Trial Information

Randomized Controlled Trial to Evaluate High Tie Versus Low Tie of the Inferior Mesenteric Artery in Rectal Anterior Resection for Rectal Cancer Patients

Patients

- This was a randomized controlled trial conducted at a single institute, which was
Yokohama City University Medical Center (Japan).

- 400 patients who underwent anterior resection for rectal cancer were randomly allocated
to receive high tie or low tie of the inferior mesenteric artery.

Surgical procedures

- All surgical procedures were performed by one specialized colorectal treatment team.
The laparoscopic surgeries were performed by a surgeon who passed the skill
accreditation system for laparoscopic gastroenterological surgery was established by
the Japanese Society for Endoscopic Surgery (JSES), and all open surgeries were
performed under the supervision of these skillful surgeons.

- All operations were performed according to the standard radical cure procedure
described in the seventh edition of the Japanese General Rules for Clinical and
Pathological Studies on Cancer of the Colon, Rectum and Anus. That is, intestinal
excision with lymph node dissection around the IMA at its origin was performed in all
surgical procedures. Patients who underwent palliative partial excision were not
included.

- In the high tie (HT) of the IMA, IMA was separated at its origin from the abdominal
aorta.

- In the low tie (LT) of the IMA, IMA was separated after branching to the left colic
artery. The lymph node dissection around the IMA at its origin was performed.

Randomization - To balance the operative backgrounds between HT and LT groups, the patients
were stratified by the approach of surgery (open or laparoscopic surgery).

Adjuvant therapy

- When the pathological stage was diagnosed as stage 3 by histological examination of the
resected specimen, adjuvant chemotherapy was done with oral fluoropyrimidine
anti-cancer drug.

- Neither radiation therapy nor preoperative chemotherapy was given to any patient.
Preoperative chemo-radiotherapy even for rectal cancer is not yet standard treatment in
Japan.

Assessment parameters

- The preoperative parameters

- Operative assessment parameters

- Postoperative assessment parameters An early postoperative complication was defined as
a complication that occurred between the finish of the operation and postoperative day
30. A late postoperative complication was defined as a complication that occurred after
postoperative day 30. The terminologies of complications were classified according to
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and grading was
done by Classification of Surgical Complication.

- The pathological results were recorded according to the 7th edition of the Japanese
General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and
Anus and 7th edition of primary tumor, regional nodes, metastasis (TNM) classification.
Circumferential margin involvement was defined as exposure of a cancer cell at the
vertical dissection surface on histological examination.

Follow-up schedule

- The follow-up schedule was as follows according to stage. Patients with stages 0 and 1
were followed up with outpatient examinations including tumor marker measurements, and
chest, abdominal and pelvic computed tomography (CT) once a year for five years. Patients
with stage 2 and 3a were examined by CT and tumor marker measurements every six months for
the first two years. These examinations were done once a year from the third year to the
fifth year. Patients with stage 3b and 3c were examined by CT and tumor marker measurements
every four months for the first two years, and every six months from the third year to the
fifth year.

Statistical analysis

- The primary endpoint was anastomotic leakage rate.

- The secondary endpoints were operation time, amount of bleeding and 5-year overall
survival. To evaluate whether a difference in the operative procedure influences
survival including death due to another disease, a comparison of overall survival has
meaning. Operation time and amount of bleeding were added to the secondary endpoints
because these parameters had a possibility of becoming grounds of selection of the
operation method if there were no differences in overall survival.

- A sample size of 392 patients was assured to achieve a power of more than 70% to detect
a difference between the groups using a two-sided Chi-squared test with type I error
rate equal to 0.05, when the true complication rates were 5% and 12% for the LT and HT
groups, respectively. The dropouts were considered and the number of accumulation
targets was assumed to be 400 patients.

- For continuous variables, data are presented as means ± standard deviation (SD). For
categorical variables, data are presented as frequencies and percentages (%).
Comparison of the endpoints was based on intention-to-treat principle, that is, the
patients who switched to another group during surgery were treated as members of the
allocated group. The Chi-squared test was applied to evaluate the significance of
differences in proportions, and t-test was used to evaluate the significance of
differences in continuous variables. A p-value of less than 0.05 was considered to be
statistically significant.