HBV infection decreases risk of liver metastasis in patients with colorectal cancer: A cohort study

March 9, 2011

http://www.wjgnet.com/1007-9327/full/v17/i6/804.htm

World J Gastroenterol. 2011 February 14; 17(6): 804-808.

Published online 2011 February 14. doi: 10.3748/wjg.v17.i6.804.

HBV infection decreases risk of liver metastasis in patients with colorectal

cancer: A cohort study

Hai-Bo Qiu, Li-Yi Zhang, Zhao-Lei Zeng, Zhi-Qiang Wang, Hui-Yan Luo, Rajiv

Prasad Keshari, Zhi-Wei Zhou and Rui-Hua Xu.

Hai-Bo Qiu, Zhao-Lei Zeng, Zhi-Qiang Wang, Hui-Yan Luo, Rajiv Prasad Keshari,

Zhi-Wei Zhou, Rui-Hua Xu, State Key Laboratory of Oncology in South China,

Guangzhou 510060, Guangdong Province, China

Hai-Bo Qiu, Zhi-Qiang Wang, Hui-Yan Luo, Rui-Hua Xu, Department of Medical

Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong

Province, China

Hai-Bo Qiu, Rajiv Prasad Keshari, Zhi-Wei Zhou, Department of Gastric and

Pancreatic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou 510060,

Guangdong Province, China

Li-Yi Zhang, Department of Clinical Oncology, University of HongKong, Pokfulam,

HongKong, China

Zhao-Lei Zeng, Department of Research, Sun Yat-Sen University Cancer Center,

Guangzhou 510060, Guangdong Province, China

Author contributions: Qiu HB and Zhang LY contributed equally to this work; Qiu

HB and Xu RH defined the research theme; Qiu HB, Zhang LY and Zeng ZL designed

the methods and wrote the paper; Keshari RP revised the manuscript; Zhang LY,

Wang ZQ and Luo HY analyzed the data and interpreted the results; Qiu HB and

Zhou ZW collected, interpreted the data, and discussed the analyses; all authors

approved the manuscript.

Correspondence to: Rui-Hua Xu, MD, PhD, Professor of Medical Oncology, Vice

President, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong

Province, China. xurh@...

Telephone: +86-20-87343468 Fax: +86-20-87343228

Received October 7, 2010; Revised November 8, 2010; Accepted November 15, 2010;

Abstract

AIM: To evaluate the effect of hepatitis B virus (HBV) infection on liver

metastasis of colorectal cancer.

METHODS: A total of 1298 colorectal cancer patients were recruited from January

2001 to March 2005 in this study. Enzyme-linked immunosorbent assay was used to

test serum HBV markers for colorectal cancer. Patients were divided into study

(infection) group and control (non-infection) group. Clinical features of

patients in two groups were compared.

RESULTS: Liver metastasis was found in 319 out of the 1298 colorectal cancer

patients. The incidence of liver metastasis was significantly lower in study

group than in control group (14.2% vs 28.2%, P < 0.01). HBV infection

significantly decreased the risk of liver metastasis [hazard ratio (HR): 0.50,

95% confidence interval (95% CI): 0.38-0.66], but the incidence of extrahepatic

metastasis was significantly higher in study group than in control group (31.9%

vs 17.0%, P < 0.01). The HR was the lowest in chronic hepatitis B group (HR:

0.29, 95% CI: 0.12-0.72). The number of liver metastatic lesions was

significantly less in study group than in control group with a higher surgical

resection rate. However, no significant difference was found in survival rate

between the two groups (P = 0.95).

CONCLUSION: HBV infection decreases the risk of liver metastasis in patients

with colorectal cancer and elevates the surgical resection rate of liver

metastatic lesions.

INTRODUCTION

Colorectal cancer (CRC) accounts for 10%-15% of all cancers and is the second

leading cause of cancer-related deaths in Western countries[1]. Approximately

half of CRC patients develop metastatic disease[2]. Of the CRC patients, 15%-25%

present with synchronous liver metastasis and 80%-90% are initially found to

have unresectable liver metastatic disease[3]. Metastatic liver disease more

frequently develops metachronous metastasis following treatment of CRC. It is

estimated that over half of dead CRC patients have liver metastasis at

autopsy[4].

Hepatitis B virus (HBV) infection is the most common cause of chronic liver

diseases worldwide, an estimated 350 million persons are chronically infected

with HBV worldwide, and China is a highly endemic area of HBV infection with

approximately 170 million HBV carriers[5]. It has been demonstrated that HBV

infection plays an important role in the development of hepatocellular carcinoma

(HCC)[6]. It was reported that HBV infection finally reduces the risk of

intrahepatic metastasis in HCC patients with a higher survival rate and

therefore can be considered an important prognostic factor for HCC patients[7].

Rare reports are available on the relation between HBV infection and hepatic

metastasis of CRC. Utsunomiya et al[8] reported that CRC seldom metastasizes to

liver of patients infected with HBV or hepatitis C virus (HCV), but most

patients in their study were infected with HCV. Song et al[9] showed that

chronic HBV infection with viral replication reduces hepatic metastasis of CRC

and prolongs the survival time of CRC patients. However, their study was hard to

demonstrate the relation between HBV infection and hepatic metastasis of CRC due

to its small sample size. Alternatively, investigation of experimentally induced

hepatic metastasis of colon cancer demonstrated that activated immune cells

residing in livers can effectively kill metastatic tumor cells, indicating that

alterations in liver-associated immunity play an important role in hindering

hepatic metastasis[10]. Thus, we designed this cohort study to observe the

relation between HBV infection and liver metastasis of CRC.

MATERIALS AND METHODS

Patients

A total of 1298 CRC patients at the age of > 16 years, admitted to Sun Yat-Sen

University Cancer Center (Guangzhou, China) from January 2001 to March 2005,

were recruited in this study and divided into study (infection) group and

control (non-infection) group. All patients gave their written informed consent

to receive a test for HBV infection at their first visit. The study was approved

by The Ethics Committee of Sun Yat-Sen University Cancer Center.

Serologic assay for viral infection

HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc were detected by enzyme-linked

immunosorbent assay and HBV deoxyribonucleic acid (HBV-DNA) was detected by

polymerase chain reaction.

Treatment

Primary colorectal adenocarcinoma was completely removed from all eligible

patients with no prior chemotherapy or radiotherapy, and staged according to

AJCC Cancer Staging Manual, 6th edition[11]. All patients received

5-fluorouracil-based FOLFOX6 or XELOX regimen. Patients with liver metastasis

underwent palliative treatment (including chemotherapy, radiotherapy, surgical

resection and radio-frequency ablation) according to the update NCCN Guidelines

for CRC[12].

Assessment of study and follow-up of patients

Patients were assessed by abdominal and pelvic computed tomography (CT) scan or

magnetic resonance imaging (MRI), thoracic radiography or thoracic CT or MRI

before surgery. Patients who underwent surgery were assessed again during

operation. All patients, after discharged from hospital, were followed up

according to a standard protocol[13]. The patients were followed up every 3 mo

in the first 2 years after surgery, during which clinical examination, routine

blood test, assessment of tumor markers, and abdominal ultrasonography or CT

scan and endoscopy were performed. In the next 3 years, the patients were

followed up every 6 mo and underwent endoscopy every 12 mo. The relapse of CRC

(defined as local recurrence or metastasis at distant sites) at other sites was

detected and staged. The follow-up was terminated in April 2010.

Statistical analysis

Differences in baseline clinical parameters and treatment outcomes between the

two groups were evaluated by chi-square test or Student t test. Hazard ratio

(HR) and 95% confidence interval (95% CI) were calculated with the

proportional-hazards model. Overall survival (OS) and disease-free survival

(DFS) curves were plotted with the Kaplan-Meier method, and compared by log-rank

test. OS rate was calculated from the date of discharge to death. DFS time was

defined as the time between discharge and first relapse of CRC. A two-tailed P

value less than 0.05 was considered statistically significant. Statistical

analysis was performed with SPSS for Windows V.13.0.

RESULTS

The 1298 patients were divided into study group and control group. Three hundred

and thirty-two patients (25.6%) with chronic HBV infection included in study

group were further divided into 3 subgroups according to their natural history

of HBV infection[14]. Chronic hepatitis B (CHB) was identified in 37 patients

(2.9%) according to the presence of HBsAg and HBeAg or HBV-DNA which are markers

of active viral replication. Inactive HBsAg carriers (IC), identified in 108

patients (8.3%), were characterized by the presence of HBsAg and anti-HBe and

the absence of HBeAg or HBV-DNA. Resolved hepatitis B (RHB) observed in 187

patients (14.4%) was characterized by negative HBsAg and the presence of

anti-HBc Â± anti-HBs. Nine hundred and sixty-four patients (74.6%) were included

in control group. No significant difference was found in sex, age, depth of

tumor invasion, lymph-node metastasis, lactate dehydrogenase, Î³-glutamyl

transpeptidase, alkaline phosphatase, albumin, and total bilirubin between the

two groups (Table 1). However, the liver function was significantly worse in

study group than in control group.

Follow-up

The mean follow-up time of patients was 6 mo after operation. The median

interval time of patients was 6 mo after operation. The median follow-up time of

patients was 57.2 mo (range 0-110.4 mo) after operation.

Liver and extrahepatic metastasis

Liver metastasis occurred in 319 patients including synchronous liver metastasis

in 193 cases and metachronous liver metastasis in 127 cases. Of the 193

patients, 39 had synchronous liver metastases. Of the 127 patients, 18 had

metachronous liver metastasis. Synchronous or metachronous extrahepatic

metastasis occurred in 270 patients was defined as distant metastasis but not as

liver metastasis. The incidence of recurrence or metastasis to the distant sites

is summarized in Table 2. The incidence of liver and extrahepatic metastasis was

comparable between the two groups. The incidence of liver metastasis was

significantly lower in study group than in control group (14.2% vs 28.2%, P <

0.01). The Manter-Haenzel Ï‡2 analysis showed that HBV infection significantly

decreased the risk of liver metastasis (HR: 0.50, 95% CI: 0.38-0.66). The

incidence of extrahepatic metastasis was significantly higher in study group

than in control group (31.9% vs 17.0%, P < 0.01). No difference was found in

liver metastasis between the two groups.

The liver metastasis rate in patients with CHB, IC and RHB is listed Tables 3, 4

and 5. CHB, IC and RHB decreased the risk of liver metastasis and increased the

risk of extrahepatic metastasis. The HR was the lowest in patients with CHB (HR:

0.29, 95% CI: 0.12-0.72).

The number, size and surgical resection rate of metastatic lesions are listed in

Table 6. The number of liver metastatic lesions was significantly less in study

group than in control group with a higher surgical resection rate (P < 0.05). No

significant difference was found in size of liver metastatic lesions between the

two groups.

Survival rate

The 5-year survival rate was 57.0% and 58.2%, respectively, for the patients in

two groups. No significant difference was found in OS and DFS rate between the

two groups (Figure 1A and .

DISCUSSION

In the current study, the risk of liver metastasis was significantly lower in

study group than in control group (HR: 0.50, 95% CI: 0.38-0.66, P < 0.05). A

significant difference was found in extrahepatic metastasis rate and no

significant difference was found in survival rate between the two groups,

suggesting that HBV infection may have a significant effect on liver metastasis

of CRC. It was reported that the liver metastasis rate is low in patients with

other malignancies due to HBV infection[7,15].

In this study, the liver metastasis rate of CRC was lower in CHB, IC and RHB

subgroups than in control group (P < 0.05). CHB was characterized by positive

HBeAg while the serum HBV DNA level and normal aminotransferase level were very

low or undetectable in IC. RHB results from previous HBV infection without

further virological, biochemical or histological evidence of active virus

infection or disease[14,16]. Thus, it is reasonable to postulate that HBV

infection with or without virus replication, may affect liver metastasis of CRC.

In this study, CHB most significantly decreased the risk of liver metastasis of

CRC followed by RHB.

Hepatic resection remains the only curative therapy for liver metastasis of CRC.

In this study, the 5-year survival rate of CRC patients was 25%-40% after

operation, which is consistent with the reported findings[17,18]. The number of

liver metastatic lesions was much less in study group than in control group,

leading to a higher surgical resection rate of liver metastatic lesions,

indicating that HBV infection plays an important role in the pathogenesis of

liver metastasis of CRC. However, no difference was found in overall survival

and disease-free survival rate between the two groups, suggesting that liver

metastasis of CRC results from the difference in extrahepatic metastasis.

Whether changes in liver-associated immunity contribute to the impediment of CRC

colonization in patients infected with HBV remains unclear. The liver has a rich

diversity of innate immune cells, particularly lymphocytes including natural

killer cells, which respond to altered expression of self-antigens and lyse

neoplastic target cells in the absence of additional activating stimuli[19]. A

large number of phagocytic and antigen-presenting cells including liver

sinusoidal endothelial cells, Kupffer cells and dendritic cells play an

important role in local innate immunity of the liver[20]. Furthermore, it was

reported that HBV replication enhances the cytotoxicity of immunocytes during

chronic HBV infection. Cytotoxic T lymphocytes (CTL) and Kupffer cells are

essential for the immune response during HBV infection. HBV replication

activates the specific lytic pathways of cell injury by CTL and Kupffer

cells[21]. A previous study showed that the hepatic microenvironment in patients

with HBV-positive metastatic liver cancer can greatly change their gene

expression profiles, and the two significant clusters in the profile revealed

notable changes-associated with gene products involved in immune function. In

fact, over 30% of the genes in these clusters are related to this process[22].

Another study on tumor and stroma interaction suggested that the propensity of

metastatic liver cancer is inherent to the tumor cells and affected by the local

environment of metastatic sites[23].

In conclusion, activation of liver-associated immunity due to HBV infection

reduces the incidence of liver metastasis in CRC patients.

COMMENTS

Background

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in

Western countries. Metastatic liver disease more frequently develops

metachronous metastasis following treatment of CRC. It was reported that

hepatitis B virus (HBV) infection finally reduces the risk of intrahepatic

metastasis in hepatocellular carcinoma (HCC) patients with a higher survival

rate and therefore can be considered an important prognostic factor for HCC

patients Rare reports are available on the relation between HBV infection and

hepatic metastasis of CRC.

Research frontiers

The authors designed a cohort study to observe the relation between HBV

infection and liver metastasis of CRC.

Applications

The major points summarized in the article can applied in further studies on the

correlation between liver metastasis and colorectal cancer.

Peer review

In this manuscript, the authors evaluated the effect of HBV infection on liver

metastases in patients with colorectal cancer. Some discussions should be added

and survival curves should be reconsidered.

Footnotes

Supported by National Natural Science Foundation of China, No. 30672408

Peer reviewers: Dr. Lucia Ricci Vitiani, Department of Hematology, Oncology and

Molecular Medicine, Istituto Superiore di SanitÃ , Viale Regina Elena, 299, Rome

00161, Italy; Hitoshi Tsuda, MD, PhD, Diagnostic Pathology Section, Clinical

Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku,

Tokyo 104-0045, Japan

S- Editor Tian L L- Editor Wang XL E- Editor Lin YP

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March 9, 2011