NEOadjuvant Chemotherapy Only Compared With Standard Treatment for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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The main clinical hypothesis is that compared to radio-chemotherapy for low and mid rectal tumors or surgery for high rectal tumors neoadjuvant chemotherapy reduces the rate of distant relapse without increasing the rate of local relapse. The aim of the present study is to compare long term and short term outcomes in rectal cancer patients undergoing standard treatment (radio-chemotherapy/surgery) or experimental neoadjuvant chemotherapy/surgery Furthermore, early surgical and medical complications, the functional outcome, toxicity and quality of life (QoL) may be improved if radiotherapy can be avoided. Exploratory analyses are planned in order to find potential predictive markers for selecting patients to either radio-chemotherapy/surgery or neoadjuvant combination chemotherapy/surgery.

Detailed Description
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The standard treatment of locally advanced but resectable cancer in the middle or lower rectum is preoperative radio-chemotherapy and in the upper part initial surgery. The clinical benefit from radio-chemotherapy is primarily through a reduction in local relapse but the treatment is associated with acute toxicity and long term functional dysfunction. Subsequently, it is important to select patients with high risk of local relapse. Intense systemic combination chemotherapy reduces the risk of distant relapse and increases survival in the postoperative setting. The biological rationale is eradication of micrometastases and hence it may be anticipated that earlier, i.e. neoadjuvant, combination therapy may improve systemic control.

Official Title
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NEOadjuvant Chemotherapy Only Compared With Standard Treatment for Locally Advanced Rectal Cancer: a Randomized Phase II Trial

Conditions
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Rectal Cancer, Colorectal Neoplasm, Colorectal Cancer, Rectal Neoplasms, Chemotherapy Effect, Intestinal Disease, Intestinal Neoplasms

Intervention / Treatment
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* Drug: Capecitabine
* Drug: FOLFOX regimen (oxaliplatin/leucovorin/5FU)
* Drug: CAPOX (oxaliplatin/capecitabine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adenocarcinoma of the rectum with the lower boarder within 15 cm from the anal verge Locally advanced tumor based on imaging T3 tumors within 10 cm from the anal verge fulfilling the criteria for preoperative radio-chemotherapy according to Danish Colorectal Cancer Group (DCCG) guidelines T3c or T4 tumors 10-15 cm from the anal verge Deemed resectable at the multidisciplinary team (MDT) conference Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Age at least 18 years Adequate bone marrow, liver and renal function allowing systemic chemotherapy Absolute neutrophil count ≥1.5x109/l and thrombocytes ≥ 100x109/l. Bilirubin ≤ 1.5 x upper normal value and alanine aminotransferase ≤ 3 x upper normal value Calculated or measured renal glomerular filtration rate at least 30 mL/min Anticonception for fertile women and for male patients with a fertile partner. Intrauterine device, vasectomy of a female subject's male partner or hormonal contraceptive are acceptable Written and orally informed consent Exclusion Criteria: Distant metastasis Invasive ingrowth into other organs Incapacity, frailty, disability and comorbidity to a degree that according to the investigator is not compatible with combination chemotherapy Previous radiotherapy to the pelvis Previous treatment with 5FU or oxaliplatin Surgery within two weeks Neuropathy NCI grade > 1 Other malignant tumor within 5 years except non-melanoma skin cancer or carcinoma in situ cervicis uteri Pregnant (positive pregnancy test) or breast feeding women

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: This is an open label, randomized phase II screening trial allocating eligible patients to either standard treatment for rectal cancer or experimental preoperative combination chemotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A, capecitabine<br>Radiochemotherapy with 50.4 Gy in 28 fractions concomitantly with chemotherapy | Drug: Capecitabine<br>* Radio-chemotherapy with 50.4 Gy in 28 fractions to tumor and regional lymph nodes concomitantly with capecitabine 825 mg/m2 b.i.d<br>|
| Experimental: B, FOLFOX or CAPOX<br>Neoadjuvant chemotherapy with CAPOX (oxaliplatin/capecitabine) or FOLFOX regimen (oxaliplatin/leucovorin/5FU), according to institutional practice | Drug: FOLFOX regimen (oxaliplatin/leucovorin/5FU)<br>* Six cycles: Oxaliplatin 85 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1 and 5FU 2400 mg/ m2 over 46-48 hours day 1-3, repeated every two weeks.<br>* Other names: FOLFOX (oxaliplatin/leucovorin/5FU);Drug: CAPOX (oxaliplatin/capecitabine)<br>* Four cycles: Oxaliplatin 130 mg/m2 day 1 and capecitabine 1000 mg/m2 b.i.d. days 1-14, repeated every 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival | All patients will be evaluated with CT and MRI scans and clinically every 6 months for 2 years and annually until the number of events is reached and the trial is stopped (max 5 years) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | All patients will be evaluated with CT and MRI scans and clinically every 6 months for 2 years and annually for maximum 5 years | 5 years | 
| Local relapse | Defined to be within the pelvis. Any relapse should be verified by biopsy | 5 years | 
| Distant relapse | Defined to be outside the pelvis. Any relapse should be verified by biopsy | 5 years | 
| Early toxicity | Evaluated using CTCEA (Common Terminology Criteria for Adverse Events) version 4. | 5 years | 
| Late toxicity | Evaluated using CTCEA version 4. | 5 years | 
| Functional outcome | Measured with LARS questionnaire | 5 years | 
| Quality of life (QoL) | Measured with EORTC QoL questionnaire | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chemotherapy, CAPOX (oxaliplatin/capecitabine), FOLFOX (oxaliplatin/leucovorin/5FU), Neoadjuvant chemotherapy,, locally advanced rectal cancer,