Improved Prognosis of Postoperative Hepatocellular Carcinoma Patients treated with Active Hexose Correlated Compound (AHCC)

Yoichi Matsui, MD, Yusai Kawaguchi, MD, Manabu Nakagawa, MD, A-Hon Kwon, MD, Yasuo Kamiyama, MD¹, Kenichi Kosuna, PhD²

1. First Department of Surgery, Kansai Medical University, Osaka 570-8507

2. Japan .Amino Up Chemical Co. Ltd., Sapporo 004-0839, Japan

Correspondence: Yoichi Matsui: First Department of Surgery, Kansai Medical University 10-15 Fumizono, Moriguchi, Osaka 570 8507, Japan, Tel: 816-6992-1001 (ext. 3262) Fax: 816-6992-7343
E-mail: kmu-lsts@po.infosphere.or.ip

Abstract

Context
Active Hexose Correlated Compound (AHCC) is a newly developed functional food. In vitro experiments showed that AHCC enhanced the natural killer cell activity and could be considered as a potent biological response modifier for treating cancer patients. However, there is no report for the effects of AHCC in the clinical field.

Objective
To evaluate the efficacy of AHCC as a biological response modifier, and to determine whether AHCC improves the prognosis of hepatocellular carcinoma patients following surgical treatment.

Design
Analysis of data collected retrospectively between February 1992 and September 1999.

Setting
First Department of Surgery, Kansai Medical University in Osaka, Japan.

Patients
A total of 175 consecutive patients with histologically confirmed hepatocellular carcinoma were studied. All of the patients underwent macroscopically curative resection of a liver tumor.

Main Outcome Measure
Time to treatment failure (disease recurrence or death) after surgery.

Results
Of the 175 patients, 70 received AHCC (3g/day) orally after undergoing surgery (AHCC group). Survival and disease-free survival of patients in the AHCC group were compared with those of patients who did not receive AHCC after surgery (control group). Serum aspartate transaminase activity, y-glutamyltransferase activity and total bilirubin were significantly lower in the AHCC group in the 4-year period after surgery. Overall survival in the AHCC group was significantly higher than that in controls.

Conclusion
This retrospective study suggests that AHCC intake significantly improves the prognosis of postoperative hepatocellular carcinoma patients. Additional more detailed studies are needed to elucidate the mechanism of the effect of AHCC.

Introduction

Hepatocellular carcinoma (HCC) is widely distributed in different geographical areas. There is a high prevalence in Asia, and its incidence now ranks next to that of stomach cancer in Japan. Moreover, the number of patients with HCC is showing a gradual but definite increase¹. Prevention and treatment of HCC recurrence following hepatic resection has been extensively studied. Treatment have included repeated hepatic resection², interventional radiology (chemoembolization)³, percutaneous ethanol injection⁴, percutaneous microwave coagulation⁵, and administration of some hormonal agents^6,7. The prognosis for HCC however, remains unsatisfactory. The overall survival rate after primary surgical treatment has been about 40% at 5-years in Japan¹.

Many attempts have also been made to treat cancer by stimulating the immune system. Although several biological response modifiers (BRMs) have been developed such as BCG, Picibanil, PSK, lentinan, interferon and interleukin-12^8,9, the clinical efficacy of these substances has not been clearly confirmed. Active Hexose Correlated Compound (AHCC) is a functional food that was developed by Amino Up Chemical Co., Ltd. (Sapporo, Japan) in 1989. It is an extract of Basidiomycotina obtained by hybridization of several types of mushrooms¹⁰. Gohnam et al. reported that AHCC enhanced the natural killer cell activity of cancer patients and could be considered as a potent BRM for treating cancer patients¹¹. Furthermore, AHCC has been recently reported to reduce metastasis of rat mammary adenocarcinom¹⁰, to induce detoxification enzymes in the liver, to protect the liver from CCl4-induced liver injury¹², and to improve diabetes induced by streptozotocin¹³ in animal models. However, there is no report for the effects of AHCC in the clinical field.

This study was initiated to evaluate the effects of AHCC as orally administered BRM on the prognosis of patients with HCC following surgical treatment.

Patients:

A total of 175 patients with histologically proven hepatocellular carcinoma were studied retrospectively. All of the patients underwent macroscopically curative resection of a liver tumor at our institution between February 1992 and September 1999. Of these 175 patients, 23 cases were excluded, including 2 cases of operative death, 7 cases of hospital death, 10 cases with previous or concurrent malignancy and 4 cases who withdrew from follow-up just after discharge. Of the other 152 patients, 70 were administered AHCC (3g/day) orally after undergoing surgery until death or until the last follow-up date for living patients (AHCC group). These 70 patients were administered AHCC in accordance with the preferences of the patients and the treating physicians. The remaining 82 patients underwent hepatectomy without AHCC administration (control group). Disease-free survival and overall survival of patients in the AHCC group were compared with those in controls.

Follow-up:

All patients had a monthly follow up with routine liver biochemical tests. Every three months, all biochemical tests were performed at the central hospital laboratory. Liver ultrasound was also performed every three months. In addition, radiologists performed computed tomography and/or magnetic resonance imaging every six months. Finally, an angiographic examination was made after admission when recurrence was suspected. Once an intrahepatic recurrence had been confirmed, the patients in both groups generally received transarterial chemo-embolization.

Methods:

The perioperative clinical parameters such as patient characteristics, preoperative liver function data, operative factors and tumor characteristics were compared between the AHCC and the control groups. Overall survival, defined as the interval between the date of surgery and the date of death or last follow-up information for living patients, was evaluated. The most common cause of death was cancer, but liver failure or variceal bleeding was included among the causes of death. Disease-free survival was also evaluated, and was defined as the interval between the date of surgery and the date that diagnosis of recurrence was confirmed by a positive sonogram, computed-tomography scan, magnetic resonance imaging or hepatic angiography. AHCC was generously provided by Amino Up Chemical Co.,.Ltd. It was developed by extraction from a cultured broth of Basidiomycotina.

Statistical Analysis:

Chi-square analysis was used to compare two or three proportions and the Student's (test was used to compare differences between two series, in order to evaluate the homogeneity of the treatment and the control group with respect to perioperative clinical factors. The data were expressed as means ± standard deviation. Kaplan-Meier survival curves were plotted and Logrank tests were performed. Survival times were recorded in months. Two-way analysis of variance was used to compare the postoperative course of laboratory data between the two groups.

Results:

AHCC had no undesirable side effects. Only two patients in the AHCC group refused to continue the use of AHCC during the study due to slight nausea. Two patients in the control group began to take AHCC during the observation period. These four cases were censored at that time. The incidence of cirrhosis and the levels of serum albumin were significantly different preoperatively. However, these differences were disadvantageous to the AHCC group, and most patients were men with underlying viral hepatitis or cirrhosis, and most of them had well-compensated liver function.

By September 1999,34 (49%) patients had recurrences in the AHCC group and 55 (67%) had recurrences in the control group. AHCC had no significant effect (p=0.081) on disease-free survival. Fifteen (21%) patients had died in the AHCC group whereas 40 (49%) had died in the control group at the end of the follow-up period. Patient survival was significantly higher (p=0.048) in the AHCC group. The survival rate in the control group was similar to that observed among 12,595 HCC patients with hepatic resection based on data collected by the Liver Cancer Study Group of Japan from 1988 to 1995. The follow-up period ranged from 2 to 73.months in the AHCC group and from 2 to 92 months in the control group. The median follow-up period was 30 months in the AHCC group and 31 months in the control group. The 50% survival rate was 68 months in the AHCC group and at 45 months in controls.

Nine biochemical parameters were investigated for a period of 4 years after surgery in the two groups. Of these nine parameters, the serum levels of aspartate transaminase activity (AST), ?? glutamyltransferase activity (GGT) and total bilirubin were significantly lower in the AHCC group than in controls in the four-year period after surgery (Figure 2). There were no significant differences in the other 6 parameters that included the serum levels of alanine transaminase activity, alkaline phosphatase activity, albumin, platelet count, ?-fetoprotein and protein induced by vitamin K absence.

Comment:

Hepatocellular carcinoma (HCC) is a major health concern worldwide, with an incidence of approximately 1 million cases a year¹⁴. Early detection of HCC has recently become possible because of progress in diagnostic imaging and the incidence of resection for HCC has increased greatly during the last decade. As a result, short-term outcome has improved greatly and operative mortality rates have been reduced to a few per cent¹⁵. However, the long-term results are not yet satisfactory. Although, hepatic resection is the most effective form of treatment for patients with HCC, the incidence of postoperative recurrence which is the main cause of poor long-term results, remains extremely high even after hepatic resection¹⁶. Moreover, the cumulative intrahepatic recurrence rate has been reported to reach 100% at 5 years after resection of a single HCC in cirrhotic patients with viral hepatitis¹⁷.

To prevent recurrence or to prolong survival, the most widely applied option is adjuvant chemotherapy through a catheter inserted into the hepatic artery³. However, the efficacy of these agents is very low, the incidence of side effects is high, and there is no evidence suggesting that administration results in improved survival¹⁴. Furthermore, therapeutic doses of anti-cancer drugs have been reported to reduce the anti-tumor immune response and postoperative use of immunosuppressants accelerates the recurrence of malignancy¹⁸. Thus, the search for other potentially useful therapeutic approaches is necessary. However, other options, such as immunotherapy or radiation, have no definite place in daily clinical practice and should be applied only within research trials¹⁴. The disappointing status of medical treatment of HCC justifies the interest in administration of the functional food AHCC as a BRM, although its antitumor effects remain uncertain in the clinical field.

AHCC is an extract obtained from several kinds of mushrooms. The active component is an oligosaccharide and its molecular weight is about 5000 daltons¹⁰, but AHCC contains various components.

Interestingly, as opposed to conventional active components which include a ?-l,3-glucan structural component which is found in PSK and lentinan, the oligomer of glucose in AHCC has ?-l,4-linkage structure and some esterified hydroxy groups¹⁰. Therefore, it has been suggested that AHCC may function as a BRM in the same way that PSK and lentinan do in patients with cancer.

In vitro experiments^?? showed that administration of AHCC restored NK cell activity depressed by UFT and stimulated peritoneal macrophage cytotoxicity, NO production and cytokine production. The combination of UFT and AHCC significantly improved prognosis in mice after excision of primary tumors. It has been reported that both NK cells and macrophages are involved in the inhibition of tumor metastasis, following activation by BRMs¹⁰. Therefore, this AHCC effect could be mediated by natural host immunity which was restored or activated by AHCC. Thus AHCC may bring about therapeutic effects on survival of HCC patients as a result of NK cell and macrophage activation. AHCC should be considered as a potent BRM and its anti-cancer activity may be through host immunomodulation.

AHCC was recently reported to protect the liver from CCl4-induced liver injury in animal models'². Therefore, the higher survival rate in the AHCC group suggests that AHCC had beneficial effects on the clinical course of patients with hepatitis or cirrhosis, in addition to anti-cancer effects. Indeed, AHCC intake seemed to inhibit the hepatitis of patients, as suggested by the reduction in postoperative levels of AST, GOT and bilirubin in our study. The effects of AHCC administration in HCC patients and their time-course are further supported by the reduction in AST, GGT and bilirubin levels. The reduction in these biochemical parameters appears to reflect a better prognosis, although we need to study a larger number of patients for a longer time period in order to confirm this preliminary observation. The mechanism of anti-cancer activity and/or the hepatitis-preventing effect of AHCC has not been explored in this study. At present, it is difficult to explain the effects of AHCC as the effect of a single ingredient, and it is similarly difficult to reach any conclusions regarding the complex effects of AHCC on patient survival.

The results of this retrospective study show that adjuvant AHCC administration improves survival of HCC patients with viral hepatitis after surgery without side effects. Moreover, improvements in the quality of life were noteworthy in the present study. Although quality of life is very difficult or even impossible to assess objectively, the general sense of well being and appetite certainly improved more in the AHCC group than in the control group. However, the validity of this observation is limited by the fact that the study was not a prospective randomized trial.

AHCC intake proved beneficial for the survival of postoperative HCC patients without adverse effects. AHCC treatment is therefore a valuable adjuvant therapy for these patients. These preliminary observations need to be confirmed in larger controlled double-blind trials. A randomized prospective study of postoperative adjuvant therapy with AHCC in patients with HCC was initiated in August. AHCC, active hexose correlated compound; TACE, transarterial chemoembolization; ICG, indocyanine green; GSA, galactosyl human serum albumin; PIVKA, protein induced by vitamin K absence; NS, not significant. Data are expressed as means ± SD.

Table 1. Clinical Background of Patients treated with AHCC and Controls

AHCC group Control group p-value

age (years) 61.7± 8.4 60.6± 10.5 NS

gender (male/female) 54 / 16 68 / 14 NS

cirrhosis (yes/no) 66 / 3 62 / 19 0.001

Child score (A/B) 51 / 19 65/17 NS

alcohol intake (ml/day) 36,1 ± 61.6 32.0 ± 44.5 NS

hepatitis viral infection

type B/type C/ none 34/36 11 / 64 / 7 NS

preoperative TACE (yes/no) 18 / 44 / 8 36 /46 NS

TACE for hepatic recurrence (yes/no) 28/6 41 / 14 NS

albumin (g/L) 37.4 ± 4.1 39.0 ± 4.3 0.028

total bilirubin (μmol/L) 15.7 ± 5.5 15.7 ± 5.8 NS

cholinesterase (U/L) 3765 ± 1123 3670 + 1253 NS

aspartate transaminase (U/L) 50.7 ± 38.6 50.4 ± 30.5 NS

alkaline transaminase (U/L) 55.6 ± 45.6 49.5 ± 27.7 NS

alkaline phosphatase (U/L) 233 ± 89 2142 ± 81 NS

y-glutamyltransferase (U/L) 71.1± 60.0 66.4 ± 60.3 NS

AHCC group Control group p-value

platelet count (x 109/L) 135 ± 64 149 ± 75 NS

prothrombin time (%) 88.2 ±13.1 91.7 ± 12.9 NS

antithrombin III (%) 81.0± 16.9 82.0± 17.7 NS

ICG R 15 mm (%) 18.6± 10.2 17.0± 8.5 NS

ICG K value 0.122 ± 0.036 0.124 ± 0.030 NS

redox tolerance index 0.588 ± 0.599 0.573 ± 0.441 NS

99mTc-GSA liver scintigraphy Rmax 0.432 ± 0.152 0.420 ± 0.172 NS

number of resected subsegments 1.87 ± 1.10 2.00± 1.27 NS

total blood loss (ml) 1808 ± 2309 1800 ± 2411 NS
blood transfusion (units) 3.94 ± 7.99 4.15 ± 7.27 NS

microscopic curative resection (yes/no) 55 / 15 66/16 NS

operation length (mm) 310 ± 102 294± 121 NS

postoperative complications (yes/no) 19 / 51 18 / 64 NS

postoperative hospital stay (days) 39.0 ± 43.0 35.3 ± 39.0 NS

size in diameter (cm) 4.41± 3.41 4.25 ± 3.28 NS

number of nodules 1.93 ± 1.94 1.66± 1.27 NS

differentiation (well/moderate/poor) 17/48/2 15/50 110 NS

capsule (yes/no) 60 / 9 68 / 12 NS

TNM stage 2.39 ± 0.89 2.40 ± 1.00 NS

basal α-fetoprotein (μg/L) 7022 ± 38489 6602 ± 39687 NS

basal PIVKA II (AU/L) 2216 ± 6710 2891 ± 9716 NS

  Figure 1: Klapan-Meier estimate of disease-free survival and overall survival of patients with hepatocellular carcinoma after hepatic resection. The solid line indicates survival in the AHCC group and the doted line represents the control group. A, disease-free survival. There was no significant difference between the two groups by Logrank test (p=0.081). B, overall survival. There was a significant difference between the two groups (p=0.048)

Figure 2: Biochemical parameters in the patients with hepatocellular carcinoma after hepatic resection. Closed circles indicate the levels of parameters in the AHCC group and open circles indicate levels in the controls. There were significant differences in the two groups by two-way analysis of variance. A, aspartate transaminase activity, p=0.030. B, y-glutamyltransferase activity, p=0.009. C, total bilirubin, p=0.012.

REFERENCES

1. The Liver Cancer Study Group of Japan. Primary liver cancer in Japan. In: Watanabe S, Tominaga S, Kakizoe T eds. Japanese Cancer Association. Cancer Treatment and Survival. Gann Monograph on Cancer Research No. 43. Tokyo, Japan: Japan Scientific Societies Press; 1995: 81-95.

2. Shimada M, Takenaka K, Taguchi K, et al. Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Ann Surg. 1998; 227: 80-85.

3. Raoul JL, Guyader D, Bretagne JF, et al. Prospective randomized trial of chemoembolization versus intra-arterial injection of ¹³¹I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology. 1997; 26:1156-1161.

4. Castellano L, Calandra M, Blanco CV, de Sio I. Predictive factors of survival and intraheparic recurrence of hepatocellular carcinoma in cirrhosis after percutaneous ethanol injection: analysis of 71 patients. J Hepatol. 1997; 27: 862-870.

5. Seki T, Wakabayashi M, Nakagawa T, et al. Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma. Cancer. 1994; 74: 817-825.

6. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut. 1998; 42:442-447.

7. Cancer of the Liver Italian Programme Group. Tamoxifen in treatment of hepatocellular carcinoma: a randomized controlled trial. Lancet. 1998; 352:17-20.

8. Mizushima Y, Yuhki N, Hosokawa M, Kobayashi H. Diminution of cyclophosphamide-induced suppression of antitumor immunity by an immunomodulator PS-K and combined therapeutic effects of PS-K and cyclophosphamide on transplanted tumor in rats. Cancer Res. 1982; 42: 5176-5180.

9. Nishioka Y, Hirao M, Robbins PD, Lotze MT, Tahara H. Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin Cancer Res. 1999; 59:4035-4041.

10. Matsushita K, Kuramitsu Y, Ohiro Y, et al. Combination therapy of active hexose correlated compound plus UFT significantly reduces the metastasis of rat mammary adenocarcinoma. Anti-Cancer Drugs. 1998; 9:343-350.

11. Ghoneum M, Ninomiya Y, Torabi M, Gill G, Wojdani A. Active hemicellulose compound (AHCC) enhance NK cell activity of aged mice in vivo. FASEB J. 1992; 6: A1213.

12. Sun B, Wakame K, Mukoda T, Toyoshima A, Kanazawa T, Kosuna K. Protective effects of AHCC on carbon tetrachloride induced liver injury in mice. Natural Medicines. 1997; 51: 310-315.

13. Wakame K. Protective effects of active hexose correlated compound (AHCC) on the onset of diabetes induced by storeptozotocin in the rat. Biomedical Res. 1999; 20:145-152.

14. Simonetti RG, Liberati A, Angiolini C, Pagliaro L. Review. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol. 1997; 8:117-136.

15. Lee CS, Sung JL, Hwang LY, et al. Surgical treatment of 109 patients with symptomatic and asymptomatic hepatocellular carcinoma. Surgery. 1986; 99:481-490.

16. Shirabe K, Kanematsu T, Matsumata T, Adachi E, Akazawa K, Sugimachi K. Factors linked to early recurrence of small hepatocellular carcinoma after hepatectomy: univariate and multivariate analyses. Hepatology. 1991; 14: 802-805.

17. Belghiti J, Panis Y, Farges 0, Benhamou JP, Fekete F. Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg. 1991; 214:114-117.

18. Mihich E. Immnosuppression in cancer therapeutics. Transpl Proc. 1975; 7: 275-278.

Copyright © 2000 AHCC Research Site Maintained By: Data~Creek Creative