A Phase I Trial of Isolated Hepatic Perfusion (IHP) Using 5-FU and Oxaliplatin in Patients with Unresectable Isolated Liver Metastases from Colorectal Cancer

Abstract

Background Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP. Methods Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined. Results All 12 patients had received ≥1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m2, resulting in expansion of DL1 at 200 mg/m2 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0–60 min) were 10.9 ± 4.5 μgPt h/mL, 49.3 ± 30.7 μg h/mL 5-FU (DL1), and 70.5 ± 35.5 μg h/mL 5-FU (DL2). Systemic exposure (AUC0–inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %). Conclusions The MTD for IHP was 200 mg/m2 5-FU with 40 mg/m2 oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

Drug resistance reversed by silencing LIM domain-containing protein 1 expression in colorectal carcinoma

“…The chemosensitivity resulting from the LIMD1 knockdown was assessed using an MTT-based cell growth determination kit (Sigma-Aldrich, St. Louis, MO, USA). The sensitivity of transfected CRC cells to the commonly used anticancer drugs, 5-FU and l-oxaliplatin (Changsha Huir Biological-tech Co., Ltd., Changsha, China), was detected in accordance with a previous study ( 6 ). The total cells were then harvested at 12, 24, 36, 48 and 60 h following drug exposure.…”

Hepatic artery infusion of melphalan in patients with liver metastases from ocular melanoma

“…While there are no consensus guidelines on which patients are most likely to benefit from treatment with IHP, our general criteria is established from clinical trials of IHP performed at our institution. 25,26 Inclusion criteria included serum bilirubin < 2.0 mg/dL, platelet count > 150 000/L, serum creatinine < 1.5 mg/dL, and limited extrahepatic disease. Some protocols limit IHP to patients with < 50% tumor replacement in the liver.…”