Brief Summary:
Colorectal cancer is the 3rd most common cancer in France and the 2nd cause of death from
cancer. Between 30 to 60% of patients develop limited or predominant liver metastases.
Surgical resection of these metastases, only curative treatment is not immediately possible
in 10-15% of cases. In unresectable patients, current palliative treatments are based on
systemic chemotherapy associated or not with the targeted therapies (anti-EGFR (panitumumab),
anti-VEGF (bevacizumab)). In this patient population, special attention was paid to
intensified treatment regimens in order to improve their efficiency and improving the tumoral
response rate, the intensity of the response and its earliness correlate with improved
overall and progression-free survival.
The intra-arterial use of oxaliplatin coupled with IV chemotherapy has yielded OR levels of
64% in patients having survived one or more lines of chemotherapy IV and 62% in patients who
have progressed on oxaliplatin IV. In addition, the HIA administration of oxaliplatin limits
systemic and especially neurological toxicities, thanks to a greater hepatic clearance.
In conclusion, the combination of systemic chemotherapy, targeted therapy and HIAC with
oxaliplatin has showed promising efficacy results associated with good tolerance from the
first line onwards. Indeed, we can expect from the Phase II recent data, a control rate close
to 100%, with high response rates associated with early maturity and depth responses as well
as prolonged survival. However, to date, in the absence of randomized trial testing this
combination, this strategy does not have sufficient evidence to be integrated in our routine
practices, and HIAC remains limited to a few expert centers in treatment catch-up.
Inclusion Criteria:
- Histologically proven colorectal adenocarcinoma with hepatic metastasis(es)
- At least one measurable hepatic metastasis according to the criteria RECIST v1.1
- No other metastatic sites except lung nodules if number ≤ 3 and < 10 mm
- RAS mutation status known (determination of KRAS mutation (exons 2,3 and 4) and
determination of the NRAS mutation (exons 2,3 and 4))
- Age ≥ 18
- WHO ≤ 2 (Appendix 4)
- No prior treatment by chemotherapy except perioperative or adjuvant chemotherapy
discontinued for more than 12 months
- Life expectancy > 3 months
- PNN > 1500/mm3, platelets > 100 000/mm3, Hb > 9 g/dLq
- Bilirubin < 25 mmol/L, AST < 5x ULN, ALT < 5 x ULN, ALP < 5 x ULN, TP > 60%,
proteinuria from 24H < 1 g
- Creatinine clearance > 50 mL/min according to MDRD formula (Appendix 4)
- Patient affiliated to a social security scheme
- Patient information and signature of the informed consent
Exclusion Criteria:
- Contraindications specific to the installation of a KTHIA: thrombosis of the hepatic
artery, arterial vascular anatomy may compromise a secondary hepatic resection.
- Patient immediately eligible for a curative therapy (surgical and/or percutaneous)
after discussion in CPR
- Following alterations in the 6 months prior to inclusion: myocardial infarction,
angina, severe/unstable angina, coronary artery bypass surgery, congestive heart
failure NYHA class II, III or IV, stroke or transient ischemic attack
- Hypertension not controlled by medical treatment (SBP > 140 mmHg and/or DBP> 90 mmHg
with blood pressure taken according to the diagram of the HAS)
- A history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess
or active gastrointestinal bleeding in the 6 months preceding the start of treatment
- Progressive gastroduodenal ulcer, wound or fractured bone
- Abdominal or major extra-abdominal surgery (except diagnostic biopsy) or irradiation
in the 4 weeks before starting the treatment
- Transplant patients, HIV positive or other immune deficiency syndromes
- Any progressive pathology not balanced over the past 6 months: hepatic failure, renal
failure, respiratory failure
- Peripheral neuropathy > 1
- Patient with interstitial pneumonitis or pulmonary fibrosis
- History of chronic diarrhea or inflammatory disease of the colon or rectum, or
unresolved occlusion or sub-occlusion in symptomatic treatment
- History of malignant pathologies during the past 5 years except basocellular skin
carcinoma considered in complete remission or in situ cervical carcinoma, properly
treated
- Patient already included in another clinical trial with an experimental molecule
- Any known specific contraindication or allergy or hypersensitivity to the drugs used
in the study (cf RCP Appendix 7)
- Known deficit in DPD
- QT/QTc range > 450 msec for men and > 470 msec for women
- K+ < LNL, Mg2+ < LNL, Ca2+ < LNL
- Lack of effective contraception in patients (men and/or women) of childbearing age,
pregnant or breastfeeding women, women of childbearing age not having had a pregnancy
test
- Persons deprived of liberty or under supervision
- Impossibility of undergoing medical monitoring during the trial for geographic, social
or psychological reasons
Primary outcome:
1. progression-free survival (Time Frame - 24 months after randomization):
comparison of radiological/clinical progression free survival
- Experimental: Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status
Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours - Active Comparator: Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status
Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours - Experimental: Experimental arm mFOLFIRINOX with oxaliplatin intraarterial + Bevacizumab
Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intraarterially Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours - Active Comparator: Reference arm mFOLFIRINOX with oxaliplatin intravenous + Bevacizumab
Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intravenously Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours
- Oxaliplatin intravenous (Oxaliplatin IV):
85 mg/m² in intravenous. 1 cycle each 15 days - 5 FU bolus (5 FU):
5 fluorouracil : 400 mg/m² in bolus of 10 minutes (intravenous) following by 2400 mg/m² during 46 hours in intravenous - Folinic acid (Folinic Acid IV):
400 mg/m² in intravenous - Oxaliplatin intra-arteriel (Oxaliplatin IA):
85 mg/m² in intra-arterial. 1 cycle each 15 days - Panitumumab (Pani):
Only for patient RAS wild: 6 mg/Kg at each cycle in intravenous - Bevacizumab (Beva):
5 mg/kg at each cycle in intravenous - 5 FU continuous (5 FU):
2400 mg/m² intravenously over 46 hours - Irinotecan (IRI):
150 mg/m² intravenous
Quelle: ClinicalTrials.gov
