This study was approved by the ethics committee of National Cancer Center Hospital. The trial was designed according to the current Declaration of Helsinki (Somerset West, South Africa, 1996). Written informed consent was obtained from each participating patient before enrollment. This study was registered with the University Hospital Medical Information Network in Japan (UMIN; number UMIN000003113) and has been completed.
Patient eligibility
We used the following eligibility criteria to screen patients for inclusion: histological or clinical confirmation of HCC by early tumor staining with dynamic computed tomography or dynamic magnetic resonance imaging; elevated serum levels of alpha-fetoprotein (AFP) or protein induced by vitamin K absence-II (PIVKA-II); age ≥ 20 years; unresectable HCC; no indication for liver transplantation, local ablation therapy (percutaneous RFA, PEI, and microwave coagulation), and TACE; Child–Pugh class A or B; Eastern Cooperative Oncology Group performance status (PS) 0–2; adequate bone marrow, renal, and cardiac function; existence of a intrahepatic lesion; adequate oral intake; and life expectancy > 60 days. For eligibility, patients also had to meet the following clinical laboratory test criteria: neutrophil count ≥ 1,500/mm3; platelet count ≥ 60,000/mm3; hemoglobin (Hb) ≥ 9.0 g/dL; serum creatinine (Cr) ≤ 1.2 mg/dL and Cr clearance ≥ 50 mL/min; alanine aminotransferase (ALT) ≤ 5 × the upper limit of the normal range (ULN); aspartate aminotransferase (AST) ≤ 5 × ULN; serum albumin ≥ 2.8 g/dL; prothrombin time and international normalized ratio ≤ 2.3; and serum total bilirubin level (T-Bil) ≤ 2.0 mg/dL.
The exclusion criteria were as follows: any treatment for HCC within 28 days before study entry; prior chemotherapy with 5-FU or a platinum-containing drug; administration of blood transfusion, blood preparation, albumin preparation, or granulocyte-colony stimulating factor within 15 days before study entry; regular use of phenytoin, warfarin, or flucytosine; severe heart failure; uncontrollable diabetes mellitus; active infection; pregnancy or lactation; childbearing age for women unless effective contraception was being used; severe drug hypersensitivity; mental disorder; watery diarrhea; moderate or marked pleural effusion or ascites; and other serious medical conditions.
Treatment
Patients received CDDP-TAI (infusion on day 1) and S-1 (daily oral administration on days 1–21) every 5 weeks. CDDP-TAI was performed via a lobar or selective approach depending on tumor number and location Figure 1. Treatment was continued until occurrence of disease progression or unacceptable adverse events. If patients did not fulfill the continuation criteria (absolute white blood cell count ≥ 2000/mm3; platelet count ≥ 50,000/mm3; Cr ≤ 1.5 mg/dL; diarrhea or mucositis ≤ grade 2; and rash ≤ grade 2), S-1 was temporarily suspended until recovery. The next course was started only when patients fulfilled the following criteria: absolute neutrophil count ≥ 1000/mm3; Hb ≥ 9.0 g/dL; platelet count ≥ 50,000/mm3; AST ≤ grade 2; ALT ≤ grade 2; Cr ≤ 1.2 mg/dL; diarrhea or mucositis ≤ grade 2; and rash ≤ grade 2. Patients who required > 49 days to begin the next cycle were withdrawn from the study.
Patients were scheduled to receive CDDP-TAI plus S-1 at 3 dosage levels (Table 1). CDDP was administered at a dosage of 65 mg/m2 at levels 1–3. S-1 was administered as follows: level 1, 50 mg/m2; level 2, 60 mg/m2; and level 3, 80 mg/m2. At level 0, the CDDP dosage was decreased to 50 mg/m2, and S-1 was administered at the same dosage as level 1.
Study design
The objective of this trial was to evaluate the frequency of DLT during the first 28 days of cycle 1 and to determine the RD that should be used in a phase II trial. At least 3 patients were enrolled at each dosage level. Level 1, which was the starting dose, was initially administered to 3 patients. If DLT was observed in 1 or 2 of the initial 3 patients, up to 3 additional patients were enrolled at the same dosage level. The highest dosage level that did not cause DLT in 3 of 3 patients or ≥ 3 of 6 patients treated during the first cycle was considered the MTD. DLT was defined as febrile neutropenia; clinically or microbiologically documented infection with grade 3 or 4 neutrophils; absolute grade 4 leukopenia or neutropenia for ≥ 7 days; grade 4 thrombocytopenia or administration of platelet transfusion; grade 3 non-hematological toxicity; AST, ALT, ALP or γ-glutamyltranspeptidase >15 × ULN; Cr > 2.0 mg/dL; any toxicity that required interruption of therapy for > 49 days between day 1 of the first cycle and day 1 of the second cycle; and interruption of S-1 chemotherapy more than 21 times during 1 cycle. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 3.0.
Assessment of efficacy and toxicity
All patients who received at least 1 dose of the study drugs were included in the response and toxicity evaluations. Every 5 weeks, tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.0. PFS was defined as the interval between the date of treatment initiation and the date of first confirmed disease progression or the date of death from any cause. OS was defined as the interval from the date of treatment initiation to the date of death from any cause. Median PFS and median OS were estimated using the Kaplan–Meier method. For each cycle, tumor markers (AFP and PIVKA-II) were assessed 5 weeks after CDDP-TAI administration.