None listed
Conditions
Brief summary
One of the ways to treat colorectal cancer that has spread to to the liver is by surgery to remove the tumours. Because surgery alone may not prevent the cancer from returning, chemotherapy may be given. The standard timing of the chemotherapy is to give all of the drugs after liver surgery. The purpose of this study is to investigate whether giving chemotherapy both before and after surgery is better at keeping the cancer from returning than giving all of the chemotherapy after surgery only.
Interventions
Chemoptherapy agents used in this trial will be mFOLFOX6, XELOX or FOLFIRI. mFOLFOX6 is the combination of Oxaliplatin, Leucovorin and Fluorouracil as set out below. XELOX is the combination of Oxaliplatin and Capecitabine set out below. FOLFIRI is the combination of Irinotecan, Leucovorin and Fluorouracil as set out below. There are two different treatment options mFOLFOX6 or XELOX which will be determined by the treating investigator prior to randomisaiotn. Patients are not permitted to chang
Chemoptherapy agents used in this trial will be mFOLFOX6, XELOX or FOLFIRI. mFOLFOX6 is the combination of Oxaliplatin, Leucovorin and Fluorouracil as set out below. XELOX is the combination of Oxaliplatin and Capecitabine set out below. FOLFIRI is the combination of Irinotecan, Leucovorin and Fluorouracil as set out below. There are two different treatment options mFOLFOX6 or XELOX which will be determined by the treating investigator prior to randomisaiotn. Patients are not permitted to change treatments during the trial. Preoperatively: mFOLFOX6 Every 2 weeks for 6 cycles: Oxaliplatin 85mg/m2 by intravenous infusion over 2 hours on day 1. Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on days 1 and 2 Fluorouracil 400mg/m2 by intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2) equivalent to 1200mg/m2/day. OR XELOX Every 3 weeks for 4 cycles: Oxaliplatin 130mg/m2 by intravenous infusion over 2 hours on day 1 Capecitabine 1000mg/m2 oral tablet twice daily on days 1-14. Followed by Surgery: Surgical resection of liver metastases will be carried out, at the earliest 4 weeks and at the latest 8 weeks after completion of cycle 6 mFOLFOX6 or cycle 4 XELOX. Patients must have recovered from side effects and liver function must be adequate for liver surgery as per local hospital guidelines. Post-operatively: Chemotherapy should not be administered until at least 4 weeks after surgery. This must not be started after surgery unless the liver, renal and haematological functions are within the same limits determined for the introduction of pre-operative chemotherapy. In the event of a surgical complication a delay of up to 12 weeks is acceptable before the patient is deemed to be off study. mFOLFOX6 Every 2 weeks for 6 cycles: Oxaliplatin 85mg/m2 by intravenous infusion over 2 hours on day 1. Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on day 1 Fluorouracil 400mg/m2 by intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2) equivalent to 1200mg/m2/day. OR XELOX Every 3 weeks for 4 cycles: Oxaliplatin 130mg/m2 by intravenous infusion over 2 hours on day 1 Capecitabine 1000mg/m2 oral tablets twice daily on days 1-14. Patients who have previously received Oxaliplatin as part of their adjuvant treatment will be permitted to receive FOLFIRI, instead of FOLFOX6/XELOX, as per their allocation to either ARM. FOLFIRI will be: every 2 weeks for 12 cycles: Irinotecan 180mg/m2 by intravenous infusion over 90 minutes on day 1 Leucovorin 400mg/m2 by intravenous infusion over 1 to 2 minutes on day 1 Fluorouracil 400mg/m2 intravenous infusion over 3 to 5 minutes on day 1 Fluorouracil 2400mg/m2 as a continuous intravenous infusion over 46 hours (Day 1 and 2 equivalent to 1200mg/m2/day).
Sponsors
Australasian Gastro-intestinal Trials Group
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age or older * Patients must have histological or cytological confirmation of a diagnosis of colorectal adenocarcinoma. * Patients with colorectal liver metastasis which in the opinion of the liver surgeon can be completely removed achieving a microscopic margin of >1mm * patients with metachronous metastases may be included only if the oncologist feels there is an indication for chemotherapy * Positron Emission Tomography (PET) scan within 4 weeks prior to randomisation demonstrating: # Hepatic metastasis; and # No evidence of extrahepatic disease * World health Organisation (WHO) performance status less than or equal to 2 * Fit for chemotherapy and surgery Absolute neutrophil count > 1.5x10-9 per litre, platelet count >100x10-9 per litre, creatinine <2 x upper limit of normal. * Adequate renal function, with calculated creatinine clearance >/= 30ml/min (Cockroft and Gault;) For patients with creatinine clearance </= 50ml.min starting dose of capecitabine may not be greater than 2000mg/m2/d * Adequate hepatic function with serum total bilirubin <1.5 x upper limit of normal range * Written consent for main study participation, including tissue banking. *There must be an estimated pre-operative margin of 5mm or greater. No restrictions are placed on the number of tumours.
Exclusion criteria
* Extrahepatic disease, including the presence of lymph node metastases or wound implantation metastasis * Patients with liver metastasis that cannot, in the opinion of the liver surgeon be resected. * Prior chemotherapy for metastatic disease. Adjuvant chemotherapy with 5-FU or FOLFOX is allowed providing it was given in association with complete resection of prirmary colon or rectal cancer, and treatment was completed at least 12 months prior * Patients in whom the surgical treatment plan includes radiofrequency ablation, synchronous resection of primary and metastatic disease, staged resection of hepatic metastases, pre-operative portal vein embolisation, tumour involving all three major hepatic veins or bilateral liver inflow involvement or any other where there is a possibility of the need for a vascular resection to achieve tumour clearance. * Previous treatment with an anti- Vascular Endothial Growth Factor (VEGF) anitbody. * WHO perfomance status >2 * Any other malignancy, other than adequately treated in situ carcinoma of the cervix or non-melanoma skin cancer (unles there has been a disease free interval of at 10 years). * Peripheral neuropathy common Terminology Criteria (CTC )> grade 1 as per version 4.0 of Common Terminology Criteria for Adverse Events (CTCAE). Patients with grade >1 neuropathy are still eligible if they are planned to receive FOLFIRI. * Uncontrolled congestive heart failure, angina, hypertension or arrhythmia. * History of Transient Ischaemic Attack (TIA) or Cerebroascular Accident (CVA) within 180 days prior to randomization; * Known bleeding diathesis or coagulopathy; * Requirement for therapeutic anticoagulation * Administration of another investigational drug within 30 days prior to randomisation. * Significant neurological or psychiatric disorders * Active infection * Serious or non-healing wound, skin ulcers or bone fracture * Active inflammatory bowel disease or history of bowel perforation <180 days of randomization * Gastro-intestinal ulceration determined by endoscopy to be active <180 days of randomization * Pregancy or lactation. Adequate contraception is required in pre-menopausal female patients. * Inability to comply with treatment schedule * Unable to give informed consent * Patients known to have Gilbert’s syndrome; and * Patients who will be required to receive the FOLFIRI chemotherapy section and are known to be homozygous for the UGT1A1 28 allele.
Outcome results
None listed