A phase 1 trial of pressurised intraperitoneal aerosolised chemotherapy (PIPAC) in the treatment of colorectal peritoneal metastases & an exploration of the genomic features of these metastases and their microenvironment
File(s)
Author(s)
Kyle, Peter
Type
Thesis
Abstract
Colorectal peritoneal metastases continue to be associated with a poor prognosis despite modern systemic chemotherapy regimens. Pressurised intraperitoneal aerosolised chemotherapy (PIPAC) has been proposed as a novel chemotherapy delivery mechanism for patients with extensive peritoneal metastases not amenable to cytoreductive surgery and heated intraperitoneal chemotherapy. In this thesis I present the first UK trial of PIPAC that focused exclusively on colorectal peritoneal metastases. Here I show that PIPAC is a safe technique that can be delivered alongside a systemic chemotherapy regimen. This correlates with international safety data, but demonstrates feasibility within the NHS. The unique opportunity for serial blood samples and biopsies alongside PIPAC facilitated novel studies into the genomic underpinning of peritoneal metastases and their tumour microenvironment. Here I show exploratory data demonstrating feasibility of ctDNA whole exome sequencing and tissue whole genome sequencing with paired s3-ATAC-seq phenotype profiling for the study of colorectal peritoneal metastases. Preliminary results point towards an increase in ctDNA 60 minutes after PIPAC, ongoing clonal and sub-clonal evolution of the tumour across treatments and reversal of a pro-cancer macrophage phenotype polarisation following one administration of PIPAC. Further study of these exploratory findings may yield insights into the mechanisms of peritoneal metastasis development and progression. The National Institute for Clinical Excellence has stated that studies with randomisation and control arms are required for the delivery of PIPAC in the UK. The work in my thesis has informed the design of the National Institute for Health and Care Research Efficacy and Mechanism Evaluation funded PICCOS randomised clinical trial (PIPAC in Cancers of the Colon, Ovaries and Stomach) which seeks to answer many of the questions outlined above and is due to commence in 2024.
Version
Open Access
Date Issued
2023-12-03
Date Awarded
01/06/2025
License URL
Advisor
Murphy, Jamie
Antoniou, Anthony
Sponsor
Imperial College London
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)