Colorectal peritoneal metastases: Current status in treatment, evaluation of the immune landscape and development of a novel platform for personalised medicine
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2022-04-20.
© 2020 Vignesh Narasimhan
Peritoneal metastases from colorectal cancer confer the worst survival in patients with metastatic colorectal cancer. Historical survival from peritoneal metastases was dismal, with the condition generally viewed with nihilism. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases (CRPM) a favorable survival. However, its uptake is variable due to skepticism about its efficacy. Additionally, most patients have inoperable disease, and are treated with systemic chemotherapy, fraught with high rates of treatment failures. With limited advances in management of peritoneal disease, there is an urgent need to explore newer avenues of treatment. In this thesis, I firstly confirm that there remains skepticism among surgeons regarding the utilisation of CRS and HIPEC for CRPM. Most recognise the role of cytoreductive surgery, however there remains deficiencies in awareness and knowledge regarding its indications and efficacy. To explore the efficacy of surgery, I evaluated outcomes from CRS and HIPEC for all peritoneal surface malignancies at a statewide referral centre. CRS and HIPEC was safe, and offered favorable survival. With CRPM specifically, median survival was 32 months, with a relapse free survival of 13 months following CRS and HIPEC. Incomplete cytoreduction and mucinous histology were key factors influencing survival. The choice of mitomycin C or oxaliplatin as HIPEC agent did not influence survival. In a meta-analysis, apart from well known factors such as PCI, completeness of cytoreduction and lymph node involvement, the use of adjuvant chemotherapy, a rectal primary and grade III/IV morbidity were significant prognostic factors influencing survival in patients undergoing CRS and HIPEC. The immune landscape of CRPM, a previously unchartered area, was then explored as a means to exploring newer treatment avenues. CRPM do have an immune infiltrate, albeit largely stromal, with a prominence of T cells, with over a fifth expressing PD-1. In an in-vitro tumouroid-TIL co-culture platform, we demonstrated that T cells in CRPM are functional, and the use of checkpoint antibodies can significantly improve T cell cytotoxicity in selected patients, offering this platform to personalise use of checkpoint antibodies in patients with CRPM. Additionally, gene expression analysis revealed most CRPM to be part of the worst prognostic CMS 4 subtype, with up regulation of immunosuppressive pathways. Another avenue garnering interest is personalised medicine, wherein drugs can be assigned based on unique molecular features of each cancer. Lastly, I led a multicentre, prospective study wherein a novel in-vitro patient derived tumouroid platform was established, that can integrate functional drug testing with genomic profiling to identify suitable therapeutic options in a clinically timely manner. Additionally, our team showed that results from this in-vitro platform successfully mirror patient drug responses in-vivo, and can help identify novel therapeutic options in patients with treatment refractory disease with no genomic-guided biomarkers. While current treatment of CRPM does offer highly selected patients a favourable survival, much remains to be improved for the remainder. Exploring a tumouroid based precision model of care has true potential in offering novel therapeutic options to an otherwise poor prognostic cohort.
KeywordsColorectal peritoneal metastases; Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy; Immunotherapy; Precision medicine
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