Perioperative vs Postoperative Chemotherapy + Bevacizumab in Colorectal Cancer, Liver Mets

A Randomized Phase II Study of Perioperative Chemotherapy Plus Bevacizumab Versus Postoperative Chemotherapy Plus Bevacizumab in Patients With Upfront Resectable Hepatic Colorectal Metastases (APPROACH)

Early-stage colorectal cancer(CRC)is localized and resectable, but 20% of the patients have metastatic disease at the time of diagnosis and 50% of all patients eventually die of the disease. The most frequent site of colorectal metastases is the liver, which accounts for 30% to 60% of cases. In these patients, the extent of liver disease is the main determinant of survival. Hepatectomy is the only potentially curative therapy for colorectal liver metastases (CLM), but when traditional criteria for resectability were used, only 10% of patients were candidates for surgical resection.

Although adjuvant systemic therapy after resection of primary colorectal tumors is well established, there are relatively few data on the use of postoperative therapy vs. surgery alone in patients who have undergone resection of liver metastases. In this trial, the absolute increase in the 3-year PFS rate with the addition of FOLFOX4 was a modest but significant 9% in patients who had resection (from 33% to 42%; P = .025). For improving survival in patients with CLM, several studies with biologic agents have been tried. The use of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has resulted in increased response rates in patients with stage IV colorectal cancer and improved OS and PFS. In an ongoing phase II trial presented in ASCO 2008, in patients who were potentially curable through resection of liver metastases, perioperative treatment with capecitabine and oxaliplatin (XELOX) plus bevacizumab yielded an overall response rate of 73% with stable disease in 21% and a mean PFS of 27 months. Response to chemotherapy significantly correlated with a prolonged PFS (P < .001).

On the basis of these backgrounds, we designed a phase II study to compare the effectiveness of combination chemotherapy with perioperative or postoperative bevacizumab treatment in patients with CLM.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Liver Metastasis
• Intervention / Treatment: Drug: Bevacizumab, mFOLFOX, FOLFIRI; Drug: Bevacizumab, mFOLFOX, FOLFIRI

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven colorectal adenocarcinoma
• With hepatic metastasis and no evidence of extrahepatic metastasis (the liver metastases must be determined by a hepatic surgeon to be resectable)
• 20~80 years
• ECOG performance status 0 - 1
• Adequate laboratory findings

Exclusion Criteria:

• Prior chemotherapy for metastatic disease
• Prior adjuvant chemotherapy, if administered within 6 months before study entry
• Previous hepatic-directed therapy including hepatic resection and/or ablation, hepatic arterial infusion therapy, or hepatic radiation therapy
• Uncontrolled medical illnesses including medically uncontrolled infection, uncontrolled hypertension, unstable angina, symptomatic congestive heart failure, myocardial infarction within 6 months
• Chronic active hepatitis or cirrhosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ArmA	Drug: Bevacizumab, mFOLFOX, FOLFIRI; ArmA (postoperative arm) Postoperative mFOLFOX or FOLFIRI regimen, every 2weeks for 12cycles Bevacizumab 5mg/kg IV, every 2weeks for 11cycles beginning with cycle 2; Drug: Bevacizumab, mFOLFOX, FOLFIRI; ArmB (perioperative arm) Perioperative CTx mFOLFOX or FOFIRI regimen, every 2 weeks for 6 cycles Bevacizumab 5mg/kg IV, every 2 weeks for 5cycles (cycles 1-5) Postoperative CTx mFOLFOX or FOLFIRI regimen, every 2weeks for 6 cycles Bevacizumab 5mg/kg IV, every 2weeks for 5cycles(cycles 8-12)
Active Comparator: ArmB	Drug: Bevacizumab, mFOLFOX, FOLFIRI; ArmA (postoperative arm) Postoperative mFOLFOX or FOLFIRI regimen, every 2weeks for 12cycles Bevacizumab 5mg/kg IV, every 2weeks for 11cycles beginning with cycle 2; Drug: Bevacizumab, mFOLFOX, FOLFIRI; ArmB (perioperative arm) Perioperative CTx mFOLFOX or FOFIRI regimen, every 2 weeks for 6 cycles Bevacizumab 5mg/kg IV, every 2 weeks for 5cycles (cycles 1-5) Postoperative CTx mFOLFOX or FOLFIRI regimen, every 2weeks for 6 cycles Bevacizumab 5mg/kg IV, every 2weeks for 5cycles(cycles 8-12)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
2 years recurrence-free survival (2Y-RFS)	2 years

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): May 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: June 28, 2012
• First Submitted That Met QC Criteria: June 28, 2012
• First Posted (Estimate): July 3, 2012

Study Record Updates

• Last Update Posted (Actual): June 27, 2018
• Last Update Submitted That Met QC Criteria: June 25, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: colorectal cancer, liver metastasis, bevacizumab, perioperative/postoperative chemotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 4-2012-0166