The aim of this study is to examine the safety and efficacy of Cinobufacini injection in transarterial chemoembolization (TACE) for treatment of huge hepatocellular carcinoma (HCC). Clinical data of 56 consecutive patients with HCC larger than 10 cm who had been treated with TACE between December 2010 and August 2014 were retrospectively analyzed. Among these patients, 31 belonged to the Cinobufacini group and 25 belonged to the epirubicin group. The clinical efficacy, survival time, and adverse events in patients in the two groups were compared. The objective response rate in the Cinobufacini group was significantly higher than that in the epirubicin group (53.6% versus 23.1%,
Patients with a tumor larger than 10 cm, which is referred to as huge hepatocellular carcinoma (HCC), are generally at the advanced or late stage of the disease, with poor prognosis [
Transarterial chemoembolization (TACE) is an important palliative treatment method for patients with unresectable HCC. All patients with Barcelona Clinic Liver Cancer (BCLC) stages’ A–C HCC are candidates for TACE treatment in Asia and most parts of North America [
Traditional Chinese medicine (TCM) is an important approach in tumor treatment in China. Cinobufacini injection (Cinobufacini), an antitumor TCM preparation, is a water soluble extract of
Data from 56 consecutive patients with huge HCC who were treated with TACE in the Department of Traditional Chinese Medicine, Changhai Hospital, Shanghai, between December 2010 and August 2014 were retrospectively analyzed. Among these patients, 31 belonged to the Cinobufacini group (27 male and 4 female; mean age 54.1 ± 11.2 years) and 25 belonged to the epirubicin group (all male; mean age 58.1 ± 12.4 years).
HCC was diagnosed according to the diagnostic criteria detailed in the Expert Consensus of the Standard Diagnosis of Primary HCC issued in 2009 [
Patients aged between 18 and 75 years, those with unresectable HCC but with indications for TACE, those in whom the tumor diameter was ≥10 cm, those with BCLC stage B or C HCC and in whom the portal vein was not completely obstructed, those with hepatic functional reserve of Child-Pugh class A or B, and those with Eastern Cooperative Oncology Group (ECOG) score <3 were included in the study. Meanwhile, patients who were participating in any other drug trial, those who had a history of malignant tumor within the 5 years preceding the study, pregnant or breastfeeding women, and patients prone to allergies were excluded from the study.
The study was approved by the Hospital Ethics Committee and all patients signed informed consents.
The femoral artery was punctured unilaterally and the Seldinger technique was used to pass the Cobra catheter over a guide wire. Common hepatic artery angiography was then performed to detect the exact location of the liver tumor, tumor-supplying blood vessels, portal vein thrombosis, and the existence of arteriovenous fistula. The Cobra catheter was further delivered to the proper hepatic artery or right/left hepatic artery and the mixture of Cinobufacini or epirubicin and Lipiodol was injected. All blood vessels in the tumor were superselected, and the procedures were performed by interventional experts from the Changhai Hospital under digital subtraction angiography (DSA). The time between two TACE procedures was 1.5–3 months.
In both patient groups, ondansetron hydrochloride was used to prevent vomiting, pantoprazole was used to inhibit gastric acid secretion, and reduced glutathione was used for liver protection. Other supportive treatments were also used.
All patients were followed up after the TACE treatment till death or till the censor time of the study (December 2014). Data regarding the disease status and survival of the patients were collected every 3 months.
SPSS version 21.0 was used for statistical analysis. The Kaplan-Meier method was used to calculate survival curves, and the log-rank test was used for survival comparisons. Quantitative data in normal distribution were represented as means and standard divisions and compared using
From December 2010 to August 2014, 56 consecutive patients with huge HCC who were treated with TACE in the Department of Traditional Chinese Medicine, Changhai Hospital, Shanghai, were retrospectively analyzed. Among these patients, 31 belonged to the Cinobufacini group (27 male and 4 female; mean age 54.1 ± 11.2 years) and 25 belonged to the epirubicin group (all male; mean age 58.1 ± 12.4 years).
The characteristics of patients in two groups in terms of age, sex, tumor size, alpha-fetal protein (AFP) levels, total bilirubin (TB), alanine transaminase (ALT) levels, and the BCLC stage, ECOG score, and the Child-Pugh classification were summarized in Table
Comparison of baseline data between the groups.
Cinobufacini group ( |
Epirubicin group ( |
|
|
---|---|---|---|
Age | 54.1 ± 11.2 | 58.1 ± 12.4 | 0.583 |
Sex | 0.120 | ||
M | 27 (87.1) | 25 (100) | |
F | 4 (12.9) | 0 (0) | |
BCLC stage | 0.611 | ||
B | 17 (54.8) | 12 (48.0) | |
C | 14 (45.2) | 13 (52.0) | |
Child-Pugh stage | 0.443 | ||
A | 26 (83.9) | 23 (92.0) | |
B | 5 (16.1) | 2 (8.0) | |
ECOG score | 0.981 | ||
0 | 13 (41.9) | 10 (40.0) | |
1 | 17 (54.8) | 14 (56.0) | |
2 | 1 (3.2) | 1 (4.0) | |
AFP | 0.386 | ||
<400 | 15 (48.4) | 15 (60.0) | |
≥400 | 16 (51.6) | 10 (40.0) | |
HBsAg | 0.153 | ||
+ | 28 (90.3) | 18 (72.0) | |
− | 3 (9.7) | 7 (28.0) | |
TB | 16.9 ± 7.8 | 16.3 ± 7.6 | 0.653 |
ALT | 46.3 ± 29.2 | 51.2 ± 44.0 | 0.351 |
Tumor size | 12.1 ± 3.2 | 11.8 ± 4.0 | 0.760 |
CT and MR imaging results showed that the objective response rate in the Cinobufacini group was significantly higher than that in the epirubicin group (
Comparison of clinical efficacy of TACE between the groups.
Group | Number of patients (%) | ||||
---|---|---|---|---|---|
PR | SD | PD | OR | DC | |
Cinobufacini group ( |
15 (48.4) | 10 (32.3) | 6 (19.4) | 15 (48.4) |
25 (80.6) |
Epirubicin group ( |
5 (20.0) | 11 (44.0) | 9 (36.0) | 5 (20.0) | 16 (64.0) |
PR: partial response; SD: stable disease; PD: progressive disease; OR: objective response; DC: disease control.
Comparison of the AFP level between the groups.
Cinobufacini group ( |
Epirubicin group ( |
|
|
---|---|---|---|
Before treatment | 885 ± 931 | 596 ± 690 | 0.256 |
After treatment | 567 ± 749 | 571 ± 726 | 0.654 |
The median OS period was 10.6 (95% CI: 8.5–12.6) months and 14.1 (95% CI: 4.6–23.6) months in the Cinobufacini and epirubicin group, respectively, and the difference between the groups was not statistically significant (
Kaplan-Meier estimates of overall survival of patients with HCC.
Kaplan-Meier estimates of time to progression of HCC.
The 1- and 2-year survival rates were 69% and 45.5% in the Cinobufacini group and 66.4% and 17.8% in the epirubicin group. No significant difference was found in the 1- and 2-year survival rates between the two groups (
The frequency and degree of increase in TB and ALT levels on day 3 after TACE were significantly lower in the Cinobufacini group than in the epirubicin group (
Comparison of the incidence of adverse events between the groups.
Parameter | Cinobufacini group ( |
Epirubicin group ( |
||||||
---|---|---|---|---|---|---|---|---|
Total | Grade 1 | Grade 2 | Grade 3 | Total | Grade 1 | Grade 2 | Grade 3 | |
Liver function | ||||||||
TB | 18 (58.0) | 13 (41.9) | 5 (16.1) | 0 (0.0) | 21 (84.0) | 4 (16.0) | 15 (60.0) | 2 (8.0) |
ALT | 16 (51.7) | 8 (25.8) | 6 (19.4) | 2 (6.5) | 22 (88.0) | 6 (24.0) | 11 (44.0) | 5 (20.0) |
AST | 18 (58.1) | 9 (29.0) | 6 (19.4) | 3 (9.7) | 20 (80.0) | 11 (44.0) | 6 (24.0) | 3 (12.0) |
Hematologic system | ||||||||
WBC | 1 (3.2) | 1 (3.2) | 0 (0.0) | 0 | 8 (32.0) | 6 (24.0) | 2 (8.0) | 0 |
HGB | 6 (19.3) | 5 (16.1) | 1 (3.2) | 0 | 5 (20.0) | 5 (20.0) | 0 | 0 |
PLT | 5 (16.1) | 4 (12.9) | 1 (3.2) | 0 | 14 (56.0) | 9 (36.0) | 2 (8.0) | 3 (12.0) |
Clinical symptom | ||||||||
Fever | 14 (45.2) | — | — | — | 17 (68.0) | — | — | — |
Liver pain | 7 (22.6) | — | — | — | 20 (80.0) | — | — | — |
Abdominal distension | 5 (16.1) | — | — | — | 13 (52.0) | — | — | — |
Nausea and vomiting | 0 (0.0) | — | — | — | 9 (36.0) | — | — | — |
TB: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; WBC: white blood cells; HGB: hemoglobin; PLT: platelets.
The frequency and degree of decrease in white blood cells (WBC) and platelets (PLT) count on day 3 after TACE were significantly lower in the Cinobufacini group than in the epirubicin group (
The incidence of liver pain and abdominal distension in the epirubicin group was significantly higher than that in the Cinobufacini group (
Because of vascular infiltration and formation of satellite lesions, patients with huge HCC are generally at the advanced or late stage of the disease. According to BCLC stage system, these patients belong to C stage, who are not recommended to receive TACE treatment in most guidelines issued by American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) and others [
Cinobufacini injection used in our study is extracted from traditional Chinese medicine
Meanwhile, Cinobufacini could protect liver function and improve quality of life [
In the present study, no severe adverse effect was observed in patients who underwent TACE with Cinobufacini, and the effects on the liver function and hematologic system and clinical symptoms were significantly lower than those observed when epirubicin was used, suggesting that Cinobufacini has obvious benefits in reducing TACE-related adverse effects. Huge HCC could continuously aggravate liver cirrhosis and portal hypertension; in addition, it does not respond to chemotherapeutic drugs. Therefore, repeated TACE could result in significant drug resistance and liver function impairment; massive hemorrhage of gastrointestinal tract and liver failure could also occur in severe cases. Meanwhile Cinobufacini may synergistically enhance the efficacy of TACE and reduce its toxicity.
Another advantage of using Cinobufacini instead of chemotherapeutic drugs observed in our study is that Cinobufacini has strong blood vessel contraction effect. The key point of TACE treatment is effective embolism of the blood supplying the major artery and collateral arteries. However, the blood supply in huge HCC is very complex; several collateral arteries could participate in the blood supply to the tumor, and additional collateral circulation could be formed after the embolism, while the collateral arteries are generally too small to be embolized. In addition, the existence of undetectable hematogenous spread could result in cancer metastases to other organs shortly after the operations. In this study we also observed that Cinobufacini could effectively contract the blood vessels through DSA in the treatment procedures; thus, the diffusion of Cinobufacini in the tumor-supplying blood vessels after injection through the hepatic artery may also potentially contract the small blood vessels, resulting in better embolism effects.
In summary, the findings of the present study showed that treating huge HCC with Cinobufacini injection in TACE is safe and effective and could be a useful antitumor treatment combining traditional Chinese medicine and western medicine. However, the present study was limited by the retrospective design, relatively small sample size, and observations restricted to huge HCC. More randomized controlled trials with larger sample sizes and those including patients with other types of primary HCC are required in order to provide more reliable evidence.
The authors declare that they have no competing interests.
Jun Dong and Xiaofeng Zhai contributed equally to this work.
The study was supported by Shanghai Municipal Commission of Health and Family Planning (ZYSNXD-CC-ZDYJ032, ZY3-LCPT-2-1004) and Changhai Hospital (CH125521200, 202-1).