Systemic chemotherapy is the only option for patients with unresectable/metastatic hepatocellular carcinoma (HCC) who are not candidates for local/regional treatment. However, the response to such treatment and survival are poor, especially in hepatitis B virus (HBV) endemic areas. The aim of this study was to determine the efficacy of cisplatin-based combination chemotherapy and identify a subgroup of advanced HCC patients with favorable responses.
The medical records of all consecutive patients with unresectable/metastatic HCC who received cisplatin-based combination chemotherapy between January 2003 and October 2009 were reviewed. Time to progression (TTP) and overall survival (OS) were determined using Kaplan-Meier analysis. Univariate and multivariate analyses were performed to identify prognostic factors for TTP and OS.
Data for 46 patients were analyzed. First-line chemotherapies consisted of cisplatin-based combination treatment with doxorubicin, fluoropyrimidines and gemcitabine. The response rate for all patients was 4.3%. The median TTP and OS were 1.8 (95%confidence interval [CI], 1.1 to 2.5) and 7.2 (95% CI, 3.0 to 11.5) months, respectively. Eastern Cooperative Oncology Group (ECOG) performance status (PS), Child classification, Cancer of the Liver Italian Program (CLIP) score and portal vein thrombosis (PVT) were identified by univariate analyses as prognostic factors for TTP and OS. ECOG PS (hazard ratio [HR], 4.51; 95% CI, 1.61 to 12.6; p=0.004) and PVT (HR, 2.12; 95% CI, 1.10 to 4.11; p=0.026) were independent prognostic factors for TTP.
Cisplatin-based combination chemotherapy in patients with advanced HCC has a low response rate and short TTP regardless of the chemotherapy regimen used. Patients with a good ECOG PS and without PVT can be considered candidates for cisplatin-based combination chemotherapy.
Patients with unresectable or metastatic hepatocellular carcinoma (HCC), who are not candidates for local/regional treatment, have a very limited number of therapeutic options (
For those patients who are not candidates for sorafenib treatment or for those who have had treatment failures after sorafenib, the only therapeutic option is systemic chemotherapy. However, there are no standard chemotherapy regimens that have been shown to improve overall survival. A large number of controlled and uncontrolled studies have been performed with most of the major classes of chemotherapy agents given as single or combination therapies. Single or combination regimens of other drugs, including doxorubicin, 5-fluorouracil (5-FU), capecitabine, cisplatin, gemcitabine, and mitoxantrone have elicited 0% to 27% response rates, 2 to 6 months time to progression (TTP) or progression-free survival, and 3 to 12 months of overall survival (OS) (
The most widely studied regimens in patients with advanced HCC are doxorubicin and cisplatin-based chemotherapies. Doxorubicin was associated with a single agent response rate of 0-15% (
Systemic chemotherapy loses efficacy due to the frequently observed development of multidrug tumor resistance, which is related to the high rate of expression of the multidrug resistance gene (MDR1), and p53 tumor suppressor gene mutations (
The aim of this study was to determine the efficacy of cisplatin-based combination chemotherapy and identify a subgroup of patients with advanced HCC who would be candidates for cisplatin-based combination chemotherapy. The records of all consecutive patients with advanced HCC who received cisplatin-based combination chemotherapy at a single center, before the sorafenib era, were retrospectively analyzed by univariate and multivariate prognostic factor analyses.
Between January 2003 and October 2009, consecutive patients with unresectable or metastatic HCC who received cisplatin-based combination as the first-line chemotherapy at Seoul National University Bundang Hospital were retrospectively enrolled. Patients had disease progression after a curative resection or other local treatment procedures, such as radiofrequency ablation (RFA), cryoablation or transarterial chemoembolization (TACE), or were not amenable to local/regional treatment. The diagnosis of HCC was confirmed by histopathology or by computed tomography (CT), magnetic resonance imaging (MRI), and angiographic findings in addition to elevated values of alpha-fetoprotein (AFP) using the guidelines proposed by the Korea Liver Cancer Study Group (
The first-line chemotherapy regimens given to patients were cisplatin-based combination chemotherapy with doxorubicin (AP), 5-FU (FP), capecitabine (XP) and gemcitabine (GP). The AP regimen consisted of doxorubicin 60 mg/m2 delivered as an intravenous infusion over 30 minutes on day 1, followed by cisplatin 60 mg/m2 infused over 30 minutes on day 1. The FP regimen consisted of 5-FU 1,200 mg/m2 administered continuously on days 1 to 4, and cisplatin 60 mg/m2 infused over 30 minutes on day 1. The XP regimen consisted of capecitabine 2,000 mg/m2 orally administered on days 1 to 14, and cisplatin 60 mg/m2 infused over 30 minutes on day 1. The GP regimen consisted of gemcitabine 1,200 mg/m2 infused on days 1 and 8, and cisplatin 60 mg/m2 infused over 30 minutes on day 1. Chemotherapy cycles were repeated every 21 days until disease progression or intolerable toxicity.
Response was assessed after every two cycles of chemotherapy by CT or MRI scan using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (
The TTP was calculated from the first day of chemotherapy to the day when progressive disease was documented. OS (in days) was calculated from the first day of chemotherapy to death by any cause. All survival distributions were calculated using the Kaplan-Meier method and the log-rank test was used for univariate analysis. The Cox proportional hazard model was used to assess the prognostic factors by multivariate analysis. All analyses were done using SPSS ver. 15.0 (SPSS Inc., Chicago, IL) and a p≤0.05 was considered statistically significant. The study was approved by an independent review board at the Seoul National University Bundang Hospital (IRB approval number: B-1003-095-102).
Between January 2003 and October 2009, 73 patients received systemic chemotherapy at Seoul National University Bundang Hospital. Among the 73, we identified 46 who underwent cisplatin combination chemotherapy as the first-line chemotherapy. The diagnosis of HCC was confirmed by pathology in five patients; for the remaining 41 patients, the diagnosis was established by CT, MRI, and angiographic findings in addition to elevated values of AFP using the guidelines proposed by the Korea Liver Cancer Study Group (
A total of 46 patients with HCC were analyzed in this study, and their clinical characteristics are summarized in
Patients received a mean of 2.3 cycles of cisplatin-based combination chemotherapy (range, 1 to 6 cycles): 10 patients received doxorubicin combination (AP); 32 fluoropyrimidine combination (FP and XP); and 4 patients received gemcitabine combination (GP) chemotherapy. The best responses to first-line chemotherapy are shown in
A total of 19 patients received second-line chemotherapy. A mean of 2.8 cycles of chemotherapy (range, 1 to 6 cycles) was given. Two patients received anthracycline-based chemotherapy, 4 fluoropyrimidine-based, 10 gemcitabine-based, and 3 patients received sorafenib. The response rate was 5.3% (1/19) and the disease control rate was 47.4% (9/19).
After a median follow-up duration of 5.5 months, the median time to progression for all patients was 1.8 months (95% CI, 1.1 to 2.5). There was no statistically significant difference in the time to progression among the regimens: 2.3 (95% CI, 0.2 to 4.4) months for the AP regimen, 1.8 months (95% CI, 0.8 to 2.2) for the fluoropyrimidine combination (FP, XP) and 1.9 (95% CI, 0.1 to 2.5) months for the GP regimen. The median OS from the start of chemotherapy was 7.2 (95% CI, 3.0 to 11.5) months. The overall survival was 8.5 (95% CI, 3.0 to 13.9) months for the AP regimen, 4.1 months (95% CI, 2.3 to 5.8) for the fluoropyrimidine combination and 4.7 months (95% CI, cannot be calculated) for the GP regimen (
On univariate analysis, poor ECOG PS, Child classification B compared to A, high CLIP score, and presence of portal vein thrombosis were statistically significant factors that indicated a poor prognosis for both TTP and OS (
Toxicities were mostly hematologic, with grade 3/4 leukopenia in six (13%), neutropenia in 14 (30.4%) and thrombocytopenia in five (10.9%) patients. A Grade 3/4 elevation of the aminotransferases occurred in 11 (23.9%) patients, and jaundice in eight (17.4%) patients. There was no significant difference in hematologic and liver-related toxicities among the cisplatin-based combination (
The results of this study confirmed the poor prognosis and poor response to cisplatin-based combination chemotherapy among patients with advanced HCC, who were not amenable to local/regional treatment outside of the clinical trial setting. In this study, cisplatin-based combination chemotherapy regimens had a response rate of 4.3%, a median TTP of 1.8 (95% CI, 1.1 to 2.5) months, and a median OS of 7.2 (95% CI, 3.0 to 11.5) months.
Our results are consistent with earlier studies that investigated the efficacy of cisplatin-based combination chemotherapy, although the results of our study are modest compared to prior studies with regard to TTP. The results of our study might more accurately reflect real clinical practice, with unselected patients. A high proportion of patients with metastases (89.1%) and portal vein thrombosis (60.9%) in this population may also explain the poor response rates. The combination of gemcitabine with cisplatin was reported to have a response rate of approximately 20% (
Although not statistically significant, the AP regimen had a longer TTP and OS than the other regimens (FP, XP, GP) (
Based on the results of multivariate analysis, the only independent prognostic factors in this study population were ECOG PS (p=0.004) and portal vein thrombosis (p=0.026) with regard to TTP, and portal vein thrombosis (p=0.005) with regard to OS (
The overall survival of patients associated with CLIP scores of 0-1, 2-3 and 4-6 were 13.3 (95% CI, 1.9 to 24.6), 7.6 (95% CI, 2.7 to 12.4) and 2.2 (95% CI, 1.6 to 2.7) months, respectively (
The results of this study are consistent with the findings of prior studies regarding prognostic factors (
If the prognostic factors associated with TTP identified in our study were used to select candidates for cisplatin-based combination chemotherapy (ECOG PS 0-1 vs. 2, and presence of PVT), the patients who had no risk factors (ECOG PS 0-1 without PVT) would have shown a statistically significant increase in TTP compared to patients with 1 or 2 poor prognostic factors (3.1 [95% CI, 1.8 to 4.3] vs. 1.3 [95% CI, 1.3 to 1.4] vs. 0.7 [95% CI, 0.5 to 0.9] months, p<0.0001) and also in OS (14.5 [95% CI, 10.5 to 18.5] vs. 4.5 [95% CI, 0.0 to 9.8] vs. 2.2 (1.1 to 3.2) months, p<0.0001). These results suggest that patient selection based on the prognostic factors described above could aid in selecting candidates who would benefit from cisplatin-based combination chemotherapy. Fifteen patients (32.6%) in the current study had ECOG PS 0-1 and no PVT, and their median TTP and OS were, respectively, 3.1 months (95% CI, 1.8 to 4.3 months) and 14.5 months (95% CI, 10.5 to 18.5 months), which compares favorably with sorafenib data in an Asian trial (
The limitations of our study include its retrospective nature. In addition, the selection of the chemotherapy regimen was not randomly assigned, but rather decided based on physician and patient preference, which could have led to biased results. Furthermore, the small sample size might have contributed to a lack of power in comparing the different chemotherapy regimens with regard to their toxicity, efficacy, and prognostic value.
Despite these limitations, our study confirmed the poor prognosis and efficacy of cisplatin-based combination chemotherapy in patients with advanced HCC in a real world setting. Our data suggest that selection of candidates for cisplatin-based combination chemotherapy based on prognostic factors - ECOG PS, and presence of PVT- would benefit select patients with advanced HCC, while sparing the others the unnecessary toxicities of combination chemotherapy. Careful classification of patients according to these prognostic variables should be part of the study design of future investigations of HCC chemotherapies.
Cisplatin-based combination chemotherapy in patients with advanced HCC showed a short TTP and a low response rate regardless of the chemotherapy regimen used. Systemic chemotherapy in patients with advanced HCC has limitations, however. Patients with a good ECOG performance status and absence of portal vein thrombosis had a longer TTP and OS, and therefore can be considered as good candidates for cisplatin-based combination chemotherapy.
(A) Time to progression according to Eastern Cooperative Oncology Group (ECOG) performance status. (B) Overall survival in patients with and without portal vein thrombosis (PVT).
Baseline patient characteristics
*Eastern Cooperative Oncology Group , †hepatitis B virus, ‡hepatitis C virus, §American Joint Committee on Cancer, ∥Cancer of the Liver Italian Program, ¶alpha-fetoprotein.
Response and survival in patients treated with each cisplatin-based combination
Values are presented as number (%).
Prognostic factors for time to disease progression and overall survival by univariate analysis
*performance status, †hepatitis B virus, hepatitis C virus, ‡American Joint Committee on Cancer, §Cancer of the Liver Italian Program, ∥alpha-fetoprotein, ¶portal vein thrombosis.
Prognostic factors for time to disease progression and overall survival by multivariate analysis
*hazard ratio, †confidence interval, ‡Eastern Cooperative Oncology Group, §portal vein thrombosis.
Hematologic and non-hematologic toxicity per patient in each cisplatin-based combination