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Keywords:

  • nasopharyngeal neoplasms;
  • hepatitis B virus;
  • comorbidity;
  • drug toxicity;
  • prognosis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

The current study investigated the prevalence and prognostic value of chronic hepatitis B virus (HBV) infection in patients with nasopharyngeal carcinoma (NPC) from an area in southern China in which HBV and NPC are endemic.

METHODS

A total of 1301 patients with nonmetastatic, histologically proven NPC who were treated with radiotherapy or chemoradiotherapy were retrospectively reviewed.

RESULTS

In this series, 142 of the 1301 patients (10.9%) had chronic HBV infection (hepatitis B surface antigen [HBsAg] seropositive). The percentages of non–cancer-related deaths (15.0% vs 12.1%; P = .618) and severe hepatic adverse events (3.5% vs 0.9%; P = .145) were similar among patients with NPC with and without HBV infection. The 5-year overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRFS) rates for patients with NPC with or without HBV infection were 70.9% and 80.8% (P = .003), 63.7% and 73.0% (P = .016), and 81.7% and 88.2% (P = .035), respectively. Multivariate analysis identified chronic HBV infection in patients with NPC as an independent unfavorable prognostic factor for OS (hazards ratio [HR], 1.684; P = .003), PFS (HR, 1.451; P = .015), and LRFS (HR, 1.573; P = .048). Further analysis revealed that chronic HBV infection was an unfavorable, independent prognostic factor in patients with locoregionally advanced NPC, but not those with early-stage disease. In patients with stage III/IV NPC, HBsAg-positive patients had poorer OS (64.0% vs 77.2%; P = .003), PFS (56.2% vs 70.6%; P = .004), and LRFS (76.2% vs 88.3%; P = .002) compared with HBsAg-negative patients. On multivariate analysis, chronic HBV infection was found to be an independent adverse prognostic predictor for OS (HR, 1.734; P = .004), PFS (HR, 1.644; P = .003), and LRFS (HR, 2.108; P = .003) in patients with stage III/IV NPC.

CONCLUSIONS

Chronic HBV infection is an independent adverse prognostic factor in patients with locoregionally advanced NPC. Cancer 2014;120:68–76. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The highest incidence of nasopharyngeal carcinoma (NPC) reportedly occurs in southern China, with the yearly incidence rate varying between 15 and 50 cases per 100,000 population.[1] Radiotherapy (RT) is the primary treatment modality for all patients with locally and regionally confined stages of NPC. As in most solid tumors, the TNM staging system is currently the most reliable method for determining clinical treatment strategies and predicting treatment outcome. However, according to recent studies, the TNM staging system is not satisfactorily accurate in terms of risk segregation and survival prediction.[2] Thus, the identification of new prognostic factors is of great importance in improving outcome prediction and tailoring individualized treatment in patients with NPC.

Southern China has one of the highest incidences of chronic hepatitis B virus (HBV) infection, with hepatitis B surface antigen (HBsAg) seropositivity rates of between 10% to 12% in the general population.[3] Therefore, it is reasonable to speculate that chronic HBV infection may be an important comorbidity in patients with NPC in southern China. Chronic HBV infection represents a serious public health problem worldwide, and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma.[4] Recently, HBV has been associated with hematopoietic cancers, including lymphoma and leukemia,[5, 6] and pancreatic cancer.[7] In addition, HBV-infected patients with cancers such as diffuse large B-cell lymphoma[8] or multiple myeloma[9] have distinct clinical characteristics and/or outcomes compared with uninfected patients.

However, to the best of our knowledge, no study to date has investigated the characteristics and outcomes of patients with NPC and chronic HBV infection. Given that both NPC and HBV are endemic in southern China, the objective of the current study was to gain insight into the prevalence of chronic HBV infection in patients with NPC, and evaluate the impact of chronic HBV infection on the clinical features and survival outcomes of NPC.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patient Selection

A retrospective review was conducted on the case records of patients with NPC treated at the Sun Yat-sen University Cancer Center (Guangzhou, People's Republic of China) between February 2003 and January 2007. A total of 1403 newly diagnosed patients with nonmetastatic and histologically proven NPC were identified. Of these, 112 cases were excluded due to a lack of substantial information or hepatitis viral infections other than HBV; the remaining 1301 cases were included in the current study. This retrospective study was conducted in compliance with the institutional policy to protect the patients' private information and was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center. Informed consent was obtained from all patients.

Clinical Staging

All patients included in the current study had undergone routine pretreatment evaluations including a complete medical history, physical examinations, and hematology and biochemistry profiles, as well as magnetic resonance imaging of the neck and nasopharynx, chest radiography, abdominal sonography, and whole-body bone scans using single-photon emission computed tomography. Furthermore, positron emission tomography-computed tomography was performed on 123 of 1301 patients (9.5%). All patients were restaged according to the seventh edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system for NPC.[10] All magnetic resonance imaging and clinical records were reviewed separately by 2 radiologists (L.Z.L. and L.T.) to minimize heterogeneity in restaging; disagreements were resolved by consensus.

Virological and Liver Function Studies

Because HBV is endemic in southern China, all patients treated at the study institution were screened for serological HBsAg, hepatitis B surface antibody, hepatitis B e antigen, hepatitis B e antibody, and hepatitis B core antibody using enzyme-linked immunoadsorbent assays at the time of diagnosis. In addition, all patients were also tested for serum human immunodeficiency virus antibody, hepatitis A virus antibody, hepatitis C virus antibody, hepatitis D virus antigen, hepatitis D virus antibody, and hepatitis E virus antibody. However, the HBV viral loads were not routinely determined. Chronic HBV infection was defined as HBsAg seropositivity.

In our department, patients who underwent chemotherapy underwent routine liver function tests including analysis of alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels every 2 weeks during treatment, as well as at every follow-up visit. The severity of hepatic dysfunction and adverse events were defined according to the National Cancer Institute Common Toxicity Criteria (version 4.0). Disruption of chemotherapy was defined as either a premature termination of chemotherapy or a delay of > 8 days between chemotherapy cycles.[11]

Treatment

All patients were treated with definitive-intent RT. The majority of the patients (761 of 1301; 58.5%) were treated with 2-dimensional conventional RT, whereas 38.9% of patients (506 of 1301) received intensity-modulated RT and the remaining 2.6% (34 of 1301) were treated with 3-dimensional conformal RT. Details of the RT techniques used at the Sun Yat-sen University Cancer Center have been described previously.[12-15]

Overall, 504 of 1301 patients (38.7%) were treated with RT only, and 797 of 1301 patients (61.3%) received neoadjuvant, concomitant, or adjuvant chemotherapy. The majority of the patients (640 of 872; 73.4%) with stage III or IV NPC (classified as T3-T4 and/or N2-N3 disease) received chemotherapy. Neoadjuvant chemotherapy was given when the waiting time was considered to be longer than acceptable or when it was considered advantageous to downsize bulky tumors. Neoadjuvant or adjuvant chemotherapy consisted of cisplatin with 5-fluorouracil or cisplatin with taxane administered every 3 weeks for 2 or 3 cycles. Concomitant chemotherapy consisted of cisplatin given on weeks 1, 4, and 7 of RT or weekly cisplatin. The regimens and dosages were not altered according to the serum HBsAg status. Seventy-six patients in the HBsAg-positive group (53.5%) and 570 patients in the HBsAg-negative group (49.2%) received concomitant chemotherapy ± neoadjuvant/adjuvant chemotherapy. Neoadjuvant or adjuvant chemotherapy or a combination of the 2 was delivered to 20 (14.1%) patients and 131 patients (11.3%) in the HBsAg-positive and HBsAg-negative groups, respectively.

Prophylactic antiviral therapy was not routinely administered. When possible, salvage treatments (including afterloading, surgery, and chemotherapy) were provided in the event of documented disease recurrence, or if the disease persisted.

Patient Follow-Up and Statistical Analysis

Patients returned for follow-up appointments at least every 3 months during the first 2 years, and then every 6 months thereafter until death. The follow-up duration was calculated from the first day of therapy to the day of death, or to the last examination. The median follow-up time was 55.0 months (range, 2.7 months-119.5 months) for the HBsAg-positive group and 58.2 months (range, 2.8 months-121.2 months) for the HBsAg-negative group. The following endpoints were assessed: overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). We calculated OS from the first day of treatment to death, and PFS was calculated from the first day of treatment to the date of disease progression or death from any cause. For LRFS and DMFS analyses, we recorded the latencies (ie, time from the first day of treatment) to the first locoregional failure or remote failure, respectively.

SPSS (version 16.0; SPSS Inc, Chicago, Ill) was used for all statistical analyses. We compared the categorical variables in different groups using the chi-square test or Fisher exact test if indicated. Actuarial rates were calculated using the Kaplan-Meier method, and the differences were compared using the log-rank test. Multivariate analysis using a Cox proportional hazards model was used to test for independent significance by backward elimination of insignificant explanatory variables. Covariates including host factors (ie, age and gender), tumor factors (ie, T and N classification), RT (ie, RT techniques), and chemotherapeutic intervention (ie, RT alone or chemo-RT) were included in all tests. The criterion for statistical significance was set at an α of .05 and all P values were based on 2-sided tests.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Baseline Characteristics of the Patients

In total, 142 of the 1301 patients (10.9%) were seropositive for HBsAg. HBsAg-positive and HBsAg-negative patients were similar in terms of the majority of host factors, histological categories, and tumor factors. In addition, there were no significant differences with regard to the RT techniques or the use of chemotherapy noted between the groups. However, the HBsAg-positive group had a higher percentage of younger patients (ie, those aged < 50 years) compared with the HBsAg-negative group (76.1% vs 65.5%; P < .012) (Table 1). Liver function data were available for 1034 of the patients at baseline (79.5%), among whom the incidence of hepatic dysfunction before any treatment was higher for HBsAg-positive patients compared with those who were HBsAg negative (42.6% vs 18.6%; P < .001) (Table 1).

Table 1. Baseline Characteristics of HBsAg-Positive Versus HBsAg-Negative Patients with NPC
CharacteristicHBsAg+ (%) n = 142HBsAg- (%) n = 1159Pa
  1. Abbreviations: +, positive; -, negative; 2-DRT, 2-dimensional radiotherapy; 3D-CRT, 3-dimensional conformal radiotherapy; HBsAg, hepatitis B surface antigen; IMRT, intensity-modulated radiotherapy; NPC, nasopharyngeal carcinoma; RT, radiotherapy; WHO, World Health Organization.

  2. a

    P values were calculated using the chi-square test or Fisher exact test if indicated.

  3. b

    According to the 7th edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system.

  4. c

    Including 1034 of 1301 patients (79.5%) for whom pretreatment liver function data were available.

Age, y   
<50108 (76.1)759 (65.5).012
≥5034 (23.9)400 (34.5) 
Sex   
Male110 (77.5)863 (74.5).437
Female32 (22.5)296 (25.5) 
WHO pathology   
Type I1 (0.7)6 (0.5).556
Type II/III141 (99.3)1153 (99.5) 
T categoryb   
T122 (15.5)252 (21.7).314
T235 (24.6)274 (23.6) 
T344 (31.0)353 (30.5) 
T441 (28.9)280 (24.2) 
N categoryb   
N051 (35.9)406 (35.0).815
N151 (35.9)415 (35.8) 
N225 (17.6)236 (20.4) 
N315 (10.6)102 (8.8) 
Stage of diseaseb   
I8 (5.6)112 (9.7).202
II36 (25.4)273 (23.6) 
III45 (31.7)415 (35.8) 
IVA-IVB53 (37.3)359 (31.0) 
RT techniques   
2-DRT95 (66.9)666 (57.5).098
3-DCRT3 (2.1)31 (2.7) 
IMRT44 (31.0)462 (39.9) 
Chemotherapy   
RT alone46 (32.4)458 (39.5).100
Chemoradiotherapy96 (67.6)701 (60.5) 
Hepatic dysfunctionc   
Yes55 (42.6)168 (18.6)<.001
No74 (57.4)737 (81.4) 

Patterns of Treatment Failure and Causes of Death

The patterns of treatment failure and causes of death are summarized in Table 2. Up to the last day of follow-up, 23 of 142 patients in the HBsAg-positive group (16.2%) and 127 of 1159 patients in the HBsAg-negative group (11.0%) experienced locoregional failure, and 30 of 142 patients in the HBsAg-positive group (21.1%) and 181 of 1159 patients in the HBsAg-negative group (15.6%) developed distant metastases. Moreover, 40 of 142 patients in the HBsAg-positive group (28.2%) and 214 of 1159 patients in the HBsAg-negative group (18.5%) died; the majority of deaths (85% and 87.9%, respectively) were attributed to NPC. There was no significant difference noted with regard to the percentage of non–cancer-related deaths between HBsAg-positive and HBsAg-negative patients (15.0% vs 12.1%; P = .618) (Table 2).

Table 2. Patterns of Treatment Failure and Causes of Death for HBsAg-Positive Versus HBsAg-Negative Patients With NPC
 HBsAg+ (%)HBsAg- (%)Pa
  1. Abbreviations: +, positive; -, negative; HBsAg, hepatitis B surface antigen; NPC, nasopharyngeal carcinoma.

  2. a

    P values were calculated using the chi-square test or Fisher exact test if indicated.

Sites of treatment failure   
Local only11 (23.4)74 (26.2).681
Local and lymph node2 (4.3)9 (3.2)1.000
Local and distant5 (10.6)12 (4.3).140
Local, lymph node, and distant1 (2.1)5 (1.8)1.000
Lymph node only4 (8.5)18 (6.4).822
Lymph node and distant0 (0.0)9 (3.2).448
Distant only24 (51.1)155 (55.0).619
Total locoregional failure23 (48.9)127 (45.0).619
Total distant failure30 (63.8)181 (64.2).963
Total47282 
Cause of death   
Cancer34 (85.0)188 (87.9).618
Non-cancer causes6 (15.0)26 (12.1) 
Total40214 

Hepatic Adverse Events

Data regarding hepatic adverse events were available for 630 of the 797 patients who received chemotherapy (79.0%). We compared the incidence of hepatic adverse events in HBsAg-positive and HBsAg-negative patients. Hepatic adverse events were found to be more common among those who were HBsAg positive (44.2% vs 19.2%; P < .001). However, the incidence of severe hepatic adverse events (grade 3) was similar between groups (3.5% vs 0.9%; P = .145); no grade 4 hepatic adverse events or deaths related to liver failure were reported to have occurred. Among the 96 HBsAg-positive patients who received chemotherapy, 4 (4.2%) experienced disruption of chemotherapy due to hepatic adverse events; these patients received hepatica (diammonium glycyrrhizinate, glycyrrhizin, reduced glutathione, or polyene phosphatidylcholine) with or without lamivudine. After the patients' hepatic function recovered, they all completed the planned chemotherapy. No patients in the HBsAg-negative group experienced disruption of chemotherapy due to hepatic adverse events.

Prognostic Value of Chronic HBV Infection in Patients With NPC

The 5-year OS rate (70.9% vs 80.8%; P = .003) (Fig. 1A), PFS rate (63.7% vs 73.0%; P = .016) (Fig. 1B), and LRFS rate (81.7% vs 88.2%; P = .035) (Fig. 1C) for HBsAg-positive patients were significantly lower than the corresponding rates for HBsAg-negative patients with NPC; the difference in the DMFS rates between HBsAg-positive and HBsAg-negative patients with NPC nearly reached statistical significance (77.3% vs 84.0%; P = .062) (Fig. 1D). Overall, on univariate analysis, patients with NPC who were HBsAg positive had a significantly poorer prognosis in terms of OS, PFS, and LRFS compared with HBsAg-negative patients.

image

Figure 1. Kaplan-Meier survival curves are shown for (A) overall survival, (B) progression-free survival, (C) locoregional recurrence-free survival, and (D) distant metastasis-free survival in hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative patients with nasopharyngeal carcinoma. Hazards ratios (HRs) were calculated using the unadjusted Cox proportional hazards model. P values were calculated using the unadjusted log-rank test. 95% CI indicates 95% confidence interval.

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Multivariate analysis was performed to adjust for various prognostic factors. Consistent with the results of the univariate analysis, HBsAg seropositivity was found to be an independent unfavorable prognostic factor for OS (hazards ratio [HR], 1.684; 95% confidence interval [95% CI], 1.198-2.366 [P = .003]), PFS (HR, 1.451; 95% CI, 1.076-1.955 [P = .015]), and LRFS (HR, 1.573; 95% CI, 1.005-2.463 [P = .048]) (Table 3). HBsAg-positive patients with NPC also had an increased risk of distant metastasis compared with HBsAg-negative patients; this difference was marginally statistically significant (HR, 1.471; 95% CI, 0.999-2.167 [P = .051]) (Table 3). Both advanced T classification and advanced N classification were associated with an increased risk of death, disease progression, and distant metastasis in the entire cohort (Table 3).

Table 3. Multivariate Analysis of Prognostic Factors for Patients With NPC (n = 1301)
EndpointVariablePaHR95% CI for HR
  1. Abbreviations: 95% CI, 95% confidence interval; DMFS, distant metastasis-free survival; HBsAg, hepatitis B surface antigen; HR, hazards ratio; LRFS, locoregional recurrence-free survival; NPC, nasopharyngeal carcinoma, OS, overall survival; PFS, progression-free survival; RT, radiotherapy.

  2. a

    P values were calculated using an adjusted Cox proportional hazards model.

  3. b

    According to the 7th edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system.

OSHBsAg status.0031.6841.198–2.366
 Age.0031.4561.132–1.872
 T categoryb<.0011.7661.357–2.298
 N categoryb<.0011.6161.254–2.083
 RT techniques.0190.7270.557–0.949
PFSHBsAg status.0151.4511.076–1.955
 Age.0081.3331.079–1.647
 Sex.0750.7960.620–1.024
 T categoryb.0031.3781.115–1.703
 N categoryb.0051.3691.102–1.702
 RT techniques.0150.7620.612–0.948
LRFSHBsAg status.0481.5731.005–2.463
 Age.0131.5111.090–2.096
 Sex.0160.5880.382–0.904
 RT techniques.0240.6690.472–0.949
 Chemotherapy.0741.3690.971–1.930
DMFSHBsAg status.0511.4710.999–2.167
 T categoryb.0081.4831.110–1.981
 N categoryb.0011.6351.227–2.179
 Chemotherapy.0610.7550.563–1.013

Prognostic Value of Chronic HBV Infection in Patients With Early-Stage and Locoregionally Advanced NPC

We analyzed the prognostic significance of chronic HBV infection in patients with early-stage NPC and locoregionally advanced NPC. In patients with stage I/II NPC, OS (87.0% vs 88.1%; P = .595) (Fig. 2A), PFS (80.8% vs 77.7%; P = .842) (Fig. 2C), LRFS (92.8% vs 88.2%; P = .418) (Fig. 2E), and DMFS (84.6% vs 88.6%; P = .617) were comparable between patients who were HBsAg positive and those who were HBsAg negative. Among patients with stage III/IV NPC, HBsAg-positive patients had poorer OS (64.0% vs 77.2%; P = .003) (Fig. 2B), PFS (56.2% vs 70.6%; P = .004) (Fig. 2D), and LRFS (76.2% vs 88.3%; P = .002) (Fig. 2E) rates, and trended toward inferior DMFS rates (74.2% vs 81.7%; P = .065) compared with HBsAg-negative patients. On multivariate analysis, chronic HBV infection was found to be an independent prognostic factor for poorer OS (HR, 1.734; 95% CI, 1.195-2.517 [P = .004]), PFS (HR, 1.644; 95% CI, 1.180-2.291 [P = .003]), and LRFS (HR, 2.108; 95% CI, 1.288-3.449 [P = .003]) (Table 4) in patients with stage III/IV NPC; the effect of chronic HBV infection on DMFS was found to be marginally significant (HR, 1.530; 95% CI, 0.989-2.366 [P = .056]) (Table 4).

image

Figure 2. Kaplan-Meier survival curves are shown for (A and B) overall survival, (C and D) progression-free survival, and (E and F) locoregional recurrence-free survival in hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative patients with (A, C, and E) stage I/II nasopharyngeal carcinoma (NPC) or (B, D, and F) stage III/IV NPC. Hazards ratios (HRs) were calculated using the unadjusted Cox proportional hazards model. P values were calculated using the unadjusted log-rank test.

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Table 4. Multivariate Analysis of Prognostic Factors for Patients With Locoregionally Advanced NPC (N = 872)
EndpointVariablePaHR95% CI for HR
  1. Abbreviations: 95% CI, 95% confidence interval; DMFS, distant metastasis-free survival; HBsAg, hepatitis B surface antigen; HR, hazards ratio; LRFS, locoregional recurrence-free survival; NPC, nasopharyngeal carcinoma, OS, overall survival; PFS, progression-free survival; RT, radiotherapy.

  2. a

    P values were calculated using an adjusted Cox proportional hazards model.

  3. b

    According to the 7th edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system.

OSHBsAg status.0041.7341.195–2.517
 N categoryb.0091.5061.106–2.050
 T categoryb.0611.5000.982–2.294
 Sex.0810.7360.522–1.038
 RT techniques.0010.5930.435–0.809
 Age.0081.4591.101–1.932
PFSHBsAg status.0031.6441.180–2.291
 RT techniques<.0010.6170.473–0.805
 Age.0141.3611.065–1.739
LRFSHBsAg status.0032.1081.288–3.449
 Sex.0480.5980.359–0.995
 RT techniques.0020.4780.302–0.757
 Age.0081.6981.149–2.508
DMFSHBsAg status.0561.5300.989–2.366
 N categoryb.0621.3420.985–1.830
 Chemotherapy.0570.7230.517–1.010
 RT techniques.0930.7510.537–1.049

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

According to previous studies, the prognosis of patients with NPC is far from clearly defined.[2] To our knowledge, the current study is the first large-scale study to determine the impact of chronic HBV infection on the prognosis of patients with nonmetastatic NPC from a population with a high prevalence of both HBV infection and NPC. The HBsAg seropositivity rate in our cohort of patients with NPC was 10.9%, which was similar to that of the general population in this area.[3] Moreover, patients with NPC and chronic HBV infection tended to be younger than patients without HBV infection. Previous studies regarding the association between HBV infection and malignant diseases have mainly focused on HBV reactivation, a complication that can be induced by immunosuppressive therapies.[16] However, to the best of our knowledge, few studies to date have investigated the influence of chronic HBV infection on the prognosis of patients with cancer, especially those with nonhematological malignancies. The current study is the first to our knowledge to provide evidence that chronic HBV infection represents a significant, unfavorable prognostic factor in patients with nonmetastatic locoregionally advanced NPC.

The extent of hepatic injury noted during chemotherapy in the current study was mild, which is consistent with our previously published clinical trial in which no grade 3-4 hepatic adverse events occurred.[17] However, HBV reactivation and the associated liver failure are crucial complications in HBV-infected patients with cancer who are receiving chemotherapy.[16, 18] Compared with uninfected patients, Yeo et al reported a significantly higher incidence of severe hepatitis in HBV-infected patients with NPC who underwent chemotherapy without antiviral prophylaxis, including 1 death that was attributable to HBV reactivation.[11] However, in the current study cohort, the incidence of severe hepatitis during chemotherapy did not differ significantly between HBsAg-positive and HBsAg-negative patients, with only 3.5% of patients developing hepatitis of grade 3 or higher and no HBV reactivation-related deaths being reported. This inconsistency might be due to some obvious differences between the patients included in the study by Yeo et al[11] and the current study. Only patients with nonmetastatic disease who were treatment-naive were eligible for the current study. However, compared with the current study, nearly one-half of the patients (9 of 21 patients) included in the study by Yeo et al[11] received salvage chemotherapy, which may include more intensive chemotherapy regimens and increased cycles of chemotherapy. Also, patients with recurrent or metastatic disease who receive salvage chemotherapy are believed to have a poorer tolerance to cytotoxic agents, and 2 patients in the study by Yeo et al had preexisting liver metastases.[11] However, given the retrospective nature of these studies, hepatic injury in HBV-infected patients with NPC undergoing chemotherapy still needs further study.

In the current study, HBV reactivation and the related liver failure were not found to be significant complications in HBsAg-positive patients with NPC who were receiving chemotherapy. The HBsAg-positive patients in the current study did not receive prophylactic antiviral agents, because such prophylaxis was not highly recommended in the guidelines at the time the treatment was administered. This makes HBV reactivation the first suspected cause of the poorer survival outcomes observed in HBsAg-positive patients with NPC. According to previous studies, HBV reactivation can occur in patients with cancer, particularly those with hematological malignancies, who are receiving treatment with corticosteroids, anthracycline, or rituximab.[16] However, these risk factors for HBV reactivation do not apply to patients with NPC. Moreover, there was no significant difference noted regarding the incidence of non–cancer-related deaths between the HBsAg-positive and HBsAg-negative patients with NPC. These results suggest that HBV reactivation was not the primary factor responsible for the poorer survival outcomes observed in HBsAg-positive patients with NPC. Consequently, it is reasonable to speculate that chronic HBV infection negatively affects the survival of patients with locoregionally advanced NPC via a mechanism other than HBV reactivation.

The latent mechanism leading to the unfavorable prognosis in HBV-infected patients with NPC may be linked to certain types of immunological dysfunction. HBV is associated with immune dysfunction, as demonstrated by hepatitis B-related nephritis[19] and its association with lymphoma.[8] Overexpression of the immunosuppressive protein programmed cell death protein 1 (PD-1) on total CD8-positive T cells[20] and the lower proliferative capability of activated B cells[21] indicate the existence of immune system dysfunction in patients with chronic HBV infection. In addition, the results of the current study suggest that chronic HBV infection has an adverse effect on the prognosis of patients with locoregionally advanced NPC, but not those with early-stage NPC. This phenomenon may be explained by immune suppression in patients with locoregionally advanced NPC. Ho et al reported that expression of the Fas ligand on the membrane of NPC cells was found to significantly and positively correlate with disease stage.[22] Klibi et al demonstrated that NPC cells could exert immune suppressive functions at the systemic level.[23] Moreover, patients with locoregionally advanced NPC tend to receive chemotherapy, which would add additional insult to the already injured immune system. Thus, a subtle interplay may exist between the influence of chronic HBV infection and NPC cells on the immune system, which may negatively affect host immunological monitoring of malignant cells in patients with locoregionally advanced NPC. However, this hypothesis needs to be addressed in future studies. In addition, the potential value of immunotherapeutic strategies in HBV-infected patients with locoregionally advanced NPC needs to be explored.[24]

The results of the current study provide what to our knowledge is the first evidence of the poor prognostic impact of chronic HBV infection on the prognosis of patients with locoregionally advanced NPC. Therefore, researchers conducting clinical trials in patients with NPC should pay attention to the HBsAg seropositivity rates in different treatment arms, especially in regions of endemic chronic HBV infection. However, because of a lack of data regarding HBV DNA load, which is a major drawback of the current study, it remains unknown whether patients with NPC who displayed higher HBV replication rates had poorer survival outcomes. Conversely, although hepatic adverse events noted in the current study were mild and no HBV-related liver failure was documented, we cannot conclude that prophylactic antiviral therapy for patients with NPC who are receiving chemotherapy is unnecessary due to the retrospective nature of the current study and the finding that HBV DNA fluctuations were not monitored. The guidelines for the management of chronic HBV infection published by the European Association for the Study of the Liver, which were updated in 2009, strongly recommend that all HBsAg-positive patients who are candidates for chemotherapy should receive antiviral prophylaxis, regardless of their HBV DNA load.[4] Moreover, the influence of antiviral prophylaxis on the survival of HBV-infected patients with NPC is of great interest and warrants further research.

Conclusions

In the current study, chronic HBV infection was found to be an independent unfavorable prognostic factor in patients with locoregionally advanced NPC. Further prospective studies of large cohorts of patients with NPC that include an analysis of HBV DNA load are warranted to confirm these results. In addition, the latent mechanism by which chronic HBV infection leads to poorer survival outcomes in patients with locoregionally advanced NPC needs to be investigated.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Supported by grants from the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2010); the Innovation Team Development Plan of the Ministry of Education (No. IRT1297); and the Combination Project of Production, Education, and Research from Guangdong Province and Ministry of Education (No. 2012B091100460).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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