Optimal survival and quality of life in metastatic colorectal cancer with irinotecan dosing based on UGT1A1 genotype and gut microbiome enzyme activity including a dietary intervention. (OPTIMA)

Irinotecan-based systemic therapy is the main chemotherapeutic choice for the treatment of metastatic colorectal cancer (mCRC). It can significantly improve overall survival (OS). Its downside is the late-onset systemic and gastrointestinal toxicity in 40% of patients, particularly severe diarrhoea. This cripples quality of life (QoL) and often results in dose reduction or treatment discontinuation, thus threatening OS. The systemic toxicity might be explained by a genetic variant in UGT1A1. The severe diarrhoea is suggested to be caused by a gut microbial enzyme, beta-glucuronidase (β-GUS). Beside side-effects, the irinotecan treatment appears unbeneficial in about 40% of patients. Consensus molecular groups (CMS) classification appears to relate to irinotecan treatment response.

The goal of OPTIMA is to increase the QoL and OS of mCRC patients. To achieve this, OPTIMA will aim to answer the following questions:

1) What is the external validity of an enzyme activity assay for gut microbiota-derived β-GUS in humans and what is the association between overall gut microbiota composition and β-GUS activity?

2) Is CMS subclassification a measurement to predict irinotecan efficacy, is low UGT1A1 activity predictive for systemic toxicity, and is a high activity of the gut microbiota-derived enzyme β-GUS before and during irinotecan therapy predictive for late-onset gastrointestinal toxicity, and do all relate to QoL and OS in mCRC patients?

3) Can we alter the microbiota composition and thereby lower xenophobic and stimulate symbiotic β-GUS activity in a validated in-vitro model of the colon and thereafter in mCRC patients with help of an intervention with dietary compounds?

The proposed consortium will create the well-needed scientific knowledge to help this vulnerable patient group. Since patient organizations and CRC-guideline members are involved in OPTIMA, the innovative diagnostic test and dietary intervention will find rapid implementation in the Netherlands.