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Peritoneal Surface Malignancies

P48: Preliminary Analysis of a Phase II Randomized Comparison of Flat vs Weight-based Mitomycin C Intraperitoneal Chemotherapy

ePoster Presenter(s)

Hannah G. McDonald, MD

General Surgery Resident
Department of Surgery, University of Kentucky
Lexington, Kentucky, United States

Submitter(s)

Hannah G. McDonald, MD

General Surgery Resident
Department of Surgery, University of Kentucky
Lexington, Kentucky, United States

Author(s)

Hannah G. McDonald, MD

General Surgery Resident
Department of Surgery, University of Kentucky
Lexington, Kentucky, United States
RM

Robert McCorkle, PhD

Staff Scientist
The University of Kentucky, College of Pharmacy, United States
AR

Anna Reagan, MD

General Surgery Resident
Department of Surgery, University of Kentucky, United States
MH

Megan Harper, MS, MD, PhD

Research Resident
The University of Kentucky College of Medicine, United States
RP

Reema A. Patel, MD

Medical Oncologist
Department of Internal Medicine, University of Kentucky, United States
SE

Scott S. Ellis, PharmD

Clinical Pharmacist
University of Kentucky College of Pharmacy, United States
HW

Heidi Weiss, PhD

Biostatistician
The University of Kentucky Markey Cancer Center, United States
MB

Mautin Barry-Hundeyin, MD

Surgical Oncologist
Division of Surgical Oncology, Department of Surgery, University of Kentucky, United States
Michael J. Cavnar, MD

Surgical Oncologist
Division of Surgical Oncology, Department of Surgery, University of Kentucky
Lexington, Kentucky, United States
JK

Joseph Kim, MD

Professor and Chief of Surgical Oncology
Division of Surgical Oncology, Department of Surgery, University of Kentucky, Kentucky, United States
JK

Jill Kolesar, PharmD

Collaborating Principal Investigator
The University of Kentucky College of Pharmacy, United States
Prakash K. Pandalai, MD (he/him/his)

Surgical Oncologist
Division of Surgical Oncology, Department of Surgery, University of Kentucky, United States

Introduction: Cytoreductive surgery (CRS) ± heated intraperitoneal chemotherapy (HIPEC) has demonstrated increased survival in patients with peritoneal carcinomatosis (PC) from advanced gastrointestinal (GI) cancer. Based on historic precedent, Mitomycin C (MMC) is the most common drug utilized worldwide with highly variable dosing practices. Neutropenic toxicity associated with high dose MMC may also increase morbidity associated with HIPEC. Two dominant dosing strategies exist: flat dose (FD) and weight-based (WB), however, neither has been directly compared and lack of dosing consensus prevents standardization of HIPEC technique.

Methods: A single institution investigator-initiated Phase II trial compared FD and WB MMC in patients undergoing CRS+HIPEC for advanced GI cancer. Eligible patients were randomized to MMC FD 40 mg vs WB 12.5 mg/m2 utilizing 1:1 allocation ratio. Plasma (PLA) and peritoneal (PER) fluid samples were collected at (0, 15, 30, 60, 90 min) in addition to PLA postoperatively (2, 4, 12 hour) for pharmacokinetic analysis including C-max (ng/mL) and area under the curve (AUC) (hour x ng/mL). Clinicopathologic data including age, sex, BSA, dose, and WBC nadir between the two arms were compared. Recurrence data was evaluated for all patients with ≥ 1-year follow-up, excluding those with low-grade mucinous appendiceal neoplasm (LAMN) and completeness of cytoreduction (CC) score = 2.

Results: Of 45 patients enrolled, 31 have undergone CRS + HIPEC, with evaluable data. Clinicopathologic characteristics were comparable between arms (Table 1). Dose (mg/m²) was significantly higher in the FD group (21.2 vs 12.2, P < 0.00001). PER and PLA C-max and AUC were higher in FD compared to WB patients, although this did not reach statistical significance. Neutropenia requiring filgrastim administration occurred in 3/14 (21.4%, P = 0.04) patients in the FD arm and 0/17 patients in the WB arm. One-year recurrence-free survival was 84% for the entire cohort and did not differ between arms.

Conclusions: Early results of a randomized comparison of FD vs. WB MMC dosing during HIPEC demonstrate a higher PER (and PLA) C-max and AUC in FD with 21.4% of these patients required filgrastim support. These preliminary data suggest higher dosing does impact systemic PLA drug concentrations and may lead to higher toxicity without additional therapeutic efficacy in the short term. Lack of consensus MMC dosing in HIPEC leads to surgical variation and further complicates efforts to standardized practice. This clinical trial is active and accruing.

Learning Objectives:

Understand that there is lack of consensus regarding Mitomycin C (MMC) dosing for heated intraperitoneal chemotherapy (HIPEC) which may lead to unintended consequences with potential equipoise in efficacy.
Identify the clinical and pathologic impact of flat dose versus weight-based dosing of MMC for HIPEC.
Weigh the risks with or without benefit between flat dose and weight-based dosing strategies for application into their own practice.