A Dose-Finding Trial for Hyperthermic Intraperitoneal Cisplatin in Gynecological Cancer Patients Receiving Hyperthermic Intraperitoneal Chemotherapy

Chui-Ying Chan, Hui Li, Miao-Fang Wu, Chang-Hao Liu, Huai-Wu Lu, Zhong-Qiu Lin, Jing Li, Chui-Ying Chan, Hui Li, Miao-Fang Wu, Chang-Hao Liu, Huai-Wu Lu, Zhong-Qiu Lin, Jing Li

Abstract

Background: To identify the maximum tolerated dose (MTD) of hyperthermic intraperitoneal cisplatin at 43°C among gynecological cancer patients. Methods: In this Phase I dose-finding trial, Bayesian optimal interval (BOIN) design was used. We sought to explore the MTD with a target dose-limiting toxicity (DLT) rate of 20%, 4 prespecified doses (70 mg/m2, 75 mg/m2, 80 mg/m2 and 85 mg/m2), and 30 patients. Results: Between 2019 and 2020, 30 gynecologic cancer patients were enrolled. No patients received bevacizumab in subsequent treatment. The most common adverse events related to cisplatin were nausea and vomiting (100%), followed by tinnitus (26.7%) and kidney injury (23.3%). Of the seven patients with kidney injury, four had persistent renal impairment, and finally progressed into chronic kidney injury. DLTs were noted only in the dose level 4 group (85 mg/m2) and included acute kidney injury, pulmonary embolism, anemia, and neutropenia. When cisplatin was given at dose level four (85 mg/m2), the isotonic estimate of the DLT rate (22%) was closest to the target DLT rate of 20%. Therefore, 85 mg/m2 was selected as the MTD, with a 51% probability that the toxicity probability was greater than the target DLT rate. Conclusions: For gynecological cancer patients who received HIPEC for peritoneal metastases, the MTD of cisplatin in HIPEC at 43°C was 85 mg/m2. Our findings apply to patients who do not receive bevacizumab (ChiCTR1900021555).

Keywords: Bayesian optimal interval design; cisplatin; dose-finding trial; gynecological cancer; hyperthermic intraperitoneal chemotherapy; kidney injury; maximum tolerated dose.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Chan, Li, Wu, Liu, Lu, Lin and Li.

Figures

Figure 1
Figure 1
Bayesian optimal interval design. According to the Bayesian optimal interval (BOIN) design, the decision to escalate or de-escalate the dose was made by a comparison of the observed dose-limiting toxicity (DLT) rate (p^) at the current dose with fixed prespecified dose escalation (λe) and de-escalation (λd) boundaries. We sought to explore the maximum tolerated dose (MTD) with a target DLT rate of 20%, 4 prespecified doses (70, 75, 80, and 85 mg/m2) and 30 patients. The corresponding dose escalation and de-escalation boundaries were λe = 0.157 and λd = 0.238, respectively. The trial protocol was generally described as follows. (1) The first cohort of three patients received cisplatin at a dose of 70mg/m2. (2) If p^ ≤ λe, the dose was escalated; If p^ ≥ λd, the dose was de-escalated; If λe<p^ < λd, the current dose was retained. (3) Step 2 was repeated until the maximum sample size was reached. *DLT rate = Total number of patients who experienced DLT at the current dose Total number of patients taking the current dose **0.157, λc, which represents the dose escalation boundary. ***0.238, λd, which represents the dose de-escalation boundary. MTD, maximum tolerated dose; DLT, dose-limiting toxicity.
Figure 2
Figure 2
Enrollment of study patients. The X-axis shows individual patients who were enrolled sequentially. The Y-axis represents the four dose levels (70, 75, 80, and 85 mg/m2). The black dots indicate patients who did not develop dose-limiting toxicity, while the black triangles indicate patients who developed dose-limiting toxicity.

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Source: PubMed

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