Ten patients were entered into the study. All patients had to have histologically confirmed hepatocellular carcinoma. To be eligible for the study, a patient had to have 1) an ECOG performance status of 0, 1 or 2, 2) one or more lesions that could be measured from each side, 3) no prior systemic chemotherapy, 4) adequate baseline organ function, defined as a WBC count of at least 4,000/μL, a platelet count of at least 100,000/μL, a total bilirubin level of less than 3.0 mg/dL, serum transaminases levels of less than 3 times the upper limit of normal, and a serum creatinine value of less than 1.5 mg/dL or a creatinine clearance more than 50 mL/min.

However, patients with symptomatic brain metastases or other severe illnesses were excluded from the study. Written informed consent was required from each patient.

A complete history, physical examination, recording of performance status according to ECOG criteria, complete blood cell count with differential, serum biochemistry, alpha-fetoprotein, urinalysis and ECG were obtained at baseline for each patient. Chest radiographs and liver CT scans were routinely performed on all patients. Other radiographic examinations, eg, isotope bone scans, brain CT scan and abdominal ultrasonography were performed if clinically indicated. Pathologic test was performed with fine-needle aspiration biopsy.

It was planned that each patient would receive chemotherapy every 28 days until evidence of progression but the course of chemotherapy was limited to a maximal six cycles. The treatment regimen consisted of cisplatin 20 mg/m²/day and topotecan 1.25 mg/m²/day intravenously on days 1 through 5, respectively. Cisplatin infusion preceded topotecan infusion by 30 min.

Full doses of chemotherapy were given if WBC and platelet counts were at least 4,000/μL and 100,000/μL on day 0, respectively. In case of WHO grade 1 leukopenia or thrombocytopenia, treatment was given at doses reduced by 25%. In patients with grade 2 or higher leukopenia or thrombocytopenia, treatment was delayed for 1 week. Granulocyte colony-stimulating factor was given if necessary. Prophylactic antiemetics were routinely administered on the day of chemotherapy with 5-HT₃ receptor antagonists.

Physical examinations, complete blood counts and biochemistry profiles were repeated every 4 weeks. Toxicities were graded according to WHO toxicity criteria. Radiographic evaluations for tumor response, including isotopic bone scan and CT scan, were performed every two courses of chemotherapy. Responses were defined as follows: a complete response was the disappearance of all clinical and radiographic signs of tumor for at least 4 weeks; a partial response was a more than 50% reduction in the sum of products of the biperpendicular diameters of all measurable lesions, with no increase in size of any lesion and no new lesions; stable disease was a decrease of less than 50% or an increase of the less than 25% in the product of the longest perpendicular diameters of measurable lesions and no new lesion; and disease progression was a 25% or greater increase in size of any lesion or the appearance of any new lesion.

The response duration was measured from the date of confirmation of the least partial tumor response to the date of disease progression. Survival was measured from the date of the beginning of therapy until the date of death or last follow-up evaluation.

Statistical analysis was performed with SPSS (version 10.0) statistical program for personal computers. Response rates were calculated by ninety-five percent confidence interval. Survival was estimated by the Kaplan-Meier method.

From November 1999 to May 2001, a total of 10 patients have been treated by topotecan and cisplatin in our institute. The main characteristics of the patients are summarized in Table 1. All patients were male. Their median age was 54 with a range of 53 to 74 years. The ECOG performance status was 0 or 1 in 6 (60%) patients and 2 in 4 (40%) patients. All patients had been pathologically proven hepatocellular carcinoma. According to UICC/AJCC staging system, one patient had stage IIIA disease, two had IIIB, one had IIIC and six had IV. Previous hepatic resection was performed with curative intent in 2 patients (20%) who relapsed thereafter. Two patients had received transarterial chemopatient embolizations. The others had no previous treatment. One had received involved field radiation therapy due to spinal metastasis. Extrahepatic metastases were observed in six patients. Sites of metastasis included spine (1 patient), intraabdominal lymph nodes (3 patients) and lung (4 patients). Among all patients, the serum alpha-fetoprotein (AFP) was 10–568,700<μg/mL (normal range, <2.5 ng/mL). A total of 24 courses of treatment were given, for a median of two courses per patients (range, 1 to 6 courses).

All of the patients were evaluable for response and toxicity. After a median two cycles of chemotherapy, there were no complete response and one partial response, for an overall response rate of 10% (95% CI, 0% to 29%). The response duration of responder was 46 weeks. Four patients demonstrated stable disease as their best response to therapy and the other five patients had progressive disease. At the time of this analysis, 9 patients were reported dead. The median progression-free survival was 16 weeks (range, 0 to 47 weeks). The median survival time was 21 (range, 17 to 54+) weeks and 1-year survival rate was 10% (Figure 1).

Hematologic and non-hematologic toxicities are listed in Table 2. WHO grade III–IV neutropenia and thrombocytopenia occurred in 33% and 33% of cycles, respectively. WHO grade III anemia occurred in 21% of cycles. Four patients experienced the life-threatening (WHO grade IV) neutropenia or thrombocytopenia. Four episodes of fever with neutropenia were observed but resolved with empiric antibiotics and granulocyte colony-stimulating factor. There were no toxic deaths and life-threatening bleeding.

All ten patients were assessable for symptomatic toxicity. There was no grade IV non-hematologic toxicity. Nausea and vomiting were documented in the majority of patients.

Three patients had experienced WHO grade III vomiting. One patient had WHO grade III diarrhea. Stomatitis of WHO grade II occurred in two patients. Alopecia occurred in a half of the patients. Renal toxicity was not developed. WHO grade III hepatotoxicity occurred in two patients who had progression of disease.