Phase I clinical trial of hepatic arterial infusion of cisplatin in combination with intravenous liposomal doxorubicin in patients with advanced cancer and dominant liver involvement

Abstract

Purpose: We conducted a phase I study of hepatic arterial infusion (HAI) cisplatin and systemic chemotherapy in patients with advanced cancer and dominant liver involvement.

Methods: Patients were treated with HAI cisplatin 100-125 mg/m(2) (and 3,000 IU heparin) intraarterially and liposomal doxorubicin (doxil) 20-35 mg/m(2) IV (day 1) every 28 days. A "3 + 3" study design was used.

Results: Thirty patients were treated (median age, 56 years). Diagnoses were breast cancer (n = 11), colorectal cancer (n = 8), ocular melanoma (n = 4), and other (n = 7). The median number of prior therapies was 5. The maximum tolerated dose (MTD) was at the 100/35 mg/m(2) level. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (n = 1) at the cisplatin 125 mg/m(2) and systemic doxil 35 mg/m(2) dose level. The most common toxicities were nausea/vomiting and fatigue. Of 24 patients evaluable for response, 4 (17%) had a partial response (PR) and 7 (29%) had stable disease (SD) for ≥4 months. Of the 11 patients with breast cancer, 3 (27%) had a PR and 5 (45%) had SD for ≥4 months. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD for 4 months. One patient with hepatocellular carcinoma had SD for 4 months. Of 12 evaluable patients treated at the MTD, 2 (17%) had a PR and 5 (42%) had SD.

Conclusion: The MTD was HAI cisplatin 100 mg/m(2) and systemic doxil 35 mg/m(2). This regimen demonstrated antitumor activity, especially in breast cancer.

Fig. 1

a Best response by RECIST to hepatic arterial infusion of cisplatin and intravenous doxil in 24 patients evaluable for response. Each red box indicates a patient with maximum response a partial response (≥30% reduction in tumor size) (n = 4), each blue box indicates a patient with stable disease (maximum response between 29% reduction in tumor size to increase by 19% in tumor size) (n = 11) and each black box indicates a patient with progressive disease (≥20% increase in tumor size) (n = 9). b Kaplan–Meier plot for overall survival. c Kaplan–Meier plot for progression-free survival