Chen Dong, Zhao Peng, Chen Wei, Yin Xiaoyu, Liang Lijian*, Peng Baogang, Li Shaoqiang,
Abstract: Objective To retrospectively analyze the efficacy of sorafenib in the treatment of advanced primary liver cancer and analyze the risk factors that affect the prognosis. Methods The clinical data and follow-up of 52 patients with advanced liver cancer treated with sorafenib from August 2008 to November 2011 in the First Affiliated Hospital of Sun Yat-sen University were retrospectively studied. Kaplan-Meier method and Cox regression were used to analyze the risk factors affecting survival. , And count the adverse reactions. Results Hepatitis B virus infection was the main cause of liver cancer. The ECOG performance scores were all in the range of 0-2. 44 cases (84.6%) had Child-Pugh A liver function, 9 cases (17.3%) had portal vein invasion, and 24 cases (46.2%) ) Distant metastasis, 12 cases (23.1%) of liver cancer were classified as stage B by BCLC, and 40 cases (86.9%) were classified as stage C. The median overall survival of sorafenib treatment was 14.2 months (95% confidence, 9.5-18.9 months). 2 cases (4%) had partial remission (PR), 22 cases (42%) had disease progression (PD), 28 cases (54%) had stable disease (SD), and the disease control rate reached 60%. Cox regression analysis showed that liver function Child-Pugh Class A (HR 0.3, P = 0.049), disease progression time greater than 2 months (HR 4.1, P = 0.049) and other forms of combination therapy (HR 0.4, P = 0.026) ) Is an independent prognostic factor that prolongs median survival. The most common grade 3 toxicity is hand-foot syndrome (17.3%) and diarrhea (7.7%). Conclusion Sorafenib has good efficacy and tolerability in the treatment of advanced patients. Whether it is combined with other treatments and the response of the treatment process may affect the long-term prognosis.
Key words: Sorafenib, primary liver cancer, prognosis, safety
Sorafenib therapy in advanced hepatocellular carcinoma: A single center’s experience
Chen Dong, Zhao Peng, Chen Wei, Yin Xiaoyu, Liang Lijian*, Peng Baogang, Li Shaoqiang. Department of Hepatobiliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080,China. Corresponding author: Liang Li-jian ,E-mail: firstname.lastname@example.org
Abstract Objective To investigate the efficacy and safety in sorafenib-treated HCC paitents and identify prognostic fatcors for survival. Methods In this retrospective study, 52 patients received sorafenib 400 mg bd in the Department of Hepatobiliary Surgery, the First Affiliated Hospital, Sun Yat-sen University. Baseline clinical parameters, adverse events (AEs) and survival were
Fund Project: Natural Science Foundation of Guangdong Province (1610451008901004816)
Author Unit: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, 510080, Guangzhou
* Corresponding author: Liang Lijian, Email: email@example.com
collected. Results HBV infection was the dominal etiology and all patients had an ECOG performance status of 0-2. 44 patients (84.6%) were in Child-Pugh A class. 9 patients (17.3%) had portal vein invasion and 24 patients ( 46.2%) had distal metastasis. 12 patients (23.1%) had stage B tumors and 40 patients (86.9%) had stage C tumors. The median OS for all sorafenib-treated patients was 14.2 months (95% CI, 9.5-18.9 months ). Overall, 2 patients (4%) had a partial response (PR), 22 (42%) had progressive disease (PD) and 28 (54%) had stable disease (SD). The disease-control rate was 60% . The multivariate analysis revealed that Child-Pugh class A (HR 0.3, P = 0.049), PD absent at 2 months (HR 4.1, P = 0.049) and receiving other combined treatment modalities (HR 0.4, P = 0.026) were independent prognostic factors for longer OS. The most common grade 3 toxicities were hand-foot syndrome (17.3%) and diarrhea (7.7%). Conclusions Sorafenib therapy showed a good outcome and tolerable toxicity in Chinese advanced HCC patients. The treatment modality and response to sorafenib therapy was associated with survival prognosis.
Key Words: sorafenib, hepatocellular carcinoma, prognosis, safety
Primary liver cancer (Hepatocellular carcinoma, HCC) ranks fifth among the most common tumors in the world, and its incidence is increasingly global1. Most patients with hepatocellular carcinoma have reached an advanced stage when they are diagnosed, so liver transplantation, liver resection, or radiofrequency ablation are not effective. The SHARP and ORIENTAL studies have shown that Sorafenib, as a multi-target kinase inhibitor, can prolong the overall survival of patients with advanced HCC2, 3. Therefore, sorafenib is currently the only approved standard targeted therapy drug that can treat patients with advanced liver cancer. More and more studies have shown that patients with Child-Pugh B liver function, poor ECOG performance score, and portal vein invasion are less effective when treated with sorafenib4, 5. However, most retrospective analyses use time to disease progression (TTP) as the statistical endpoint4. TTP was selected as the statistical end point because of its advantages: death caused by liver function deterioration can interfere with survival, and TTP has a greater correlation with tumor self-factors6; in addition, these studies may be effective for sorafenib treatment The observation period of the patients is short, and the survival period has not yet been statistically analyzed. Since China approved the use of sorafenib for the treatment of advanced liver cancer in August 2008, we have been able to observe the HCC patients treated with sorafenib for a long time, and obtain a series of survival data for analysis, so as to treat China with sorafenib The patient's efficacy and safety are evaluated.
2Materials and methods
From August 2008 to November 2011, a total of 623 HCC cancer patients were treated in our department. Among them, 60 patients were treated with sorafenib. Of these 60 cases, 8 cases were discontinued after 4 weeks (3 cases due to disease progression, 2 cases due to serious adverse reactions, 2 cases due to economic reasons, 1 case due to unexpected death not related to sorafenib), due to treatment time Shorter, these 8 patients were excluded, so 52 cases were included in this retrospective analysis.
The diagnosis of primary liver cancer is based on the standards of the European Association for the Study of Liver Diseases, the standards of the American Association for the Study of Liver Diseases and the liver histological type 7 of liver disease. Before receiving sorafenib treatment, some patients had received local treatments, such as surgical resection, radiofrequency ablation, or hepatic artery chemoembolization. No patient has received systemic chemotherapy.
All patients had an ECOG performance score of 2 or better, Child-Pugh liver function of A or B, and life expectancy of 12 weeks or longer. Other laboratory indicators include: absolute peripheral neutrophil count ≥ 1,000 mm3, platelet count ≤ 40,000, serum creatinine ≤ 1.4 mg/dL, and total bilirubin ≤ 3.0 mg/dL.
2.2 Treatment plan and assessment of toxicity
The dose of sorafenib is 400 mg orally twice daily. During the follow-up, the safety and tolerability of the patients were evaluated every 4 weeks. According to the General Adverse Reaction Terminology Standard (National Cancer Institute's Common Terminology Criteria Adverse Events, NCI-CTCAE) version 3.0, the side effects were rated. For patients with side effects above grade 3, the operation was performed according to the dose adjustment plan provided in the instructions, and the dose was reduced (each dose 400 mg once a day) or the dose is temporarily interrupted until the side effects are assessed as grade 1 or 2, and the dose is gradually increased to 400 mg twice a day. When the patient has unacceptable toxicity or judged that it is not suitable to continue to use sorafenib treatment, the administration is terminated.
According to the provisions of the Response Evaluation Criteira in Solid Tumors (RECIST) version 1.0, computer tomography (CT) or nuclear magnetic resonance (MR) scans are used to evaluate the response to treatment every 8 weeks during treatment. The time from the first treatment with sorafenib to the death of the patient is the overall survival (OS). The time from the first treatment with sorafenib to the discovery of tumor progression is the time to disease progression (TTP).
2.3 Statistical analysis
The median and range were used to describe the continuous variables, the percentages were used to describe the categorical variables, the Kaplan-Meier curve was used to evaluate OS and TTP respectively, and the Log-rank test was used for comparison, and Cox regression analysis was used to analyze the independent predictors of OS. After univariate analysis (P <0.10) for all variables, follow-up multivariate analysis was introduced. For all analyses, P <0.05 was considered statistically significant. All analyses of the study were done by SPSS 17.0.
3.1 Baseline clinical characteristics of patients
Table 1 shows the baseline clinical characteristics of the 52 patients included in the statistics. The median age of the patients was 45 years (21-71 years). Chronic hepatitis B virus infection was the main cause. The ECOG performance scores of all patients were 0-2, and 44 cases (84.6%) had liver function Child-Pugh Grade A, 8 cases of liver function Child-Pugh Grade B, and none of these 8 cases had ascites, obvious jaundice or hepatic encephalopathy. 9 cases (17.3%) had portal vein invasion, 24 cases (46.2%) had distant metastasis, 12 cases (23.1%) had liver cancer BCLC stage B, 40 cases (86.9%) had C stage, 44 cases had previous history Treatment history (most of which was surgery), of which 16 patients had received two or more treatment methods in the past. The median α-fetoprotein concentration of the patients was 7134 ng/mL (1.7-58344 ng/mL), days The median concentration of aspartate aminotransferase is 88 U/L (17-278 U/L).
3.2 The efficacy of sorafenib
The patient’s median TTP was 5.2 months (95% confidence level, 3.2-6.8 months), and the median OS was 14.20 months (95% confidence level, 9.5-18.9 months), 1 and 2 years The overall survival rates were 52% and 6%, respectively. 32 patients died during the observation period, that is, as of the end of follow-up, 20 patients were still alive. Overall, 2 cases (4%) had partial response (PR), 22 cases (42%) had disease progression (PD), and 28 cases (54%) had stable disease (SD). The disease control rate reached 60%.
Table 2 shows that the ECOG fitness score is good, the liver function is Child-Pugh grade A, the liver cancer BCLC staging is B, the previous treatment history before receiving sorafenib treatment, the disease progression time is greater than 2 months, and the receiving sorafil The overall survival of patients who were combined with other treatment modalities during the treatment period was significantly prolonged (P <0.05). Among the patients receiving other combined treatment methods: 10 cases only used hepatic artery chemoembolization, 6 cases only used radiofrequency ablation, 3 cases only used radiotherapy, and 5 cases received more than 2 other comprehensive treatment methods (hepatic artery chemoembolization + radiofrequency Ablation, n = 3; hepatic artery chemoembolization + radiotherapy, n = 1; hepatic artery chemoembolization + radiotherapy + radiofrequency ablation, n = 1).
Table 3 and Figure 1 show that the Child-Pugh rating of liver function, whether PD occurs at 2 months, and whether or not to receive other combination treatments are three factors that are independent risk factors for predicting OS.
In order to exclude the deviation of baseline characteristics, we used Chi-Square analysis to compare the baseline characteristics of patients receiving and not receiving combination therapy (Table 4). There was no significant difference in baseline characteristics between the two.
After treatment with sorafenib, 15 patients (28.8%) underwent dose reduction, and the median application time of dose reduction was 2.1 weeks (1.0-5.1 weeks). Among these 15 cases, there were 8 cases of hand-foot syndrome, 1 case of skin rash, 1 case of hemorrhoid bleeding, 3 cases of severe diarrhea, and 2 cases of elevated aspartate aminotransferase level (maximum value> 1000U/L). Six cases (11.5%) discontinued treatment, including 2 cases of tumor progression, 2 cases of severe hand-foot syndrome, 1 case of severe diarrhea, and 1 case of gastrointestinal bleeding.
Table 5 shows the adverse effects of sorafenib treatment. 45 cases (86.5%) had at least one adverse reaction caused by the drug. All adverse reactions during the treatment period were temporary and reversible, and no adverse reaction would be life-threatening. The most common adverse reactions were hand-foot syndrome (42.3%), hair loss (25.0%) and diarrhea (25.0%). Grade 3 toxicity (25.0%) occurred in 12 cases, the most common of which were hand-foot syndrome (17.3%) and diarrhea (7.7%). No patients had Grade 4 toxicity.
This study shows that after sorafenib treatment, the median overall survival of patients with advanced HCC reached 14.2 months, and the disease control rate was 60%, which was higher than the data of the SHARP study (10.7 months and 43%) 2; disease The progression time was 5.2 months, which was similar to the SHARP study (5.5 months). The Child-Pugh grade of liver function is better (84.6% Child-Pugh grade A), which may be the reason for the prolonged median OS compared with the SHARP study. Other reasons include: there are more patients (35 cases, 67.3%) The main part of the tumor was surgically removed, and fewer patients (17.3%) had portal vein invasion.
Screening out factors that have a predictive effect on the efficacy of sorafenib in the treatment of HCC will help us to screen HCC patients before treatment with sorafenib. As shown in the univariate analysis in Table 2, the ECOG fitness score is better, the liver function is Child-Pugh grade A, the liver cancer BCLC staging is B, there is a history of previous treatment before receiving sorafenib treatment, and no PD occurred at 2 months. The overall survival of patients who received sorafenib combined with other treatments during the treatment period was significantly prolonged (P <0.05). However, the multivariate analysis in Table 3 showed that only three factors, namely the Child-Pugh rating of liver function, the absence of PD at 2 months, and the acceptance of other combination treatments, are independent prognostic factors that affect OS. More and more studies have shown that the Child-Pugh rating of liver function is the main prognostic factor affecting the overall survival of patients with advanced liver cancer treated by sorafenib8, 9. Our research shows that some other factors related to treatment can also be used as expected factors. For example, patients without PD at 2 months have a longer median survival of 20.0 months (compared to patients with PD at 2 months 6.0 months). This shows the importance of imaging evaluation after treatment with sorafenib.
At present, in clinical practice, hepatic artery chemoembolization (TACE) and sorafenib are mostly used independently for the treatment of hepatocellular carcinoma. There are few literatures that hepatic artery chemoembolization and sorafenib, or radiofrequency ablation and sorafenib The effect of fenib combination therapy. Our study shows that combined treatment can prolong the median overall survival to 20.4 months (compared to 8.6 months without combined treatment).A study by Cabrera et al. showed that in 47 patients who received hepatic artery chemoembolization and sorafenib combined treatment, the disease control rate reached 6 months (68%); the median overall survival was also longer, reaching 18.5 months ( 95% confidence interval, 16.1-20.9 months)11. In our statistics, a total of 15 cases (15/24) received hepatic artery chemoembolization and sorafenib combined treatment, suggesting that the combination of TACE and sorafenib has a good effect. Sorafenib is now being tried as an adjuvant treatment after radiofrequency ablation or partial hepatectomy, and it is in phase III clinical trials. [https://clinicaltrials.gov/ct2/show/NCT00692770]. As for sorafenib combined with radiotherapy for the treatment of advanced HCC, based on our experience, radiotherapy is helpful for alleviating severe pain in patients with bone metastases. Therefore, we believe that radiotherapy is used as a palliative therapy, not a curative method. However, the clinical efficacy of sorafenib and hepatic arterial chemoembolization or other combined therapy requires more in-depth research.
The toxicity of sorafenib observed in this study is similar to the results in previous clinical studies. Skin and gastrointestinal symptoms are the most common adverse reactions4. The most common adverse reactions were hand-foot syndrome (42.3%), hair loss (25.0%) and diarrhea (25.0%). The reasons leading to dose reduction and interruption of treatment were hand-foot syndrome and diarrhea. In the SHARP study, 21% of patients showed different levels of hand-foot syndrome, but in Asia, the adverse reaction rate of hand-foot syndrome was as high as 40%. This study showed that when combined with TACE, radiofrequency ablation, or radiation therapy as a combination therapy, the probability of side effects did not increase. Some experts believe that the increased chance of side effects may be related to the severity of underlying cirrhosis9. Because most of the patients in this study have good liver function Child-Pugh grade (84.6% of Child-Pugh grade A), only a few patients have liver function Child-Pugh grade B, so we cannot be sure of this. The current Phase IV study of GIDEON will start from clinical practice, and judge the safety of drugs and patients' tolerance to drugs according to different subtypes and stages of the disease, which will provide very useful information for clarifying these issues13.
All in all, we have obtained more evidence from this study to show that the better the Child-Pugh rating of liver function, the longer the overall survival. The combination therapy of sorafenib and other treatment modalities and the imaging response during treatment may be beneficial to predict the long-term prognosis of patients with advanced HCC.
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