Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence

Abstract

Aim: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection.

Methods: A total of 143 patients (83.1% of the 172 participants in the phase II study) participated in the follow-up study. Of these patients, 50 had received no treatment, 48 had received 160 mg/d PI-88, and 45 had received 250 mg/d PI-88 during the phase II trial. Safety parameters and the following efficacy endpoints were investigated: (1) time to recurrence; (2) disease-free survival; and (3) overall survival.

Results: PI-88 at 160 mg/d delayed the onset and frequency of HCC recurrence, and provided a clinically significant survival advantage for up to 3 years after treatment compared with those of the control group: (1) the recurrence-free rate increased from 50% to 63%, and (2) time to recurrence at the 36th percentile was postponed by 78%. The efficacy of administering PI-88 at 250 mg/d was confounded by a high dropout rate (11 out of 54 patients). Additionally, subgroup analyses of patients with (1) multiple tumors or a single tumor ≥ 2 cm; and (2) hepatitis B or C revealed that administering PI-88 at 160 mg/d conferred the most significant survival advantage (56.8% improvement in disease-free survival, P = 0.045) for patients with both risk factors for recurrence.

Conclusion: Administering PI-88 at 160 mg/d is a safe and well-tolerated dosage that may confer significant clinical benefits for patients with HCC.

Trial registration: ClinicalTrials.gov NCT00247728.

Keywords: Adjuvant therapy; Antiangiogenesis; Antimetastasis; Disease-free survival; Heparanase inhibitor; Hepatocellular carcinoma; PI-88; Tumor recurrence.

Figures

Figure 1

Graphic representation of phase II and follow-up study design, timeline and cohort relationships. ITT: Intent-to-treat; Rec.: Recovery.

Figure 2

3-year probability for Groups A, B and C. A: Time-to-recurrence; B: Disease-free survival.

Figure 3

Subgroup analysis of 3-year disease-free survival probability for high-risk subgroups in Groups A, B and C.