Trial Information

Randomized Controlled Clinical Trial: Endoluminal Loco-regional Resection (ELRR) by Transanal Endoscopic Microsurgery (TEM) Versus Laparoscopic Total Mesorectal Excision (LTME) in it2n0m0 Small Low Rectal Cancer

From April 1997 to April 2004, patients with cT2 rectal cancer and no suspicion for positive
lymph-nodes or distant metastases (cN0 M0) were enrolled in this study.

History, routine laboratory tests including tumour markers, digital examination to evaluate
tumour fixation and sphincter tone, clinical evaluation, were recorded for each patient in a
data base.

At admission, staging included: 1) endorectal ultrasound (EUS) 2) rigid rectoscopy and
tumour biopsies; 3) total colonoscopy with vital dye staining of the rectum and 6-8 standard
biopsies of normal mucosa at a distance of approximately 1 cm around the tumour with India
ink tattooing of biopsy sites; 4) helical Total Body Computerized Tomography (CT), and 5)
pelvic magnetic resonance imaging (MRI). Rigid rectoscopy was performed in order to measure
the exact distance of the tumour from the anal verge and to select the most appropriate
patient's position on the operative table in case of TEM surgery.

Positive lymph-node status at imaging was established according to the following criteria:

1. at EUS, diameter > 0.8 cm, circular or irregular shape, hypervascularization at colour
Doppler and hypoechogenicity.

2. at CT and MRI, diameter of > 0.8 cm, circular or irregular shape. All patients with
suspicious nodes or contradictory response at EUS, CT or MRI T staging were not
enrolled in the present study.

Inclusion criteria were: tumour located within 6 cm from the anal verge, tumour diameter not
larger than 3 cm, and staged as cT2 N0 M0, G1-2. Patients classified as American Society of
Anaesthesiologists (ASA) 3 or 4 were excluded.

All patients underwent preoperative radiotherapy. The total dose given was 50.4 Gy in 28
fractions over 5 weeks. The irradiated areas were: anus, rectum, mesorectum, regional and
iliac lymph-nodes. Continuous infusion of 5-FU 200 mg/m2/day was performed during
radiotherapy treatment.

Forty days after the end of NT, staging as described above (except for total colonoscopy)
was repeated. Downsizing was classified in two groups: patients with tumour mass reduction
more than 50% (responders) and patients with tumour mass reduction less than 50% (low or non
responders). According to the study protocol, patients with disease progression were
excluded.

Randomization was performed the day before operation. Patients were stratified in two
groups and subsequently allocated 1:1 to the two arms of the study, ELRR by TEM (arm A) or
LTME (arm B) by means of sealed opaque envelopes containing computer-generated random
numbers. In the end, 50 patients underwent ELRR by TEM (arm A) and 50 patients underwent
laparoscopic resection (LTME) (laparoscopic low anterior resection or abdominal-perineal
resection) (arm B). The recruitment was interrupted when 100 patients had undergone
operation.

Surgery was performed between 45 and 55 days after the end of radio-chemotherapy.
Preoperative washout of the colon (polyethyleneglycol) and short-term antibiotic prophylaxis
(metronidazole and second generation cephalosporin) were administered to all patients.
Surgical procedures were performed only by two surgeons expert in open rectal surgery and
skilled in both laparoscopic and TEM procedures.

TEM procedures were performed with the Wolf Company (Tuttlingen, Germany) instrumentation.
The surgical technique of ELRR was as follows: mucosal incision included all the tattoo
spots performed at admission staging, in order to excise a minimum of 1 cm of normal mucosa
around the tumour, according to its diameter before NT. Starting from the mucosal incision
the dissection was continued deeply in order to remove all the mesorectum adjacent to the
tumour, following a cutting line with an angle of approximatively 120-135° with respect to
the mucosal plane. For posterior and lateral lesions the bottom dissection plane was carried
down to the "holy plane" and for anterior lesions to the level of the vagina septum or the
prostatic capsule. In case of tumour with the distal limit at the level of the anal canal,
the incision included the dentate line and the internal sphincter fibres were partially
removed. For distal tumours, in order to maintain the CO2 rectum insufflation it is
recommended to adjust the rectoscope axis so as to keep its inferior circumference adherent
to the anal canal. In all patients the defect was closed by multiple running stitches,
according to the technique described by Buess.

The surgical technique of Arm B was laparoscopic low anterior resection or abdominal
perineal resection.

Primary endpoint in this study was the oncological result in terms of local recurrence,
distant metastases and cancer related mortality with minimum follow-up time of 5 years.
Secondary endpoints were: operative time, blood loss, analgesic use, morbidity, hospital
stay and 30 day mortality. Major morbidity was defined as complications requiring surgical
treatment. In order to evaluate local and/or systemic recurrence, all patients were
prospectively followed-up by clinical examination, tumour markers' assay and rectoscopy
every 3 months for the first 3 years, then every six months. Total body CT, and pelvic MRI
were repeated every 6 months for the first 5 years. According to the study protocol, no
adjuvant therapy was administered, as recommended by the consultant oncologist in T2N0
rectal cancer patients.