A dose titration study and a combined superiority registry-based open-label randomized control trial is planned to answer the trial objectives. The study will be registry-based to allow simpler and more comprehensive follow-up. Patients with colorectal cancer will be treated with cytoreductive surgery (CRS) together with either standard oxaliplatin HIPEC (the control for the efficacy study) or oxaliplatin/irinotecan HIPEC in combination with 5-FU 24-hour EPIC. The 5-FU will be administered postoperatively when the abdomen is completely sutured. The drug is divided equally into 2 injections of 200 ml each and injected through two abdominal drains that are clamped for 16 hours.

For dose escalation, the titration groups (á 3 or 6 patients) are followed for 30 days postoperatively after which the Data Monitoring Committee (DMC) will determine whether or not to increase the 5-FU dose for the following group of patients.

To study efficacy, randomization is performed intraoperatively. The patient is followed up postoperatively for a total of 3 years for the secondary endpoints which may be extended by the study committee to 5 years. Since the trial is registry based, the long-term follow-up does not require separate eCRF evaluations. These evaluations can be automatically retrieved from the registry - both recurrence data, quality of life, and morbidity data. Some specific eCRF evaluations will be integrated as a separate study part of the HIPEC registry, such as inclusion/exclusion criteria and adverse event reporting (including SUSAR reporting).

Not detailed description entered.

Inclusion criteria:

1. Provision of written informed consent prior to any study specific procedures.
2. ECOG Performance Status Score 0,1 or 2 alternatively Karnofsky 60-100
3. Adequate kidney, liver, bone marrow function according to laboratory tests
4. For females of childbearing potential, a negative pregnancy test must be documented
5. ≥ 18 years old and ≤78 years old
6. Colorectal cancer with peritoneal metastases +/- liver metastases (maximum 3)
7. Concomitant resectable pulmonary metastases are allowed
8. All patients deemed eligible for CRS and HIPEC according to clinical routine management during a HIPEC multidisciplinary board at each respective hospital can be included.

Exclusion criteria:

1. Previous severe toxicity/allergic reactions to systemic chemotherapy agents oxaliplatin or irinotecan or 5-fluorouracil
2. Unable to tolerate intensified HIPEC treatment due to comorbidity
3. Metastasis other than peritoneum or liver or lung
4. Complex liver-perenchymal sparing surgery or hemihepatectomy procedures are to be excluded.
5. Previous CRS or HIPEC
6. Pregnant or lactating (nursing) women
7. Active infections requiring antibiotics
8. Active liver disease with positive serology for active hepatitis B, C, or known HIV
9. Concurrent administration of any cancer therapy other than planned study treatment within 4 weeks prior to and up to 4 weeks after study treatment
10. Incomplete cytoreduction defined as completeness of cytoreduction score 2-3
11. Histopathology of other origin than colorectal cancer

Completely anonymized IPD will be shared. All dates, HIPEC center treatment, referral city, and personal identification will be removed.

To be shared at the time of phase 3 trial publication. Available for 10 years.

Access by request only from the corresponding author. Study protocol, SAP, ICF will be publicly available without request.