Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy

W. Yeo1,*, K. C. Lam1, B. Zee1, P. S. K. Chan1,2, F. K. F. Mo1, W. M. Ho1, W. L. Wong1, T. W. T. Leung1, A. T. C. Chan1, B. Ma1, T. S. K. Mok1 and P. J. Johnson1

Departments of 1 Clinical Oncology and 2 Microbiology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong

* Correspondence to: Dr. W. Yeo, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong. Tel: +852-2632-2118; Fax: +852-2649-7426; Email: winnieyeo{at}cuhk.edu.hk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Cancer patients who are hepatitis B virus (HBV) carriers and undergoing chemotherapy (CT) may be complicated by HBV reactivation. Over 80% of hepatocellular carcinoma (HCC) patients are HBV carriers; however, the incidence of HBV reactivation during CT has not been well-reported. A prospective study was conducted to determine the incidence of HBV reactivation, the associated morbidity and mortality, and possible risk factors.

Patients and methods: 102 HBsAg-positive patients with inoperable HCC underwent systemic CT. Patients received either combination cisplatin, interferon, doxorubicin and fluorouracil (PIAF) or single-agent doxorubicin. They were followed up during and for 8 weeks after CT.

Results: In 102 patients, 59 (58%) developed hepatitis amongst whom 37 (36%) were attributable to HBV reactivation. Twelve (30%) died of HBV reactivation. CT was interrupted in 32 patients (86%) with reactivation and 54 (83%) without reactivation (P>0.05). The median survivals were 6.00 and 5.62 months, respectively (P=0.694). Elevated baseline alanine aminotransferase (ALT) was found to be a risk factor.

Conclusion: HBV reactivation is a common cause of liver damage during CT in HBsAg-positive HCC patients. The only identifiable associated risk factor was elevated pre-treatment ALT. Further studies into the role of antiviral and novel anticancer therapies are required to improve the prognosis of these patients.

Key words: chemotherapy, HBsAg, liver cancer, viral reactivation


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer morbidity and mortality in Southeast Asia [1Go]. It is highly aggressive with only 10% of patients being candidates for curative surgery. For the remaining 90% of patients, the median survival is only 4 months [2Go]. Chemotherapy is a palliative treatment that has been shown to be effective in a proportion of patients [3Go, 4Go]. However, even for patients who respond to chemotherapy, severe treatment-induced toxic effects have been observed, amongst which one of the most commonly observed toxic effects has been hepatic dysfunction. In Southern China, 85% of HCC patients have chronic hepatitis B virus (HBV) infection [5Go, 6Go]. It is well recognized that for chronic carriers of HBV undergoing cytotoxic chemotherapy, hepatic dysfunction occurs more frequently than in non-HBV carriers, and this has mainly been attributed to the development of HBV reactivation [7Go–9Go].

The reactivation is characterized by raised levels of serum HBV DNA, abnormal liver function tests and clinical hepatitis of varying severity [10Go]. Most of the earlier reports have been on patients with hematological malignancies [8Go–10Go]. In Chinese lymphoma patients, up to 30% have been found to be hepatitis B surface antigen (HBsAg) seropositive, among whom 40% were found to develop reactivation of HBV during chemotherapy, resulting in 5% mortality [10Go]. In patients with other malignancies, HBV reactivation has been reported to be 20% among HBsAg seropositive cancer patients receiving cytotoxic chemotherapy [11Go, 12Go]. While HBV reactivation may spontaneously resolve in some, its occurrence inevitably leads to delay in chemotherapy schedules and disruption on cytotoxic treatment regimens in most cases and, in more severe cases, anticancer treatment is frequently terminated prematurely, with the consequence of compromising an individual's prognosis of cancer. Further, in the most severe form, HBV reactivation leads to fatal hepatic failure.

Associated factors that have been suggested in the development of the condition include male sex, young age, hepatitis B e-antigen (HBeAg) seropositivity, pre-chemotherapy HBV viral load, the diagnosis of lymphoma and the use of certain cytotoxic agents including doxorubicin and corticosteroids [10Go, 12Go–14Go]; however, not all studies have been conclusive.

Patients with inoperable HCC who are treated with chemotherapy in our locality may present a unique clinical entity that may potentially lead to a higher risk of developing HBV reactivation. First, HCC patients have the highest rate of chronic HBV infection and chronic liver disease with an HBV carriage rate of about 85%. HCC is a male-predominant disease (male to female ratio is 3.4 to 1) [1Go], and one of the most effective cytotoxic agents in the treatment of HCC to date is doxorubicin [3Go, 15Go], which forms a main component of the standard chemotherapy for this disease. In an area with a high incidence of HCC, in which the majority of the patients are being offered palliative chemotherapy, the objective of this prospective study is to determine the incidence of HBV reactivation during chemotherapy, associated morbidity and mortality in patients who develop the condition, and to identify the associated risk factors.


    Patients and methods
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 Patients and methods
 Results
 Discussion
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As part of an ongoing phase III randomized study comparing the efficacy of PIAF (cisplatin, doxorubicin, 5-fluorouracil and interferon-{alpha}2b) combination chemotherapy [16Go] with single-agent doxorubicin, HCC patients who were positive for HBsAg were consented into the present prospective study. Patients' eligibility included: HBsAg seropositive, unresectable or metastatic disease HCC, age >15 but <75, Karnofsky Performance Scale >70%, adequate hematological function (white cell count >3 x 109/l, platelet count >100 x 109/l), adequate hepatic function (total bilirubin ≤30 µmol/l), adequate renal function (creatinine clearance >50 ml/min). Those who have a history of prior malignancy except skin cancer, significant concurrent medical illness such as cardiac and renal diseases, anti-hepatitis C antibody positivity, intractable ascites that could not be controlled by medical therapy, sole bone or brain metastasis, prior chemotherapy for HCC, chronic use of anti viral therapy known to have activity against HBV infection apart from study medications (e.g. famciclovir, ganciclovir, lamivudine, adefovir dipivoxil) within previous 6 months and female patients who were pregnant or breast-feeding were excluded from the study. Eligible patients had a separate consent to this study.

Patients were randomized to receive either single-agent doxorubicin (60 mg/m2 on day 1 every 3 weeks) or PIAF (cisplatin 20 mg/m2 days 1–4, doxorubicin 40 mg/m2 day 1, 5-fluorouracil 400 mg/m2 days 1–4, interferon-{alpha}2b 5 mU/m2 days 1–4 every 3 weeks). Only patients receiving PIAF were pre-medicated with dexamethasone 8 mg as part of the anti-emetic regimen. Patients who received single-agent doxorubicin were not given dexamethasone pre-medication. The chemotherapy was administered for up to six cycles.

Demographic data of patients were recorded. HBeAg status and HBV DNA level were checked at study entry. Cirrhosis was defined either histologically or radiologically at the baseline. All the HCC patients were followed up on day 1 and day 10 of each cycle of chemotherapy; after the last cycle of chemotherapy, they were followed up 4-weekly for 8 weeks. Serum biochemistry, which included albumin, alanine aminotransferase (ALT) and total bilirubin (TB), and prothrombin time (INR) were checked; serum for HBV DNA was collected at each visit.

Hepatitis B markers were detected by commercial enzyme immunoassays (Auszyme MC Dynamic, Abbott Laboratories, North Chicago, IL). HBV DNA levels were measured from the stored serum sample by using the branched DNA hybridization assay [QUANTIPLEX HBV DNA assay (bDNA), Chiron Corporation, Berkeley, CA], which has a lower detection limit of 0.7 x 106 genome equivalents/ml (g.e./ml).

The following definitions, based on a definition of Lok et al. [10Go] and subsequently modified by us [12Go], were applied to this study. Hepatitis was defined as a ≥3-fold increase in serum ALT level that exceeded the reference range (<58 IU/l) or an absolute increase of ALT to >100 IU/l. Hepatitis was attributed to HBV reactivation when there was a ≥10-fold increase in HBV DNA levels when compared with baseline HBV DNA levels or the appearance of HBV DNA from an undetectable level at baseline, or an absolute increase of HBV DNA level that exceeded 1000 x 106 g.e./ml during chemotherapy, in the absence of clinical or laboratory features of other acute systemic infections. Based on an earlier study [17Go] which showed that peak HBV DNA may precede peak ALT by 11–13 days during viral reactivation, HBV DNA levels were quantified from the stored sample taken within 2 weeks before the time of peak ALT.

For patients who had a raised baseline HBV DNA level before chemotherapy, which fluctuated subsequently without a definite rise in HBV DNA titer (as defined above), and in the absence of other infections, the raised ALT was attributed to chronic active hepatitis B infection. Morbidity due to hepatitis was defined in terms of ‘severity of hepatitis’, ‘development of icteric hepatitis’ and ‘disruption in chemotherapeutic treatment’. The severity of hepatitis was defined as mild when the rise in ALT was ≤2 x UNL (upper normal limit); moderate when ALT rose between >2x and ≤5 x UNL; and severe when ALT was >5 x UNL. Icteric hepatitis was defined as serum TB level that exceeded twice the reference range (normal <15 µmol/l). A disruption of chemotherapy was defined as either a premature termination of chemotherapy, or a delay of eight or more days of chemotherapy in between cycles. Mortality related to HBV reactivation was recorded. Survival duration was calculated from the first day of the first course of chemotherapy (day 1) to the time of death or last event.

Statistical methods
The risk factors associated with HBV reactivation were determined using Fisher's exact test for categorical variables and Student's t-test for numerical variables. Two-tailed P values of ≤0.05 were regarded as significant.


    Results
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 Abstract
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 Patients and methods
 Results
 Discussion
 References
 
From January 2000 to March 2002, a total of 102 patients were recruited. Fourteen patients were not eligible for the chemotherapy study due to recurrent disease (7), borderline resectability (3), refusal for randomization (4); they were included in this study. Eight patients (8%) were female. The median age was 51 (range 23–73 years). Sixty-two patients (61%) had baseline cirrhosis. Twenty patients (20%) were HBeAg positive. Fifty-two patients (51%) received PIAF and 50 received single-agent doxorubicin. The mean baseline value for ALT was 4.20 IU/l (loge values; SD = 0.59, range 2.77–5.32), that of total bilirubin was 12.0 µmol/l (SD = 5.15, range 2.0–29.0) and that of albumin was 33.4 g/l (SD = 4.55, range 22–45). The mean baseline INR was 1.12 (SD = 0.096, range 0.93–1.41).

Fifty-nine patients developed hepatitis during the chemotherapy, of whom 37 (63%) were attributed to HBV reactivation (HBV reactivation group), giving an overall HBV reactivation rate of 36% in HBsAg-positive HCC patients undergoing chemotherapy. For these patients who developed reactivation, 32 had a 10 times rise in viral titers when compared with the baseline values (12 had a rise of over 100 times while another nine had a rise of over 1000 times), four had appearance of viral DNA from an undetectable baseline sample, and one had an absolute rise in HBV DNA that exceeded 1000 g.e./ml.

The details of the clinical outcomes of patients who did and did not develop HBV reactivation are illustrated in Table 1. In the HBV reactivation group, the median number of cycles of chemotherapy received was three (range 1–6 cycles). The median number of cycles the patient received before developing HBV reactivation was three (range 1–5). Twenty-four patients (65%) with HBV reactivation had received lamivudine orally at 100 mg/day soon after the development of hepatitis and the median duration of treatment was 112.5 days (range 2–218 days). The severity of hepatitis was mild in three patients (8%), moderate in 11 (30%) and severe in 23 (62%). Eighteen patients (49%) developed icteric hepatitis (total bilirubin ranged from 31 to 404 µmol/l). Five patients had albumin level reduced to <28 g/l, four had prolonged prothrombin time with INR >1.5, and seven patients had both complications. Thirty-two patients (86%) had disruption in chemotherapy as a result of HBV reactivation, including six who had delay in chemotherapy, 14 who had premature termination of their chemotherapy and 12 who had both complications. Twelve of the 37 patients (30%) died of HBV reactivation; seven of whom had received lamivudine while five had not.


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Table 1. Morbidity and mortality of HCC patients with and without HBV reactivation

 
For the non-reactivation group, 22 patients developed hepatitis during chemotherapy. Ten patients had hepatitis attributable to chronic active hepatitis B infection (they were found to have raised HBV DNA, the extent of rise did not reach the stipulated definition of HBV reactivation) and 12 patients had hepatitis attributable to the use of cytotoxic chemotherapy. The median number of cycles of chemotherapy received was three (range 1–6 cycles). The severity of hepatitis was moderate in 20 patients and severe in 14; 10 had icteric hepatitis (total bilirubin ranged from 34 to 509 µmol/l). Forty-three patients did not develop any hepatitis during the course of chemotherapy. Disruption in chemotherapy occurred in 54 of these 65 patients (83%), including 24 who had a delay in chemotherapy, 22 who had premature termination of their chemotherapy and eight who had both complications.

When compared with the patients who did not develop viral reactivation, the clinical course of hepatitis was significantly more severe in the patients who developed reactivation (P=0.028). The median survival of the patients who did and did not develop HBV reactivation was similar (6.00 versus 5.62 months, respectively, P=0.694).

The characteristics of those patients with and without HBV reactivation are shown in Table 2. Reactivated patients had a significantly higher mean baseline ALT than non-reactivated patients (loge values 4.36 versus 4.11 IU/l, P=0.04). The mean ages, HBeAg seropositivity, pre-existing cirrhosis, baseline INR, total bilirubin and albumin, and type of chemotherapeutic regimens (PIAF versus doxorubicin), were not shown to be significantly different between the two groups of patients.


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Table 2. Baseline characteristics of the patients with or without HBV reactivation

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
HBV infection is endemic in many parts of the world, and in Hong Kong about 10% of the population has chronic HBV infection [6Go]. HBV reactivation during chemotherapy has been well documented in non-HCC patients who were carriers of HBV and undergoing cytotoxic chemotherapy [7Go–12Go]. With as many as 85% of HCC patients being HBsAg-positive, the complication of HBV reactivation is expected to be more frequently observed in HCC patients undergoing chemotherapy. This study is the first to investigate HBV reactivation in HBsAg-positive HCC patients undergoing systemic cytotoxic chemotherapy.

In our study, 59 out of 102 patients (58%) developed hepatitis during the chemotherapy, amongst whom 37 cases were attributable to HBV reactivation, giving an HBV reactivation rate of 36%. However, it has to be noted that another 10 patients (10%) developed hepatitis attributable to chronic active HBV infection; further, for the 12 patients who had hepatitis attributable to cytotoxic drugs, it would be difficult to exclude the co-existing HBV-related chronic liver disease as contributory to the cytotoxic drug-induced hepato-toxicity. The incidence of HBV-associated hepatitis appears to be similar to that reported in lymphoma patients from the same geographical region [13Go], with a similarly high associated morbidity and mortality rate. Patients who developed the viral reactivation in the present series had a more severe clinical course, with 62% developing severe hepatitis and 30% dying as a result of hepatic failure.

Several risk factors in association with HBV reactivation have been reported in non-HCC patients undergoing cytotoxic chemotherapy. These include male sex, younger age, detectable HBV DNA, and the diagnosis of lymphoma or breast cancer [10Go, 12Go–14Go]. Although HBeAg positivity in immunocompromised cancer patients appears to be a risk factor for HBV reactivation [11Go, 12Go], this has not been found to be universally the case [6Go, 18Go], and it has been partly attributed to the presence of the precore/core promoter HBV mutant (i.e. HBeAg-negative/anti-HBe-positive) which had been associated with severe fulminant hepatitis [8Go, 16Go]. The use of certain cytotoxics such as anthracyclines, vinca alkaloids and corticosteroids [12Go, 20Go, 21Go] has also been associated with the condition.

In contrast to this study which specifically examined the cause of hepatitis in HCC patients undergoing systemic chemotherapy, a recent study investigated non-cause specific hepatic damage in HCC patients undergoing regional (trans-hepatic arterial) chemotherapy. HBeAg positivity was found to be the only factor associated with the exacerbation of hepatic damage, while age, sex, pre-chemotherapy liver function, HBV DNA levels and differences in therapeutic regimens were not found to be associated factors [22Go]. In this study, while HBV reactivation was found not to associate with HBeAg status, the high incidence of raised baseline transaminase in conjunction with a low HBeAg seropositivity strongly suggested the presence of precore mutant.

In this study, an elevated baseline ALT was identified to be the only risk factor associated with HBV reactivation in HCC patients undergoing systemic chemotherapy. In this male predominant disease, other factors such as age, HBeAg status, cirrhosis and other baseline biochemical parameters were not associated with the occurrence of this condition. In addition, having universally received doxorubicin, the incidence of HBV reactivation was similarly high in the studied groups irrespective of the regimens used, supporting the close association of anthracyclines with this condition. The effect of steroids reported in other studies was, however, not observed in this study. This could have been outweighed by a higher proportion of HCC patients having coexisting chronic active hepatitis (as evidenced by a relatively high baseline ALT) and cirrhosis when compared with non-HCC cancer patients described in other reports [14Go]. Further, pre-chemotherapy HBV DNA load has not been found to be significant. This could have been limited by the lack of a more sensitive real-time PCR assay for the measurement of pre-chemotherapy HBV DNA titer, which has been shown to be able to identify those at risk of developing HBV reactivation [14Go].

Interferon has immunodulatory, anti-proliferative and anti-angiogenic effects on tumor cells. When used as a part of the PIAF regimen, interferon did not seem to affect the HBV reactivation rate. At a therapeutic dose of 5 mU per day or 10 mU three times a week for 4–6 months, interferon has been shown to be effective in chronic HBV infection in Western countries, with a response rate of 30% [23Go]. The mean level of HBV DNA fell by 70% within the first 4 weeks and clearance of HBV DNA occurred at 16 weeks of treatment in the responders [24Go]. However, the same dosage of interferon has been shown to be less effective in Asian chronic HBV infection with a response rate reported to be ~10% [25Go]. In addition, from long-term follow-up data, there is no significant benefit in the clearance of HBV virologic markers and the prevention of complications of cirrhosis [26Go]. This may be associated with the fact that a high proportion of Asian carriers contracted the virus in the perinatal period or early childhood and are immuno-tolerant to HBV. Furthermore, the dosage of interferon in the PIAF regimen was much lower (only 5 mU/m2 daily for 4 days) than that used for the treatment of chronic HBV infection and, hence, it is unlikely to have a therapeutic effect on the chronic HBV infection in our HCC population.

In conclusion, hepatitis occurs in a high proportion (60%) of HCC patients undergoing cytotoxic chemotherapy in our locality. Although 80% of these were evidently related to chronic HBV infection (63% HBV reactivation, 17% chronic active hepatitis B), it is difficult to exclude HBV-related chronic liver disease as a contributing factor in the remaining 20% of patients who developed hepatotoxicity that was attributable to cytotoxic agents. Prophylactic use of lamivudine has been shown to minimize the hepatic damage related to chemotherapy-related HBV reactivation in non-HCC populations [27Go, 28Go]. Although this approach alone may not improve the prognosis of HBsAg-positive patients with inoperable HCC, the potential benefit of such treatment, in terms of improving quality of life and reducing the overall cost of treatment of HCC patients has not been addressed in this study and should not be overlooked. The adverse prognosis of patients with inoperable HCC is a combination of the high chemo-resistant nature of this malignancy, coupled with poor hepatic reserve with extensive hepatic parenchymal tumor involvement, co-existing chronic liver disease in addition to viral reactivation during chemotherapy. Thus, optimizing treatment for this patient population would need to involve novel anticancer as well as antiviral therapies.

Received for publication May 5, 2004. Revision received June 18, 2004. Accepted for publication June 23, 2004.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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