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Japanese Journal of Clinical Oncology Advance Access published online on June 26, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn054
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© The Author (2008). Published by Oxford University Press. All rights reserved

Phase II Trial to Evaluate Laparoscopic Surgery for Stage 0/I Rectal Carcinoma

Seiichiro Yamamoto1, Kenichi Yoshimura2, Fumio Konishi3 and Masahiko Watanabe4

1 Division of Colorectal Surgery, National Cancer Center Hospital, Tokyo
2 Biostatistics and Epidemiology Section, Clinical Trials and Practice Support Division, Center for Cancer Control and Information Services, National Cancer Center Research Institute, Tokyo
3 Department of Gastroenterology, Jichi Medical University, Omiya Medical Center, Saitama
4 Department of Surgery, Kitasato University Hospital, Kanagawa, Japan

For reprints and all correspondence: Seiichiro Yamamoto, Division of Colorectal Surgery, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: seyamamo{at}ncc.go.jp

Received March 17, 2008; accepted May 30, 2008


   Abstract
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Recently reported randomized controlled trials demonstrated that laparoscopic surgery (LS) was comparable or superior to open surgery with regard to the long-term outcome for colon and rectosigmoidal carcinoma; however, controversy persists with regard to the appropriateness of LS for patients with rectal carcinoma. To examine the technical and oncological feasibility of LS for rectal carcinoma, a phase II trial was started in patients with a preoperative diagnosis of Stage 0/I rectal carcinoma, under the direction of the Japan Society of Laparoscopic Colorectal Surgery. Surgeons in 39 specialized institutions will recruit 350 patients. The primary end-point in the first stage is the anastomotic leakage rate by double-stapling technique and that in the second stage is overall survival. Secondary end-points are relapse-free survival, short-term clinical outcome, adverse events, the rate of histologically curative operation, the proportion of completion of LS and the conversion rate.

Key Words: laparoscopic surgery • rectal carcinoma • phase II trial


   INTRODUCTION
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 Abstract
 INTRODUCTION
PROTOCOL DIGEST OF THE...
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Recently reported randomized controlled trials (RCTs) demonstrated that laparoscopic surgery (LS) was comparable or superior to open surgery with regard to the long-term outcome for colon and rectosigmoidal carcinoma (1–6); however, controversy persists with regard to the appropriateness of LS for patients with rectal carcinoma because of the uncertainty of the long-term outcome, and of concerns over the safety of the procedure (7–10).

Despite many reports of LS for advanced rectal carcinoma in Western countries, advanced rectal carcinoma is seldom treated laparoscopically in Japan. Lateral lymph node dissection combined with total mesorectal excision remains the standard surgical procedure for patients with advanced lower rectal carcinoma in Japan, and lateral lymph node dissection by laparoscopy is still an unexplored frontier (11–13). Moreover, LS for rectal carcinoma remains controversial because of concerns over the safety of the procedure, especially in low anterior resections for lower rectal carcinoma.

With regard to the complications of LS for rectal carcinoma, the most difficult complication is anastomotic leakage. In rectal carcinoma, anastomotic leakage requires not only prolonged hospitalization, but also a temporary or permanent stoma in some patients, thereby resulting in unavoidable deterioration in their quality of life. Moreover, anastomotic leakage may cause fatal peritonitis, or may promote intrapelvic recurrence in some cases. To examine the technical and oncological feasibility of LS for rectal carcinoma, a phase II trial has started in patients with a preoperative diagnosis of Stage I rectal carcinoma, under the direction of the Japan Society of Laparoscopic Colorectal Surgery, of which leading hospitals in LS for colorectal carcinoma in Japan are members.

The study protocol was approved by the Ethics Committee of the Japanese Society for Cancer of the Colon and Rectum (JSCCR) on 2 August 2007, and the study was started on February 2008.


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Purpose
The purpose of this study is to evaluate short- and long-term outcomes of LS for clinical stage 0/I rectal carcinoma.

Study Setting
A multi-institutional (39 specialized centers), non-randomized and one-arm (laparoscopic) trial (phase II).

Resources
Research grant from JSCCR.

End-points
The primary end-point in the first stage is the anastomotic leakage rate by double-stapling technique (DST) and that in the second stage is overall survival. Secondary end-points are relapse-free survival, operative mortality rate, the rate of histologically curative operation, the proportion of completion of LS, conversion rate, intraoperative and postoperative complication rate, re-operation rate and postoperative hospital stay.

All laparoscopic cases, which require skin incision >8 cm, are counted as a conversion, except for those in which retrieval of the resected specimen alone requires this length of incision. The completion of LS is defined as the completion of the curative operation without conversion.

Eligibility Criteria
Tumors are staged according to the TNM classification system. Tumor location was defined according to the JSCCR General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (14). When the tumor was located between the inferior margin of the second sacral vertebra and the peritoneal reflection, the location was recorded as the upper rectum. When the tumor was located below the peritoneal reflection, its location was recorded as the lower rectum. The location of the tumor was determined by pelvic CT scan, colonoscopy and/or barium enema preoperatively and confirmed during surgery.

Inclusion Criteria
For inclusion in the study, patients must fulfill the following requirements preoperatively:

  1. Histologically proven rectal adenocarcinoma.
  2. Tumor located in the rectum.
  3. Clinical Tis-T2/N0/M0.
  4. Without multiple lesions other than carcinoma in situ
  5. Tumor size ≤8 cm.
  6. Age ≥20 and ≤75 years.
  7. No bowel obstruction.
  8. No history of major colorectal surgery.
  9. No prior chemotherapy or radiotherapy for any malignancy.
  10. Sufficient organ function.
  11. Written informed consent.

Exclusion Criteria
Exclusion criteria are as follows:

  1. Synchronous or metachronous (within 5 years) malignancy other than carcinoma in situ.
  2. Pregnant or lactating women.
  3. Severe mental disease.
  4. History of acute myocardinal infarction within 6 months before registration, or unstable angina.
  5. Severe pulmonary emphysema, interstitial pneumonitis or ischemic heart disease.
  6. Continuous systemic steroid therapy.

Registration
Eligible patients are registered by calling the registration office at Kitasato University after confirmation of the inclusion/exclusion criteria. An eligibility report form is sent to the Data Center at the Clinical Trial Coordinating Office at the National Cancer Center Hospital.

Quality Control of Surgery
Surgeons with experience of more than 30 laparoscopic and 30 open operations for rectal carcinoma are accredited by the study chair. To control the quality of the operation, only accredited surgeons participated in this study. We perform a central review of the surgical procedure by photographing all patients and by videotape of arbitrarily selected patients.

Treatment Method
Laparoscopic resection of the rectum with adequate lymphadenectomy is performed according to the JSCCR General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (14). The extent of lymphadenectomy and site of ligation and division of the inferior mesenteric vessels were decided by the surgeon in charge. Pneumoperitoneal approaches are used to explore the abdomen, mobilize the left-side colon, identify critical structures and ligate the vascular pedicle. Mobilization of the rectum, excision of the mesorectum, rectal transection, removal of the specimen and reconstruction are performed by the pneumoperitoneal approach or the extracorporeal approach via a small incision (<8 cm). For sphincter-preserving operations, the decision to make a protective ileostomy is based on the surgeon’s technical evaluation of the quality of the anastomosis. Hand-assisted LS is permitted when required for the control of intraoperative complications, but sliding window and moving window methods are not permitted. When an incision longer than 8 cm is required for the control of intraoperative complications or tumor extension, the operation is counted as a conversion.

Additional Treatment
When pathological stage III, assessed by histological examination of the resected specimen, is reached three cycles of adjuvant chemotherapy with fluorouracil (500 mg/m2 by bolus infusion on Days 1, 8, 15, 22, 39 and 36) and L-leucovorin (250 mg/m2 by 2 h drip infusion on Days 1, 8, 15, 22, 39 and 36) are recommended.

Follow-up
For surveillance after curative surgery, patients are observed periodically by their surgeon: every 12 months for 5 years for pathological stage 0/I patients; every 4 months for the first 2 years and then every 6 months for 3 years for pathological stage II/III patients. Blood tests, abdominal and pelvic computed tomography and plain chest X-ray are carried out at each visit.

Study Design and Statistical Method
This trial has been designed to evaluate the feasibility of LS for rectal carcinoma in terms of short- and long-term outcome.

In the first stage, the expected anastomotic leakage rate by DST is 12% and the threshold value is 20%. The sample size has been calculated as 160 DSTs (one-sided {alpha} = 0.05 and β = 0.1). If the anastomotic leakage rate is higher than the permitted rate, LS for rectal surgery is not accepted. If the leakage rate is within the permitted rate, we move on to the second stage to evaluate oncological safety. In the second stage, the expected 5-year overall survival rate is 88% and the threshold value is 83%. The sample size has been calculated as 350 (one-sided {alpha} = 0.05 and β = 0.2). The planned accrual period is 3 years, and the follow-up period has been set as 5 years after completion of accrual.

Interim Analysis and Monitoring
The Data and Safety Monitoring Committee (DSMC) independently review the trial monitoring report with regard to efficacy and safety data from the present study. Based on this monitoring, DSMC can consider early termination of a treatment regimen during the study and modification of the study protocol, including increasing the sample size if no definitive selection is possible at the end of study. Protocol compliance, safety and on-schedule study progress are also monitored by the DSMC.

ClinicalTrials.gov Registration
This study protocol was registered in the ClinicalTrials.gov (NCT00635466 [ClinicalTrials.gov] ), a service of the United States National Institute of Health, on 14 March 2008 (http://clinicaltrials.gov/ct2/show/NCT00635466).


   PARTICIPATING INSTITUTIONS
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 Abstract
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Sapporo Medical University, Iwate Medical University, Sendai City Medical Center, Sendai Open Hospital, Jichi Medical University, Jichi Medical University Saitama Medical Center, Saitama Medical University International Medical Center, National Cancer Center Hospital East, Juntendo University Urayasu Hospital, Juntendo University Hospital, Cancer Institute Hospital of Japanese Foundation for Cancer Research, National Cancer Center Hospital, Keio University Hospital, Tokyo Medical and Dental University Hospital, Toho University School of Medicine Ohashi Medical Center, Kitasato University Hospital, Showa University Northern Yokohama Hospital, Yokohama City University Medical Center, St Marianna University Hospital, Ishikawa Prefectural Central Hospital, Fukui Prefecture Saiseikai Hospital, Nagano Municipal Hospital, Fujita Health University, Kyoto Prefectural University of Medicine, Kyoto Medical Center, Kyoto University, Osaka Red-cross Hospital, Osaka University, Osaka Medical College, Minoh City Hospital, Suita Municipal Hospital, Nishinomiya Municipal Hospital, Fukuyama City Hospital, Hiroshima University Hospital, Yamaguchi University Graduate School of Medicine, Shikoku Cancer Center Hospital, Kochi Medical School, Kochi Health Sciences Center, Oita University Faculty of Medicine.


   Funding
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 Abstract
 INTRODUCTION
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References
 
This study was supported in part by JSCCR.

Conflict of interest statement

None declared.


   References
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 Abstract
 INTRODUCTION
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1 Lacy AM, Garcia-Valdecasas JC, Delgado S, Castells A, Taura P, Piqué JM, et al. Laparoscopic-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomized trial. Lancet (2002) 359:2224–9.[CrossRef][Web of Science][Medline]

2 Leung KL, Kwok SPY, Lam SCW, Lee JFY, Yiu RYC, Ng SSM, et al. Laparoscopic resection of rectosigmoid carcinoma: prospective randomised trial. Lancet (2004) 363:1187–92.[CrossRef][Web of Science][Medline]

3 Fleshman J, Sargent DJ, Green E, Anvari M, Stryker SJ, Beart RWJ, et al. Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg (2007) 246:655–62.[CrossRef][Web of Science][Medline]

4 Jayne DG, Guillou PJ, Thorpe H, Quirke P, Copeland J, Smith AMH, et al. Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol (2007) 25:3061–8.[Abstract/Free Full Text]

5 Liang JT, Huang KC, Lai HS, Lee PH, Sun CT. Oncologic results of laparoscopic D3 lymphadenectomy for male sigmoid and upper rectal cancer with clinically positive lymph nodes. Ann Surg Oncol (2007) 14:1980–90.[CrossRef][Web of Science][Medline]

6 Kitano S, Inomata M, Sato A, Yoshimura K, Moriya Y, Colorectal Cancer Study Group (CCSG) of Japan Clinical Oncology Group. Randomized controlled trial to evaluate laparoscopic surgery for colorectal cancer: Japan Clinical Oncology Group study JCOG 0404. Jpn J Clin Oncol (2005) 35:475–7.[Abstract/Free Full Text]

7 Guillou PJ, Quirke P, Thorpe H, Walker J, Jayne DG, Smith AM, et al, MRC CLASICC trial group. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet (2005) 365:1718–26.[CrossRef][Web of Science][Medline]

8 Moloo H, Mamazza J, Poulin EC, Burpee SE, Bendavid Y, Klein L, et al. Laparoscopic resections for colorectal cancer: does conversion affect survival? Surg Endosc (2004) 18:732–5.[Web of Science][Medline]

9 Thorpe H, Jayne DG, Guillou PJ, Quirke P, Copeland J, Brown JM, MRC CLASICC trial group. Patient factors influencing conversion from laparoscopically assisted to open surgery for colorectal cancer. Br J Surg (2008) 95:199–205.[CrossRef][Web of Science][Medline]

10 Laurent C, Leblanc F, Gineste C, Saric J, Rullier E. Laparoscopic approach in surgical treatment of rectal cancer. Br J Surg (2007) 94:1555–61.[CrossRef][Web of Science][Medline]

11 Moriya Y, Sugihara K, Akasu T, Fujita S. Importance of extended lymphadenectomy with lateral node dissection for advanced lower rectal cancer. World J Surg (1997) 21:728–32.[CrossRef][Web of Science][Medline]

12 Fujita S, Yamamoto S, Akasu T, Moriya Y. Lateral pelvic lymph node dissection for advanced lower rectal cancer. Br J Surg (2003) 90:1580–5.[CrossRef][Web of Science][Medline]

13 Yamamoto S, Watanabe M, Hasegawa H, Kitajima M. Prospective evaluation of laparoscopic surgery for rectosigmoidal and rectal carcinoma. Dis Colon Rectum (2002) 45:1648–54.[CrossRef][Web of Science][Medline]

14 Japanese Society for Cancer of the Colon and Rectum. General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (in Japanese). (2006) 7th edn. Tokyo: Kanehira-Syuppan.


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