Pre- and Post-operative FOLFOX Based Therapy for Patients With Colorectal Cancer With Liver Involvement

Study Overview
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Brief Summary
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The purpose of this study is to determine the effect of short-duration pre-operative FOLFOX based therapy on postoperative problems after liver surgery for patients with metastatic colorectal cancer.

Detailed Description
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Although early stage, localized colon and rectal cancers are associated with 5 year survival rates of nearly 90%, only a minority of patients present with localized disease. Unfortunately, at the time of their initial presentation, approximately 35% of patients with colon or rectal cancer have metastatic disease. Nearly two thirds of these patients with stage IV disease have evidence of extrahepatic spread and have a median overall survival rate of 8-10 months in the absence of further treatment. Even with the most intensive chemotherapeutic regimens, the median overall survival for these patients ranges from 12 months to 20 months. However, a small subset of patients with stage IV disease has isolated hepatic metastatic disease and can undergo resection. The patients with completely resected liver metastases enjoy a significantly higher overall five-year survival, which is as high as 58% in carefully selected patients. Ten-year overall survival has been reported in 22% of patients. Despite this improvement, the five-year disease-free survival for these patients is at best 35%, with hepatic recurrences occurring in 46%. The fact that adjuvant chemotherapy improves the three-year survival rate for stage II disease and five-year survival rates for stage III disease implies that it can treat micrometastatic disease in some fraction of patients. Because micrometastatic disease is likely the cause of the high recurrence rate in patients who undergo liver resection, there is a clear biologic rationale for using postoperative adjuvant chemotherapy after liver resection. Although this strategy is a common practice in many centers, no convincing data that this improves survival have been reported. A large randomized phase III trial (EORTC 40983) examining this question is currently ongoing and effect on survival has not yet been reported. Given that systemic chemotherapy after liver resection remains of unproven benefit at the present time, many have wondered if preoperative treatment might have more promise in improving recurrence rates.

Official Title
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Effect of Short-duration Preoperative Neoadjuvant Therapy With FOLFOX Based Therapy on Morbidity After Liver Resection for Colorectal Cancer Metastases

Conditions
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Colorectal Cancer, Metastases

Intervention / Treatment
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* Drug: Cetuximab
* Drug: Bevacizumab
* Drug: Leucovorin
* Drug: Oxaliplatin
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Synchronous or metachronous colorectal metastases Technically resectable liver metastases Four or fewer metastases No tumors in porta hepatis Resection of no more than 70% of liver needed Medically suitable candidate for major liver resection FDG-PET scan without metastatic disease outside the liver Exclusion Criteria: Near-obstructing or obstructing colon lesions in patients in whom combined resection is planned (as delay for preoperative chemotherapy would be medially impossible) Treatment with FOLFOX or cetuximab within 12 months Treatment with irinotecan within 12 months Abnormal liver function (ALT or AST > 5x ULN, bilirubin > 3x ULN) Body mass index >/= 35 kg/m² (as the risk for steatohepatitis is increased) Renal insufficiency (Cr > 2.5mg/dL) Interstitial lung disease (because cetuximab has been rarely associated with development of interstitial lung disease) ECOG performance score >/= 3 Patients unable to give informed consent Pregnant patient (as cetuximab is a Class C drug) Peripheral neuropathy >/= grade II (as oxaliplatin causes neuropathy to worsen)

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - Wildtype<br>Neoadjuvant therapy Week 1 Leucovorin 400 mg/m^2 IV Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m2 IV 5FU bolus 400 mg/m^2 5FU CIVI 1200 mg/m^2/day over 46 hours Weeks 2, 4, 6, 8 *Cetuximab 250 mg/m^2 IV weekly Weeks 3, 5, 7 Leucovorin 400 mg/m^2 IV Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV 5FU bolus 400 mg/m^2 5FU CIVI 1200 mg/m^2/day over 46 hours Wait 3-8 weeks after completion of therapy Liver resection Wait 4 weeks or until clinical status allows Adjuvant Therapy Week 1, 3, 5, 7, 9, 11, 13, 15 Leucovorin 400 mg/m^2 IV Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV 5FU bolus 400 mg/m^2 5FU CIVI 1200 mg/m^2/day over 46 hours Weeks 2, 4, 6, 8, 10, 12, 16 *Cetuximab 250 mg/m^2 IV weekly | Drug: Cetuximab<br> <br> * Other names: Erbitux;Drug: Leucovorin<br> <br> Drug: Oxaliplatin<br> <br> Drug: Fluorouracil<br> <br> |
| Experimental: Arm 2 K-Ras 12/13 codon mutation<br>Neoadjuvant Therapy Weeks 1, 3, 5 Leucovorin 400 mg/m^2 IV Oxaliplatin 85 mg/m^2 IV Bevacizumab 5 mg/kg IV 5FU bolus 400 mg/m^2 5FU CIVI 1200 mg/m^2 Week 7 Leucovorin 400 mg/m^2 IV Oxaliplatin 85 mg/m^2 IV 5FU bolus 400 mg/m^2 5FU CIVI 1200 mg/m^2 Wait 3-8 weeks after completion of therapy Liver resection Wait 4 weeks or until clinical status allows Adjuvant Therapy Weeks 1, 3, 5, 9, 11, 13 Leucovorin 400 mg/m^2 IV Oxaliplatin 85 mg/m^2 IV Bevacizumab 5 mg/kg IV 5FU bolus 400 mg/m^2 5FU CIVI 1200 mg/m^2 Week 7, 15 Leucovorin 400 mg/m^2 IV Oxaliplatin 85 mg/m^2 IV 5FU bolus 400 mg/m^2 5FU CIVI 1200 mg/m^2 | Drug: Bevacizumab<br> <br> * Other names: Avastin;Drug: Leucovorin<br> <br> Drug: Oxaliplatin<br> <br> Drug: Fluorouracil<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative Complication Rate | Fraction of patients with any grade of complication I-V | 30 days following surgery | 
| Major Postoperative Complication Rate | Fraction of patients with any complication grades IV and V | 30 days following surgery | 
| All-cause Mortality |  | 30 days following surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative Recurrence Patterns | Liver only vs distant disease | Up to 5 years | 
| Histologic Hepatic Toxicity at Surgery |  | Time of surgery (approximately 11-16 weeks) | 
| Nonalcoholic Steatohepatitis Score (0-3) | NASH Scoring Steatosis **<5% = 0 **5-33%=1 **>33-66%=2 **>66%=3 Lobular inflammation **No foci=0 **<2 foci per x 200 field=1 **2-4 foci per x 200 field=2 **>4 foci per x 200 field=3 Hepatocellular ballooning **None=0 **Few balloon cells = 1 **Many cells/prominent ballooning=2 | Time of surgery (approximately 11-16 weeks) | 
| Liver Injury Scale Score (0-27) |  | Time of surgery (approximately 11-16 weeks) | 
| Effect of Preoperative Chemotherapy on Tumor Size | Number of participants whose tumor size decreased from baseline to completion of preoperative chemotherapy. | Upon completion of neoadjuvant chemotherapy (approximately 2 months) | 
| Change in Tumor Size From Pretreatment to Preoperative CT Scan | -Compare total longest diameter from baseline to preoperative CT scan. | Completion of neoadjuvant therapy (approximately 8 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer, Metastasis, Neoadjuvant Therapy