A phase II trial of S-1 and oxaliplatin in patients with advanced hepatocellular carcinoma

This study was a multicenter, open-label, single-arm, phase 2 trial that evaluated the efficacy of SOX in advanced hepatocellular carcinoma. Patients with hepatocellular carcinoma of Barcelona Clinic Liver Cancer stage C that was either refractory or not amenable to locoregional therapy were eligible for the present study. Hepatocellular carcinoma was diagnosed based on 2005 AASLD practice guidelines [13]. Either histopathological findings from tumor tissue or non-histological diagnosis based on triphasic CT scan and/or gadolinium enhanced MRI was required [13]. Without histological confirmation, liver mass ≥ 2 cm with characteristic vascularization (either on a triphasic CT scan or gadolinium-enhanced MRI) or AFP ≥ 200 μg/L was required. In patients with a 1 to 2 cm liver mass, characteristic vascularization on both a triphasic CT scan and gadolinium-enhanced MRI were required with concomitant liver cirrhosis. At least one measurable extrahepatic lesion based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 was required. Other main inclusion criteria were an age of over 18 years; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 2; Child-Pugh class A; adequate bone marrow, hepatic, and renal function [absolute neutrophil count (ANC) ≥ 1500/μL; platelet count ≥100,000/μL, total bilirubin ≤2 X upper limit of normal (ULN); serum transaminases ≤2.5 X ULN; alkaline phosphatase ≤2.5 X ULN; serum creatinine ≤1.5 X ULN]. Patients with serum transaminases and alkaline phosphatase ≤5 X ULN could be included if they had a normal total bilirubin level. Patients were excluded if they had either previous systemic chemotherapy (except prior sorafenib) or history of another malignancy within the last 5 years.

The study protocol was reviewed and approved by the institutional review board of Seoul National University Hospital, Seoul, Korea [H-1010-054-336]. This study was conducted in accordance with the recommendations of the Declaration of Helsinki for biomedical research involving human subjects and the Guidelines for Good Clinical Practice (ClinicalTrial.gov Identifier: NCT01429961). Written informed consent was obtained from each patient before enrollment.

S-1 was administered orally at a dose of 40 mg/m² twice daily for 14 days (80 mg/m²/day), followed by a 7-day rest period. Oxaliplatin was given as a 120–minute infusion on day 1 of each cycle at a dose of 130 mg/m². Dose reduction of S-1 (30 mg/m² twice daily, which is 60 mg/m²/day) and Oxaliplatin (100 mg/m²) was allowed per the discretion of the treating physician, as most patients with HCC have compensated liver cirrhosis despite a Child-Pugh class A score. Treatment was repeated every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of patient consent. Drug administration was delayed until an ANC of ≥1500/μL and platelet counts of ≥100,000/μL, and recovery from non-hematological toxicity to baseline or less than or equal to grade 1. S-1 was reduced to a dose of 30 mg/m² twice daily (60 mg/m²/day) and oxaliplatin was reduced to a dose of 100 mg/m² on all subsequent cycles for febrile neutropenia, grade 4 neutropenia, grade 3/4 thrombocytopenia, or greater than or equal to grade 3 non-hematological toxic effects.

Baseline assessments included medical history, physical examination, electrocardiography, chest X-rays, abdominal and pelvic CT scans (gadolinium enhanced MRI when necessary), complete blood counts, serum electrolytes and chemistry, and urine analysis. Tumor response was assessed using RECIST criteria 1.1, with contrast-enhanced triphasic CT scans at baseline and every two cycles (6 weeks). Toxicity was evaluated at each cycle per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

The primary end point of this study was time to progression (TTP), which was defined as the time from study enrollment to tumor progression. Deaths without progressive disease were censored in the TTP analysis. Secondary end points were OS, PFS, response rate, and toxicity. OS was calculated from the date of study enrollment to the date of death. PFS was defined as the interval between the date of study enrollment and first date of documented progressive disease or the date of death from any cause. Tumor response was assessed using RECIST criteria 1.1. TTP, PFS, and OS were estimated using the Kaplan-Meier method and comparisons were made using log-rank tests. Statistical analysis was performed using SPSS software for Windows, version 18.0 (SPSS, Chicago, IL, USA).

We hypothesized an increased TTP from 2.8 months to 4.0 months in the SOX group. With an alpha of 0.10 and a power of 80%, 34 patients were required for this study. Considering a 10% loss to follow-up rate, the target enrollment was 38 patients.

Between May 27, 2011, and August 28, 2014, 36 patients were enrolled. All patients included in our cohort met the diagnostic criteria for both 2005 and 2010 AASLD guidelines [14]. Baseline characteristics of the patients are summarized in Table 1. The median patient age was 58 years (range, 21–74), and 33 patients (91.7%) were male. All patients had at least 1 extrahepatic measurable lesion and good ECOG PS. Per the inclusion criteria, all patients were classified as Child-Pugh class A and had adequate hepatic function. On the baseline CT/MRI, 94.4% (34/36) showed liver cirrhosis. Of the 36 patients, 31 patients were treated with prior sorafenib or locoregional therapy (TACE, PEIT, or RFA). One patient did not receive either prior sorafenib or locoregional therapy.

Response evaluation was available for all 36 patients. One patient achieved a complete response (CR, 2.8%), 4 had a partial response (PR, 11.1%), 13 had stable disease (SD, 36.1%), and 18 had progressive disease (PD, 50.0%). The overall response rate (ORR) was 13.9% and the disease control rate (DCR) was 50.0%.

With a median follow-up of 10.9 months, 35 progression events and 34 deaths occurred. PFS and TTP were the same in our cohort as no patients died without progression. The median TTP and PFS were 3.0 months (95% confidence interval (CI), 0.7–5.3) (Fig. 1), and the median OS was 10.3 months (95% CI, 6.4–14.3) (Fig. 2). The trial did not meet its primary end point of a 4-month TTP. Bone metastasis was associated with poorer survival (hazard ratio (HR) for TTP 2.31, 95% CI 1.02–5.21, p = 0.045) (HR for OS 2.36, 95% CI 1.05–5.30, p = 0.037) (Fig. 3). Gender, age, PS, AFP level, PIVKA level, prior sorafenib treatment, prior locoregional therapy, and lung or liver metastasis were unassociated with TTP and OS. In patients treated with prior sorafenib (31/36, 86.6%), median TTP and OS were 3.0 (95% CI, 1.2–4.8) months and 9.5 (95% CI, 5.4–13.7) months, respectively.

Patients received a total of 199 treatment cycles, with a median of 3 cycles (range, 1–27) per patient. Study treatments were discontinued in 2 patients (5.5%) because of severe adverse events, including spontaneous bacterial peritonitis and hepatocellular carcinoma rupture. Nine patients (25.0%) started chemotherapy at a reduced dose and 27 (75.0%) started chemotherapy at the regular dose. Of the 27 patients who started chemotherapy at the regular dose, 11 (40.7%) had their dose reduced during the chemotherapy cycle due to toxicity. This includes four cases of grade 3 thrombocytopenia, three cases of grade 3 diarrhea, one case of grade 3 neutropenia, one case of grade 3 sensory neuropathy, one case of grade 2 gastrointestinal bleeding, and one case of septic shock due to pneumonia. All 11 patients recovered from the adverse event and received subsequent chemotherapy at a reduced dose. No treatment-related death or grade 4 toxicity occurred during the study. Detailed toxic events per patient are shown in Table 2. The most common adverse event of any grade was sensory neuropathy (52.8%), followed by thrombocytopenia (41.7%), diarrhea (38.9%), nausea (36.1%), anorexia (33.3%), and neutropenia (30.1%). The most common grade 3 toxicities were neutropenia (13.9%), thrombocytopenia (13.9%), and diarrhea (8.3%).