TNT to Increase the Clinical Complete Response Rate for Distal LARC

Study Overview
=================
Brief Summary
-----------------
This is a open-label, single-arm study to investigate the safety and efficacy of total neoadjuvant treatment (TNT) in patients with locally advanced resectable rectal cancer.

Detailed Description
-----------------
Standard treatment of rectal cancer is neoadjuvant capecitabine chemotherapy with radiotherapy, followed by total mesorectal excision. A new concept suggests organ preservation as an alternative to rectal excision in good responders after neoadjuvant radiochemotherapy to decrease surgical morbidity and increase quality of life. The rational is the fact that 15%-20% of patients have sterilized tumours after chemoradiotherpay for locally advanced rectal cancer. As compared to capecitabine alone, oxaliplatin and more intensified chemotherapy have been shown to increase tumor regression in the neoadjuvant chemoradiation setting. Meanwhile, prolong of time interval from the end of radiotherapy to assessment of tumor response could further increase pathologic complete response rate and complete clinical response rate. The objective of this trial is to increase the rate of clinical complete response for distal rectal cancer patients by optimizing tumour response. The investigators expect to increase chance of clinical complete response by using total neoadjuvant treatment regimen as compared to conventional chemoradiotherapy alone.

Official Title
-----------------
Total Neoadjuvant trEatment to Increase the Clinical Complete reSponse Rate for diStal Locally Advanced Rectal Cancer (TESS)

Conditions
-----------------
Rectal Cancer, Rectal Cancer Stage II, Rectal Cancer Stage III, Chemoradiation

Intervention / Treatment
-----------------
* Drug: Capecitabine, Oxaliplatin
* Radiation: External beam radiotherapy
* Procedure: Surgery
* Other: Watch and wait strategy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Rectal adenocarcinoma cT3-4aNany or cTanyN+ Location ≤5 cm from the anal verge No distant metastasis No gastrointestinal obstruction or relieved obstruction No previous surgery of the rectum, no previous chemotherapy, no previous pelvic radiation, no previous biotherapy ECOG 0-1 Expected survival length ≥ 2 years Age 18-70 Sufficient bone marrow, kidney and liver function Effective contraception during the study Patient and doctor have signed informed consent Exclusion Criteria: Distant metastasis Chronic intestinal inflammation and/or bowel obstruction Contra indication for chemotherapy and/or radiotherapy Previous pelvic radiotherapy or chemotherapy Severe renal, hepatic insufficiency (serum creatinine<30ml/min) Peripheral neuropathy > grade 1 Pregnant or breast-feeding woman Certain or suspicious allergy to research drug Cachexia, organ dysfunction Active severe infection Multiple primary cancers Epileptic seizures Malignant history within 5 years, except cervical carcinoma in situ or cutaneous basal cell carcinoma Severe arrhythmia, cardiac dysfunction (NYHA grade III or IV ) Uncontollable severe hypertesion Persons deprived of liberty or under guardianship Impossibility for compliance to follow-up

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNT arm<br>Drug: Neoadjuvant chemotherapy Capeox (Capecitabine + Oxaliplatin), 6 cycles; adjuvant chemotherapy, Capecitabine, 2 cycles or physicians' decision. External beam radiotherapy: Neoadjuvant, 50 Gy, 2 Gy/session; 25 fractions. Procedure: 'Watch and wait strategy' or surgery including local excision, intersphincter resection or total mesorectal excision or other kinds of surgeries. | Drug: Capecitabine, Oxaliplatin<br>* Drug: Capecitabine, Oxaliplatin<br>Radiation: External beam radiotherapy<br>* External beam radiotherapy to the primary tumor, regional lymph nodes and clinical target volume<br>Procedure: Surgery<br>* 'Local excision' or 'Intersphincter resection' or 'Total mesorectal excision' or other surgeries<br>Other: Watch and wait strategy<br>* Watch and wait strategy recommendation and discussion for cCR patients<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinical complete response | Rate of clinical complete response | 1.5 year after diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of sphincter preservation strategy | Number of patients with sphincter preservation through Watch and wait strategy, or local excision, or intersphincter resection, or low anterior resection, etc. | 1.5 year after diagnosis | 
| Rate of pathological complete response and tumor regression grade distribution | Rate of pathological complete response and tumor regression grade distribution | 1.5 year after diagnosis | 
| Acute toxicity | Acute toxicity according to CTCAE 5.0 | Within the first course of anti-tumor treatment | 
| Rate of surgical complications | Rate of surgical complications | 1.5 year after diagnosis | 
| Long-term anal function | Long-term anal function according to Wexner Continence Grading Scale | 1.5 year after diagnosis | 
| Long-term toxicity grading | Long-term toxicity grading according to CTCAE 5.0 | 3 year after the end of the first course of anti-tumor treatment | 
| ECOG standard score | ECOG standard score | 1.5 year after diagnosis | 
| 3 year disease free survival | 3 year disease free survival | 3 year after the end of the first course of anti-tumor treatment | 
| 5 year overall survival | 5 year overall survival | 5 year after the end of the first course of anti-tumor treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
rectal cancer, chemoradiation, total neoadjuvant treatment