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

Phase 2

Terminated

Conditions: Colorectal Cancer
Metastases

Interventions: Drug: Cetuximab
Drug: Bevacizumab
Drug: Leucovorin
Drug: Oxaliplatin
Drug: Fluorouracil

Registration Number: NCT00537823

Lead Sponsor: Washington University School of Medicine

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 - Wildtype	Leucovorin	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
Arm 1 - Wildtype	Cetuximab	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
Arm 1 - Wildtype	Oxaliplatin	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
Arm 2 K-Ras 12/13 codon mutation	Bevacizumab	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
Arm 1 - Wildtype	Fluorouracil	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
Arm 2 K-Ras 12/13 codon mutation	Leucovorin	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
Arm 2 K-Ras 12/13 codon mutation	Oxaliplatin	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
Arm 2 K-Ras 12/13 codon mutation	Fluorouracil	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

Primary Outcome Measures

Name	Time	Method
Postoperative Complication Rate	30 days following surgery	Fraction of patients with any grade of complication I-V
Major Postoperative Complication Rate	30 days following surgery	Fraction of patients with any complication grades IV and V
All-cause Mortality	30 days following surgery

Secondary Outcome Measures

Name	Time	Method
Postoperative Recurrence Patterns	Up to 5 years	Liver only vs distant disease
Change in Tumor Size From Pretreatment to Preoperative CT Scan	Completion of neoadjuvant therapy (approximately 8 weeks)	-Compare total longest diameter from baseline to preoperative CT scan.
Liver Injury Scale Score (0-27)	Time of surgery (approximately 11-16 weeks)
Histologic Hepatic Toxicity at Surgery	Time of surgery (approximately 11-16 weeks)
Effect of Preoperative Chemotherapy on Tumor Size	Upon completion of neoadjuvant chemotherapy (approximately 2 months)	Number of participants whose tumor size decreased from baseline to completion of preoperative chemotherapy.
Nonalcoholic Steatohepatitis Score (0-3)	Time of surgery (approximately 11-16 weeks)	* 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