Clinical Investigation
Hepatitis B Virus Reactivation After Three-Dimensional Conformal Radiotherapy in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma

https://doi.org/10.1016/j.ijrobp.2007.04.005Get rights and content

Purpose

To investigate whether three-dimensional conformal radiotherapy (3D-CRT) influences hepatitis B virus (HBV) reactivation and chronic hepatitis B (CHB) exacerbation in patients with HBV-related hepatocellular carcinoma (HCC).

Methods and Materials

Of the 48 HCC patients with HBV who underwent 3D-CRT to the liver, 16 underwent lamivudine therapy before and during 3D-CRT (Group 1) and 32 did not receive antiviral therapy before 3D-CRT (Group 2). To analyze spontaneous HBV reactivation, we included a control group of 43 HCC patients who did not receive any specific treatment for HCC or CHB.

Results

The cumulative rate of radiation-induced liver disease for Groups 1 and 2 was 12.5% (2 of 16) and 21.8% (7 of 32), respectively (p > 0.05). The cumulative rate of HBV reactivation was significantly greater in Group 2 (21.8%, 7 of 32) than in Group 1 (0%, 0/16) or the control group (2.3%, 1 of 43; p < 0.05 each). The cumulative rate of CHB exacerbation, however, did not differ significantly between Groups 2 (12.5%, 4 of 32) and 1 (0%, 0 of 16) or the control group (2.3%, 1 of 43; p > 0.05 each). The CHB exacerbations in the 4 Group 2 patients had radiation-induced liver disease features but were differentiated by serum HBV DNA changes. Two of these patients required antiviral therapy and effectively recovered with lamivudine therapy.

Conclusions

In patients with HBV-related HCC undergoing 3D-CRT, HBV reactivation and consequent CHB exacerbation should be considered in the differential diagnosis of radiation-induced liver disease, and antiviral therapy might be considered for the prevention of liver function deterioration after RT.

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.

Section snippets

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

References (33)

Cited by (82)

  • Abdomen and pelvis: Symptoms and toxicities

    2023, Palliative Radiation Oncology
  • Radiation-Induced Liver Disease and Modern Radiotherapy

    2018, Seminars in Radiation Oncology
    Citation Excerpt :

    For cirrhotic patients who are transplant candidates, a new liver may be the only cure after decompensation from liver-directed radiotherapy. The reactivation of hepatitis B is a well-recognized phenomenon with both radiation100 and chemotherapy,101 and can have devastating consequences. Treatment of the chronic infection prior to radiation may mitigate this risk, as discussed earlier.

View all citing articles on Scopus

Supported by the National Cancer Center, Korea (Grant 0510090).

Conflict of interest: none.

View full text