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

• ClinicalTrials.gov Identifier: NCT00537823
• Recruitment Status: Terminated
• First Posted: October 1, 2007
• Results First Posted: December 20, 2016
• Last Update Posted: December 20, 2016
• Sponsor: Washington University School of Medicine
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer; Metastases	Drug: Cetuximab; Drug: Bevacizumab; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Fluorouracil	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Short-duration Preoperative Neoadjuvant Therapy With FOLFOX Based Therapy on Morbidity After Liver Resection for Colorectal Cancer Metastases
• Study Start Date: June 2007
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: July 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1 - Wildtype; 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; Other Name: Erbitux; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Fluorouracil
Experimental: Arm 2 K-Ras 12/13 codon mutation; 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; Other Name: Avastin; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Fluorouracil

Outcome Measures

Primary Outcome Measures :

1. Postoperative Complication Rate [ Time Frame: 30 days following surgery ]
   Fraction of patients with any grade of complication I-V
2. Major Postoperative Complication Rate [ Time Frame: 30 days following surgery ]
   Fraction of patients with any complication grades IV and V
3. All-cause Mortality [ Time Frame: 30 days following surgery ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, Missouri

Washington University School of Medicine

St. Louis, Missouri, United States, 63110

Sponsors and Collaborators

Washington University School of Medicine

Investigators

• Principal Investigator: David Linehan, M.D.; Washington University School of Medicine

More Information

Additional Information:

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine 

Publications:

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• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT00537823
• Other Study ID Numbers: 07-0182
• First Posted: October 1, 2007
• Results First Posted: December 20, 2016
• Last Update Posted: December 20, 2016
• Last Verified: October 2016

Keywords provided by Washington University School of Medicine:

Colorectal Cancer; Metastasis; Neoadjuvant Therapy

Additional relevant MeSH terms:

Colorectal Neoplasms; Neoplasm Metastasis; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes; Leucovorin; Bevacizumab; Cetuximab; Fluorouracil; Oxaliplatin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Immunosuppressive Agents