Complete Neoadjuvant Treatment for REctal Cancer (CONTRE)

Study Overview
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Brief Summary
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The purpose of this study is to find out how well patients with cancer of the rectum do if they get all of their other treatment - chemotherapy by itself followed by chemotherapy and radiation together - before surgery. Patients have recently been diagnosed with rectal cancer, and the doctors have recommended neo-adjuvant chemo treatment to try to shrink the cancer before removing it.

Detailed Description
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The goals of treatment of locally advanced (T3-4 or N1-2) rectal cancer are to eliminate the primary tumor and any involved adjacent lymph nodes, minimize the risk of distant recurrence, and, when possible, preserve anal sphincter function. Standard treatment consists of surgery, concurrent chemotherapy and radiation (RT) and adjuvant chemotherapy. As the present time, the chemoradiation portion of the treatment is often administered before, as opposed to following, surgical resection. This approach has been associated with tumor down-staging, leading to higher rates of tumor resectability and an increase in the ability to perform sphincter-saving surgeries. (1). However, while advances in treatment of the primary tumor and regional nodes, specifically administration of preoperative chemoradiation and more aggressive surgical approaches, such as total mesorectal excision (TME), have been shown to improve locoregional disease control, toxicities and complications of these treatments may result in delay or omission of adjuvant chemotherapy, which could increase the risk of distant recurrence. In this pilot study, standard adjuvant chemotherapy (8 cycles of modified FOLFOX6) will be administered prior to chemoradiation and definitive surgery, eliminating the need for post-operative systemic therapy. The investigators will evaluate the ability of patients to tolerate this treatment and its impact on achievement of pathologic complete responses (pCRs), negative surgical margins and sphincter preservation.

Official Title
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Complete Neoadjuvant Treatment for REctal Cancer (CONTRE)

Conditions
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Colon Cancer, Rectal Cancer

Intervention / Treatment
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* Drug: FOLFOX6
* Radiation: RT with concurrent chemotherapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must have histologically proven adenocarcinoma of the rectum with no evidence of distant metastases. The tumor must be clinically Stage II (T3-4 N0 with N0 being defined as all imaged lymph nodes are < 1.0cm) or III (T1-4 N1-2 with the definition of a clinically positive node being any node > 1.0cm). Stage of the tumor may be determined by CT scan, endorectal ultrasound or MRI. Patients must have no evidence of distant metastases including liver metastases, peritoneal seeding, or inguinal lymphadenopathy. Patients must not have received prior chemotherapy or pelvic radiation for rectal cancer, or prior pelvic radiation for any other malignancy that would prevent the patient from receiving the required radiation treatments for this study. Patients must have a life expectancy of 5 years, excluding their diagnosis of cancer (as determined by the investigator). Patients must not have an active concurrent invasive malignancy. Patients with prior malignancies, including invasive colon cancer, are eligible if they are deemed by their physician to be at low risk for recurrence. Patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma of the cervix, or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years prior to randomization. Patients must be > 18 years of age, ECOG performance status 0-1. ANC > 1,500/µl, platelets > 100,000/µl, total bilirubin < 2.0 mg/dl or direct bilirubin < 1.0 mg/dl, alkaline phosphatase < 3xULN, ALT < 3xULN, creatinine < 1.5xULN. The patient must have been evaluated by a surgeon, radiation oncologist and medical oncologist and all must concur that the patient is appropriate for this study. Signed informed consent; able to comply with study and/or follow- up procedures Peripheral neuropathy < grade 1 Exclusion Criteria: Evidence of metastatic disease. Rectal cancers other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, cloacogenic carcinoma, etc. Pregnancy or lactation at the time of proposed randomization. Eligible patients of reproductive potential (both sexes) must agree to use adequate contraception. Any therapy for this cancer prior to randomization. Synchronous invasive colon cancer. Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude the patient from receiving any chemotherapy treatment option or would prevent required follow-up. Patients with active inflammatory bowel disease, abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to Day 0 or other serious medical illness which might limit the ability of the patient to receive protocol therapy. Prior pelvic irradiation for any indication. Known hypersensitivity to 5-fluorouracil or oxaliplatin Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment<br>Induction therapy - Modified FOLFOX6 - Oxaliplatin 85 mg/m2 + Leucovorin 400 mg/m2 IV, followed by 5-FU 400 mg/m2 IV, followed 5-FU 2400 mg/m2 IV by continuous infusion over 46 hours - Repeat q14 days x 8 cycles Concurrent Chemoradiation 50.4 Gy Radiation in 28 fractions (45 Gy IMRT, 5.4 Gy 3D conformal boost) Surgery | Drug: FOLFOX6<br>* FOLFOX6<br>* Other names: 5-FU 400 mg/m2 IV followed 5-FU 2400 mg/m2 IV by continuous over 46 hours;Radiation: RT with concurrent chemotherapy<br>* IMRT 50.4Gy with chemotherapy<br>Procedure: Surgery<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Complete Resection | The primary objective of this study is to determine the incidence of pCRs and complete (R0) resections at surgery after induction chemotherapy with 8 cycles of modified FOLFOX6 followed by standard chemoradiation with IMRT with concurrent infusional 5-FU or capecitabine | approx 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the Toxicity of Study Therapy | Evaluate the toxicity of induction FOLFOX and subsequent infusional 5-FU or capecitabine/radiation. Results show number of patients who experienced a SAE. This does not mean all SAEs were deemed related to treatment. •Secondary efficacy measures include the clinical response rate, as measured endorectal ultrasound or pelvic MRI, and incidence and severity of toxicities seen during the various phases of study treatment, including treatment delays, bleeding and post-op complications. Each visit will have a toxicity assessment completed | approx 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoadjuvant, chemo/radiation, rectal cancer, rectum cancer, colon cancer, colorectal cancer