan-Meier curves estimating cumulative local recurrence rate stratified by presence or absence of lymph node (HR 3.000; 95% CI 1.295-6.948; p=0.010). 21
Fig. 5. Kaplan-Meier curves estimating cumulative local recurrence rate stratified by T stage (HR 2.540; 95% CI 1.093-5.903; p=0.030). Fig. 6. Kaplan-Meier curves estimating cumulative local recurrence rate stratified by TNM stage (HR 3.281; 95% CI 1.288-8.358; p=0.013). 22
Table 5. Univariate analysis of local recurrence: outcomes by risk factor stratification Local recurrence (%) Factor Patients 2y 5y HR p-value Age 1 1.0 0.240 Size 1.2 0.422 Sex 0.295 Male 74 10.6 18.3 1.0 Female 58 18.4 27.3 1.6 HG 2. 0.086 1/2 107 11.4 18.0 1.0 3/4 17 30.8 37.9 3 2.6 Lymph node 0.010 Negative 87 8.7 15.5 1.0 positive 45 24.3 37.6 3.0 Ulceration 0.237 Non-ulcer 86 14.9 23.8 1.0 Ulcer 39 7.1 11.4 0.5 T stage 0.030 T1/T2 77 7.3 15.0 1.0 T3/T4 55 23.2 31.4 2.5 TNM stage 0.010 Ⅰ 61 5.3 12.8 4 1.0 Ⅱ/Ⅲ 5 71 21.9 30.1 3.3 1 Age at diagnosis 2 Histologic grade: 1.well differentiated 2.moderate differentiated 3.poor differentiated 4.undifferentiated 3 마지막재발이 41.4개월, 당시누적발생율을표기 4 마지막재발이 23개월, 당시누적발생율을표기 5 stageⅢ에해당하는환자가 3명으로적어 stageⅡ/Ⅲ군과 stageⅠ군을비교함 23
나. 국소재발에영향을미치는인자에대한다변량분석단변량분석결과에서의미있었던인자를대상으로다변량분석을시행한결과, 국소재발에대한의미있는위험인자는없었다 (Table 6). Table 6. Multivariate analysis of local recurrence: outcomes by risk factor stratification Local recurrence Factor HR P value H3/H4 grade 1 2.2 0.168 T3/T4 classification 1.8 0.449 Positive lymph node 2.3 0.168 Stage Ⅱ/Ⅲ 1.3 0.829 1 Poor differentiated and undifferentiated histologic grade 24
4. 원격재발에영향을미치는인자 가. 원격재발에영향을미치는인자에대한단변량분석 2년, 5년누적원격재발율은각각 28.5%, 34.8% 이었다. 재발부위에따라간이 44명의원격전이환자중 30명으로가장많았고, 암종증 11명, 폐 9명의분포를보였다. 원격전이에영향을미치는인자에대한단변량분석을시행한결과, 종양의크기, 조직학적등급 (Fig. 7), 림프절전이여부 (Fig. 8), T병기 (Fig. 9), TNM병기 (Fig. 10) 가의미있는인자였다 (Table 7). Fig. 7. Kaplan-Meier curves estimating cumulative distal recurrence rate stratified by Histologic grade (HR 2.465; 95% CI 1.126-5.397; p=0.024). 25
Fig. 8. Kaplan-Meier curves estimating cumulative distant recurrence rate stratified by lymph node (HR 2.987; 95% CI 1.626-5.489; p=0.000). Fig. 9. Kaplan-Meier curves estimating cumulative distant recurrence rate stratified by T stage (HR 2.738; 95% CI 1.472-5.094; p=0.001). 26
Fig. 10. Kaplan-Meier curves estimating cumulative distant recurrence rate stratified by TNM stage (HR 5.832; 95% CI 2.590-13.132; p=0.000). 27
Table 7. Univariate analysis of distant recurrence: outcomes by risk factor stratification Distant recurrence (%) Factor Patients 2y 5y HR p-value Age 1 1.0 0.165 Size 1.3 0.047 Sex 0.163 Male 74 26.3 28.2 2 1.0 Female 58 33.1 44.5 1.5 HG 3 0.024 1/2 107 25.3 34.4 1.0 3/4 17 49.2 54.2 4 2.5 LN 5 0.000 Negative 87 20.1 29.1 1.0 positive 45 48.0 55.9 3.0 Ulceration 0.389 Non-ulcer 86 25.9 31.9 1.0 Ulcer 39 32.9 41.8 1.3 T stage 0.001 T1/T2 77 17.3 23.0 1.0 T3/T4 55 46.1 54.1 2.7 TNM stage 0.000 Ⅰ 61 8.4 12.9 6 1.0 Ⅱ+Ⅲ 7 71 47.3 53.4 5.8 1 Age at diagnosis 2 마지막재발이 41.4개월, 당시누적발생율을표기 3 Histologic grade 4 마지막재발이 41.4개월, 당시누적발생율을표기 5 Lymph node 6 마지막재발이 29.5개월, 당시누적발생율을표기 7 stageⅢ에해당하는환자가 3명으로적어 stageⅡ+Ⅲ군과 stageⅠ군을비교함. 28
나. 원격재발에영향을미치는인자에대한다변량분석단변량분석에서의미있는인자들을대상으로다변량분석을시행한결과 TNM stage Ⅱ/Ⅲ 군이 TNM Stage Ⅰ 군에비해원격재발의가능성이높은것을알수있었다 (Table 8). Table 8. Multivariate analysis of distant recurrence: outcomes by risk factor stratification Distant recurrence Factor HR P value Size 1.0 0.843 T3/T4 classification 0.8 0.546 Positive lymph node 1.4 0.423 Stage Ⅱ/Ⅲ 5.2 0.015 Poor histologic grade 1.8 0.149 29
5. 치료군에따른생존기간의차이 가. 치료군에따른위험인자의분포 지금까지단변량분석에서생존기간, 국소전이또는원격전이의위험인자로밝혀진 T병기 (3/4), TNM병기 (stage Ⅱ/Ⅲ), 불량한조직학적등급, 림프절전이등네가지인자모두가수술후보조항암요법을시행받은환자군에서빈도가높음을확인할수있었다 (Table 9,10). Table 9. Distribution of adverse risk factors between treatment groups Treatment group Factor Surgery only Adjuvant therapy P value T3/T4 40(36.7%) 15(65.2%) 0.019 Stage Ⅱ/Ⅲ 50(45.9%) 21(91.3%) 0.000 Poor histologic grade 11(10.7%) 6(28.6%) 0.041 Positive lymph node 28(25.7%) 17(73.9%) 0.000 Table 10. Distribution of adverse risk factors between adjuvant therapy modality Treatment group Surgery Adjuvant Adjuvant P value Factor only CTx CCRTx T3/T4 39(36.4%) 9(56.2%) 7(77.8%) 0.020 Stage Ⅱ/Ⅲ 49(45.8%) 14(87.5%) 8(88.9%) 0.000 HG3/4 11(10.7%) 3(20.0%) 3(37.5%) 0.070 Positive LN 28(25.7%) 12(75.0%) 5(55.6%) 0.000 30
나. 고위험군에서치료군에따른생존기간의차이 고위험군에서보조항암요법이생존기간에미치는영향에대해서 연구한결과, 수술군과보조항암요법군사이에통계학적으로의미 있는차이는보이지않았다 (Table 11,12). Table 11. Effect of adjuvant therapy on overall survival, stratified by negative prognostic categories Hazard ratio Factor Surgery only Adjuvant therapy P value T3/T4 1.0 1.7 0.197 Stage Ⅱ/Ⅲ 1.0 1.7 0.134 Positive lymph node 1.0 0.7 0.421 Table 12. Effect of adjuvant therapy modality on overall survival, stratified by negative prognostic categories Factor Surgery only Hazard ratio Adjuvant CTx 1 Adjuvant CCRTx 2 P value T3/T4 1.0 1.2 1.8 0.732/0.269 Stage Ⅱ/Ⅲ 1.0 1.2 2.2 0.620/0.115 Positive LN 1.0 0.5 1.7 0.204/0.418 1 Chemotherapy 2 Concurrent chemoradiotherapy 31
6. 치료군에따른재발율의차이 가. 고위험군에서치료군에따른국소재발율의차이고위험군에서수술후보조항암요법이국소재발에미치는영향에대해서조사한결과, 수술군과보조항암요법군사이에통계학적으로의미있는차이는보이지않았다 (Table 13,14). Table 13. Effect of adjuvant therapy on local recurrence, stratified by negative prognostic categories Hazard ratio Factor Surgery only Adjuvant therapy P value T3/T4 1.0 0.9 0.841 Stage Ⅱ/Ⅲ 1.0 0.5 0.398 Positive lymph node 1.0 0.2 0.128 Table 14. Effect of adjuvant therapy modality on local recurrence, stratified by negative prognostic categories Factor Surgery only Hazard ratio Adjuvant CTx 1 Adjuvant CCRTx 2 P value T3/T4 1.0 0.6 0.8 0.652/0.876 Stage Ⅱ/Ⅲ 1.0 0.4 0.5 0.394/0.559 Positive LN 1.0 0.3 0.0 0.247/0.984 1 Chemotherapy 2 Concurrent chemoradiotherapy 32
나. 고위험군에서치료군에따른원격재발율의차이고위험군에서수술후보조항암요법이원격재발에미치는영향에대해서조사한결과, 수술군과보조항암요법군사이에통계학적으로의미있는차이는보이지않았다 (Table 13,14). Table 15. Effect of adjuvant therapy on distant recurrence, stratified by negative prognostic categories Hazard ratio Factor Surgery only Adjuvant therapy P value T3/T4 1.0 2.2 0.054 Stage Ⅱ/Ⅲ 1.0 1.8 0.104 Positive lymph node 1.0 1.1 0.810 Table 16. Effect of adjuvant therapy modality on distant recurrence, stratified by negative prognostic categories Factor Surgery only Hazard ratio Adjuvant CTx 1 Adjuvant CCRTx 2 P value T3/T4 1.0 2.2 1.4 0.090/0.585 Stage Ⅱ/Ⅲ 1.0 2.0 1.0 0.071/0.957 Positive LN 1.0 1.4 0.5 0.505/0.489 1 Chemotherapy 2 Concurrent chemoradiotherapy 33
Ⅳ. 고찰 바터팽대부암은근치적절제술후 5년생존율이 30~60% 으로알려져있는데 7-10, 15, 이는담도폐쇄에의한증상이병의경과중초기에관찰되고, 이로인해조기진단이가능하기때문이다. 이렇듯주변의혈관구조로의침범이일어나기전에담도폐쇄와관련된증상이나타나조기에발견되는경우가많고, 이로인해진단당시수술가능한경우도많다고알려져있다 6. 하지만진단당시국소림프절전이가발견된경우 5년생존율은 20% 내외로급격히감소하는것으로보고되고있다 5, 16. 또한이러한고위험군에서의근치적절제술후보조항암요법에대한치료법이확립되어있지않은상태이다. 다른췌담도계암중췌장암의경우에는근치적절제술후에보조동시화학방사선요법이국소재발을줄이지못했고, 생존기간또한증가시키지못한데비해, 보조항암화학요법이생존기간증가에기여한다는사실이입증되었다 12, 13 는점에착안하여바터팽대부암에서보조항암화학요법을포함한보조항암요법의치료효과에대해알아보고자하였다. 지금까지알려진바터팽대부암의예후인자로서 TNM병기, 국소림프절전이, 신경주위침범, 혈관침범, 조직학적등급등이알려져왔다 4, 6, 15, 17-21. 이번연구에서는국소림프절전이가 34
생존기간에영향을미치는독립적인예후인자임이밝혀졌다 (HR 2.523, p=0.0021). 다변량분석결과국소재발을예측할수있는독립적인예후인자는찾지못하였고, 원격재발의경우 TNM병기, 특히 stage Ⅰ에비해 stage Ⅱ/Ⅲ에서누적재발율의증가를관찰할수있었다. 이러한결과는기존연구와크게다르지않았다. 단변량분석과다변량분석을통하여예후인자로확인된불량한조직학적등급, T병기 (3/4), TNM병기 (stage Ⅱ/Ⅲ), 국소림프절전이등의인자들에대한치료군간분포를살펴본결과네가지위험인자모두가수술군에비해보조항암요법군에서의미있게높은빈도를나타냈었다. 보조항암요법군의생존기간이수술군의생존기간과비교하여오히려낮았던이유가바로이러한위험인자의불균등한분포에서기인하는것으로생각된다. 바터팽대부암에서는근치적절제술후보조항암요법에대한대규모전향적연구가이루어져있지않은상태로현재까지근치적절제술만이유일하게생존기간을증가시킬수있는치료방법으로생각되고있다. 대신바터팽대부암에서근치적절제술후보조항암요법의효과에대해서는몇몇후향적연구들이있어왔다. 전체 39 명의환자를대상으로행해진연구결과위험인자유무에상관없이모든환자를대상으로분석하였을때는보조동시화학방사선요법이생존기간에영향을주지못하지만, 췌장침범 (T3), 국소림프절전이 (N1) 의위험인자를갖는 35
고위험군을대상으로하였을때에는보조동시화학방사선요법이 생존기간을증가시켰다고보고하였다 22. 또한비교적대규모 환자군 (n=125) 을대상으로한최근의후향적연구에서도비슷한결과를보였는데, 고위험군으로분류된국소림프절전이환자군에서수술후보조동시화학방사선요법이생존기간을증가시켰다는보고가있었다 6. 1990 년 5 월부터 2006 년 1 월까지근치적절제술을시행받은바터팽대부암 96 명을대상으로한또다른후향적연구에서는, 이중고위험군으로밝혀진 T3/T4 환자군에서보조동시화학방사선요법이생존기간을증가시킨다는 보고를하였다 17. 지금까지살펴본몇몇후향적연구에서는 고위험군에서보조동시화학방사선요법이생존기간을늘리거나 재발율을낮추는데기여한다는증거들을제시하였다. 반대로 보조항암요법이생존기간을늘리는데에도움이되지않는다는 연구결과도있었다. 41 명을대상으로한후향적연구에서 췌장침범, 불량한분화도, 국소림프절침범을보이는고위험군에서 근치적절제술후보조방사선치료가국소재발을줄이기는하지만 생존기간의향상에는기여하지못한다는결과를보였다 23. 하지만 앞서말한바와같이이러한연구들이모두전향적대조군연구가아니었고, 대상환자수가적었다는것을고려할때추가적인연구가필요한상황이다. 본연구에서는결과에서이미언급했듯이고위험군에서보조동시항암방사선요법, 보조항암화학요법이 36
생존기간의향상에기여하지못하였다. 또한보조항암요법이국소재발이나원격재발을감소시키는데에도기여하지못한다는생존기간을증가시킬수있는유일한치료법으로생각된다. 최근에는 Erlotinib 과같은 molecular targeted agent 가담도암환자와췌장암환자에서생존기간을연장시켰다고보고되는등팽대부주위암에서항암화학치료는그약제가다양해지고있다 24, 25. 바터팽대부암에서도이러한 molecular targeted agent 를이용한 보조항암요법의시도가이루어져야할것으로생각된다. 다만본연구가전향적대조군연구가아니었기때문에근치적절제술을시행받은바터팽대부암환자에있어서수술후보조항암요법이생존기간을증가시키거나재발율을감소시키는데에기여하지못한다고단정할수는없을것으로생각된다. 또한어떤환자에대해서보조항암요법을시행할지에대한의사의판단이국소림프절전이여부나 TNM 병기와같은객관적기준뿐만아니라수행능력 (Performance status) 이나체중감소등주관적기준에의해서도행해졌을개연성이있으며. 이러한편견 (bias) 은후향적연구라는한계때문에교정할수없는변수였고, 이러한이유로고위험군환자에서보조항암요법이생존기간을향상시키지못했다는결론이잘못된연관관계에의한것일가능성이있다. 이번연구에서는보조동시항암방사선요법군과보조항암화학요법군에서항암제조합이통일되지않았고, 각각의치료군의환자들에서 37
위험인자의분포가달라이후통계결과에영향을미쳤을것으로생각된다. 결론적으로바터팽대부암환자에서근치적절제술후나쁜예후를예측하게하는위험인자는국소림프절전이였고, 이러한위험인자를갖는고위험군환자에서근치적절제술후보조항암요법은생존기간을증가시키는데기여하는것을증명하지못하였다. 추후전향적대조군연구를통하여바터팽대부암에서근치적절제술후보조항암요법의역할에대한전향적연구가이루어져야할것으로생각된다. 38
Ⅴ. 결론 1987년 1월부터 2007년 8월까지연세대학교세브란스병원에서바터팽대부암으로진단받고근치적절제술을시행받은환자들을대상으로수술후생존기간, 국소재발, 원격재발등의예후를예측할수있는수술전인자들을조사하고, 불량한예후를예측하게하는위험인자를갖는고위험군에서근치적절제술후보조항암요법이생존기간과재발율에미치는영향을조사하였고, 다음과같은결론을얻었다. 1. 수술전국소림프절전이가의미있는위험인자임이밝혀졌고 (HR 2.8, p=0.015), 원격재발의경우 TNM병기 Ⅱ/Ⅲ 에서누적원격재발율의증가를관찰할수있었다 (HR 5.3, p=0.016). 2. 고위험군에서의누적국소재발율, 누적원격재발율을분석한결과, 치료군 ( 수술군, 보조항암화학요법군, 보조동시화학방사선요법군 ) 간누적국소재발율과누적원격재발율에서차이는없었다. 고위험군에서의생존기간을분석한결과, 치료군 ( 수술군, 보조항암화학요법군, 보조동시화학방사선요법군 ) 간생존기간에는차이가없었다이상의결과를토대로바터팽대부암환자에서근치적절제술 39
후나쁜예후를예측하게하는위험인자는수술전국소림프절전이이며, 고위험군환자에서근치적절제술후보조항암요법은생존기간을증가시키는데기여하는것을증명하지못하였다. 추후바터팽대부암환자중고위험군에해당되는환자에서근치적절제술후보조항암요법의역할에대한전향적대조군연구가필요할것으로생각된다. 40
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<Abstract Abstract> Risk factors in patients with ampulla of Vater cancer after curative resection Moon Jae Chung Department of Medicine The Graduate School, Yonsei University (Directed by Professor Seung Woo Park ) Objectives: Among periampullary cancer, ampulla of Vater cancer makes up about 6-20%, and has better prognosis and is more likely to be resectable than pancreatic cancer or CBD cancer. In pancreatic cancer, curative resection and adjuvant chemotherapy has been proved to increase overall survival by prospective controlled studies, but such has not been proved for ampulla of Vater cancer for adjuvant chemotherapy or adjuvant 46
concurrent chemoradiotherapy after curative resection. Methods: This study aimed to analyze patients who were diagnosed with ampulla of Vater cancer and received curative resection at Yonsei University Medical Center from January 1987 to August 2007. Total of 132 patients was included for analysis. Average follow-up period were 63.2 months. The patients data were analyzed for pre-surgical factors predicting prognosis such as overall survival after surgery, local recurrence, and distant recurrence, and in high risk groups with risk factors, the role of post operative adjuvant therapy on overall survival and recurrence rate. Results: Median overall survival were 43.1months(range; 3-237months), and 2 and 5 year survival rate were 79.7%, 60.4% each. Local lymph node metastasis before surgery was significantly meaningful prognostic factor(hr 2.8, p=0.015), and in case of distant recurrence, TNM stage II/Ⅲ showed increased cumulative recurrence rate(hr 5.3, p=0.016). Overall survival was analyzed in high risk group, and there were no significant differences of overall survival among treatment groups(surgery only, adjuvant chemotherapy, and adjuvant concurrent chemoradiotherapy). 47
Conclusions: In this study, poor prognostic factor in patients who underwent curative resection in ampulla of Vater cancer was local lymph node metastasis before surgery, and adjuvant therapy after curative resection in high risk patients might not improve overall survival. ---------------------------------------------- Key Words : Ampulla of Vater cancer, curative resection, prognostic factor, adjuvant chemotherapy, adjuvant concurrent chemoradiotherapy, overall survival, local recurrence, distant recurrence 48