A Phase III Study Evaluating the Role of Perioperative Chemotherapy in Patients With Potentially Resectable Hepatic Colorectal Metastases
A Phase III Study Evaluating the Role of Perioperative Chemotherapy in Patients With Potentially Resectable Hepatic Colorectal Metastases
RATIONALE: Drugs used in chemotherapy work in different ways to kill tumor cells or stop them from growing. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving combination chemotherapy after surgery may kill any remaining tumor cells. It is not yet known whether giving combination chemotherapy before and after surgery is more effective than giving combination chemotherapy after surgery.
PURPOSE: This randomized phase III trial is studying giving combination chemotherapy before and after surgery to see how well it works compared to giving combination chemotherapy after surgery in treating patients with colorectal cancer with liver metastases that could be removed by surgery.
OBJECTIVES:
Primary
Secondary
Tertiary
OUTLINE: This is a multicenter study. Patients are stratified by number of liver metastases (1-3 vs 4+), chemotherapy regimen* (mFOLFOX6 vs FOLFIRI), and synchronous** primary colorectal cancer (yes vs no). Patients are randomized to 1 of 2 treatment arms.
NOTE: *Patients who have not received previous oxaliplatin receive mFOLFOX6 chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1. Patients who have received previous oxaliplatin receive FOLFIRI chemotherapy comprising irinotecan hydrochloride IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1.
NOTE: **Synchronous is defined as the detection (by imaging) of suspicious liver metastases within 90 days before or after the date of histologic diagnosis of the primary colon or rectal cancer.
Blood and tumor tissue samples may be collected periodically for correlative studies.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
DISEASE CHARACTERISTICS:
Histologically confirmed colorectal adenocarcinoma
Hepatic metastasis (no histologic confirmation required) and no evidence of extrahepatic metastatic disease within the past 4 weeks by one of the following imaging studies*:
No history of or concurrent evidence of extrahepatic metastases
No radiographic evidence of metastases to portal lymph nodes (node > 1 cm in diameter) unless the node(s) are proven by biopsy to be negative
No anal, small bowel, or appendiceal carcinoma
No sarcoma, lymphoma, or carcinoid colorectal malignant diseases
Within 4 weeks before randomization, the liver metastases must be determined by a hepatic surgeon to be resectable based on meeting both of the following criteria:
Meets one of the following criteria:
No unresected primary tumor in the colon or rectum with significant symptoms related to obstruction or that will require radiotherapy
PATIENT CHARACTERISTICS:
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Life expectancy ≥ 5 years (excluding the diagnosis of metastatic CRC)
absolute neutrophil count (ANC) ≥ 1,200/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 10 g/dL
Total bilirubin ≤ upper limit of normal (ULN)
aspartate aminotransferase (AST) ≤ 5.0 times ULN
Alkaline phosphatase ≤ 5.0 times ULN
Serum creatinine ≤ ULN OR calculated creatinine clearance ≥ 30 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for ≥ 180 days after completion of study treatment
Considered a potential candidate for a major hepatic surgical procedure
No grade 3 or 4 anorexia, grade 3 nausea, or vomiting ≥ grade 2 (per CTCAE v4.0) related to metastatic disease
No paresthesias, peripheral sensory neuropathy, or peripheral motor neuropathy ≥ grade 2 per Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0 (patients with grade 2 neuropathy who will receive FOLFIRI are eligible)
No uncontrolled high BP defined as systolic BP ≥ 160 mm Hg OR diastolic BP ≥ 100 mm Hg, with or without antihypertensive medication (patients with initial BP elevations are eligible provided initiation or adjustment of BP medication lowers pressure to meet this criteria)
Documented history of congestive heart failure requiring chronic medical therapy
No active inflammatory bowel disease
No active infection or chronic infection requiring chronic suppressive antibiotics
No known bleeding diathesis or coagulopathy
No symptomatic interstitial pneumonitis OR definitive evidence of interstitial pneumonitis described on CT scan, MRI, or chest x-ray in asymptomatic patients
No other malignancies unless the patient is considered to be disease-free and has completed therapy for the malignancy ≥ 1 year ago
No known Gilbert syndrome
Not known to be homozygous for the UGT1A1 allele (for patients who will receive FOLFIRI chemotherapy)
No prior serious hypersensitivity reaction to any of the agents administered as part of study treatment (determination of "serious" is at the investigator's discretion)
No other serious concurrent medical condition that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to participate in the study, or cause a delay in the initiation of therapy (surgery or chemotherapy) longer than 4 weeks following randomization
No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
No pre-existing chronic hepatic disease (e.g., chronic active hepatitis, cirrhosis) that, in the opinion of the investigator and hepatic surgeon, would limit the patient's ability to undergo hepatic metastasectomy
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
No previous hepatic-directed therapy, including hepatic resection and/or ablation, hepatic arterial infusion therapy, or hepatic radiotherapy
No previous chemotherapy or any other systemic therapy for metastatic colorectal cancer (CRC)
No prior or concurrent portal vein embolization or other hepatic preconditioning techniques
At least 30 days since prior investigational products
No intent to use ablation to treat any hepatic lesion
No concurrent therapeutic doses of coumadin or equivalent
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