Brazilian Total Neoadjuvant Therapy Trial

Study Overview
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Brief Summary
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Standard therapy for localized rectal cancer includes chemotherapy and radiation therapy, followed by a recovery period of 7-12 weeks, surgery and adjuvant chemotherapy for 3-6 months. Even though this protocol achieves high cure rates, many patients need a rectal amputation with placement of definitive colostomies. About 10-20% of patients have a complete clinical response to chemo-radiation and no tumor can be found in the surgical specimen. These patients can be followed with close surveillance and avid surgery. The aim of this study is to evaluate if a strategy including the use of a highly active chemotherapy called FOLFIRINOX during the 12 weeks between the end of radiation therapy and evaluation for surgery increases the rates of complete response and, therefore, allows more patients to undergo non-surgical management.

Detailed Description
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Adult patients with locally advanced rectal cancer who have completed conventional long-course chemo-radiation of 54Gy with capecitabine will be randomized 1:1 to a total neo-adjuvant therapy (TNT) protocol or to a control group. Patients in the TNT arm will receive 4 cycles of interval chemotherapy with FOLFIRINOX (5-FU, irinotecan, oxaliplatin) between the end of chemo-radiation and re-staging and those in the control group will undergo standard post-radiation care during this period. All patients will be re-staged with colonoscopy and pelvic MRI 12 weeks after the end of chemo-radiation. Those with a complete clinical response will be placed under a watch-and-wait protocol with digital rectal examinations every 2 months and pelvic MRI and sigmoidoscopy every 6 months. Those wih residual tumors will undergo resection with total mesorectal excision (TME). Patients with a near complete response, as defined by a multidisciplinary tumor board, will be re-staged at week 16 or 18 after chemo-radiation before undergoing surgery. Adjuvant chemotherapy will be done following the local standard of care.

Official Title
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A Prospective Randomized Controlled Trial of Total Neo-adjuvant Therapy vs Conventional Chemo-radiation Aiming at Increasing Rates of Clinical Complete Response in Locally Advanced Rectal Cancer

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: Folfirinox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 y/o Biopsy-confirmed rectal adenocarcinoma Tumor Stage T3+ or N+ M0 Adequate liver function (total bilirubin < = 4.0) Adequate kidney function (calculate creatinine-clearance >=30ml/m2/min) Adequate bone marrow function (Platelet counts >=90.000, hemoglobin >=8mg/dl, neutrophile count >= 1.500/cm3) Completed chemo-radiation with at least 54Gy and capecitabine 1650mg/m2/d Exclusion Criteria: Prior tumor resection Prior radiation to the pelvis Prior chemotherapy for rectal cancer Life expectancy < 6 months Unfit for surgery Need for urgent/ immediate surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized 1:1 to one of two arms: TNT and conventional therapy (control). Randomization will be stratified by study site and tumor stage (II vs III)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Total neoadjuvant therapy (TNT)<br>4 cycles of mFOLFIRINOX every 14 days: Oxaliplatin 85 mg/m2 Irinotecan 150mg/m2 5-FU 2.400mg/m2 Dexamethasone 12mg Atropine 0.5mg Netupitant/palonosetron | Drug: Folfirinox<br>* 5-FU 2400mg/m2; Oxaliplatin 85 mg/m2, Irinotecan 150mg/m2<br>* Other names: 5-FU, oxaliplatin, irinotecan;|
| No Intervention: Standard of care<br>Standard post-radiation care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cCR + PathCR | Complete clinical response or pathological response | 12 weeks after the end of chemoradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of R0 resection | Rate of tumor resection with negative margins | 12 weeks | 
| Rate of organ preservation | Rate of patients who remain colostomy-free | 6 months after surgery | 
| Overall toxicity | Grade 3-4 toxicities according to CTCAE 4.0 | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal cancer, Neoadjuvant chemo-radiation, Total neoadjuvant therapy, Watch-and-wait