Clinical effect of Cidan capsule on primary hepatocellular carcinoma in 325 cases

Zheng Dongjing（鄭東京），Zheng Donghi（鄭東海）， Zheng Weihong（鄭偉鴻），Xu Xin（許鑫）， Zheng Weid（鄭偉達）*， Yng Yige（楊一格）， nd Yng Yiting（楊奕婷）

a：Beijing University of Chinese Medicine，Beijing 100029， China；Dongzhimen Hospital， Beijing100029，Chinab：Beijing Oncology Hospital Of Weida TCM， Beijing 100023， China；Beijing University of Chinese Medicine， Beijing100029，China*Corresponding author： E-mail：444732614@qq.com

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Clinical effect of Cidan capsule on primary hepatocellular carcinoma in 325 cases

Zheng Dongjing（鄭東京）a，Zheng Donghai（鄭東海）a， Zheng Weihong（鄭偉鴻）b，
Xu Xin（許鑫）b， Zheng Weida（鄭偉達）b*， Yang Yige（楊一格）b， and Yang Yiting（楊奕婷）b

a：Beijing University of Chinese Medicine，Beijing 100029， China；Dongzhimen Hospital， Beijing100029，China
b：Beijing Oncology Hospital Of Weida TCM， Beijing 100023， China；Beijing University of Chinese Medicine， Beijing100029，China
*Corresponding author： E-mail：444732614@qq.com

ABSTRACT

OBJECTIVE： To observe the clinical effect of Cidan capsules，a traditional Chinese medicine applied as an antitumor drug for decades， on the treatment of primary hepatocellular carcinoma（HCC）. A two-month experiment was carried out.

METHODS： A total of 325 patients with primary HCC were randomly divided into 3 groups. The 125 patients in Group A were treated with Cidan capsules exclusively. The 100 patients in Group B were treated with Cidan capsules combined with chemotherapy. And as control group， the 100 patients in Group C were treated by chemotherapy only. The efficacy of Cidan was analyzed by monitoring associated symptoms and liver function tests and measuring the levels of the NK cell， CD3， CD4， CRJ and CD8， alpha fetoprotein（AFP）. The evaluation of Cidan's effects on enhancing the patients' life quality was through clinical and pathological observations.

RESULTS： The result showed that the steady rate following the standard for evaluation of Kamofsky was over 87.0% in group B， 72.0% in Group A and 57.0% in Group C， respectively. The life quality of the patients treated with Cidan capsules and chemotherapy was improved more obviously than that in Group A and C. The NK cell，CD3， CD4，CRJ and CD8 in Group C were obviously decreased， while those in Group A and Group B were without apparent vacillation. AFP descended markedly in Group A and B， but did not in Group C.

CONCLUSION： Cidan capsules combined with chemotherapy had superior curative effects on primary HCC.

primary hepatocellular carcinoma； liver cancer，Cidan capsules； Chinese medical therapy； chemotherapy

INTRODUCTION

Cidan Capsules， an antitumor drug， have been used for over 30 years since they came into market in 1998. Cidan capsules are compound medicines consisting of more than ten kinds of plant extracts， including Rhizoma Curcumae， Astragalus，Cremastra appendiculata， Salvia miltiorrhiza， hive and Bombyx batryticatus. According to the study （by Eastern Hepatobiliary Surgery Hospital）， Cidan capsules have two advantages in HCC treatment. They can directly inhibit the growth of tumor cells almost without any poisonous side effects on immune system. Professor Zheng invented this kind of medicine following holistic concepts of Chinese medicine and his unique concept of treatment is based on the traditional pattern， utilizing modern knowledge on tumor1. HCC is always considered to be terminal since its original symptoms are not apparent， which results in the difficulty in HCC's prognosis and cure， as well as the high relapse rate. In China， the incidence rate of HCC is increasing sharply due to the large number of patients with cirrhosis caused by chronic hepatitis. Meanwhile， its incidence trends to rise year by year in the world and therapies of HCC primarily include surgery， local ablation， interventional and radiation therapies， and medication. Superior curative effects have been achieved for HCC treatment when Cidan is combined with chemotherapy. And the curative effects were showed in the present study which discussed the effects of clinically treatments on HCC with or without Cidan and Cidan combined with chemotherapy. The comparisons were made on the level of the sizes of tumors， life quality， cell viability of immune cell， the level of AFP， and 3-year survival rate of the patients in the different groups.

PATIENTS AND METHODS Patients' selection

In aggregate， 325 patients diagnosed with HCC by histopathologic assay， and imageological examination were included in the study. In addition， they were diagnosed as blood stasis and virulence， which is concept of TCM to distribute the complex disease. All patients participated of their own accord，and some still had tumors after chemotherapies or surgeries. The age of volunteers ranged from 18-70. Life quality of patients attained 60 and higher following Kamofsky Performance Status. These patients had no severe jaundice， ascites， cachexia， hepatic coma or migration of central nervous system.

A total of 125 patients comprised the Group A， which were treated by Cidan capsules， the 100 patients in Group B were treated by Cidan capsules combined with chemotherapy and the 100 in Group C were treated by chemotherapy only. Among group A， the number of males were 106， while that of female was 19. The oldest one was 70 years old. The youngest one was 24. And the average age was 45.6. According to clinical stages，the number of Stage I was 9， 50 in stage II and 66 in stage III. In Group B， the number of male was 84， and that of female was 16. The oldest one was 70 years old， while the youngest one was 21. And the average age was 46.8. The number of Stage I was 8， II was 46， and III was 46. In Group C， the number of male was 81，and that of female was 19. The oldest one was 70 years old. The youngest was 24. And the average age was 47.4. The number of Stage I was 8， II was 41，and III was 51. All of the patients had the ability to live independently. In addition， there was barely significant difference among three groups of patients on quality of life and illness degree following statistics processing （P＞0.05）.

Therapeutic methods

In the treatment with Cidan， patients orally administered 1.35g Cidan capsules （Weida Pharmaceutical Co， Ltd， Beijing， China）four times a day， while the control group received chemotherapy including fluorouracil （5-FU） 750 mg/m2， carboplatin 200mg/ m2， adriamycin（ADM） 60 mg/m2， 40% lipiodol as embolizational agent 8-10mL. Furthermore， the treatment of Group C was drug combination. After two-month experiment， symptoms and life quality of patients were mainly observed， and liver functions， the level of AFP， level of immune cell and the sizes of tumor were investigated. During three-year follow-up period， the survival rate of all the patients were reported and compared.

Table 1.Comparison curative effect of CR， PR， SD and PD of patients with HCC among the three groups

RESULTS

In order to make further observation on the curative effect on Cidan Capsule the patients of HCC，we divided the patients into three groups （Cidan group 125， chemotherapy group 100 and Cidan plus chemotherapy group100） Three groups were similar in number. As shown in table 1， we can obviously find that the number of patients with complete response of tumor was zero， but only one in Cidan-plus-chemotherapy group in which the tumor was completely disappeared. The patients number of partial remission in Cidan-plus-chemotherapy group was significantly more than that in the control group. SD is the highest in the Cidan group. While only 13 patients' diseases in the Cidan-pluschemotherapy group progressed. The percentage of being in stable condition and in improved condition in Cidan-plus-chemotherapy group was 87%. It was obviously higher compared with that of the control group. The result revealed that Cidan-plus-chemotherapy group was superior to the chemotherapy（control group） and the Cidan group（control group） in the curative effect（P＜0.01）. The significant differences were in the curative effects between the Cidan group and the chemotherapy group.

1. complete response（CR）： The tumor completely disappeared and lasted for more than 1 month.

2. partial response（PR）： The two largest diameter of the tumor was reduced by more than 50% and lasted for more than one month.

3. stable disease（SD）： The tumor's two largest mutual vertical diameter product reduced by less than 50% or increased by less than 25% and last for more than 1 month.

4. progression disease（PD）： The two largest diameter of the tumor is increased by more than 25%.

The following is the analysis of life quality of the patients' with HCC after treatment. As shown in table 2，100 people were still chosen as the chemotherapy group， 125 as the Cidan group and the number of patients in the Cidan-plus- chemotherapy group was 100. The Cidan group has the largest number of patients who were rated as 60. The Cidan-plus-chemotherapy group has the largest number of patients who were rated as 70. 80 points indicated the patients' better recovering. Cidan grouphas 27 people who attained 80 points， while for the Cidan-pluschemotherapy group， 24 attained the points， and the number is more than chemotherapy group. About 70 and over 70 points， we can obviously see that the percentage of Cidan-plus-chemotherapy group was significantly higher than that in the control groups，which was 83%.

With Ridit analysis， we got the conclusion that the quality of patients' life in Cidan-plus-chemotherapy group was significantly better than that of the Cidan group（control group） and chemotherapy group（control group）（P＜0. 01 ）. There was no significant differences about the quality of life between the Cidan group and the chemotherapy group after treatment.

Table 2. Comparison of life quality of patients with HCC among the three groups

Table 3. Comparison of NK cell changes before and after treatment between group B and group C（±s）

Table 3. Comparison of NK cell changes before and after treatment between group B and group C（±s）

PS： Compared with before treatment， P＜0. 05； compared with the control group， P＜0. 05.

GroupscasesBefore treatment（%）After treatment （%）47.21±6. 70 45.89±6.37 B C 60 50 50.32±7.10 57.00±5.88

Table 4. Comparison of the CD3， CD4， CD8 index before and after treatment of Cidan-plus-chemotherapy group （B） and chemotherapy group （C） （±s）

Table 4. Comparison of the CD3， CD4， CD8 index before and after treatment of Cidan-plus-chemotherapy group （B） and chemotherapy group （C） （±s）

PS：Compared with before treatment， P＜0. 05； compared with the chemotherapy control group， P＜0.05.

GroupcasesCD3CD4 CD8 Before treatmentAfter treatmentBefore treatmentAfter treatmentBefore treatmentAfter treatment B6052.63±6.6650.78±7. 1437.57±7.3636.21±6. 5630.59±8.67 25.53±7.37 C3051.60±7. 66 43.37±7.4638.63±7.7931.98±6.7830.25±6.82 22.71±6.90

Table 5. Comparison of AFP of before and after treatment between Cidan group （A） and Cidan-plus-chemotherapy group （B）

The activity of NK cells reflects the current immune status of the patients， the detection includes of the activity of NK cells in the chemotherapy group with 50 patients and 60 patients in Cidan-plus-chemotherapy group. The differences between the two groups before and after the treatment were decreased. There were significant differences in the two groups（P＜0.05）. But the decline range was different. Chemotherapy control group was significantly decreased compared with the Cidan-pluschemotherapy group. The differences had significant meaning in the activities of NK between the two groups.

As shown in Table 3， the percentage of NK cells in the chemotherapy treatment dropped 11.11%， from 57% before the treatment to 45.89%. In Cidan-plus-chemotherapy group， the percentage of NK cells was 50.32% before treatment， and after the treatment it was 47.21%， fell by only 3.11%. This illustrated that chemotherapy has a killing effect on the patients' NK cells，which led to the reduction of the patients'immunity. However，after treatment with Cidan， NK cells significantly reduced. This indicated that the Cidan had a protective effect on immune cells.

We examined 30 patients of the chemotherapy control group and 60 patients of Cidan-plus chemotherapy group for CD3，CD4， CD8 index， the results are shown in Table 4. After being treated with chemotherapy CD3， CD4 and CD8 of control group were significantly decreased （P＜0.05）； In Cidan-pluschemotherapy group only CD8 decreased significantly， CD3 and CD4 declined but the decline was of no significant difference. After chemotherapy treatment， CD3 and CD4 of control group was less than the chemotherapy combined with Cidan group （P＜0. 05）； CD4 levels after treatment in the two groups decreased，but the decreasing was of no significant difference. Above statistics suggested that Cidan had certain protective effect onchemotherapy-induced immune suppression.

The patients of three groups stopped using the drugs and accepting chemotherapy after three years of treatment. After the treatment we recorded the patients' survival time. There were 56 patients who lived over three years in Cidan-plus-chemotherapy group， which was significantly more than that in the control group， while the number of survivals in the Cidan group and Cidan-plus-chemotherapy group in one to two years was more than that of the control group.

The Ridit analysis showed the survival rate of follow-up comparison after three years， the survival rate of Cidan-pluschemotherapy group was significantly higher than that of Cidan group and chemotherapy group （P＜ 0.01）， Cidan group was higher than that of the chemotherapy group （P＜0.05）.

Table 6. Comparison of survival rate after treatment of patients with HCC treated with Cidan（A）and chemotherapy only（C） or with Cidan and chemotherapy（B）. HCC， hepatocellular carcinoma

From above， the result revealed that Cidan positively affected the prognosis of the patients with HCC，including the inspection index and living conditions. The effects of Cidan on prognosis of patients were satisfactory. Patient's quality of life and survival time improved significantly. And Cidan also had protective effects on human immune cells. The combination of Cidan and chemotherapy in clinical application can maximize the efficacy of treatment compared with the chemotherapy alone or exclusive usage of Cidan. Cidan has brought the gospel for the majority of cancer patients in clinical application.

DISCUSSION

Primary carcinoma of the liver in TCM belongs to“accumulation”， “mass”， “yellow addiction” category in TCM. HCC is so-called a viscera blood deficiency， qi stagnation and blood stasis， there are six evil poison invasion， imaginary evil，evil coagulation poison knot， falling into the product according to the result2，3. A theory， we pay particular attention to the“toxin”， and put forward the “stasis， detumescence， treatment of qi and blood.” Cidan capsule system -the Zheng family recipe， contains Chinese medicine such as Curcuma， Shan CI mushroom， Strychnos， honey， Brucea javanica， artificial bezoar，astragalus， angelica， Codonopsis， radix salviae miltiorrhizae， and composition of ice sheet. Take Xin Wen Qi blood prescription，Xiaoyuzhitong zedoary and ganhan Sanjie Huayu， swelling detoxification Iphigenia as monarch drug. Morrison medicinal to detumescence， strychnos Tongluozhitong， toxic swelling of the hive， heat dampness detoxification of Brucea javanica， Qingxin Huatan， Lidan town scared of the artificial bezoar. Comparison of patients' life quality before and after chemotherapy in chemotherapy group shows the curative effect of primary curative effect of Angelica， Astragalus， and Salvia miltiorrhiza of silkworm， promoting blood circulation to remove blood stasis，the medicine Buzhong Yiqi， has the effect of promoting blood circulation， relieving swelling and pain of borneol.

Cidan also has curcumin and elemene. Curcumin is a number of phytochemical exhibit with anti-inflammatory effect which is a polyphenolic compound derived from rhizomes of Curcuma4，5.The curcumin-mediated attenuation of the NF-κB-activated inflammatory cascade is a critical mechanism of its therapeutic effects. In addition， elemene is the anticancer component extracted from Rhizoma Curcumae， which has been proved that it has an anticancer effect by inducing apoptosis in tumor cells. All in all， various drugs are used in combination to improve the treatment of liver cancer. Among 325 cases of hepatocellular carcinoma （HCC），comparisons among three groups， proved that Cidan-plus-chemotherapy group was better than that of the Cidan group， and the Cidan was obviously better. Cidan-plus-chemotherapy treatment can obviously improve the life quality and it can also improve the body immunity，and prolong the survival period， which has suggested the good curative effects6，7.With CT scan， part of the patients'tumors even obviously reduced. Thus， Cidan can effectively reduce tumor recurrence and improve the survival time when applied as Cidan and chemotherapy treatment for HCC. However， further studies are required to clarify the exact mechanisms involved in the antitumor effects of Cidan， with particular focus on the activity of the individual ingredients.

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