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

作者：Magge D^*; Zureikat A H; Bartlett D L; Holtzman M P; Choudry H A; Beumer J H; Pingpank J F; Holleran J L; Strychor S; Cunningham D E; Jones H L; Zeh H J III

来源：Annals of Surgical Oncology, 2013, 20(7): 2180-2187.

DOI：10.1245/s10434-013-2960-3

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.
Standard 3 x 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.
All 12 patients had received a parts per thousand yen1 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/m(2), resulting in expansion of DL1 at 200 mg/m(2) 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 (AUC(0-60 min)) were 10.9 +/- A 4.5 mu gPt h/mL, 49.3 +/- A 30.7 mu g h/mL 5-FU (DL1), and 70.5 +/- A 35.5 mu g h/mL 5-FU (DL2). Systemic exposure (AUC(0-inf)) relative to IHP exposure was negligible for both platinum (1.1 +/- A 1.5 %) and 5-FU (0.09 +/- A 0.10 %).
The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

• 出版日期2013-7