Author ORCID Identifier

https://orcid.org/0000-0002-4523-907X

Date Available

1-1-2026

Year of Publication

2024

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Clinical and Translational Science

Advisor

Dr. Joseph Kim

Abstract

Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) with Mitomycin C (MMC) has more than doubled the overall and disease-free survival in patients with peritoneal metastases (PM) due to colorectal cancer (CRC) over the past two decades. Although MMC is the most used HIPEC drug for PM due to CRC, dosing protocols vary dramatically between and within institutions across the world. Additionally, little is known about the impact of hyperthermia and MMC on intracellular pathways for CRC. The aim of this work is to determine the optimal dosing strategy in the clinical application of MMC and hyperthermia for treatment of CRC and to identify cellular processes impacted by this duo in vitro.

Despite the release of consensus guidelines in 2020 recommending a single weight-based (WB) and flat dose (FD) strategy for MMC in HIPEC for CRC PM, vast heterogeneity still exists worldwide. This lack of consensus prevents standardization of care, cohorting for large multicenter studies, and can lead to undue MMC toxicities, including neutropenia. To address this lack of consensus and better define the pharmacokinetic parameters of intraperitoneal MMC, a phase II prospective randomized trial investigated differences in peritoneal (PER) and plasma (PLA) area under the curve (AUC; mg/mL*hr) between patients who receive FD (40mg) vs. WB (12.5mg/m2) MMC. After HIPEC was completed in 31 patients, we found that PER and PLA AUC were significantly higher in the FD arm compared to WB (P < 0.05) with a linear rate of PER:PLA absorption. This indicates that higher peritoneal MMC dose leads to a proportional increase in systemic MMC concentration. This manifested clinically as significantly increased incidence of neutropenia requiring treatment in the FD arm (21 vs. 0%, P = 0.044).

DNA damage, which is caused by both heat and chemotherapy, leads to a multitude of defects including mispaired bases requiring mismatch repair (MMR). MMR proteins and their cofactors function to repair these mismatches, with the help of heat shock protein (hsp) stabilization. Multiple factors including hyperthermia and chemotherapy have been shown to impact the interaction and function of both hsps and MMR proteins. Dysregulation of MMR leads to microsatellite instability (MSI) which is associated with favorable outcomes and improved response to immunotherapy in CRC. Given the previous studies of MMR dysregulation with hyperthermia and chemotherapy, we sought to characterize the impact of these by mimicking the conditions of HIPEC using MMR-proficient (pMMR) CRC cell line (HT29). We found that hyperthermia led to a decrease in the 50% cytotoxic dose (IC50) in pMMR CRC cells. Furthermore, hyperthermia and MMC led to an increase in cytoplasmic and decrease in nuclear MSH2, which has been clinically linked to MSI in CRC.

This body of work examines the impact of hyperthermia and MMC on CRC in vitro and in vivo. This is the first report of linear absorption of MMC during HIPEC and the first prospective comparison of dosing strategies. This is also the first report of increased resistance to MMC with hyperthermia in CRC cells. Finally, our findings suggest an avenue to use the induction of MMR dysregulation to better treat patients with metastatic CRC.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.458

Funding Information

National Institutes of Health T32 CA60003 (2022-2024)

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