Intraperitoneal Irinotecan With Concomitant FOLFOX and Bevacizumab

Progression-free survival

calculated from the interval from the start of trial treatment until first evidence of intraperitoneal and/or systemic disease progression, and/or start of second-line systemic therapy, or last follow-up

Time frame: 3 year

Toxicity in CTCAE grading

Defined as the number of patients who experience / the total number of Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) grade 3-5 adverse events, measured up to four weeks after the last cycle of intraperitoneal irinotecan (75 mg) with concomitant palliative systemic therapy. With the exception of peripheral neuropathy, which will be reported indefinitely, ranging from CTCAE grade 1-5.

Time frame: 28 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Toxicity measured up to four weeks after last cycle.

Patient-reported outcomes (PROs) with EQ-5D-5L

Assessed with the 5-level EQ-5D by EuroQol group (EQ-5D-5L) at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.

Patient-reported outcomes (PROs) with EORTC QLQ-C30

Assessed with the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The EORTC QLQ-C30 comprises 30 items, 24 of which are aggregated into nine multi-item scales, that is, five functioning scales, three symptom scales and one global health status scale. The remaining six single-item assess symptoms. All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient).

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.

Patient-reported outcomes (PROs) with EORTC QLQ-CR29

Assessed with the European Organization for Research and Treatment for Cancer Quality of Life Questionnaire, specifically for colorectal cancer (EORTC QLQ-CR29) at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The resulting QLQ-CR29 consisted of four scales and 19 individual items. Higher scores indicate a higher level of symptoms (i.e. a worse state of the patient).

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.

Healthcare costs

According to the Dutch manual for cost analysis in health care research, and assessed with the iMTA Medical Consumption Questionnaire at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle. The volumes of used healthcare costs were multiplied with the unit costs of these corresponding services.

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.

Productivity loss costs.

Assessed with the iMTA Productivity Cost Questionnaire at baseline, one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured one week after the first cycle, one week after the fourth cycle, one week after the eighth cycle, and one week after the twelfth cycle.

Occurrence and degree of nephrotoxicity

Assessed during standard-of-care laboratory assessment for nephrotoxicity (creatinine, eGFR, and ureum) analysis before each subsequent cycle and graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.

Occurrence and degree of hepatotoxicity

Assessed during standard-of-care laboratory assessment for hepatotoxicity (albumin, bilirubin, AST, ALT, LD, AF, yGT) analysis before each subsequent cycle and graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.

Occurrence and degree of haematological toxicity

Assessed during standard-of-care laboratory assessment for haematological toxicity (haemoglobin, leucocytes, thrombocyte) analysis before each subsequent cycle and graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.

Response of Tumor marker during treatment

Assessed by carcino-embryonic antigen (CEA) analysis during standard laboratory analysis before each subsequent cycle

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.

Number of patients that completed twelve cycles

To determine the number of patients completing twelve cycles of treatment with intraperitoneal irinotecan (75 mg) and concomitant palliative systemic therapy, required dose reductions, and reasons for discontinuation.

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles.

Objective radiological response

assessed by thoracoabdominal CT at baseline, after the fourth cycle, after the eighth cycle, and after the twelfth cycle according to RECIST.

Time frame: 24 weeks. Each cycle is 2 weeks, maximum of 12 cycles. Measured at baseline, after the fourth cycle, after the eighth cycle, and after the twelfth cycle.

Peritoneum/plasma ratio of intraperitoneal irinotecan

To determine the the peritoneum/plasma ratio of intraperitoneal during the first and fourth cycle of intraperitoneal irinotecan (75 mg) and concomitant palliative systemic therapy. Whole blood and peritoneal fluid will be drawn from a peripheral intravenous access and the peritoneal access port, respectively, and collected in 3 mL lithium heparin tubes and 2 mL cryotubes, respectively, at the following moments after the start of irinotecan infusion; t=0, at the end of infusion (EOI), t=30 minutes after EOI and t =2 hrs after EOI and t = 4hrs after EOI. The ratio between the Area Under the Curve (AUC) between irinotecan measured in the peritoneum and measured in the plasma is taken.

Time frame: 8 weeks. Each cycles is 2 weeks. Measured during cycle 1 and cycle 4.