Cui-Hong Zhu,Jian Hao,Xue Yang,Xiao-Dong Wang,Chang Liu,Xiong-Zhi Wu*

1 Zhong-Shan-Men Inpatient Department,National Clinical Research Center for Cancer;Key Laboratory of Cancer Prevention and Therapy,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300171,China

Background

Hepatocellular carcinoma(HCC)ranks the fifth most common malignant tumor and is third on causes of death related to cancer[1,2].HCC is a grave threat to life,whose prognosis is dependent on the tumor stage at the time of diagnosis and the possibility of providing radical treatment[3].Based on gross morphological characteristics,hepatocellular carcinoma can be classified into three types:nodular,massive,and diffuse[4].The prominent clinical features of diffuse-type HCC are high malignancy,lack of early diagnosis and poor prognosis[5,6].Although many treatment strategies including surgical resection,liver transplant or locoregional therapy such as radiofrequency ablation(RFA)and transarterial chemoembolization(TACE)have been developed for HCC[7,8].However,In cases of diffuse type HCC,many treatment options are limited given the poor prognosis of diffuse type HCC.There are no curative treatment for patients with diffuse type HCC.Traditional Chinese medicine(TCM)treatment had been reported to prolong survival time of patients with unresectable HCC[9,10].TCM products,alone or in combination with standard of care are the potential therapeutic approach to be used as an assistant for whom no therapy was previously available.

Here,we reported a case of diffuse type HCC,which were completely treated with TCM therapy and had maintained a CR status.We also describe our experience for THM used in patients with HCC.This case may provide a rareopportunity for further study.

Case presentation

In June 2011,a 47-year-old man was admitted to our hospital due to the presence of multiple hepatic mass lesions.He did not smoke,but drank alcoholic beverages socially.He had a history of fatty liver.He had been no blood transfusion or hepatitis episode in the past.There was no evidence of hepatitis,liver cirrhosis,or hepatocellular cancer in his family members.Abdominal contrast-enhanced CT demonstrated multiple low density nodules with heterogeneous enhancement in the arterial phase in his right lobe of the liver and the largest nodule diameter is about 5 cm.In addition,lymphadenopathy and as cites fluid were observed in abdominal areas.The size of the liver enlarged (Figure 1A). The patient’s serum alpha-fetoprotein(AFP)level was elevated to 10.5μg/ml(normal level is less than 20 ng/ml)(Table 1).The clinical diagnosis was hepatocellular carcinoma(diffuse-type).Hepatic resection was not performed considering the patient’s hepatic functional reserve(Child-Pugh classification was grade B).Regular treatment for HCC was recommended,including chemotherapy and transcatheter arterial chemoembolization(TACE).However,the patient refused the proposed treatment regime.

He received TCM therapy as an alternative.TCM formulas were granted according to the syndrome differentiation.Patient dissolved the herbal granul in boiled water according to instructions.The herbal granulas were taken orally 3 times a day,30 minutes after meals.The prescriptions of patient were presented in Table 2.An abdominal CT scan was conducted every month. After 1 months of TCM therapy,abnormal strengthening signals nearly complete shrank in the right hepatic lobe in CT scans(Figure 1B).The patient’s alpha-fetoprotein also remained normal.After 8 months of TCM therapy,the lesions mostly disappeared with no new local tumor formation.Only multiple nodular sclerosis were noted in CT scans(Figure 1C).He continued with the herbal decoction daily until August 2014.In November 2014,CT showed that multiple nodules were found to have completely regressed in the right lobe of the liver and had no evidence of tumor recurrence after 38 months TCM therapy(Figure1D).

Table1 Patient baseline characteristics.

Figure 1 Arterial phasescans of contrast enhanced multiphase computed tomogram of abdomen.

Table2 Prescriptions of traditional Chinese medicine treatment.

知子)3g subtract Radix Notoginseng(三七)2g Lilac pink herb(瞿麥)30g Gekko japonicus Dumeril et Bibron(天龍)6g Rhizoma Curcumae Longae(姜黃)6g Root of Valvate Actinidia(貓人參)30g 2012.11.13 add Radix Notoginseng(三七)2g Lilac pink herb(瞿麥)30g Gekko japonicus Dumeril et Bibron(天龍)6g Rhizoma Curcumae Longae(姜黃)6g Root of Valvate Actinidia(貓人參)30g subtract Processed pinellia tuber(法半夏)6g Nidus Vespae by stir-frying炒蜂房6g Radix Actinidiae chinensis(藤梨根)30g Akebia fruit(預知子)3g 2013.11.14 add Fresh bone fossil of big mammals生龍骨15g Coix seed(薏苡仁)10g subtract Rhizoma Atractylodis Macrocephalae(白術(shù))20g oyster shell(牡蠣)15g

Discussion

Diffuse-type HCC has poor prognosis due to its high malignancy and lack of curative treatment.Although several systemic cytotoxic agents have been developed,none has shown survival benefit in diffuse-type HCC[5,6].Acquiring effective intervention and long term survival is an important clinical problem for diffuse-type HCC.Many studies have demonstrated that Traditional Chinese medicine-derived agents had important roles in inhibiting tumor development and progression[11,12],Which were widely applied to prevent recurrence for cancer patients and reduce the side effects of chemotherapy[13,14].Clinical report also provided evidence on the possible efficacy of TCM to increase survival in HCC[10].Moreover,a multivariate Cox proportional hazard model revealed that TCM was an independent favorable prognostic factor for OS[10].Although many studies have been conducted on the role of traditional herbs in the treatment of cancer,which showed significant differences in survival between an TCM group and the control group[16,17].There has been a small number of patients with HCC who developed a complete response.The objective of the study was to present a evaluated and validated case with TCM treatment.

In this case,although a pre-operative histological diagnosis was not performed for the present patient,HCC was suspected depend on abdominal contrast-enhanced CT demonstrated multiple low density nodules with heterogeneous enhancement in his right lobe of the liver and the largest nodule diameter was about 5 cm.There were larger lymph nodes.As cites fluid was observed in abdominal areas.The size of the liver enlarged(Figure 1A).

The patient received TCM treatment according to an overall differentiation of symptoms and signs.The principle that focus on the systemic functional adjustments of the entire body is in accordance with tumor-treating theory.In November 2014,CT showed that multiple nodules were found to completely regressed in the right lobe of the liver(Fig.1D).He had never received any treatment in hospital for HCC.The achievement of CR was predominantly attributed to TCM therapy.

Carapacis Trionycis Bolus(Synopsis of Golden Chamber)was used by the patient initially,which was common used for cirrhosis,chronic liver disease and hepatocellular carcinoma.Some herbals of this formulae have been studied.For example,Baical skullcap root(黃芩)has been demonstrated to exert anticancer effects mainly through induction of tumor cell apoptosis and cell cycle arrest[18,19].Acidic polysaccharide(CPPA)extracted from the roots of Codonopsis pilosula(黨參)had an efficient anti-proliferation and inhibit invasion and migration effect on tumor cells[20]. Previous studies have demonstrated that extracts of Carapax Trionycis(鱉甲)were able to protect liver against fibrosis and inhibits cultured HSC-T6 cell activation and proliferation via the TGF-β1/Smad pathway[21].The aqueous extracts of India madder root(茜草)can suppress the fibroblasts proliferation and expression of procollagen mRNA [22].Some researches had reported Phytolaccahad efficience of anti-cancer and anti-viral.

It remains unclear whether traditional herbs were involved in the mechanism of tumor regression in this patient.More researches should be conducted to evaluate efficacy of TCM in treating cancer. TCM treatment based on syndrome differentiation,like every scientific and efficient system of medicine,should be worthy to study deeply.

Conclusion

Here,we present an evaluated and validated case of diffuse-type HCC.The patient had no other therapies and achieved long-term CR only using TCM herbal.We hope that this case presentation serves as a stimulus for further investigation to clarify the anti-tumor effect of TCM.

Acknowledgments

This work was supported by the National Science Foundation of China(No.81173376)and New Century Excellent Talent(NCET-11-1068).

Consent

Written informed consent was obtained from the patient for the publication of the case report and images.

Competing interests

The authors declare that they have no competing interests.

1.Min S K,Jin Y J,Lee J W,et al.Complete remission of advanced hepatocellular carcinoma by sorafenib:A case report[J].World Journal of Gastrointestinal Oncology,2013,5(02):38-42.

2.Demirjian A,Peng P,Geschwind JF,Cosgrove D,Schutz J,Kamel IR, Pawlik TM: Infiltrating hepatocellular carcinoma:seeing the tree through the forest.J Gastrointest Surg 2011,15:2089–2097.

3.Takeda Y,Wakui N,Asai Y,et al.Spontaneous complete necrosis of hepatocellular carcinoma:A case report and review of the literature[J].Oncology Letters,2015,9(4):1520-1526(7).

4.Kanematsu M,Semelka RC,Leonardou P,Mastropasqua M,Lee JK:Hepatocellular carcinoma of diffuse type:MR imaging findings and clinical manifestations.J Magn Reson Imaging 2003,18:189–195.

5.Yang JD,Roberts L:Epidemiology and management of hepatocellular carcinoma.Infect Dis Clin North Am 2010,24:899–919.

6.Song L,Zhang Y,Zhao G,et al.Complete remission of diffuse hepatocellular carcinoma in a young adult after GSP-TACE:a case report[J].World Journal of Surgical Oncology,2014,12(1):1-4.

7.World Health Organization,International Agency for Research on Cancer. GLO-BOCAN 2008.(http://globocan.iarc.fr)

8.Lau W Y,Lai E C.The current role of radiofrequency ablation in the management of hepatocellular carcinoma:a systematic review.[J]. Annals of Surgery, 2009,249(1):20-25.

9.Yang,Xue,Hao,Jian,Zhu,Cui-Hong,et al.Survival Benefits of Western and Traditional Chinese Medicine Treatment for Patients With Pancreatic Cancer[J].Medicine,2015,94.

10.Ya-Nan,Man,Xiao-Hui,Liu,Xiong-Zhi,Wu.Chinese medicine herbal treatment based on syndrome differentiation improves the overall survival of patients with unresectable hepatocellular carcinoma[J].Chinese Journal of Integrative Medicine,2015,21(1):49-57.

11.Ruan,W.J.;Lai,M.D.;Zhou,J.G.,Anticancer effects of Chinese herbal medicine,science or myth?JZhejiang Univ Sci B 2006,7(12),1006-14.

12.Tan,W.;Lu,J.;Huang,M.;Li,Y.;Chen,M.;Wu,G.;Gong,J.;Zhong,Z.;Xu,Z.;Dang,Y.;Guo,J.;Chen,X.;Wang,Y.,Anticancer natural products isolated from chinese medicinal herbs.Chin Med 2011,6(1),27.

13.Hsiao,W.L.W.;Liu,L.,The role of traditional Chinese herbal medicines in cancer therapy--from TCM theory to mechanistic insights.Planta medica 2010,76 (11),1118-31.

14.Konkimalla,V.B.;Efferth,T.,Evidence-based Chinese medicine for cancer therapy.J Ethnopharmacol 2008,116(2),207-10.

15.Fan,Cheung,Xuanbin,Wang,Ning,Wang,et al.Chinese Medicines as an Adjuvant Therapy for Unresectable Hepatocellular Carcinoma during Transarterial Chemoembolization:A Meta-Analysis of Randomized Controlled Trials.[J].Evidence-based Complementary and Alternative Medicine : eCAM, 2013,2013(3):487919-487919.

16.Lee YW,Chen TL,Shih YR,et al.Adjunctive traditional Chinese medicine therapy improves survival in patients with advanced breast cancer:a population-based study.Cancer 2014;120:1338–1344.

17.Xu Y,Zhao AG,Li ZY,et al.Survival benefit of traditional Chinese herbal medicine(a herbal formula for invigorating spleen)for patients with advanced gastric cancer.Integr Cancer Ther 2013;12:414–422.

18.Xianjiao Z,Xu T,Hanqiang L,et al.Autophagy induced by baicalin involves downregulation of CD147 in SMMC-7721 cells in vitro[J].Oncology Reports,2012,27(4):1128-1134.

19.Li-Weber M:New therapeutic aspects of flavones:the anticancer properties of Scutellaria and its main active constituents Wogonin,Baicalein and Baicalin.Cancer Treat Rev 35:57-68,2009.

20.Xin T,Zhang F,Jiang Q,et al.The inhibitory effect of a polysaccharide from Codonopsis pilosula on tumor growth and metastasis in vitro.[J].International Journal of Biological Macromolecules,2012,51(5):788-793.

21.Yingpin T,Chunling H,Yanwen L.Effect of bioactive peptide of Carapax Trionycis on TGF-β1-induced intracellular events in hepatic stellate cells[J].Journal of Ethnopharmacology,2013,148(1):69–73.

22.Lv X,Li M,Weng M,et al.Effects of the aqueous extracts of Red Peony Root and India Madder Rooton on proliferation and collagen metabolism of dermal fibroblasts from systemic sclerosis[J].Pharmacology&Clinics of Chinese Materia Medica,2007.