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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00537823
• Other study ID #: 07-0182
• Status: Terminated
• Phase: Phase 2
• First received: September 27, 2007
• Last updated: July 22, 2013
• Start date: June 2007
• Est. completion date: July 2011

Study information

• Verified date: July 2013
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: July 2011
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Metastases
• Neoplasm Metastasis

Intervention

Drug:
• Cetuximab

• Bevacizumab

• Leucovorin

• Oxaliplatin

• Fluorouracil

Locations

Country	Name	City	State
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (42)

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Gruenberger T, Sorbye H, Debois M, Bethe U, Primrose J, Rougier P, Jaeck D, Finch-Jones M, Van Cutsem E, Nordlinger B. Tumor response to pre-operative chemotherapy (CT) with FOLFOX-4 for resectable colorectal cancer liver metastases (LM). Interim results of EORTC Intergroup randomized phase III study 40983. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3500.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. — View Citation

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Karoui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, Rougier P, Nordlinger B. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006 Jan;243(1):1-7. — View Citation

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Nordlinger B, Sorbye H, Debois M, Praet M, Glimelius B, Poston GJ, P. Schlag M, Walpole ET, Bechstein W, Gruenberger T. Feasibility and risks of pre-operati ve chemotherapy (CT) with Folfox 4 and surgery for resectable colorectal cancer liver metastases (LM). Interim results of the EORTC Intergroup randomized phase III study 40983. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 3528.

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Reddy GK. The addition of bevacizumab to FOLFOX4 prolongs survival in relapsed colorectal cancer: interim data from the ECOG 3200 trial. Clin Colorectal Cancer. 2005 Jan;4(5):300-1. — View Citation

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* Note: There are 42 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total postoperative complication rate (Fraction of patients with any grade of complication I-V)		30 days following surgery	Yes
Primary	Major postoperative complication rate (Fraction of patients with any complication grades IV and V)		30 days following surgery	Yes
Primary	All-cause mortality postoperatively		30 days following surgery	Yes
Secondary	Study postoperative recurrence patters (liver only vs distant disease)		1, 3, 5 years	No
Secondary	Calculate liver recurrence-free survival at one, three, and five years		1, 3, 5 years	No
Secondary	Document the histologic hepatic toxicity at operation		Time of surgery (approximately 11-16 weeks)	Yes
Secondary	Provide the nonalcoholic steatohepatitis score (0-3)		Time of surgery (approximately 11-16 weeks)	No
Secondary	Provide the liver injury scale score (0-27)		Time of surgery (approximately 11-16 weeks)	Yes
Secondary	Describe the effect of preoperative chemotherapy on tumor size		Upon completion of neoadjuvant chemotherapy (approximately 2 months)	No
Secondary	Calculate change in tumor size from pretreatment to preoperative CT scan		Completion of neoadjuvant therapy (approximately 8 weeks)	No

External Links

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