Adjuvant hepatic arterial infusion pump chemotherapy after resection of colorectal liver metastases in patients with a low clinical risk score – a randomized controlled trial

• Age ≥ 18 years.

• ECOG performance status 0 or 1 (Appendix C).

• Histologically confirmed colorectal cancer (CRC).

• Radiologically confirmed CLM, amenable for local treatment (resection or open ablation). Criteria are outlined in section 5.1.1.

• Clinical Risk Score (CRS) of 0-2 (Appendix D). In patients with unknown nodal status (in case of synchronous resection of primary tumor and CLM), the nodal status is counted as zero.

• Positioning of a catheter for HAIP chemotherapy is technically feasible (see chapter 5) based on a CT with excellent arterial phase. The default site for the catheter insertion is the gastroduodenal artery (GDA). Accessory or aberrant hepatic arteries are no contraindication for catheter placement. The GDA should have at least one branch to the liver remnant; accessory or aberrant hepatic arteries should be ligated to allow for cross perfusion to the entire liver through intrahepatic shunts.

• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 15 days prior to randomization:

o absolute neutrophil count (ANC) ≥1.5 x 109/L

o platelets ≥100 x 109/L

o Hb ≥ 5.5 mmol/L

o total bilirubin ≤ 1.5 UNL

o ASAT ≤ 5 x UNL

o ALAT ≤ 5 x UNL

o alkaline phosphatase ≤ 5 x UNL

o (calculated) glomerular filtration rate (GFR) >30 ml/min.

• Written informed consent must be given according to ICH/GCP, and national/local regulations.

• Presence of extrahepatic disease (including positive portal lymph nodes) at the time of liver resection or any time since CRC diagnosis. Patients with small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible.

• Second primary malignancy except in situ carcinoma of the cervix, adequately treated non-melanoma skin cancer, or other malignancy treated at least 5 years previously without evidence of recurrence.

• Prior hepatic radiation, resection, or ablation.

• CLM requiring two-staged resections.

• Liver-first resections.

• Postoperative radiation of not (adequately) treated CLM during surgery.

• (Partial) portal vein thrombosis.

• Known DPD-deficiency (heterozygous or homozygous)

• Pregnant women or lactating women.

• History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for HAIP chemotherapy.

• Serious concomitant systemic disorders that would compromise the safety of the patient or his/her ability to complete the study, at the discretion of the investigator.

• Organ allografts requiring immunosuppressive therapy.

• Serious, non-healing wound, ulcer, or bone fracture.

• Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent excluding inhaled steroids).

• Serious infections (uncontrolled or requiring treatment).

• Participation in another interventional study for CRLM with survival as outcome.

• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.