연구분야 ( 코드 ) G0202 과제번호 1110221 과제성격 ( 기초, 응용, 개발 ) 실용화대상여부실용화 연구과제명 과제책임자 세부과제 지원기관고유프로그램공개가능여부공개 ( 공개, 비공개 ) ( 국문 ) ( 영문 ) 구분 1 2 3 소속위암외과직위과장 성명 전공위암외과 세부과제명 세부과제책임자 성명 소속 ( 직위 ) 전공 총연구기간 2011 년 1 월 ~ 2013 년 12 월 ( 총 3 년 ) 참여연구원수 ( 단위 : 명, MY) 연구기간및 연구비 ( 단위 : 천원 ) 구분연구기간계 계 제 1 차 제 2 차 제 3 차 국립암센터 기업부담금소계현금현물 354,000 34 N/A N/A N/A 118,000 8 N/A N/A N/A 118,000 13 N/A N/A N/A 118,000 13 N/A N/A N/A 참여기업명칭 N/A 전화 FAX 기관고유연구사업관리규칙에따라본연구개발사업을성실히수행하였으며아래와같이최종보고서 를제출합니다. 2013 년 10 월 30 일 과제책임자김영우 ( 서명 )

연구목표 (200 자이내 ) < 최종목표 > < 당해연도목표 > 진행성위암에서의복강경위아전절제술시 D2 림프절절제술의가용성을 검증연구일차결과분석완료, 연구결과출판 등재환자외래 F/U 관리, 재발및생존여부에대해지속적자료수집과 2 차및 3 차논문게재 cstage IB 또는 II 의진행성위암환자에서 D1+ 위아전절제술의가용성 을검증하기위한제 3 상다기관임상연구그룹구축및수술표준화, 프 로토콜, CRF 개발 각기관에서 IRB 서류작업및승인 -

연구내용및방법 (500 자이내 ) 연구개발에따른기대성과 제 3상임상연구환자등재시작 cstage IB 또는 II 의진행성위암환자에서 D1+ 위아전절제술의가용성 을검증하기위한제 3 상다기관임상연구그룹구축및수술표준화, 프 로토콜, CRF 개발 Ÿ 환자등재현재본원 89 명등재, 총 204 명등재완료 ( 본원 89 명 ) Ÿ Ÿ Ÿ Ÿ F/U 관리및지속적인 Data 수집으로환자의삶의질, 재발및 생존률추적.

Ÿ Ÿ Ÿ 한차례의자문단회의와네차례의제3상연구 protocol개발을위한다기관연구자회의및국내, 해외연자초청 D1+ 와 D2 수술비디오세미나개최로다각적의견수렴, D1+ 와 D2 수술표준화및수술술기의발전도모 COACT연구그룹결성을위해대한위암학회를통해전회원에게공지메일발송, 모든회원에게연구문호개 방하여총 50 개이상기관연구자참여다기관임상연구팀구 Ÿ 축으로위암과관련된다양한임상연구활성화 ( 모든참여연구자의전체위절제수술건수, 위절제수술보조건수, 복강경위절제수술건수, 보조건수등자료기본적으로수집 ) 색인어 국문진행성위암림프절절제범위다기관임상시험 영문 advanced gastric cancer, lymph node dissection, multicenter clinical trial

* Accordion Severity Classification of Postoperative Complications; Expanded Classification (ASCPC) 1. Mild complication Requires only the bedside such as insertion minor invasive procedures that can be done at of intravenous lines, urinary catheters, and NG tubes, and drainage of wound infection. Physiotherapy and the following drugs are allowed-antiemetics, antipyretics, analgesics, diuretics, electrolytes, and physiotherapy 2. Moderate complication Requires pharmacologic treatment with drugs other minor complications, for instance antibiotics. Blood also included 3. Severe : invasive procedure without general anesthesia than such allowed for transfusions and TPN are Requires management by an endoscopic, interventional procedure or re-operation without general anesthesia 4. Severe : operation under general anesthesia Requires management by an operation under general 5. Severe : organ system failure * 6. Death anesthesia Postoperative death * Such complications would normally be managed in an increased acuity setting but in some cases patients with complications of also be admitted to an ICU lower severity might

Scoring Method for D2 Lymph Node Dissection complete incomplete partial none : 3명연구자모두 85점이상인경우 2군 림프절절 3 2 1 0 제인정

No. 1 Right paracardial LN No. 2 Left paracardial LN No. 3 LN along the lesser curvature No. 4sa LN along the short gastric vessels No. 4sb LN along the left gastroepiploic vessels No. 4d LN along the right gastroepiploic vessels

No. 5 Suprapyloric LN No. 6 Infrapyloric LN No. 7 LN along the left gastric artery No. 8a LN along the common hepatic artery(anterosuperior group) No. 8p LN along the common hepatic artery(posterior group) No. 9 LN around the celiac artery No. 10 LN at the splenic hilum No. 11p LN along the proximal splenic artery No. 11d LN along the distal splenic artery No. 12a LN in the hepatoduodenal ligament(along the hepatic artery) No. 12b LN in the hepatoduodenal ligament(along the bile duct) No. 12p LN in the hepatoduodenal ligament(behind the portal vein) No. 13 LN on the posterior surface of the pancreatic head No. 14v LN along the superior mesenteric vein No. 14a LN along the superior mesenteric artery No. 15 LN along the middle colic vessels No. 16a1 LN in the aortic hiatus No. 16a2 LN around the abdominal aorta(from the upper margin of the celiac trunk to the lower margin of the left renal vein) No. 16b1 LN around the abdominal aorta(from the lower margin of the left renal vein to the upper margin of the inferior mesenteric artery) No. 16b2 LN around the abdominal aorta(from the upper margin of inferior mesenteric artery to the aortic bifurcation) No. 17 LN on the anterior surface of the pancreatic head No. 18 LN on the inferior margin of the pancreas No. 19 Infradiaphragmatic LN No. 20 LN in the esophageal hiatus of the diaphragm No. 110 Paraesophageal LN in the lower thorax No. 111 Supradiaphagmatic LN No. 112 Posterior mediastinal LN

기관 첫환자등재일 Enrolled (%) * Screen Off Study Total Arm A & Arm B # Failures 국립암센터 2010.06.21. 89 45 44 1 대구보훈병원 2010.06.24. 4 3 1 건양대병원 2010.08.16. 12 6 6 2 경상대병원 2010.08.26. 21 11 10 1 화순전남대병원 2010.10.14. 58 28 30 고신대병원 2010.10.21. 11 6 5 1 경북대병원 2011.06.01. 9 6 3 Total 204 (100.0%) 105 99 0 5

Official Title : A multicenter randomized clinical trial of D1+ versus D2 gastrectomy for stage IB & II advanced gastric cancer (COACT1301) Abbreviated Study Name: Assessment of D1+ vs D2 gastrectomy for Clinical stage IB & II gastric cancer (ADDICT Trial) Coordinating Principal Co-investigators investigator : Young-Woo Kim, National Cancer Center : COACT group (open for participation) Objectives: Primary objective: To test non-inferiority of survival of D1+ gastrectomy versus D2 gastrectomy for clinical stage I B & II advanced gastric cancer. Primary endpoint: 5 year overall survival Secondary objectives: 1)3 year disease free survival 2)Subgroup analysis of Laparoscopic surgery versus open surgery in terms of 3 year relapse free survival and 5 year overall survival 3)Operating time 4)Early postoperative complications 5)Long term postoperative complications 6)Quality of life of the patients in terms of European quality of life questionnaire (EQ-5D) 7)Overall cost for the treatment

8) Finding biomarkers predicting lymph node metastasis and recurrence Rationale: There have been debates for D1 vs. D2 for 30 years and several clinical studies were done so far. One of recent meta-analysis of those clinical Memon et al. revealed D2 has no benefit for survival and just recent meta-analysis done by Seevaratnam et al. rates of morbidities and did not undergo studies done by increasing morbidity. But, showed that recent trials have similar there is a trend of improved survival among D2 patients who resection of the spleen or pancreas, as well as for patients with T3/T4 cancers. Actually, D2 gastrectomy is now accepted worldwide as for resectable gastric cancer. Many groups of gastric recommendations for their practice. But, because; 1) data from recent meta-analysis a standard treatment surgeons are now adopting these spectrum of D2 looks might be too wide showed benefit of D2 only on T3/T4 disease 2) therapeutic index of No.11p and 12a for earlier advanced disease is slim in our previous COACT1001 study. option every time. one. It JCOG 9501 study has shown aggressive surgery is not a best Best conserved surgery while maintaining survival must be an optimal could enhance safety, reduce complications, operative time, cost, and improve quality of life of the patients. Our recent COACT 1001 study showed feasibility of a laparoscopic D2 gastrectomy for advanced gastric cancer. In subgroup analysis, laparoscopic D2 was feasible only in stage I and II. In improving quality of life of the patients, important issue when a minimal dissection. There have never been clinical trials for argument, a new clinical disease? Eligibility terms of tailored surgical therapy optimizing surgical extent must be the most invasive laparoscopic surgery is comparable even for D2 D1+ for gastric cancer. From above mentioned question arises; Is there a room for D1+ in stage IB and II Inclusion Criteria : Patients are included in the trial if they meet all of the followingcriteria:(i)histologicallyprovenprimarygastricadenocarcinoma,(ii)t2n0,t2n1,t3n0,t 3N1,whichareassessedbycomputedtomography(CT)scan(AJCC7thclassification)andintraoper ativesurgicalstaging(evaluation after LN 4sb, 5, 6 dissection iii) location of primary tumor; antrum, or angle, or lower body of the stomach (iv) No evidence of other distant metastasis, (v) aged 20-80 year old,(vi) performance status (PS) of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) scale, (vii) no prior treatment of chemotherapy or radiation therapy against any other malignancies, and no prior treatment for gastric cancer including endoscopic mucosal resection, (viii) adequate organ functions defined as indicated below: (a) WBC 3000/mm3 12,000/mm3, (b) > serum Hemoglobin 8.0 g/dl (c) > serum Platelet 100 000/mm3, (d) < serum AST 100 IU/l, (e) <serum ALT 100 IU/l, (f) < Total Bilirubin 2.0 mg/dl, (g) written signed informed consent. Exclusion Criteria: Patients are excluded if they meet any of the following criteria: (i) active double cancer (synchronous double cancer and metachronous double cancer within five disease-free years), excluding carcinoma in situ (lesions equal to intraepithelial or intramucosal cancer), (ii) gastric remnant cancer (iii) >T4a in surgical staging before resection (iv) N2 or more (number of metastatic lymph nodes 3) in CT scan (v) pregnant or breast-feeding women, (vi) severe mental disorder, (vii) systemic

administration of corticosteroids, (viii) unstable angina or myocardial infarction within 6 months of the trial, (ix) unstable hypertension, (x) severe respiratory disease requiring continuous oxygen therapy (xi) previous upper abdominal surgery except laparoscopic cholecystectomy Stratification factors 1) Institution 2) Clinical stages: IB or IIA or IIB 3) Approach: Open surgery or Laparoscopic surgery Randomization method By evelos data management system Timing: Intraoperative evaluation after LN 4sb, 5, 6 dissection Treatment Plan Arm A (Control arm) ; D2 distal subtotal gastrectomy D2 includes Nos.1.3,4sb,4d,5,6,7,8a,9,11p,and 12a nodes in Japanese classification. Systemic en bloc lymph node dissection is mandatory. Resection margin should be negative for malignancy with intraoperative frozen biopsy. Arm B (Test arm) ; D1+ distal subtotal gastrectomy D1+ includes Nos.1,3,4sb,4d,5,6,7,8a,and 9 nodes in Japanese classification. Systemic en bloc lymph node dissection is mandatory. Resection margin should be negative for malignancy with intraoperative frozen biopsy * Laparoscopic or open approach and total or partial omentectomy are optional * If the disease is more advanced than preoperative staging, and final clinical staging is over stage IIB, the patient is excluded from the study (screening failure) and best treatment should be chosen for the patients. * If postoperative pathological stage is stage II and more, adjuvant chemotherapy should be recommended.(capecitabine +oxaliplatin 6 months or TS-1 12 months) Statistical Consideration The primary objective of this trial is to test non-inferiority of 5 year overall survival of D1+ gastrectomy versus D2 gastrectomy for clinical stage I & II advanced gastric cancer. *Sample size: Based on one-sided type I error 2.5%, power of 80%, accrual period for 3 year, follow-up 5 year after the last accrual and Non-inferiority margin as hazard ratio of 1.40, total number of events needed are 277 events(death). Therefore, number of patients needed per arm is 846 patients. After considering 10% of follow-up loss, 940 patients per arm, and a total of 1,880 patients should be enrolled. *The target was chosen from the primary end point of the study. PatientsEvaluation(Pretreatmentandfollow-upTesting) (i) Preoperative tests; WBC, Hb, Platelet, AST, ALT, albumin, total bilirubin, esophagogastroduodenography (EGD), abdominopelvic computed tomogram (ACT), serum tumor markers; carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9) (ii) Surgical outcomes: operating time, intraoperative events, postoperative complications with Accordion Severity Grading, time to first flatus, hospital stay after operation, serum C-reactive protein (CRP), reoperation rate

(iii) Oncological outcomes: overall number of retrieved lymph nodes, number of retrieved lymph nodes at each stations, distance to resection margins, R0 resection rate, peer review of video and picture documentation for adequacy of D1+ and D2 (iv) Follow-up evaluation for disease and survival: survival time with 6 months interval follow-up, time of recurrence of disease with 6 months interval serum tumor makers (two elevated ones preoperatively, if no elevated ones, CEA and CA19-9, mandatory), 6 months interval ACT, and annual EGD. In any suspicion of recurrence, PET, percutaneous needle biopsy for suspicious lesion, diagnostic laparoscopy with washing cytology or biopsy for suspicion of peritoneal recurrence can be performed. (v) European quality of life questionnaire (EQ-5D): baseline, 1month, 6 month, 1 year, 3 year.

Mitsuru Sasako

Table 1. Characteristics of Patients Variables LADG group (n=100) ODG group (n=96) P Sex 0.846 * Male 69 (69%) 65 (67.7%) Female 31 (31%) 31 (32.3%) Age, yr Mean 58.6 60.1 Range 26.7-80.2 29.9-79.1 Mean BMI +SD,kg/m 2 23.7 ± 3.0 23.3 ± 3.1

Clinical T classification 0.279 * (7 th AJCC/UICCstaging) T2 46 (46%) 35 (36.5%) T3 41 (41%) 42 (43.8%) T4a 13 (13%) 19 (19.8%) Clinical N classification 0.238 * (7 th AJCC/UICCstaging) N0 37 (37.0%) 40 (41.7%) N1 35 (35.0%) 32 (33.3%) N2 27 (27%) 19 (19.8%) N3 1 (1%) 5 (5.2%) Clinical Stage 0.324 * (7 th AJCC/UICCstaging) IA 0 (0%) 0 (0%) IB 23 (23.0%) 22 (22.9%) IIA 23 (23.0%) 28 (29.2%) IIB 29 (29.0%) 18 (18.8%) IIIA 20 (20.0%) 17 (17.7%) IIIB 4 (4.0%) 10 (10.4%) IIIC 1 (1.0%) 1 (1.0%) Table 2. Surgical Outcomes Variables LADG group ODG group P (n=100) (n=96) Operation Type 0.280 * Distal Gastrectomy 94 (94%) 94 (%) Total Gastrectomy 6 (6%) 1 (%) Open Biopsy 0 (0%) 1 (%) Open Conversion 2 (2%) Operating Time +SD,min 257.4 ± 86.7 183.0 ± 52.5 <0.001 Resectability 0.056 * R0 100 (100%) 92 (%) R1 0 (0%) 1 (%) R2 0 (0%) 3 (%)

Combined Resection 0.413 No 92 (92%) 85 (%) Yes 8 (8%) 10 (%) Combined disease 3 (3%) 6 (%) Adjacent organ 1 (1%) 3 (%) Injury 1 (1%) 0 (0%) Extent of lymph node 0.113 * dissection D1+ alpha 0 (0%) 0 (0%) D1 + beta 1 (1%) 4 (%) D2 99 (99%) 91 (%) Table 3. Complications LADG group ODG group P (n=100) (n=96) Intraoperative 8 (8%) 4 (4.2%) 0.263 * Bleeding 3 (3%) 2 (2.1%) Organ injury 2 (2%) 3 (6.3%) Other 2 (2%) 0 (0%) Early postoperative complications 17 (17%) 18 (18.8%) 0.749 * ASCPC classification Mild 6 (6%) 2 (2.1%) Moderate 9 (9%) 14 (14.6%) Severe : invasive without GA 1 (1%) 1 (1.0%) Severe : operation under GA 1 (1%) 0 (0%) Severe : Organ system failure 0 (0%) 0 (0%) Death 0 (0%) 1 (1.0%) Table 4. Compliances cstage LADG group ODG group P (n=100) (n=96)

I 0.458 * Compliant 13 (56.5%) 10 (45.5%) Noncompliant 10 (43.5%) 12 (54.5%) II 0.788 * Compliant 28 (53.8%) 23 (51.1%) Noncompliant 24 (46.2%) 22 (48.9%) III 0.043 * Compliant 12 (48.0%) 21 (75.0%) Noncompliant 13 (52.0%) 7 (25.0%) Total 0.648 * Compliant 53 (53%) 54 (56.8%) Noncompliant 47 (47%) 41 (43.2%)

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41(10): pp 1424-14 27 online Pub. DOI 10.1002

/jso.220 Journal of Surgical Oncology 83 online Pub. DOI 10. 100 2/jso.22 124

27(4):pp 1211-1218 P. 511 522 2013: DOI 10.1007/s00268-013-2301-5 2013: 27(9): pp 3247-3253 1110221 13(3):164-171 1110221

2013

그림 1. LADG D2 dissection 에대한비디오세미나

A multicenter randomized clinical trial of D1+ versus D2 distal gastrectomy for stage IB & II advanced gastric cancer(addict) 연구자모임 기관 국립암센터 대구보훈병원 건양대병원 경상대병원 화순전남대병원 고신대병원 경북대병원 Total 첫환자 등재일 2010.06. 21. 2010.06. 24. 2010.08. 16. 2010.08. 26. 2010.10. 14. 2010.10. 21. 2011.06. 01. Total Enrolled (%) * Arm A & Arm B # Scree n Failur 89 45 44 1 4 3 1 12 6 6 2 21 11 10 1 58 28 30 11 6 5 1 9 6 3 204 (100. 105 99 0 5 es Off Study

0%) Ÿ Ÿ

➀ ➁ ➂ ➀ ➁ ➂ ➀ ➁ ➂ Experts Invitational Seminar for ADDICT Trial Development

1 차 ADDICT Trial Seminar

장소 : 프레지던트호텔

2 차 ADDICT TrialSeminar

3 차 ADDICT Trial Seminar 장소 : 서울대암연구소이건희홀

ADDICT Trial, Protocol Development Workshop 장소 : 서울대암연구소이건희홀 Total gastrectomy Total gastrectomy 를포함할경우결론의해석이복잡할수있으므로제외하는것으로함. -Total gastrectomy 를포함하자는의견을주셨던분이이번모임이참석하지않으셨으나개인적으로설명드릴예정임. Omentectomy Omentectomy 여부가 survival 에영향을미친다는 evidence 는없으므 로복강경수술을고려했을때 omentectomy 는 surgeon 의재량에맡 기기로함. 즉복강경수술일경우 partial omentectomy 시행가능함. Preoperative diagnosis 각기관별 CT protocol 이다르고판독의사마다소견이다를수있음. 한명의판독의사가판독하기로하고기본적인 protocol 을정해서각기관에협조공문을통해정해진 protocol 대로촬영하도록함. -COACT study 의경우 over estimation 된경향이있었으므로판독의사를복수로했으면좋겠음. -N2 의기준을미리마련하는게좋음.( 8mm 이상, round shape, N2 area..) 대부분의병원에서 LN 개수로 stage 정함. Topographic N2 는이 study 에서제외됨. -미리영상의학과선생님과상의해서 study 진행에차질이없도록해야함. 수술의표준화 D1+ 와 D2 수술이확실히달라야함. Pf. Sasako는 LN#9 를 splenic artery 의 3cm 정도를포함하는것으로제시하였으나그렇게할경우 11p 가포함될가능성있으므로 celiac axis 까지만 dissection 하기로함. LN#8a 의경우 CHA 앞쪽만 dissection 함. 이외 LN#4sb, 5, 6 도표준화되어야함. D1 에대한 Standard surgey 비디오를만들어서공유할예정임. - Pf. Sasako 의의견이원칙은아니므로반드시따라야하는것은아님.

Pathologic diagnosis Sample collection for biomarker - D2 가아니면무조건 D1+ 로포함시키는것이좋음. -비디오를먼저만들어서보고그대로따르면좋을것같음. -LN 가연결되었을경우는? contamination 은불가피하므로환자에게최상의수술을하도록함. -D1+ 에대해아직까지 consensus 가이루어지지않은것같음. (1) consensus 이루어질때까지기다림 (2) PI 가정하고동의하는사람만참가함. 이둘중정해야함. 또 ITT 와 PP 를명확하게해야함. - D1+ 가 study 의목적이므로 D1+ vs 나머지를비교하는것이좋을것같음. - 림프절절제가 spectrum 임을인정하며, 이는 surgical trial 의한계임. 미리 criteria 를정하는것이좋겠음. - independent reviewer 가 category 를결정해야함. 병원마다 report 양식이다름. 미리병리과선생님과상의해야함. - 정해진양식을주면상의하도록하겠음. 병원마다여건이어려울것으로예상되어가능한병원만하는것으로함. - biomarker study 는모든환자에서다할필요가없고 500-600 명정도만포함되면됨. -NCC 이외한두기관만하면될것으로예상됨. - 병리의사의협조가필요하므로 biomarker study 에 authorship 등의 reward 가있어야할것으로판단됨. - SENORITA trial 의경우참여의사에게자문료를지급하고있음. Fund < 유완식선생님 의견 > 현재 NCC 에서년간 1억 2천을지원받고있음. Study 가시작되면 8억 /yr 정도가예상되고매우부족한실정임. 따라서각병원에연구간호사를지원하기는힘들며, data 입력은각병원에서자체적으로담당해야할것으로생각됨. 단, active 한병원일부에는 CRC 지원가능함. 일단이상태로 study 시작하고차후에 fund 를받을수있도록노력할것임. - 동아대병원의경우자체적으로가능함. -수술의표준화가가장중요하며환자의 anatomy 가 spectrum 이므로불가피하다. -D1+ 의정의와 omentectomy 시행여부는 PI 가정하고나머지는따라가면됨. -radiologist 와 pathologist 판독의통일성이중요한데 pathology 도가능하다면중앙판독을고려했으면함. -예상하는 biomarker 가있는가? 아직없음. -지역마다종양은행이있고분양가능한데, 꼭모아야하는가? -fund 는대부분인건비인데, evelos 사용이어려운것이관건임. 사용하지않는건어떤가? -일본의경우 case 적은곳이많아일부에서는약간의 flexibility 를두

기도함. - 안되는경우 paper CRF 를 center 로보내는방법도있음. - 입력 IP 추적을일부러하지는않지만입력 site 는알수있음. < 자유토론 > 김기한 : QOL 의목적이 lapa vs open 인가? 아님. D1+ vs D2 임. 크게차이가나지않을것같은데연구간호사의노력이많이들므로다시검토하면좋겠음. 남병호 : EQ-5D와같이간단한것도있으므로되도록하는것이좋고여건이안되는기관은안해도됨. 채현동 : omentectomy 가 option 이라면 D1+ partial omentecotmy vs D2+ full omentectomy 로하는건어떤가? 김영우 : 두가지가함께있으면결과해석에혼동이있음. 권오경 : n 수가충분하므로묶지않아도분석가능할것으로생각됨. 배재문 : 매번회의할때마다같은문제를반복함. 개인적으로는이연구에 motivation 이크지않고직접 evelos 에입력해야한다면하지않을것같음. 수술후 upstaging, down stating 이많이되어 screen failure 될가능성높음. 유완식 : upstaging, down stating 은 screen failure 아니고 cstage 에따르면됨. 김영우 : 현재 protocol 도의미있다고생각하는사람도많음. 오늘논의된것으로정하도록함.

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