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1 Protocol No. : NCC Protocol Summary Title Comparison of open versus laparoscopic surgery for mid and low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial) - Randomized Prospective Trial Summary The investigators designed the randomized prospective trial of comparing open and laparoscopic resection in locally advanced rectal cancer after preoperative chemoradiation in order to determine the oncologic and functional efficacy of laparoscopic rectal resection. Background, including rationale and any previous systematic reviews During the past two decades, there has been increasing enthusiasm for the use of laparoscopic techniques in the operative treatment of patients with colorectal disease. Laparoscopic colectomy has been demonstrated to be safe for patients with colon cancer by several randomized clinical trials. 1-4 For rectal cancer, the role of laparoscopic surgery is less clear. One trial raised concerns about laparoscopic rectal resection. 4 The conversion rate was 34% in rectal cases. In the rectal surgery subgroup, circumferential radial margin positivity was greater in laparoscopic than open surgery group, specific to the laparoscopic low anterior resection. These finding raise concerns as to the level of precision that is achievable in laparoscopic surgery and the question of whether laparoscopic resection is a safe, effective oncologic approach to rectal cancer. So solid level 1 evidence to support the practice of laparoscopic approach in the treatment of rectal cancer is still lacking. The adoption of laparoscopic proctectomy for rectal cancer has been relatively slow, because of the technical difficulty of the procedure and the oncologic consequence of surgical misadventure. Prospective analysis of outcomes by expert laparoscopic colorectal surgeons is the

2 Protocol No. : NCC first step toward determining whether patients should undergo laparoscopic protectomy for rectal cancer. The German Rectal Cancer Study Group trial showed that pre-operative chemoradiotherapy improves the five-year locoregional recurrence rate and sphincter preservation compared with postoperative chemoradiotherapy in patients with clinical stage T3 or T4 or node-positive disease. 5 The introduction of pre-operative chemoradiotherapy for rectal cancer is the most recent significant landmark in the treatment of rectal cancer. Until recently, there have been no randomized trials demonstrating the safety of laparoscopic surgery after pre-operative chemoradiotherapy for mid and low rectal cancer. This trial is designed to assess the safety and efficacy of laparoscopic surgery for mid or low rectal cancer. This trial will provide information about the appropriate place of laparoscopic surgery in regards to the short-term outcomes and oncologic outcomes associated with laparoscopic resection. 1. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 2004;350: Lacy AM, Garcia-Valdecasas JC, Delgado S, et al. Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet 2002;359: Veldkamp R, Kuhry E, Hop WC, et al. Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial. Lancet Oncol 2005;6: Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of conventional versus laparoscopicassisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet 2005;365: Sauer R, Becker H, Hohenberger W, et al. German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:

3 Protocol No. : NCC Principal investigator Jae Hwan Oh, M.D. Main centers Research Institute and Hospital, National Cancer Center, Goyang, Korea Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea Contact details Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do , South Korea jayoh@ncc.re.kr Fax: Aim To compare efficacy of laparoscopic and open resection for locally advanced rectal cancer after preoperative chemoradiotherapy (A. comparison of oncologic outcomes, B. comparison of quality of life, C. comparison of anorectal function) Design Study Type: Interventional Study Design: Treatment, Parallel Assignment, Open Label, Randomized, Active Control,

4 Protocol No. : NCC Safety/Efficacy Study Inclusion and exclusion criteria Inclusion Criteria: Mid to low rectal cancer (within 9cm from AV, measured by RS) Histologically proven adenocarcinoma Locally advanced (T3, determined by CT, MRI and TRUS) Completion of preoperative chemoradiation Age: Hb 10g/dl, WBC 3,000/mm3, Plt 100,000/mm3 Cr 1.5 mg/dl Adequate cardiopulmonary function Informed consent from patient or patient's relative Exclusion Criteria: Metastasis in liver, lung, brain, bone, paraaortic LN, subclavicular LN, inguinal LN Second primary malignancy (except CIS of the cervix or adequately treated skin cancer or prior malignancy treated more than 5 years ago without recurrence) Cardiopulmonary dysfunction Active, uncontrolled infection Active, uncontrolled psychosis Intervention or method a. Chemoradiotherapy Pre-operatively a dose of 50.4 Gy of radiotherapy, which included 45 Gy in 25 fractions to the pelvis and a 5.4 Gy boost in three fractions to the primary tumour over 5.5 weeks with

5 Protocol No. : NCC fluoropyrimidine-based chemotherapeutic regimen. Post-operatively adjuvant chemotherapy for 4 months. b.operation: Time of operation weeks after end of preoperative chemoradiation, Surgical technique - standard total mesorectal excision and high ligation of inferior mesenteric vessels, Two active comparator- conventional open rectal resection versus laparoscopic rectal resection (Phase Ⅲ) Figure 1. Scheme of study

6 Protocol No. : NCC How randomised Call to central office at the National Cancer Center Operation method will be randomized using the table of random sampling numbers, stratified by sex and preoperative chemotherapeutic regimen. Randomly allocated to receive either laparoscopic or open surgery at a one-to-one ratio Primary and any secondary endpoint Primary endpoint : Disease free survival (3 years after surgery) Secondary endpoints a. Short-term outcomes: Surgical length of incision, op time blood loss, intraoperative complications, conversion rate, pathological resection margins (proximal, distal, circumferential), number of harvested lymph nodes, tumor regression grade (Dworak's grading), TNM staging, perioperative recovery, duration of use of parenteral narcotics, initiation of peristalsis, initiation of oral intake, duration of hospital stay, 30-day postoperative mortality, morbidity b. Long-term outcomes: overall survival, local recurrence, port-site and wound site recurrence c. Quality of life: QOL assessment EORTC QLQ C30, EORTC QLQ CR38 d. Urinary and sexual function: Duration International Prostate Symptom Score (IPSS), Male sexual function International Index of Erectile Function (IIEF), Female sexual function Female Sexual Function Index (FSFI) e. Anorectal function: Anorectal manometry (Maximum Resting Pressure, Maximum Squeezing Pressure, High Pressure Zone, Sphincter Length, Sensory Threshold, Rectal Capacity, Rectal Compliance, Rectoanal Inhibitory Reflex), Fecal Incontinence Severity Index (FISI) Statistical analysis plan, including Short term outcome: Chi-test, Fisher s exact test, Student s t test, Wilcoxon rank-sum test

7 Protocol No. : NCC (depending on the distribution of the variables) Disease free survival: Kaplan-Meier method with Log-rank test, Cox regression analysis QOL, urinary & sexual function, anorectal function: analysis of covariance method Sample size and power calculations Estimated Enrollment: 340 Sample size calculation for non-inferiority trial; estimated 3yr-DFS: 75%, survival difference: 15%, power = 0.85, significance level=0.025, 10% expected loss of follow up Type of analysis Intention to treatment Ethics committee approval The study was approved and overseen by the Institutional Review Boards of each participating centre (National Cancer Center, NCCCTS ; Seoul National University Hospital, H ; Seoul National University Bundang Hospital, B ). Informed consent form and information sheet Korean version (Not attached) Interim analyses and stopping rules None Is there an independent data-monitoring committee? Yes

8 Protocol No. : NCC Funder This trial was supported by a grant from the National Cancer Center (grant ). Start date April 2006 Finishing date (Estimated Study Completion Date): August 2012

9 Protocol No. : NCC Title: Comparison of open versus laparoscopic surgery for mid and low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial) - Randomized Prospective Trial Protocol Number: Principal investigator : Co-investigator : Center for Colorectal Cancer National Cancer Center Department of Surgery Seoul National Unviersity Hospital Center for Colorectal Cancer National Cancer Center Department of Surgery Seoul National University Bundang Hospital Center for Colorectal Cancer National Cancer Center Department of Surgery Seoul National University Bundang Hospital Center for Colorectal Cancer National Cancer Center Center for Colorectal Cancer National Cancer Center Center for Colorectal Cancer National Cancer Center Center for Colorectal Cancer National Cancer Center Center for Colorectal Cancer National Cancer Center Center for Colorectal Cancer National Cancer Center Center for Colorectal Cancer National Cancer Center Center for Clinical Trials National Cancer Center Jae Hwan Oh Seung-Yong Jeong Hyo Seong Choi Sung-Bum Kang Seok-Byung Lim Duck-Woo Kim Ji Won Park Dae Yong Kim Kyung Hae Jung Hee Jin Chang Yong Sang Hong Sun Young Kim Dae Kyung Sohn Byung Ho Nam NATIONAL CANCER CENTER 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, , Republic of Korea TEL: FAX:

10 Protocol Abstract Title : Comparison of open versus laparoscopic surgery for mid and low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial) - Randomized Prospective Trial Study Chairman : Jae Hwan Oh Study Co-chairman: Seung-Yong Jeong, Hyo Seong Choi, Sung-Bum Kang, Seok-Byung Lim, Duck-Woo Kim, Ji Won Park, Dae Yong Kim, Kyung Hae Jung, Hee Jin Chang, Yong Sang Hong, Sun Young Kim, Dae Kyung Sohn, Byung Ho Nam Objectives : Primary objectives :: Disease free survival (3 years after surgery) Secondary objectives : Short-term outcomes, overall survival, local recurrence, quality of life, urinary and sexual function, anorectal function Rationale : In 1991, laparoscopy was introduced as a surgical treatment for colon cancer, but it was not actively used for technical reasons regarding anatomical characteristics of the large intestine, oncological safety, and other issues. In recent years, the technical issues of laparoscopic colectomy have been greatly resolved through technical improvements and new equipment development. Many retrospective and prospective studies have reported on oncological safety, and the general conclusion from these studies was that there is no difference in short-term survival and relapse rates between laparoscopic surgery and laparotomy for colon cancer. In particular, according to the Clinical Outcome of Surgical Therapy (COST) study group report from the United States, the early survival rate over 3 years of follow-up of 372 patients in the laparotomy and laparoscopic groups were respectively 93% and 93% for the stage 1, 82% and 72% for the stage 2, 58% and 53% for the stage 3, and 10% and 10% for the stage 4, as classified according to the tumor, node, and metastasis staging system. This study provided a theoretical background on laparoscopic surgery for colon cancer. Rectal cancer requiring a technically difficult approach was excluded from the COST research. The MRC CLASSICC trial group in the United Kingdom in 2005 reported more positive rates of the circumferential resection margin on laparascopic surgery for rectal cancer compared with open, but if total mesorectal excision, as the basic technique of rectal cancer surgery, is performed, it does not become an oncological problem. Therefore, prospective research is necessary since a consistent conclusion has not been derived regarding the use of laparoscopic surgery for rectal cancer. For mid to less progressive rectal cancer, chemoradiation therapy is currently performed prior to surgery as a treatment method. It is well known that the use of chermoradiation therapy prior to surgery reduces the tumor size to ease surgical resection, increases the rectal preservation rate, and reduces the local relapse rate. Prospective comparative research on laparoscopic surgery and laparotomy in patients who received chemoradiation therapy prior to surgery has not been 1

11 reported, so research in this area is necessary. Eligibility : Inclusion Criteria Mid to low rectal cancer (within 9cm from AV, measured by RS) Histologically proven adenocarcinoma Locally advanced (T3, determined by CT, MRI and TRUS) Completion of preoperative chemoradiation Age: Hb 10g/dl, WBC 3,000/mm3, Plt 100,000/mm3 Cr 1.5 mg/dl Adequate cardiopulmonary function Informed consent from patient or patient's relative Exclusion Criteria Metastasis in liver, lung, brain, bone, paraaortic LN, subclavicular LN, inguinal LN Second primary malignancy (except CIS of the cervix or adequately treated skin cancer or prior malignancy treated more than 5 years ago without recurrence) Cardiopulmonary dysfunction Active, uncontrolled infection Active, uncontrolled psychosis 2

12 Treatment Plan : a. Chemoradiotherapy Pre-operatively a dose of 50.4 Gy of radiotherapy, which included 45 Gy in 25 fractions to the pelvis and a 5.4 Gy boost in three fractions to the primary tumour over 5.5 weeks with fluoropyrimidine-based chemotherapeutic regimen. Post-operatively adjuvant chemotherapy for 4 months. b.operation: Time of operation weeks after end of preoperative chemoradiation, Surgical technique - standard total mesorectal excision and high ligation of inferior mesenteric vessels, Patient Evaluation : Pretreatment and Interim Testing : 1. Baseline test CBC and platelet, LFT, BUN/Cr, glucose, serum electrolyte, serum calcium and magnesium, EKG, chest PA, U/A with micro HBsAg/Ab, VDRL, HIV, (prn, ABGA, PFT, Cardiac Echo) 2. Work-up for colorectal cancer CEA, Colonoscopy with tissue biopsy, abdominal CT, pelvic MRI, endorectal sono, rigid sigmoidoscopy, pelvic MRI 3. Postoperative surveillence Digital rectal examination, CEA, Chest X-ray, Abdomen and pelvis CT, Colonoscope Statistical Consideration : We will check the upper limit of the 95% confidence boundary of the difference in 3-year disease-free survival between the two groups (open surgery minus laparoscopic surgery) to examine whether the difference exceed the pre-specified non-inferior margin (15%) or not. Survival analysis will be performed using the Kaplan-Meier method, while the log-rank test will be used to analyze survival curves. Quality of life scales will be analyzed using the analysis of covariance (ANCOVA) method with repeated measures. Estimated Accrual : - Accrual period : 3 years - Follow up period : 3 years - Sample size: Sample size calculation for non-inferiority trial; estimated 3yr-DFS: 75%, survival difference: 15%, power = 0.85, significance level=0.025, 10% expected loss of follow up 3

13 Site of Study : This protocol is performed as an : Inpatient Outpatient Both Where will study be conducted : Only at NCC NCC + Community Program Independent Multicenter Arrangements Name of Sponsor / Funding Source : NCC grant Sponsor Contact / Company Address / Telephone / Fax : Competing Protocol : None Name of Research Nurse / Data Manager Responsible for Protocol : NR Ja Young Yang Submit Protocol to Clinical Research Center Review Committee : Yes No 4

14 Table of Contents A. B. Protocol Abstract C. 1 Background D. 2. Objectives... 6 E. 3. Investigational Plan... 6 F. 4. Study Population... 7 G. 5. Patient Registration... 8 H. 6. Study Assessment... 8 I. 7. Statistical Methods... 9 J. 8. Safety... 9 K. 9. Ethical Considerations... 9 L. 10. References... 9 Appendix : Informed Consent 5

15 1. Background A. Research Background Since the introduction of laparoscopic cholecystectomy in 1988, the surgical area has been broadened to other organs in the abdominal cavity, cardiothoracic surgery, thyroid, and others because laparoscopic surgery results in a lesser decrease in immune function and quick shortterm recovery after surgery, is aesthetically outstanding, has high patient satisfaction, and boasts other advantages over laparotomy. Large intestinal surgery using a laparoscope was first reported in 1991, while large intestinal surgery using a laparoscope was first performed in South Korea by Park et al. in However, only a fraction of surgeons perform these procedures in large intestinal surgery using laparoscopy because of high complexity, a long adjustment period, the risk of cancer metastasis via the trocar insertion area and inadequate lymphadenectomy, the uncertain securement of the safety resection margin, and the relatively high conversion rate to laparotomy; however, laparoscopic surgery application in patients with colon cancer has increased rapidly after the report of no difference in oncological safety in comparison with laparotomy according to a recent prospective randomized study on colon cancer. However, the role of laparoscopic surgery for rectal cancer is less clear. B. Existing Domestic and Foreign Research Reports In 2002, Lacey et al. of the Barcelona Group reported no difference in relapse rate between the laparoscopic and laparotomy groups in a prospective randomized study of patients with colon cancer, and when stratified by tumor, node, metastasis stages, the laparoscopic surgery group had lower relapse and death rates related to cancer in stage 3 patients and a higher overall survival rate. According to the Clinical Outcomes of Surgical Therapy (COST) Study Group in 2004, the postsurgical complication and death rates did not differ significantly in patients with colon cancer, excluding those with transverse colon and rectal cancers between the laparoscopic and laparotomy groups of a manifold prospective randomized study; in fact, the overall relapse rate, lacerated area relapse rate, and 3-year survival rates did not differ significantly over the mid follow-up period of 4.4 years. However, shorter hospitalization periods, lower pain reliever usage, and faster postsurgical recovery periods were observed. On the other hand, the safety of laparoscopic surgery in rectal cancer has not been confirmed through large-scale prospective randomized studies. Especially within a narrow and crowded pelvis, performing total mesorectal excision (TME) while securing adequate distal and circumferential resection margins is the most important limitation because of its difficulty. In 2005, the United Kingdom MRC CLASICC trial reported the short-term result of comparing laparoscopic surgery and laparotomy for colon cancer including rectal cancer; accordingly, the positive rate of the circumferential resection margin was higher in the laparoscopic surgery group and the possibility of a higher local relapse rate henceforth was of concern. However, 6

16 although a nonrandomized clinical study reported similar results, another study reported that it does not become an oncological problem if the basic technique of rectal cancer, TME, is performed. Therefore, no consistent conclusion has been derived thus far about laparoscopic surgery for rectal cancer, and prospective research is required. Chemoradiotherapy is currently performed prior to surgery as a treatment method for mid to less progressive rectal cancer. Chemoradiotherapy prior to surgery reduces the tumor size to ease surgical resection, increases the rectal preservation rate, reduces the local relapse rate, and has other advantages. In addition, it is becoming the standard treatment for locally advanced rectal cancer. Prospective comparative research on laparoscopic and open surgery in patients who received chemoradiotherapy prior to surgery has not been reported, so research in this area is necessary 2. Objectives A. Hypothesis In patients who receive chemoradiotherapy prior to surgery, the oncological results of laparoscopic surgery are not inferior to those of open surgery B. Objectives The present research established the following final research objective and three detailed research objectives based on the above hypothesis. Final research objective: To compare treatment results between laparoscopic and open surgery after chemoradiotherapy prior to surgery in rectal cancer patients. Detailed research objectives: The first detailed assignment: Comparison of oncological outcomes between laparoscopic and open surgery after chemoradiotherapy prior to surgery in rectal cancer patients The second detailed assignment: Comparison of quality of life between laparoscopic and open surgery after chemoradiotherapy prior to surgery in rectal cancer patients. The third detailed assignment: Comparison of functional outcomes between laparoscopic and open surgery after chemoradiotherapy prior to surgery in rectal cancer patients 3. Investigational Plan 7

17 A. Overall research summary and promotion plan Rectal cancer patients Subject selection Tests to identify the status of patients Subject enrollment In case of consent Chemoradiotherapy prior to surgery Randomized allocation Open surgery Laparoscopic surgery Adjuvant chemotherapy Collection of survival data, quality of life data and anal function data B. Investigation Period - Clinical experiment period: authorization date of institutional review board ~ year Accrual period: 3 years - Follow-up period: 3 years C. Number of Subjects Number of subjects: 340 To determine the required number of study subjects, alpha errors, power, and survival differences were set at 0.025%, 0.85%, and 15%, respectively; loss during the follow-up observation period was predicted to be 10%. As such, 170 subjects in each group was decided, for a total of 340 study subjects. 4. Study Population 8

18 A. Inclusion Criteria: Mid to low rectal cancer (within 9cm from AV, measured by RS) Histologically proven adenocarcinoma Locally advanced (T3, determined by CT, MRI and TRUS) Completion of preoperative chemoradiation Age: Hb 10g/dl, WBC 3,000/mm3, Plt 100,000/mm3 Cr 1.5 mg/dl Adequate cardiopulmonary function Informed consent from patient or patient's relative B. Exclusion Criteria: Metastasis in liver, lung, brain, bone, paraaortic LN, subclavicular LN, inguinal LN Second primary malignancy (except CIS of the cervix or adequately treated skin cancer or prior malignancy treated more than 5 years ago without recurrence) Cardiopulmonary dysfunction Active, uncontrolled infection - Active, uncontrolled psychosis 5. Patient Registration For patients who show interest in participating, consent will be obtained prior to the study and a study subject account will be created. Trained researchers will complete a questionnaire in a direct patient interview. Trained researchers will perform the anorectal physiological test for each participant. 6. Study Assessment A. Assessment 9

19 Staging workup prior to preoperative chemoradiotherapy : digital rectal examination, carcinoembryonic antigen level, colonoscopy, chest radiography, computed tomography of the abdomen and pelvis, and pelvic magnetic resonance imaging with or without transrectal ultrasonography. Tumor location: determine from the distance from the anal verge to the lowest tumor margin using rigid scope. B. Treatment 1) Chemotherapy prior to surgery - Performed according to the chemotherapy protocol of rectal cancer patients 2) Radiation therapy prior to surgery - A 4,500-cGy radiation on the tumor area and the surrounding lymph node over 25 sessions, and then an additional 540-cGy radiation on primary tumor area over three sessions. 3) Surgery - Surgery time: 6 8 weeks after the completion of the chemoradiotherapy - Applied randomized selection between laparoscopic and open surgery prior to the surgery. - Surgical Method A. Open surgery: application of standard procedure for rectal cancer, including high ligation of inferior mesenteric artery and total mesorectal excision. - low midline incision - sigmoid colon mobilization - high ligation of inferior mesenteric artery and ligation of inferior mesenteric vein - sharp rectal dissection between mesorectal fascia and parietal fascia with autonomic nerve preservation - rectal transection with adequate distal margin or perineal resection in case of abdominoperineal resection - if necessary, splenic flexure mobilization for tension-free anastomosis - colo-rectal / colo-anal anastomosis using circular stapler/ hand sewn suture or creation of colostomy in case of abdominoperineal resection - creation of temporary ileostomy in case of sphincter-saving surgery (can omit ileostomy according to the decision of surgeons) 10

20 B. Laparoscopic surgery: application of oncologic resection principles equal to open surgery, including high ligation of inferior mesenteric artery and total mesorectal excision. - 5 ports insertion, including umbilical optic port - sigmoid colon mobilization using laparoscopic grasper and monopolar cautery or ultrasonic scalpel - high ligation of inferior mesenteric artery and ligation of inferior mesenteric vein using polymer vascular clips - sharp rectal dissection between mesorectal fascia and parietal fascia with autonomic nerve preservation - rectal transection with adequate distal margin using endo-stapler or perineal resection in case of abdominoperineal resection - if necessary, splenic flexure mobilization for tension-free anastomosis - specimen retrieval through small extended incision of LLQ port or perineal incision - colo-rectal / colo-anal anastomosis using circular stapler/ hand sewn suture or creation of colostomy in case of abdominoperineal resection - creation of temporary ileostomy in case of sphincter-saving surgery (can omit ileostomy according to the decision of surgeons) 4) Chemotherapy after surgery - Performed according to the adjuvant chemotherapy protocol of rectal cancer patients. C. Allocation of surgery Random allocation, open labelled Operation methods will be randomized using block permutation approach. The random numbers will be generated by computers, stratified according to sex and preoperative chemotherapeutic regimen. This process will be blinded and remote to the investigator. Patients will be randomly allocated to receive either laparoscopic or open surgery at a one-to-one ratio, by telephone by the trial coordinator at the central office at the National Cancer Center (the person in charge: NR. Ja Young Yang). D. Pathologic examination 11

21 Post-chemoradiotherapy pathologic stage (yp): determine according to the TNM classification system recommended by the American Joint Committee on Cancer Tumor regression grade: assess using Dworak s tumor regression grading system for semiquantitative evaluation of histopathologic tumor regression Circumferential resection margin (CRM): According to the protocol described by Quirke et al., the non-peritonealized surfaces of the specimen will be painted with black ink, and the specimen will be fixed in 10% formaldehyde overnight. The whole tumor, including surrounding non-neoplastic tissue and the suspected original lesion, will be sectioned (4 mm thick) and embedded. To determine the CRM, the shortest distance will be measured from the primary tumor to the adjacent mesorectal fascia. If a lymph node or tumor deposit is located nearer to the mesorectal fascia than the primary tumor, it will be used to measure CRM. Definition of CRM involvement is within 1 mm of the CRM. Macroscopic quality of the specimen: grade as described by Nagtegaal et al; complete / nearly complete / incomplete E. Follow-up Follow-up intervals: every 3 months for the first 2 years, every 6 months for the next 3 years, every 6 months or yearly thereafter Physical examination, serum CEA tests, and chest radiography: every visit Abdominal and pelvic computed tomography: every 6 months Colonoscopic examinations: 1 year postoperatively and then once every 2 years Event of disease-free survival: recurrence, death from any causes, or second primary cancer. Recurrence: diagnose pathologically by surgical resection or biopsy, and/or by the detection of radiologically apparent lesions that increased in size over time Local recurrence: define as any recurrences within the pelvic cavity or the perineum. Systemic recurrence: define as any recurrences outside the pelvic cavity. 12

22 Overall survival: define as time from surgery to death from any causes as the event of interest. F. Case report form (CRF) for patient group 13

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26 G. Main outcomes 1) Short-term outcomes: Surgical length of incision, op time blood loss, intraoperative complications, conversion rate, pathological resection margins (proximal, distal, circumferential), number of harvested lymph nodes, tumor regression grade (Dworak's grading), TNM staging, perioperative recovery, duration of use of parenteral narcotics, initiation of peristalsis, initiation of oral intake, duration of hospital stay, 30-day postoperative mortality, morbidity 2) Long-term outcomes: overall survival, local recurrence, port-site and wound site recurrence H. Questionnaire related to quality of life and physiological function evaluation 1) Quality of life measurement Questionnaire: evaluate the quality of life of the study subject group using the Korean version of the cancer patient life quality evaluation tool EORTC QLQ-C30 and the Korean version of the colorectal cancer patient life quality evaluation tool EORTC QLQ-CR38. Questionnaire contents will be explained and filled out by the trained researcher during patient interviews. Survey time: assess preoperatively, 3, 12, 24, 36, 48 and 60 months after proctectomy or ileostomy takedown in patients who underwent diverting ileostomy. 2) Physiological function evaluation Questionnaire: Trained researchers will fill out the questionnaire during a direct patient interview of urinary and sexual function (International Prostate Symptom Score (IPSS) for urinary function, 5-item Version of the International Index of Erectile Function (IIEF-5) for sexual function, and Female Sexual Function Index (FSFI) for female sexual function) Survey time: assess preoperatively, 3, 12, 24, 36, 48 and 60 months after proctectomy or ileostomy takedown in patients who underwent diverting ileostomy 17

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29 I. Ano-rectal function Questionnaire: the fecal incontinence severity index (FISI), Fecal Incontinence Quality of Life Scale Manometry examination: resting pressure, squeezing pressure, maximal tolerable volume, rectal capacity, high pressure zone, and other categories Survey time: assess preoperatively, 3, 12, 24, 36, 48 and 60 months after proctectomy or ileostomy takedown in patients who underwent diverting ileostomy for questionnaire; assess preoperatively, 6, 12, 24, 36, 48 and 60 months after proctectomy or ileostomy takedown in patients who underwent diverting ileostomy for manometry 20

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31 J. Systemic inflammatory response analysis Among the patients who consent to a blood sample draw, serum will be collected prior to surgery and 2 hours, 1 day, and 5 days after surgery to determine differences in interleukin (IL)-1, IL-2, IL-6, or C-reactive protein levels between groups. 7. Statistical Method Type of analysis is Intention to treatment We will check the upper limit of the 95% confidence boundary of the difference in 3-year disease-free survival between the two groups (open surgery minus laparoscopic surgery) to examine whether the difference exceed the pre-specified non-inferior margin (15%) or not. Depending on the distribution of the variables, variables of short-term outcomes will be analyzed using Chi-test, Fisher s exact test, Student s t test,or Wilcoxon rank-sum test. Survival analysis will be performed using the Kaplan-Meier method, while the log-rank test will be used to analyze survival curves. For adjusting confounding factors, Cox regression analysis will be performed. Quality of life scales, urinary/sexual function scales, anal function scales and the level of systemic inflammatory response will be analyzed using the analysis of covariance (ANCOVA) method with repeated measures. 8. Safety Laparoscopic surgery is a safe procedure performed in many surgical fields worldwide. Due to the development of various laparoscopic tools and the standardization of techniques, randomized prospective study results have shown that the frequency of complications in laparoscopic surgery for colon cancer is not higher than that of laparotomy. The sole adverse effect of laparoscopic surgery is caused by increased abdominal pressure due to the undulation that is performed to ease its performance, but this effect is temporary easily remedied. Other than that, damage to internal organs from insertion of the trocar and cancer relapse at the trocar insertion point have been reported, but these complications are sufficiently preventable with the recent development of new laparoscopic equipment and techniques. Various studies have reported that laparoscopic rectal cancer surgery is technically possible. Surgeons techniques are the most important factor in safe laparoscopic surgery for colon cancer. Various studies along with the COST study have stated that a minimum of 20 cases of laparoscopic surgery in the large intestine must be performed to be part of the research. A. Treatment modifications Laparoscopic proctectomy is only performed when the patient s safety can be secured. If the 22

32 surgeon faces a dangerous situation in the process of laparoscopic proctectomy, the approach is changed to open surgery. Also, if thorough surgery is not possible oncologically using laparoscopic proctectomy, the procedure is changed to open surgery to maximize the result. B. Serious Adverse Events (SAE) Serious adverse events (SAEs) are defined as those that require hospitalization of 2 months or a status resulting in death due to surgical complications during the clinical study. C. Reporting Serious Adverse Events During the study, if fatal or SAEs were to occur, researchers must immediately report the incident to the supervising researcher within 24 hours. All complications must be medically recorded in detail, and in the case of SAE, a report needs to be made to the head of the ethics commission, hospital director, and department director. 9. Ethical Considerations By signing the study participation consent form after sufficient explanation of the study design, the patients and examinees indicate their agreement that the researcher efficiently and faithfully perform the research following the present research plan. 10. References 1. Delgado S, Lacy AM, Filella X, et al. (2001) Acute phase response in laparoscopic and open colectomy in colon cancer: randomized study. Dis Colon Rectum 44: Delgado S, Momblan D, Salvador L, et al. (2004) Laparoscopicassisted approach in rectal cancer patients; lesson learned from >200 patients. Surg Endosc 18: Franklin MEJ, Rosenthal D, Abrego-Medina, et al. (1996) Prospective comparison of open vs. laparoscopic colon surgery for carcinoma:.ve.years results. Dis Colon Rectum 39:S35.S46 4. Hartley JE, Mehigan BJ, Qureshi AE, et al. (2001) Total mesorectal excision: assessment of the laparoscopic approach. Dis Colon Rectum 44: Hazebroek EJ, for the Color Study Group (2002) COLOR: a randomized trial comparing laparoscopic and open resection for colon cancer. Surg Endosc 16: Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. (2001) Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for respectable rectal cancer. N Eng J Med 345: Lacy AM, Garcia-Valdecasas JC, Delgado S, Castells A, Taura` P, Pique` JM, Visa J (2002) 23

33 Laparoscopy assisted colectomy versus open colectomy for treatment of nonmetastatic colon cancer: a randomised trial. Lancet 359: Lacy AM, Garcia-Valdecasas JC, Pique JM (1995) Short term outcome analysis of a randomised study comparing laparoscopic versus open colectomy for colon cancer. Surg Endosc 9: Leroy J, Jamali F, Forbes L, Smith M, Rubino F, Mutter D, Marescaux J (2004) Laparoscopic total mesorectal excision (TME) for rectal cancer surgery. Surg Endosc 18: Morino M, Parini U, Giraudo G, Salval M, Brachet R, Garrone C (2003) Laparoscopic total mesorectal excision. A consecutive series of 100 patients. Ann Surg 237: Simunovic M, Sexton R, Rempel E, et al. (2003) Optimal preoperative assessment and surgery for rectal cancer may greatly limit the need for radiotherapy. Br J Surg 90: Weeks JC, Nelson H, Gelber S, et al. (2002) Short term quality of life outcomes following laparoscopic assisted colectomy versus open colectomy for colon cancer: a randomised trial. J Am Med Assoc 287: Jayne DG, Brown JM, Thorpe H, Walker J, Quirke P, Guillou PJ (2005) Bladder and sexual function following resection for rectal cancer in a randomized clinical trial of laparoscopic versus open technique. Br J Surg 92(9) Guillou PJ. Quirke P. Thorpe H, Walker J, Jayne D, Smith A, Heath R, Brown J (2005) Shortterm endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet 365: Greene FL, Rage DL, Fleming ID, et al. (2002) AJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag 16. Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12: Quirke P, Durdey P, Dixon MF, Williams NS (1986) Local recurrence of rectal adenocarcinoma due to inadequate surgical resection. Histopathological study of lateral tumour spread and surgical excision. Lancet 2: Nagtegaal ID, van de Velde CJ, van der Worp E, Kapiteijn E, Quirke P, van Krieken JH (2002) Cooperative Clinical Investigators of the Dutch Colorectal Cancer Group. Macroscopic evaluation of rectal cancer resection specimen: clinical significance of the pathologist in quality control. J Clin Oncol 20:

34 동의서 연구제목 : 진행성직장암에서수술전항암화학방사선요법후 복강경절제술과개복절제술의전향적무작위비교연구 참여자이름 : 병록번호 : 귀하께서는본연구에참여하시도록제안받았습니다. 본연구는연구에참여하는참여자의권리를보호할책임이있는국립암센터연구심사위원회의승인을받았습니다. 이동의서는왜우리가이연구를하며귀하의권리와역할이무엇인지에대해설명합니다. 귀하께서연구에참여하기로동의하시기전에이동의서를읽고이해하는것이중요합니다. 동의서에는이연구의목적, 과정, 이점, 부작용, 그리고주의사항등이포함되어있습니다. 또한귀하의선택권과참여중단에대한권리를설명하고있으며, 만일귀하께서본연구에참여하신다면, 귀하는이동의서를보관할수있도록사본을받게되실것입니다. 연구의목적 진행성직장암의치료방법으로현재가장많이이용되고있는치료방법은수술전에항암방사선치료를먼저시행하고, 이후수술을시행하는것입니다. 수술은개복하여직장을절제하는방법과복강경하에서직장을절제하는방법이있습니다. 최근의치료경향은수술후환자의생존율뿐아니라치료후의삶의질이나, 조기회복등의중요성이부각되고있고, 같은치료성적을갖는다면환자가보다쉽게회복하고장기적인삶의질이우수한치료가바람직하다는인식하에이러한점들을장점으로내세우는새로운치료방법이대두되고있습니다. 그러나이러한새로운치료방법은반드시시술의안전성, 부작용, 경제성, 생존률이나삶의질에대한장점과단점등이올바른비교검토를통해과학적으로검증을하여야합니다. 이론적인배경이나동물실험등을통한증명은기본적인것이며, 가장중요한것은실제환자치료에일정하게적용시켜기존의치료방법과비교하는것입니다. 본임상연구의목적은진행성직장암에서수술전항암방사선치료를먼저시행한후에복강경직장절제술과기존의개복직장절제술을생존률, 수술후회복, 통증의정도, 합병증, 삷의질, 항문기능검사등여러가지면에서비교하여표준적인치료방법으로서의의의를검증하는것입니다. 25

35 환자의권리 연구전혹은도중에귀하는몇가지중요한권리를가집니다 : 연구참여에관한중요한결정을내릴필요가있는모든것에대해알권리 언제든지연구참여를거부할수있는권리 연구절차 국립암센터대장암센터혹은서울대학교분당병원외과에서진행성직장암으로최종진단된환자중본임상연구의참여기준에합당하다고판단되는환자분가운데, 임상연구에동의하는분을대상으로연구를진행하게됩니다. 임상연구에동의하신후에는항암방사선치료를먼저시행받고이후약 6-8주후에개복직장절제수술을받을환자와복강경직장절제수술을받을환자를임상시험센터에서소정의방법에의하여무작위로결정합니다. 수술방법이결정되면환자에게즉각적으로해당수술에대한안내와설명이이루어집니다. 두가지수술은수술의범위와내용면에서근본적으로차이가없게이루어지며, 단지, 복강경적으로접근하는지, 개복으로접근하는지의수술기법에관한차이가있을뿐입니다. 수술방법에따른담당외과의사의변화는없으며, 원래담당한의사가계속치료를전담하게됩니다. 수술후의환자치료과정도두수술간에근본적인차이가없습니다. 또한, 임상연구에 참여한경우와참여하지않은경우의차이도근본적으로 없습니다. 단지, 임상자료수집과 연구용으로사용여부에있어서만의차이가있습니다. 임상연구참여기간 수술받는시점으로부터수술후 5 년간외래추적과정까지를기본으로합니다. 임상 연구에참여한경우와하지않는경우의외래추적관찰계획에근본적으로차이가없습니다. 환자의경제적부담 기본적으로두수술은같은수술이나복강경수술의경우단지복강경과작은절개를통해개복시의수술과정을시행하는것이며, 보험적용을똑같이받게됩니다. 그러나복강경수술의경우개복수술에비해수술시특수한재료가사용되어비보험재료비가추가됩니다. 반대로수술용실이나바늘등봉합재료비는적습니다. 따라서복강경수술환자의경제적부담은개복수술에비하여 만원정도추가될수있습니다. 임상연구에동의해서수술을할경우복강경직장절제술은 50만원개복직장절제술은 20만원의수술재료비가 26

36 연구비에서지원됩니다. 예상되는이점 1) 복강경수술의예측되는이점은개복수술에비하여수술후회복이빠르며, 창상이적고, 통증이적습니다. 장관손상이적어장유착의빈도가적어장기적으로도이점이있을수있습니다. 최소침습수술의장점의하나로, 암환자에서생존률의향상이가능할수있다는보고가몇가지있으나, 아직완전히증명되지않았습니다. 2) 개복수술의경우수십년간의여러외과들의경험을통해수술기법이정착되어있어, 결과의예측가능성이높은장점이있으며, 육안을통해암병소를확인하고직접수술자의촉감으로만져가며수술하므로수술시과오가적을수있습니다. 출혈등이발생시에빨리대처할수도있습니다. 두수술은장단점을가질수있고, 어느한쪽이우수하다는현단계에서결론을내릴수없기에, 본임상연구를통해그러한점들이밝혀지게될수있습니다. 연구참여에따른부작용복강경수술에따른부작용은복압상승으로인한것으로서, 수술중순환장애, 뇌압상승, 신부전등과이산화탄소의과다흡수로인한대사성산증등의생리적부작용과, 피하기종, 공기색전증등이있으나, 극히드물게발생하며공기색전증이외에는환자의생명에위해한것은없습니다. 복강경수술중출혈이나장관의손상등이있는경우개복으로전환할수있습니다. 본연구에참여하는경우설문지를작성하는과정에서피로와불편함을겪으실수있습니다. 또한직장항문생리검사과정에서불편함이발생할수있습니다. 그러나설문과직장항문생리검사과정에예상치못한불편함이발생하는경우에는조사자에게알려주십시오. 이러한경우에는언제든지설문과직장항문생리검사중단등적절한조치를취할것입니다. 해당질환에대한다른치료방법 진행성직장암에서의치료는현재로서는항암방사선치료후근치적수술이가장좋은 방법입니다. 참고로복강경절제술은개복술과같은절제범위와림프절곽청술을 시행합니다. 27

37 자발적참여 본연구참여여부는완전히귀하의자유의사에의한것입니다. 따라서, 귀하는본연구에참여하지않을수도있고, 또한언제라도동의를철회하고귀하의참여를중단할수도있으며, 그에따른어떠한불이익이나차별도없을것입니다. 귀하가본양식에서명하거나본연구참여에동의함으로써귀하의법적권리를포기하는것이아니라는사실을다시한번알려드립니다. 피해발생시보상및치료대책 국립암센터는연구계획서에따른연구절차와직접관련되어상해가발생한경우, 이에 대한적절한의학적조치를취할것입니다. 그러나그에따른경제적인보상은없습니다. 자료보호 본연구의모든자료는엄격하게환자의비밀이유지되어보호를받게됩니다. 귀하가본 연구에참가하기로동의할경우, 본연구에서수집된자료는익명으로다루어질것입니다. 언제라도본연구에대한의문사항이있을때에는담당의사또는책임연구자오재환에게알려주시기바랍니다. 또한만일귀하가연구에참여하는데대하여귀하의권리에관해의문이있으면국립암센터연구심사위원회위원장서홍관또는담당자김순미에게로문의하시기바랍니다. 서명란 본인은본연구에대한목적, 방법, 기대효과, 부작용등에대하여충분한설명을듣고이해하였으며, 위의사항들에대하여서면으로받아보았습니다. 그리고, 본연구에참여를동의한경우라도언제든지철회할수있음을확인하였습니다. 이에본인은자유로운의사에따라본연구에참가함을동의합니다. 동의항목 설문직장항문생리검사수술방법 28

38 날짜 200 년월일시분날짜 200 년월일시분 환자 ( 인또는서명 ) 보호자 ( 인 또는서명 ) 주소 전화 주소 전화 본인은연구에대하여환자또는환자의대리인에게연구에관하여충분히설명하였음을 확인합니다. 날짜 200 년월일시분 담당의사 ( 인 ) 또는서명 다음은각각해당사항이있는경우에만서명하십시오. 본대리인 ( 친권자또는배우자 ) 은환자의의사표현능력결여로동의가불가능하여, 환자를대신하여임상연구참가에동의합니다. 대리인 ( 인 ) 또는서명환자와의관계주소전화 본인은환자가동의서및기타문서화된정보를읽지못하는상황에서, 담당의사가 본임상연구에대하여환자 ( 또는대리인 ) 에게충분히설명하였고환자 ( 또는대리인 ) 는 설명을이해하고임상연구의참여를동의 ( 가능한경우, 자필서명 ) 하였음을확인합니다. 또는서명 공정한입회자 ( 인 ) 29