Systemic antitumor treatment with or without pressurized intraperitoneal aerosol chemotherapy (PIPAC) for colon peritoneal metastases – a multicentre phase II randomized trial (PIPOX02)

Prior treatment

• Concomitant treatment with brivudine, sorivudine or their chemically related analogues (according to the SmPC of fluorouracile)
• Live attenuated vaccines and for 6 months following cessation of chemotherapy (according to the SmPCs of fluorouracile and irinotecan);
• Concomitant use with St John's Wort (according to the SmPC of irinotecan);
• Relevant proteinuria (nephrotic syndrome); arterial thromboembolisms or severe haemorrhages within 6 months before study enrolment (except a bleeding tumour before tumour resection surgery) precluding the use of anti-VEGF drug;
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess within 6 months prior to enrolment;

Other illness

• Other cancer treated within the last 3 years, with the exception of in situ cervical carcinoma or basocellular carcinoma;
• Clinically relevant and uncontrolled coronary heart disease, myocardial infarction within the past 12 months;
• Known history of hypersensibility to fluorouracil, folinic acid, irinotecan, oxaliplatin, capecitabine, cetuximab, panitumumab, bevacizumab or to any of their excipients, according to the SmPCs of these products.
• Uncontrolled arrhythmia;
• History of allergy to red meat or tick bites or positive results of tests for IgE antibodies against cetuximab (α-1-3-galactose) (according to the SmPC of cetuximab);
• Interstitial lung disease (according to the SmPCs of cetuximab and panitumumab);
• Hypersensitivity to Chinese hamster ovary (CHO) cell products (according to the SmPC of bevacizumab)
• Medical, geographical, sociological, psychological or legal conditions that would not permit the patient completing the study or signing the informed consent form.
• Uncontrolled hypertension;
• Inflammatory bowel disease;
• No reversible electrolyte disorders such as hypokalemia, hypocalcemia or hypomagnesemia.
• Rectal cancer primary (tumor <15 cm from the anal verge);
• Appendix cancer
• Extraperitoneal polymetastatic diseases. (Only oligometastatic1 diseases are allowed for inclusion) 1. 1oligo-metastatic disease as defined up to 3 liver metastases less than 5 cm in diameter and/or up to 3 lung nodules less than 10 mm in diameter and/or ovarian metastasis of any size.
• Active gastrointestinal bleeding;
• Severe ongoing infection;

Lab values

• Severe renal insufficiency (creatinine clearance < 30 mL/min, according to the SmPC of capecitabine;
• QT/QTc interval longer than 450 msec for men and longer than 470 msec for women on the inclusion ECG

Other

• Pulmonary fibrosis (according to the SmPC of panitumumab);
• Pregnancy or breast-feeding period;
• Ongoing non-healing wounds, ulcers or bone fractures;
• Haemorrhagic diathesis or thrombotic tendency;
• Peripheral neuropathy oxaliplatin-related according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0;
• Mutational status corresponding to microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR)
• Complete or partial bowel obstruction unresponsive to medical treatment;

• Age ≥ 18 years;
• Men and women* must use effective contraceptive measures during the treatment and for at least 15 months after the last dose received; (* of childbearing age);
• Creatinine clearance ≥ 30 mL/min
• No known risk of irinotecan toxicity
• No Dihydropyrimidine dehydrogenase deficit (uracil blood Level <16ng/ml);
• Patient is willing and able to comply with the protocol for the duration of the study, including treatment and scheduled visits and examinations, including follow up;
• Patient has valid health insurance.
• Written informed consent obtained from the patient before any study procedure;
• ECOG performance status of 0 to 2;
• Histopathologically confirmed colonic adenocarcinoma with synchronous or metachronous peritoneal metastasis (PM);
• Unresectable PM defined as any of the following: - PCI >15 - Extended small bowell involvement - Poor general condition contra-indication to a major abdominal surgery (eg: a complete cytoreductive surgery ), as decided by the medico-surgical team of the investigator’s site specialised in peritoneal carcinomatosis in charge of the patient.
• A surgical exploration performed less than 4 weeks before inclusion (if not, a laparoscopic exploration must be performed);
• Indication of first line systemic chemotherapy for advanced / metastatic colonic adenocarcinoma. Systemic chemotherapy in an adjuvant setting is allowed if completed more than 6 months before recurrence and without persistent oxaliplatin-induced neuropathy;
• No extended intraperitoneal adherences confirmed by surgical exploration (laparoscopy or laparotomy) in at least 9 out of 13 abdominal regions;
• Neutrophils count ≥ 1.5 x 109/L, platelet count ≥ 100 x109/L, hemoglobin ≥ 9 g/dL; Total bilirubin < 1.5 x ULN (upper limit of normal), ASAT and ALAT <3 x ULN, Alkaline phosphatase <1.5 x ULN, Serum creatinine < 1.5 x ULN;