Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil

Abstract

We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m², on days 1 and 8) and 5-FU (170-330 mg/m², continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m² of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m² are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing.

Transarterial Chemoembolization in Combination with a Molecular Targeted Agent: Lessons Learned from Negative Trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2)

“…However, in previous combination studies with TACE, the median OS ranged from 18 months (shortest) to 32 months (longest) ( Table 1 ), suggesting that the duration of the study needs to be extremely long when evaluating OS as a primary endpoint. In clinical studies that are terminated early because of tumor progression or adverse effects, patients often receive various post-trial treatments, such as hepatic artery infusion chemotherapy [20][21][22] , ablation [23][24][25] , or systemic therapy [26][27][28][29] . In such cases, post-trial treatment likely affects OS, making it difficult to evaluate treatment outcomes using OS, especially in studies of TACE in patients with intermediate-stage HCC.…”

Regorafenib as Second-Line Systemic Therapy May Change the Treatment Strategy and Management Paradigm for Hepatocellular Carcinoma

“…Because HCC responds extremely well to locoregional therapy, it is often used as post-trial treatment even in cases in which locoregional therapy is no longer applicable and molecular targeted agents are subsequently administered in accordance with the protocol, provided that the patient's general condition is stable. This rarely happens with other types of cancer and is therefore essentially unique to HCC, owing to the availability of powerful locoregional therapies such as intra-arterial infusion chemotherapy [5][6][7], transcatheter arterial chemoembolization (TACE) [8,9], and radiofrequency ablation [10][11][12]. These post-trial treatments are capable of canceling out any difference in the primary endpoint OS by prolonging PPS [13].…”

Validation of Kinki Criteria, a Modified Substaging System, in Patients with Intermediate Stage Hepatocellular Carcinoma

“…These reports suggested that surgical resection could be the best option for HCC patients with BCLC stage B disease. Furthermore, in some patients, TACE resistance due to the repeated TACE procedure should end up in the selection of other treatment strategies, including sorafenib and hepatic arterial infusion chemotherapy (HAIC) [15,16,17,18,19,20,21]. Although TACE is the most frequently selected treatment for the patients in BCLC stage B, other treatment options should be applied depending on the condition of individual patients in the clinical setting.…”