International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationHepatitis B Virus Reactivation After Three-Dimensional Conformal Radiotherapy in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma
Introduction
Hepatocellular carcinoma (HCC) accounts for >80% of all primary liver cancers and is the fourth greatest cause of cancer-related deaths worldwide. HCC is particularly prevalent in East Asia, including Korea, where hepatitis B virus (HBV) is endemic 1, 2. Overall, the outcomes of HCC are poor, because diagnosis often occurs in patients with advanced-stage tumors and underlying chronic liver disease. In general, the tumor stage and underlying liver function are both used to determine the treatment strategy for HCC patients (3). Liver resection, liver transplantation, radiofrequency ablation therapy, and percutaneous ethanol injection therapy are used as curative treatments for HCC (4). Because HCC is frequently diagnosed at the intermediate or advanced stage, transarterial chemoembolization (TACE) is often used as a palliative treatment 5, 6.
Radiotherapy has been limited and unsatisfactory for HCC, primarily because the liver has a low irradiation tolerance 7, 8. The advent of three-dimensional conformal radiotherapy (3D-CRT) and computerized treatment planning techniques have significantly increased the use of RT in patients with unresectable HCC (9); however, radiation-induced liver disease (RILD) remains a major complication even when using 3D-CRT 10, 11.
Radiation-induced liver disease has generally been characterized as a veno-occlusive disease with anicteric elevation of alkaline phosphatase (ALP) (12). In Asia, most HCC patients are HBV carriers and subclinical or ongoing cirrhosis of the liver and the possibility of HBV reactivation could lower the tolerance of the liver regions to RT 13, 14, 15, 16. Patients with HBV-related HCC have a greater susceptibility to RILD after RT, and RILD patients who had HBV-related HCC present with elevated transaminase more often than with anicteric elevation of ALP and nonmalignant ascites, which have been commonly reported 14, 15, 16. These findings indicate that radiation damage occurs more often in the hepatocytes than in the bile ducts, and RILD in patients with HBV-related HCC could be associated with another unique pathway such as HBV reactivation 13, 14, 15, 16. To date, however, no studies of HBV reactivation or associated chronic hepatitis B (CHB) exacerbation have been done in patients with HBV-related HCC after 3D-CRT. We, therefore, assessed whether 3D-CRT influences HBV reactivation and consequent CHB exacerbation, which might be required as a part of the differential diagnosis of RILD in patients with HBV-related HCC.
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Patients
Between January 2003 and December 2005, 96 patients with HBV-related HCC underwent complete 3D-CRT schedule for liver tumors at the National Cancer Center Hospital (Goyang, South Korea). Of the 96 patients, 48 were excluded because of incomplete records relating to pre- and post–3D-CRT HBV DNA levels and laboratory examination findings. The data of the remaining 48 patients were retrospectively analyzed by chart review. All 48 patients had been scheduled for 3D-CRT because of unresectable HCC
Baseline characteristics
The baseline characteristics of all patients are shown in Table 1. Age, gender, ALP, ratio of HBeAg positivity, radiation dose, and tumor characteristics were similar in Groups 1 and 2. The AST, ALT, and serum HBV DNA levels were significantly greater in Group 1 than in Group 2 (p < 0.05), because Group 1 patients had active HBV hepatitis requiring antiviral therapy and were receiving LMV treatment for a median of 0 months (range, 0–6) before 3D-CRT. Except for ALP, Group 2 was similar to the
Discussion
Recent studies in Asia, exclusively involving HCC patients with HBV or HCV, have shown that most patients with RILD present with elevated transaminase rather than elevated ALP and nonmalignant ascites 14, 15, 16. Although these studies have suggested the striking difference in RILD characteristics between HBV associated and nonassociated cases, they could not explain this difference on the base of HBV virology (14). We found that 3D-CRT increased serum HBV DNA >2 log10 copies/mL (HBV
Conclusions
The present study is the first to demonstrate that 3D-CRT can induce HBV reactivation in patients with HBV-related HCC. Furthermore, some RILD patients with elevated transaminase might have CHB exacerbation, rather than only RT complications. Finally, LMV therapy protected against HBV reactivation in patients with HBV-related HCC who were undergoing 3D-CRT. Therefore, in patients with HBV-related HCC undergoing 3D-CRT, CHB exacerbation should be considered in the differential diagnosis of RILD
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Supported by the National Cancer Center, Korea (Grant 0510090).
Conflict of interest: none.