Summary of the trial

Colorectal cancer is the third most common cancer and second cause of cancer related death in the Netherlands with 13,500 new cases each year. Due to the introduction of the bowel cancer screening a shift is expected towards more early cancers being detected.
Current therapy for early colorectal cancer is radical Total Mesorectal Excision (TME). Colorectal surgical resections are accompanied with high morbidity of up to 33% and 90 days mortality of up to 9% in the fragile elderly patients. Additionally, rectal cancer surgery is associated with substantial loss of health related quality of life due to defecation disorders, incontinence, sexual dysfunction and stoma related morbidity.

These disadvantages are acceptable when radical surgery is the only option for cure. Advances in technology enabled the development of local excision of early rectal cancer with precise endoluminal microsurgery or local endoscopic excision resulting in a significant decrease in short- and long term morbidity. However current evidence is of inadequate quality to conclude on the oncologic safety of local treatment for early rectal cancer. Imaging can predict outcome and tailors treatment in more advanced cancer but fails in early cancer. Pathological assessment of the excised tumor tissue provides the optimal information on tumor stage, tumor characteristics and tumor differentiation, thereby it enables to predict the risk of recurrence after local treatment alone.

For early rectal cancers, with a low risk on recurrence based on favourable tumour characteristics local excision is seen as safe and these patients do not require an additional treatment. However, for patients with early rectal cancer with a higher risk on recurrence based on tumor characteristics there is no consensus on the additional treatment after local excision. According to the National guideline these patients receive a TME procedure. However, for this subgroup of patients local treatment followed by chemoradiotherapy might also be oncological safe. Current evidence is of inadequate quality to be conclusive.

For this subgroup of patients with early rectal cancer with high risk tumorcharacteristics the TESAR trial is designed, in which patiens will be randomised after local endoluminal excision between an additional TME-procedure (standard) and adjuvant chemoradiotherapy. Primary endpoint of the study will be local recurrence at 3 three year follow-up.


Hypotheses

Rectal preserving therapy with adjuvant chemoradiation after local excision is non-inferior to completion TME for early rectal cancer.

Outcomes

Primary study parameters/outcome of the study:
Local recurrence after 3 year follow-up.
Secondary study parameters/outcome of the study (if applicable):
Mortality, morbidity, stoma rate, long term interventions, functional outcomes, health related quality of life (HRQoL) and costs.

Inclusion Period

Inclusion period: 3 years.
Total follow-up per patient: 5 years.

Study design

Multicenter randomized trial, with 28 participating centres.

Intervention

The study treatment consists of adjuvant chemo-radiotherapy (25x1.8 Gy) limited to the mesorectum with concurrent capecitabine (825 mg/m2 twice daily). To monitor the risk of recurrence, there will be additional follow up through frequent MRI and endoscopy.

Sample size calculation

This trial is designed as a non-inferiority trial. The expected percentage of patients with a local recurrence after TME surgery is 2%. The percentage of patients with a local recurrence after radical local excision combined with adjuvant chemo-radiotherapy will probably be higher: 4%.

If there is a true difference in favour of the standard treatment of 2%, then 288 patients are required to be 80% sure that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of the TME group of more than 7%. Because a drop out of 5% of patients is expected, a sample size of 302 patients is needed.

Population

Patients who underwent complete (no carcinoma in resection plane) local excision of a rectal adenocarcinoma with an intermediate risk of recurrence: T1 > 3cm with good differentiation or a T1 tumor with a maximum size of 3 cm and at least poor differentiation, and /or deep mucosal invasion (SM3/Haggitt4), and/or lymphatic and/or vascular invasion, and/or tumor budding. Or cases of a T2 adenocarcinoma with a maximum size of 3 cm, well/moderately differentiated and without lymphatic or vascular invasion.