Combination Chemotherapy Before or After Surgery in Treating Patients With Colorectal Cancer With Liver Metastases That Could Be Removed By Surgery
Condition: Colorectal Cancer; Metastatic Cancer
MeSH terms: Colorectal Neoplasms; Neoplasm Metastasis
Intervention: Postoperative chemotherapy; Perioperative chemotherapy
Intervention description: Patients undergo hepatic resection. Beginning 31-56 days after surgery, patients receive mFOLFOX6 or FOLFIRI chemotherapy IV on day 1 over 3 hours. Patients receive an additional dose of fluorouracil over 46 hours using a portable pump. Treatment repeats every 2 weeks for 12 cycles.; Patients receive mFOLFOX6 or FOLFIRI chemotherapy IV over 3 hours on day 1. Patients receive an additional dose of fluorouracil over 46 hours using a portable pump. Treatment repeats for every 2 weeks for 6 cycles. Patients then undergo hepatic resection. Beginning 31-56 days after surgery, patients receive an additional 6 cycles of mFOLFOX6 or FOLFIRI chemotherapy.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stage IV colon cancer; adenocarcinoma of the colon; stage IV rectal cancer; adenocarcinoma of the rectum; liver metastases

Summary:

      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.
    

Eligibility criteria:

        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*:

                    -  PET/CT scan with contrast

                    -  PET scan AND CT scan with contrast

                    -  PET scan AND MRI with contrast

                    -  PET/CT scan without contrast AND MRI with contrast NOTE: *If findings noted
                       in imaging study reports are equivocal, the determination of whether or not
                       the findings represent extrahepatic disease will be at the investigator's
                       discretion.

               -  No history of or concurrent evidence of extrahepatic metastases

                    -  Patients with regional nodes that are suspicious on imaging and are
                       associated with the primary colorectal tumor are eligible provided the nodes
                       will be resected with the primary tumor after randomization

               -  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:

               -  A complete resection can be performed in a single operation

               -  There are ≥ 2 uninvolved contiguous segments of the liver

          -  Meets one of the following criteria:

               -  Primary tumor and regional nodes resected with clear surgical margins and no
                  evidence of extrahepatic disease

               -  Unresected primary tumor with plans to resect the primary tumor before
                  randomization

               -  Unresected primary tumor with plans to resect the primary tumor and the liver
                  metastases in a single surgical procedure performed after randomization

          -  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

               -  Patients with carcinoma in situ of the cervix, CRC in situ, melanoma in situ, or
                  basal cell or squamous cell carcinoma of the skin diagnosed and treated at any
                  time before study treatment are eligible

          -  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

               -  Patients who have only had an incision or excisional biopsy are eligible

          -  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