The efficacy for unresectable hepatocellular carcinoma may be improved by transcatheter arterial chemoembolization in combination with a traditional Chinese herbal medicine formula

A retrospective study

Abstract

Transcatheter arterial chemoembolization (TACE) is the most widely used primary treatment for unresectable hepatocellular carcinoma (HCC) because of its survival benefit, although its clinical effect is still far from satisfactory. In China, there has been a long history of using traditional Chinese medicine in the treatment of liver cancer and other malignancies. In this study, the authors evaluated the effect of combined therapy with TACE and JDF granule preparation (a traditional Chinese herbal medicine formula) in the treatment of patients with unresectable HCC on survival. Clinical data, including baseline, performance status change, and survival time of 165 patients with unresectable HCC seen between January 2002 and December 2007 were retrospectively analyzed. Among the 165 patients, 80 patients (study group) received combined therapy consisting of TACE and a long-term maintenance treatment with oral JDF granule preparation, and 85 patients (control group) received TACE alone. The survival rate of both groups was calculated by the Kaplan-Meier method. Factors possibly affecting survival were assessed by multivariate analysis in the Cox proportional hazard model. The median overall survival was 9.2 months (95% confidence interval [95% CI], 6.94-1.46) in the study group versus 5.87 months (95% CI, 4.21-7.52) in the control group. In the study group (TACE + JDF), 1-year, 2-year, and 3-year survival rates were 41.2%, 18.4%, and 9.6%, respectively. The Cox regression analysis revealed the therapy model to be an independent predictor of patient prognosis. Current study data demonstrated that TACE combined with JDF granule preparation could improve the prognosis of patients. TACE combined with JDF granule preparation may prolong survival of patients with unresectable HCC. Cancer 2009. © 2009 American Cancer Society.

Hepatocellular carcinoma (HCC) is 1 of the most common malignancies worldwide, with 717,000 new cases reportedly diagnosed in 2007.1 Chronic hepatitis B virus infection is the predominant risk factor for HCC in Southeast Asia and Africa, and chronic hepatitis C virus infection is the predominant risk factor for HCC in Western countries and Japan.2 Surgical resection has been considered the treatment of choice for long-term control of HCC. However, no more than 40% patients are surgical candidates at diagnosis.3 At the current time, there is to our knowledge no consensus regarding a common treatment strategy for patients with unresectable HCC, although several proposals have been published.4

Transcatheter arterial chemoembolization (TACE) is the most widely used primary treatment for unresectable HCC, for it has been shown to improve survival.4-8 However, the curative effect of TACE for HCC is limited because of the limitations of TACE. The main limitations of TACE are that,9 first, liver function deteriorates with more frequent use of TACE; second, necrosis remains incomplete despite repetition treatment; and finally, the potential risk of lung metastasis increases with TACE. Therefore, the curative effect of TACE awaits improvement.

A Question Was Raised

In China, there has been a long history of using traditional Chinese medicine (TCM) in the treatment of liver cancer and other malignancies. As the theory of TCM in the treatment of tumors focuses on integrity and functional regulation of the whole body, which coincides with oncology of modern medicine, its position in combination therapy for liver cancer has attracted more attention. JDF granule preparation is a commonly used Chinese herbal medicine formula for HCC, composed of cancer-fighting and detoxifying endotoxic Chinese herbal medicines, according to the traditional Chinese herbal medicine theory. JDF granule preparation is a systemic treatment rather than a local therapy such as percutaneous ablation and radiotherapy. Previous studies have demonstrated that some herbal compositions (root of Actinidia valvata and bulb of Cremastra appendiculata) in JDF granule preparation showed the efficacy of antiangiogenesis and cytotoxic activity in vitro against the BEL-7402 and SMMC-7721 tumor cell lines,10, 11 and these effects could be effective in remedying the limitations of TACE. This raises the question of whether the efficacy of TACE in combination with JDF for unresectable HCC can be superior to that of TACE alone.

A Retrospective Study Was Performed

Recently, we performed a retrospective case-control study to report the result of TACE in combination with JDF for unresectable HCC. Between January 2002 and December 2007, 516 patients were confirmed to have unresectable HCC at Changhai Hospital (Shanghai, China). The diagnosis of unresectable HCC was confirmed from clinical diagnosis criteria issued by the Chinese Liver Cancer Association in 2001 and TNM Staging Manual in 2002.12, 13 The inclusion criteria were the following: 1) both a definite diagnosis and initial therapy at our hospital, 2) aged 18 to 80 years, 3) only receiving TACE or TACE + JDF therapy. The exclusion criteria were as follows: 1) history of previous anticancer treatment, 2) second primary malignancy, 3) performance status >3 on the Eastern Cooperative Oncology Group (ECOG) scale, and 4) Child-Pugh classification of liver function as C. There were 165 patients who met the above inclusion and exclusion criteria. Among the 165 patients, 80 patients (study group) received combined therapy consisting of TACE and a long-term maintenance treatment with oral JDF granule preparation, and 85 patients (control group) received TACE alone. The 2 groups were comparable in sex, age, tumor burden, serum α-fetoprotein levels, Child-Pugh classification, ECOG performance status, and TNM stage.

All 165 patients received TACE therapy using a uniform technique. The main chemotherapeutics used were epirubicin and cisplatin. The dose of the anticancer agent Lipiodol emulsion and fine pieces of the embolic material used for TACE were determined based on the tumor size and lesion extension. The patients were followed by dynamic computed tomography or magnetic resonance imaging at least once every 6 months. When local disease recurrence, intrahepatic metastasis, and/or second primary HCC was found, repeated TACE was determined based on the tumor response and tolerance of the patients. The interval of repetition treatment was at least 8 weeks.

After a week of TACE, the patients in the study group were started on a long-term maintenance treatment with oral JDF granule preparation (produced by Good Manufacturing Practice certificated Tianjiang Pharmaceutical Factory, Jiangsu, China; Production License No. Su ZzY20010266) at a dose of 8 g (equal to 80 g raw herbal material) at a time, twice per day, 30 minutes after meals. The JDF granule preparation is composed of 4 traditional Chinese herbal medicines, root of Actinidia valvata, root of Salvia chinensis, bulb of Cremastra appendiculata, and gizzard membrane of Gallus gallus domesticus in a proportion of 1:1:0.4:0.4, which are extracted by hot water and lyophilization.

RESULTS

TACE Combined With JDF May Prolong Survival of Patients With Unresectable HCC

Characteristics of the 165 patients (138 men, 27 women; ratio, 5:1) are summarized in Table 1. The follow-up was ended on July 31, 2008, and the mean follow-up period was 11.99 ± 1.69 months (range, 8 to 40 months). Of the 85 patients in the control group using TACE alone, 8 patients survived, and the remaining 77 patients died; of the 80 patients in the study group using TACE + JDF, 12 patients survived, and the remaining 68 patients died. The overall median survival time of the 165 patients was 7.97 months (95% confidence interval [95% CI], 6.86-9.08 months). The median overall survival was 9.2 months (95% CI, 6.94-11.46 months) in the study group versus 5.87 months (95% CI, 4.21-7.52 months) in the control group. The overall median survival of the patients in the study group was significantly longer than that in the patients of the control group (9.2 vs 5.87 months; relative risk, 0.637; 95% CI, 0.458-0.887 [P < .001]). The 1-year, 2-year, and 3-year survival rates of the study group versus the control group were 41.2% versus 26.9%, 18.4% versus 12.6%, and 9.6% versus 2.4%, respectively. There was a significant difference in the survival rate between the 2 groups (log-rank test chi-square, 6.87; P < .01) (Fig. 1).

Figure 1. Overall survival was found to be significantly longer in the study group (transcatheter arterial chemoembolization [TACE] + JDF) compared with the control group (TACE alone) (median of 9.2 vs 5.87 months; relative risk [RR], 0.637 [P < .001]). 95% CI indicates 95% confidence interval.

Table 1. Patient Characteristics

Characteristic	TACE (n = 85)	TACE+JDF (n = 80)	P
TACE indicates transcatheter arterial chemoembolization; HBsAg, hepatitis B virus surface antigen; AFP, α-fetoprotein; ECOG, Eastern Cooperative Oncology Group.
Age, y	55.92 ± 11.2	55.33 ± 10.5	.728
Sex			.407
Men	69 (81.2)	69 (86.3)
Women	16 (18.8)	11 (13.7)
Serum HBsAg			1.000
Negative	14 (16.5)	14 (17.5)
Positive	71 (83.5)	66 (82.5)
Cirrhosis			.023
No	30 (35.3)	15 (18.7)
Yes	55 (64.7)	65 (81.3)
Maximum tumor size, cm			.944
<5	21 (24.7)	18 (22.5)
5-10	37 (43.5)	39 (48.7)
≥10	27 (31.8)	23 (28.8)
No. of lesions			.896
1	33 (38.8)	33 (41.3)
2	11 (12.9)	8 (10.0)
≥3	41 (48.3)	39 (48.7)
Portal vein invasion			.857
Absent	65 (76.5)	60 (75.0)
Present	20 (23.5)	20 (25.0)
AFP, μg/L			.700
<30	29 (34.1)	30 (37.5)
30-400	27 (31.8)	24 (30.0)
≥400	29 (34.1)	26 (32.5)
Child-Pugh classification			.669
A	71 (83.5)	69 (86.3)
B	14 (16.5)	11 (13.7)
ECOG performance status			.190
0	32 (37.7)	20 (25.0)
1	46 (54.1)	54 (67.5)
2	7 (8.2)	6 (7.5)
TNM stage			1.000
I	25 (29.4)	27 (33.8)
II	6 (7.1)	6 (7.5)
IIIA	44 (51.8)	38 (47.5)
IIIB	0 (0.0)	0 (0.0)
IIIC	8 (9.3)	7 (8.7)
IV	2 (2.4)	2 (2.5)

The model of multivariate Cox regression analysis included 19 potential confounders as follows: age, sex, serum hepatitis B surface antigen, cirrhosis, maximum tumor size, number of lesions, portal vein invasion, Child-Pugh classification, ECOG performance status, TNM stage, serum α-fetoprotein, serum bilirubin, serum albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, TACE therapy frequency, and therapy model. The results of Cox regression analysis showed the following 5 parameters as independent prognostic risk factors (Table 2): serum hepatitis B surface antigen (P = .014), maximum tumor size (P = .027), number of lesions (P < .001), portal vein invasion (P < .001), and therapy model (P = .006). The relative risk of each variable ranged from 0.62 to 4.18. Among these factors, the regression coefficient of the therapy model was negative, and the relative risk (0.62) in the therapy model was <1, belonging to the protective factor. The relative risk in the other 4 factors was >1, belonging to the hazard factor.

Table 2. Cox Regression Analysis of Independent Prognostic Risk Factors Associated With Survival

Variables	No. of Patients	Regression Coefficient	Standard Error	Chi-Square Test	Relative Risk	95% CI
95% CI indicates 95% confidence interval; HBsAg, hepatitis B virus surface antigen; TACE, transcatheter arterial chemoembolization.
Serum HBsAg
Negative	28	—	—	—	1	—
Positive	137	0.577	0.234	6.071	1.781	1.125-2.818
No. of lesions
Solitary	66	—	—	—	1	—
Multiple (≥2)	99	0.451	0.204	4.885	1.570	1.052-2.342
Maximum tumor size, cm
≤5	39	—	—	35.019	1	—
5-10	76	0.346	0.237	2.143	1.414	0.889-2.249
≥10	50	1.431	0.258	30.652	4.182	2.520-6.941
Portal vein invasion
Absent	125	—	—	—	1	—
Present	40	0.968	0.201	23.259	2.633	1.777-3.903
Therapy model
TACE	85	—	—	—	1	—
TACE + JDF	80	−0.477	0.173	7.583	0.620	0.442-0.871

Drug-Related Adverse Effects of JDF Are Not Striking

No significant drug-related adverse effects were observed in the study group. Only 5 (3.3%) patients reported mild to moderate diarrhea caused by JDF granule preparation after the start of administration. This symptom improved at around the third week after the beginning of therapy in the study group. In addition, no clinically meaningful changes in laboratory and physical examinations were found after administration of JDF granule preparation.

DISCUSSION

HCC is a multifactor and multistage process, and therefore it is relatively difficultly to find a specific medication, as is the case with streptomycin for tubercle Bacillus. Therefore, a wide consensus that combination therapy is most likely the way leading to develop new therapy strategies for HCC in the future has been reached in academia.14 Marelli et al15 reviewed studies on combination treatment strategies and found that TACE combined with percutaneous ablation, percutaneous ethanol injection, or radiofrequency ablation improved survival. Combination treatment with TACE and local radiotherapy has been demonstrated to improve survival in patients with tumor thrombosis of the portal vein in some cohort studies and comparative nonrandomized studies (all from Asia).16-19 But other studies indicated that TACE combination treatment did not improve survival significantly.20-22 Tang14 believed that the combination therapy research for unresectable HCC was still at a preliminary stage and had a great development potential in the future.

The results of the current study demonstrated that median survival time and 1-year, 2-year, and 3-year survival rates in the study group were better than those in the control group, suggesting that JDF granules played an active role in assisting TACE to prolong survival of the patients with unresectable HCC. That the 1-year, 2-year, and 3-year survival rates in the study group of our study were far below those of some studies using TACE for unresectable HCC may be because of the following reasons: 1) the high survival rate of some studies can be ascribed both to the restrictive selection of candidates and to the exclusion of patients with the worst prognosis, such as those with cirrhosis, portal vein invasion, and distant metastasis5, 23-27; 2) with respect to the independent prognostic hazard factors, the proportion of tumor size ≥5 cm (76.4%) and the number of lesions more ≥2 (60%) in the current series were both greater than those in previous studies; and 3) the causal factors in Chinese patients are distinctly different from those in Japanese and Western patients, and chronic hepatitis B infection is the most common etiology. It has been shown that untreated patients who had positive results for hepatitis B surface antigen had a worse prognosis.28

Multivariate analysis of our study revealed the therapy model to be an independent predictor of patient prognosis. It proved that TACE combined with JDF granule preparation could improve the prognosis of patients. We hope that these prognostic variables serve as invaluable information for clinicians, patients, and their families in selecting treatment strategies. Although cirrhosis, a background factor, was significantly different between the 2 groups in the current study, this variable did not reach independent prognostic significance in the multivariate analysis. Hence, the analysis of the outcomes from the 2 groups was not influenced.

We are also aware of some limitations in our study. First, we could not sufficiently elucidate the exact mechanism of JDF granule preparation in improving survival rate because of its intricate components. Further basic research for JDF granule preparation is therefore needed. Second, because the sample size of our study was not large enough, we did not use stratified analysis from TNM stage and absence or presence of vascular invasion when analyzing the relationship between survival and therapy model. Third, the retrospective nature of this study limited its ability to provide robust evidence. Therefore, larger-scale, multicentric, placebo-controlled, and prospective studies are needed to test our results. Despite these limitations, we believe the current study provides preliminary and powerful data to support future evaluation of Chinese herbal medications in combination therapy for HCC in a large-cohort, randomized clinical trial study.

In conclusion, the results of the current study suggest that TACE combined with Chinese herbal medications may prolong survival. More attention should be paid to the active role of Chinese herbal medications in combination therapy for unresectable HCC.

Conflict of Interest Disclosures

The authors made no disclosures.