Clin J Gastroenterol (2009) 2:214–217 DOI 10.1007/s12328-009-0063-2
CASE REPORT
Use of entecavir to prevent hepatitis B virus reactivation during cytotoxic chemotherapy for solid malignancy Riki Okita Æ Mamoru Takahashi Æ Hiroyuki Narahara Æ Yuichi Sanada Æ Morihito Okada Æ Yoshiiku Kawakami Æ Kazuaki Chayama Æ Kiwamu Okita
Received: 14 September 2008 / Accepted: 18 December 2008 / Published online: 21 February 2009 Ó Springer 2009
Abstract Reactivation of hepatitis B virus (HBV) infection is a frequent complication of cytotoxic chemotherapy that includes steroids. International studies have shown that lamivudine reduces the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy to treat malignancies. However, prolonged lamivudine therapy is associated with an increased risk of drug-resistant tyrosinemethionine-aspartate-aspartate (YMDD) mutations. Here, we studied the role of entecavir in preventing morbidity and mortality associated with HBV reactivation. Three patients with both solid malignancies and hepatitis B surface antigen-positive hepatitis B underwent cytotoxic chemotherapy with steroids. They were followed up for at
R. Okita M. Takahashi H. Narahara Department of Clinical Oncology, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan M. Takahashi Department of Breast Surgery, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan Present Address: R. Okita (&) Y. Sanada M. Okada Department of Surgical Oncology, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan e-mail: [email protected] Y. Kawakami K. Chayama Department of Medicine and Molecular Science, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan K. Okita Department of Gastroenterology, Shimonoseki Kosei Hospital, Kamishinchi-cho 3-3-8, Shimonoseki, Yamaguchi 750-0061, Japan
123
least 6 months after the completion of chemotherapy. The chemotherapeutic regimens comprised carboplatin and paclitaxel for non-small-cell lung cancer, and docetaxel monotherapy or cyclophosphamide plus epirubicin for breast cancer, respectively. All patients completed chemotherapy with steroids without developing severe hepatitis that could be attributable to HBV reactivation. Entecavir prevented the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy for malignancies. Although further studies are required to evaluate whether entecavir can prevent the increased risk of YMDD mutation and decrease the rates of disrupted chemotherapy due to severe hepatitis more effectively than lamivudine, entecavir should be considered before lamivudine for such patients. Keywords Solid malignancy Chemotherapy Hepatitis B virus Entecavir Steroid
Introduction Reactivation of hepatitis B virus (HBV) replication is an established complication among patients with chronic HBV infection who undergo cytotoxic chemotherapy for several malignancies [1–3]. Lamivudine was the first nucleoside analogue to inhibit HBV replication and reduce the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy [4–7]. However, prolonged lamivudine therapy is associated with an increased risk of drug-resistant mutants with amino acid substitutions in the tyrosinemethionine-aspartate-aspartate (YMDD) motif [5]. Entecavir is a highly selective HBV inhibitor that does not affect mitochondrial DNA synthesis [8]. Several phase III studies have demonstrated that the rates of histological, virological,
Clin J Gastroenterol (2009) 2:214–217
215
and biochemical improvement are significantly higher in patients with chronic hepatitis B who receive entecavir as the primary therapy compared with lamivudine [9, 10]. Here, we examined the role of entecavir in preventing HBV reactivation-associated morbidity and mortality.
of HBV-DNA were measured using the TMA-HPA (Fujirebio). The measurement range of the assay is 103.7–108.7 genome equivalents (GE)/ml (3.7–8.7 LGE/ml). Anti-HCV antibody was tested using a third-generation enzyme immunoassay (Ortho HCV, Orthoclinical Diagnostics, Tokyo, Japan).
Patients and methods Definition of hepatitis Patients with solid malignancies who were positive for hepatitis B surface antigen (HBsAg) underwent cytotoxic chemotherapy with regimens containing steroids as follows: carboplatin (CBDCA) combined with paclitaxel (Pac) in the induction setting with concurrent radiotherapy for patients with non-small-cell lung cancer, second line docetaxel (Doc) monotherapy and third line cyclophosphamide (CPA) combined with epirubicin (Epi) for patients with metastatic breast cancer, and CPA combined with Epi in the adjuvant setting for patients with breast cancer.
Based on the definition described by Yeo et al. [4], breakthrough hepatitis was defined as an increase of more than threefold in the ALT level that exceeded 1.25 9 ULN of 50 U/l or an absolute increase in the ALT level to [100 U/l compared with the baseline, before starting chemotherapy. The severity of hepatitis was judged according to the criteria established by the World Health Organization as: grade 1, ALT or total bilirubin [1.25– 2.5 9 ULN; grade 2, [2.5 9 ULN; grade 3, up to 5.0 9 ULN.
Investigations Use of entecavir The following parameters were measured in all patients before starting therapy: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), HBV-DNA, hepatitis C antibody (HCVAb), complete blood count (CBC), renal function (RF; urea and creatinine), and liver function (LF; albumin, total bilirubin, ALT; alkaline phosphatase). The CBC, RF and LF were monitored with clinical signs and symptoms in all patients on day 1 of each chemotherapy cycle. Toxicity of the chemotherapy was evaluated with the National Cancer Institute Common Toxicity Criteria Tumor (NCI-CTC; version 3.0). These parameters were measured for at least for 6 months after chemotherapy had been completed.
Hepatitis serology and HBV-DNA assay Hepatitis B markers were measured using commercial enzyme immunoassays (Fujirebio, Tokyo, Japan). Levels
Entecavir (0.5 mg/day) was administered p.o. from 1 to 7 days before chemotherapy and continued at least for 6 months after the completion of chemotherapy.
Results Table 1 shows the backgrounds of the three patients. Case 1 involved primary breast cancer in a 35-year-old Japanese woman with chronic hepatitis B who received surgical treatment. A histological examination disclosed invasive ductal carcinoma, pT1N0M0 stage I with positive estrogen receptor (ER), negative progesterone receptor (PgR), and no human epidermal growth factor receptor-2/ neu (HER2/neu) expression. Adjuvant chemotherapy was advised following the recommendation for adjuvant therapy of breast cancer by the International Expert Consensus on Primary Therapy for Early Breast Cancer 2005 [11]. However, only adjuvant endocrine therapy was administered,
Table 1 Background of patients Patient
Age/gender
Baseline serology/titer (IU/ml)
Case 1 Case 2
35/F 49/F
HBsAg?/2,000 HBsAg?/2,000
Case 3
72/M
HBsAg?/6.4
HBV-DNA (log copies/ml)
HBeAb (%)
HCV Ab
Diagnosis
Stage
Type of CTx
4.4 5.5
? (100) ? (99.5)
-
BC BC
Distant mets pT2N0M0 stage IIA
For rec Adjuvant
\2.6
? (88.5)
?
NSCLC
cT2N2M0 stage IIIA
Induction
BC breast cancer, NSCLC non-small-cell lung cancer, mets metastases, rec recurrence
123
216
Clin J Gastroenterol (2009) 2:214–217
because both cytotoxic chemotherapy and steroids as support therapy comprise high risk factors for worsening hepatitis due to HBV reactivation among carriers. Therefore, she received only adjuvant endocrine therapy. Unfortunately, metastatic lesions were discovered 1 year later. After confirming the ineffectiveness of additional endocrine therapy and first line chemotherapy using capecitabin, second line Doc monotherapy without steroid combined with entecavir was administered. However, the metastatic lesions continued to proliferate despite three courses of Doc monotherapy. She then underwent third line chemotherapy using CPA combined with Epi and entecavir prophylaxis, and seven courses of CPA ? Epi therapy without worsening. Nevertheless, the patient died of advanced breast cancer without improvement by several active therapies. Hepatitis never worsened until her death. Case 2 involved a 49-year-old Japanese woman with chronic hepatitis B without evidence of cirrhosis who was diagnosed with primary breast cancer that was surgically resected. Pathological findings revealed stage IIA invasive ductal carcinoma. Adjuvant chemotherapy was administered because the tumor was at high risk for recurrence. She underwent four cycles of CPA ? Epi therapy without disruption of chemotherapy. Hepatitis did not occur during the concomitant use of entecavir. Case 3 involved a 72-year-old Japanese man with stage IIIA NSCLC accompanied by chronic hepatitis B and C who was treated with four cycles of weekly CBDCA ? Pac Table 2 Chemotherapeutic regimens Patient Dose Steroid Regimen no. reduction/ skip
Concurrent Course RTx no.
Case 1 -
?
2nd Doc
-
2
3rd EC
?
7
Case 2 Case 3 ?
? ?
EC CBDCA ? Pac ?
4 1
RTx radiotherapy, Doc docetaxel, EC epirubicin and cyclophosphamide, CBDCA carboplatin, Pac paclitaxel
therapy combined with radiation therapy (total dose, 40 Gy). Entecavir was simultaneously administered to prevent worsening hepatitis. Before enrollment, LF tests did not reveal a remarkable increase in ALT and AST except for 1.8 mg/ml of total bilirubin. After partial remission, right sleeve upper lobectomy and mediastinal lymph node dissection proceeded without complications. Although entecavir administration for 6 months inhibited an increase in the amount of HBV-DNA, NSCLC recurred 6 months after surgery.
Discussion Patients with hematological or solid malignancies generally undergo standard chemotherapy. Because of the cytotoxicity of regimens containing steroids and during the period of immunosuppression resulting from chemotherapy, HBV replication can reappear in carriers, and the rapid recovery of host immunity after the cessation of chemotherapy sometimes results in severe liver disease [2, 12]. Recent reports indicate that lamivudine, an inhibitor of HBV replication, significantly reduces worsening hepatitis even in HBV carriers undergoing chemotherapy [4–7]. International recommendations have been established to reduce such complications among HBV carriers treated with steroids or anti-cancer drugs. Lamivudine should be started 2–4 weeks before the administration of anti-cancer therapies with steroids or cytotoxic agents that induce host immunosuppression, or at the first signs of hepatitis exacerbation, and maintained for 6 months or even 1 year after chemotherapy is completed [13, 14]. However, lamivudine therapy for over 6 months often induces HBV variants accompanied by the YMDD mutation, which confers resistance to lamivudine [15]. Two reports indicated that these mutations appeared in up to 32% of patients 1 year after lamivudine therapy [16, 17]. Therefore, lamivudine therapy does not always confer an advantage. Entecavir is a selective guanosine analogue that potently blocks HBV replication. Several phase III studies have
Table 3 Serological status and adverse events during chemotherapy with entecavir Patient no. Case 1
Pre HBV-DNA/ HBe Ag
In HBV-DNA/ HBeAg
Post HBV-DNA/ HBeAg (titer)
T-bil
ALT/AST
BUN/Cre
WBC
Hgb
Plt
Others
4.4
ND
\2.6
G0
G1
G0
G4
G1
G0
Alopecia G2
G0
G0
G0
G2
G1
G0
Alopecia G2
G2
G1
G0
G1
G1
G1
Esophagitis G1
0.1 Case 2 Case 3
ND
5.5
2.9
3.2
0.21
ND
ND
\2.6
\2.6
\2.6
0.22
0.23
0.30
Pre before starting entecavir, In a month after starting entecavir, Post more than 6 months after starting entecavir, ND no data, G grade by NCICTC version 3.0
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Table 4 Outcome of hepatitis B and overall survival after starting chemotherapy with entecavir Patient no.
Pre-severity of hepatitis
Post-severity of hepatitis
Incidence of hepatitis
Outcome about malignancy
Outcome about CH-B
OS time (month)
Case 1
G0
G1
–
Death for BC
Stable
Case 2
G0
G0
–
No rec
Stable
7
Case 3
G1
G0
–
6 M rec
Stable
10
8
Outcome about malignancy Dead by BC Alive without rec Alive with rec
CH-B chronic hepatitis B, BC breast cancer, M month, rec recurrence, OS time overall survival time from starting chemotherapy with entecavir
demonstrated that histological, virological, and biochemical improvements are significantly more obvious among patients administered entecavir than with lamivudine [9, 10]. Clinical studies have also demonstrated that resistance develops less frequently to entecavir than to lamivudine [18]. In our results, all patients completed several cytotoxic chemotherapies with steroids without developing severe hepatitis that could be attributable to HBV reactivation (Tables 2, 3, 4). Entecavir may prevent the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy for malignancies. Worsening hepatitis is a critical issue among patients with cancer, because induced liver failure might contribute to an increase in mortality. Colson et al. [19] reported a successful case of HBV reactivation undergoing cytotoxic chemotherapy by entecavir; however, it is more important to prevent worsening hepatitis to increase the compliance of chemotherapy and decrease the mortality. Entecavir should be considered both before cytotoxic chemotherapy and before lamivudine from these viewpoints. Conflict of interest statement
None declared.
References 1. Galbraith RM, Eddleston AL, Williams R, Zuckerman AJ. Fulminant hepatic failure in leukemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet. 1975;2:528–30. 2. Wands JR, Chura CM, Roll FJ, Maddrey WC. Serial studies of hepatitis associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology. 1975;68:105–12. 3. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology. 2001;120:1009–22. 4. Yeo W, Ho WM, Hui P, Chan PKS, Lam KC, Lee JJ, et al. Use for lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients. Breast Cancer Res Treat. 2004;88:209–15. 5. Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519–28.
6. Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, et al. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology. 2008;47:844–53. 7. Li YH, He YF, Jiang WQ, Wang FH, Lin XB, Zhang L, et al. Lamivudine prophylaxis reduces the incidence and severity of hepatitis in hepatitis B virus carriers who receive chemotherapy for lymphoma. Cancer. 2006;106:1320–5. 8. Innaimo SF, Seifer M, Bisacchi GS, Standring DN, Zahler R, Colonno RJ. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus. Antimicrob Agents Chemother. 1997;41:1444–8. 9. Chang TT, Gish RG, Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAgpositive chronic hepatitis B. N Engl J Med. 2006;354:1001–10. 10. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAgnegative chronic hepatitis B. N Engl J Med. 2006;354:1011–20. 11. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ, Panel Members. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; 16: 1569–1583. 12. Liang R, Lau GKK, Kwong YL. Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem. J Clin Oncol. 1999;17:394–8. 13. EASL Jury. EASL international consensus conference on hepatitis B. J Hepatol 2003; 38: 533–540. 14. Lok ASF, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857–61. 15. Ling R, Mutimer D, Ahmed M, Boxall EH, Elias E, Dusheiko GM, et al. Selection of mutation in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine. Hepatology. 1996;24:711–3. 16. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med. 1998;339:61–8. 17. Villeneuve JP, Condreay LD, Willems B, Pomier Layrargues G, Fenyves D, Bilodeau M, et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology. 2000;31:207–10. 18. Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob Agents Chemother. 2004; 48:3498–507. 19. Colson P, Borentain P, Coso D, Chabannon C, Tamalet C, Gerolami R. Entecavir as a first-line treatment for HBV reactivation following polychemotherapy for lymphoma. Br J Haematol. 2008;143:148–50.
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CASE REPORT
Use of entecavir to prevent hepatitis B virus reactivation during cytotoxic chemotherapy for solid malignancy Riki Okita Æ Mamoru Takahashi Æ Hiroyuki Narahara Æ Yuichi Sanada Æ Morihito Okada Æ Yoshiiku Kawakami Æ Kazuaki Chayama Æ Kiwamu Okita
Received: 14 September 2008 / Accepted: 18 December 2008 / Published online: 21 February 2009 Ó Springer 2009
Abstract Reactivation of hepatitis B virus (HBV) infection is a frequent complication of cytotoxic chemotherapy that includes steroids. International studies have shown that lamivudine reduces the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy to treat malignancies. However, prolonged lamivudine therapy is associated with an increased risk of drug-resistant tyrosinemethionine-aspartate-aspartate (YMDD) mutations. Here, we studied the role of entecavir in preventing morbidity and mortality associated with HBV reactivation. Three patients with both solid malignancies and hepatitis B surface antigen-positive hepatitis B underwent cytotoxic chemotherapy with steroids. They were followed up for at
R. Okita M. Takahashi H. Narahara Department of Clinical Oncology, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan M. Takahashi Department of Breast Surgery, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan Present Address: R. Okita (&) Y. Sanada M. Okada Department of Surgical Oncology, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan e-mail: [email protected] Y. Kawakami K. Chayama Department of Medicine and Molecular Science, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan K. Okita Department of Gastroenterology, Shimonoseki Kosei Hospital, Kamishinchi-cho 3-3-8, Shimonoseki, Yamaguchi 750-0061, Japan
123
least 6 months after the completion of chemotherapy. The chemotherapeutic regimens comprised carboplatin and paclitaxel for non-small-cell lung cancer, and docetaxel monotherapy or cyclophosphamide plus epirubicin for breast cancer, respectively. All patients completed chemotherapy with steroids without developing severe hepatitis that could be attributable to HBV reactivation. Entecavir prevented the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy for malignancies. Although further studies are required to evaluate whether entecavir can prevent the increased risk of YMDD mutation and decrease the rates of disrupted chemotherapy due to severe hepatitis more effectively than lamivudine, entecavir should be considered before lamivudine for such patients. Keywords Solid malignancy Chemotherapy Hepatitis B virus Entecavir Steroid
Introduction Reactivation of hepatitis B virus (HBV) replication is an established complication among patients with chronic HBV infection who undergo cytotoxic chemotherapy for several malignancies [1–3]. Lamivudine was the first nucleoside analogue to inhibit HBV replication and reduce the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy [4–7]. However, prolonged lamivudine therapy is associated with an increased risk of drug-resistant mutants with amino acid substitutions in the tyrosinemethionine-aspartate-aspartate (YMDD) motif [5]. Entecavir is a highly selective HBV inhibitor that does not affect mitochondrial DNA synthesis [8]. Several phase III studies have demonstrated that the rates of histological, virological,
Clin J Gastroenterol (2009) 2:214–217
215
and biochemical improvement are significantly higher in patients with chronic hepatitis B who receive entecavir as the primary therapy compared with lamivudine [9, 10]. Here, we examined the role of entecavir in preventing HBV reactivation-associated morbidity and mortality.
of HBV-DNA were measured using the TMA-HPA (Fujirebio). The measurement range of the assay is 103.7–108.7 genome equivalents (GE)/ml (3.7–8.7 LGE/ml). Anti-HCV antibody was tested using a third-generation enzyme immunoassay (Ortho HCV, Orthoclinical Diagnostics, Tokyo, Japan).
Patients and methods Definition of hepatitis Patients with solid malignancies who were positive for hepatitis B surface antigen (HBsAg) underwent cytotoxic chemotherapy with regimens containing steroids as follows: carboplatin (CBDCA) combined with paclitaxel (Pac) in the induction setting with concurrent radiotherapy for patients with non-small-cell lung cancer, second line docetaxel (Doc) monotherapy and third line cyclophosphamide (CPA) combined with epirubicin (Epi) for patients with metastatic breast cancer, and CPA combined with Epi in the adjuvant setting for patients with breast cancer.
Based on the definition described by Yeo et al. [4], breakthrough hepatitis was defined as an increase of more than threefold in the ALT level that exceeded 1.25 9 ULN of 50 U/l or an absolute increase in the ALT level to [100 U/l compared with the baseline, before starting chemotherapy. The severity of hepatitis was judged according to the criteria established by the World Health Organization as: grade 1, ALT or total bilirubin [1.25– 2.5 9 ULN; grade 2, [2.5 9 ULN; grade 3, up to 5.0 9 ULN.
Investigations Use of entecavir The following parameters were measured in all patients before starting therapy: hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), HBV-DNA, hepatitis C antibody (HCVAb), complete blood count (CBC), renal function (RF; urea and creatinine), and liver function (LF; albumin, total bilirubin, ALT; alkaline phosphatase). The CBC, RF and LF were monitored with clinical signs and symptoms in all patients on day 1 of each chemotherapy cycle. Toxicity of the chemotherapy was evaluated with the National Cancer Institute Common Toxicity Criteria Tumor (NCI-CTC; version 3.0). These parameters were measured for at least for 6 months after chemotherapy had been completed.
Hepatitis serology and HBV-DNA assay Hepatitis B markers were measured using commercial enzyme immunoassays (Fujirebio, Tokyo, Japan). Levels
Entecavir (0.5 mg/day) was administered p.o. from 1 to 7 days before chemotherapy and continued at least for 6 months after the completion of chemotherapy.
Results Table 1 shows the backgrounds of the three patients. Case 1 involved primary breast cancer in a 35-year-old Japanese woman with chronic hepatitis B who received surgical treatment. A histological examination disclosed invasive ductal carcinoma, pT1N0M0 stage I with positive estrogen receptor (ER), negative progesterone receptor (PgR), and no human epidermal growth factor receptor-2/ neu (HER2/neu) expression. Adjuvant chemotherapy was advised following the recommendation for adjuvant therapy of breast cancer by the International Expert Consensus on Primary Therapy for Early Breast Cancer 2005 [11]. However, only adjuvant endocrine therapy was administered,
Table 1 Background of patients Patient
Age/gender
Baseline serology/titer (IU/ml)
Case 1 Case 2
35/F 49/F
HBsAg?/2,000 HBsAg?/2,000
Case 3
72/M
HBsAg?/6.4
HBV-DNA (log copies/ml)
HBeAb (%)
HCV Ab
Diagnosis
Stage
Type of CTx
4.4 5.5
? (100) ? (99.5)
-
BC BC
Distant mets pT2N0M0 stage IIA
For rec Adjuvant
\2.6
? (88.5)
?
NSCLC
cT2N2M0 stage IIIA
Induction
BC breast cancer, NSCLC non-small-cell lung cancer, mets metastases, rec recurrence
123
216
Clin J Gastroenterol (2009) 2:214–217
because both cytotoxic chemotherapy and steroids as support therapy comprise high risk factors for worsening hepatitis due to HBV reactivation among carriers. Therefore, she received only adjuvant endocrine therapy. Unfortunately, metastatic lesions were discovered 1 year later. After confirming the ineffectiveness of additional endocrine therapy and first line chemotherapy using capecitabin, second line Doc monotherapy without steroid combined with entecavir was administered. However, the metastatic lesions continued to proliferate despite three courses of Doc monotherapy. She then underwent third line chemotherapy using CPA combined with Epi and entecavir prophylaxis, and seven courses of CPA ? Epi therapy without worsening. Nevertheless, the patient died of advanced breast cancer without improvement by several active therapies. Hepatitis never worsened until her death. Case 2 involved a 49-year-old Japanese woman with chronic hepatitis B without evidence of cirrhosis who was diagnosed with primary breast cancer that was surgically resected. Pathological findings revealed stage IIA invasive ductal carcinoma. Adjuvant chemotherapy was administered because the tumor was at high risk for recurrence. She underwent four cycles of CPA ? Epi therapy without disruption of chemotherapy. Hepatitis did not occur during the concomitant use of entecavir. Case 3 involved a 72-year-old Japanese man with stage IIIA NSCLC accompanied by chronic hepatitis B and C who was treated with four cycles of weekly CBDCA ? Pac Table 2 Chemotherapeutic regimens Patient Dose Steroid Regimen no. reduction/ skip
Concurrent Course RTx no.
Case 1 -
?
2nd Doc
-
2
3rd EC
?
7
Case 2 Case 3 ?
? ?
EC CBDCA ? Pac ?
4 1
RTx radiotherapy, Doc docetaxel, EC epirubicin and cyclophosphamide, CBDCA carboplatin, Pac paclitaxel
therapy combined with radiation therapy (total dose, 40 Gy). Entecavir was simultaneously administered to prevent worsening hepatitis. Before enrollment, LF tests did not reveal a remarkable increase in ALT and AST except for 1.8 mg/ml of total bilirubin. After partial remission, right sleeve upper lobectomy and mediastinal lymph node dissection proceeded without complications. Although entecavir administration for 6 months inhibited an increase in the amount of HBV-DNA, NSCLC recurred 6 months after surgery.
Discussion Patients with hematological or solid malignancies generally undergo standard chemotherapy. Because of the cytotoxicity of regimens containing steroids and during the period of immunosuppression resulting from chemotherapy, HBV replication can reappear in carriers, and the rapid recovery of host immunity after the cessation of chemotherapy sometimes results in severe liver disease [2, 12]. Recent reports indicate that lamivudine, an inhibitor of HBV replication, significantly reduces worsening hepatitis even in HBV carriers undergoing chemotherapy [4–7]. International recommendations have been established to reduce such complications among HBV carriers treated with steroids or anti-cancer drugs. Lamivudine should be started 2–4 weeks before the administration of anti-cancer therapies with steroids or cytotoxic agents that induce host immunosuppression, or at the first signs of hepatitis exacerbation, and maintained for 6 months or even 1 year after chemotherapy is completed [13, 14]. However, lamivudine therapy for over 6 months often induces HBV variants accompanied by the YMDD mutation, which confers resistance to lamivudine [15]. Two reports indicated that these mutations appeared in up to 32% of patients 1 year after lamivudine therapy [16, 17]. Therefore, lamivudine therapy does not always confer an advantage. Entecavir is a selective guanosine analogue that potently blocks HBV replication. Several phase III studies have
Table 3 Serological status and adverse events during chemotherapy with entecavir Patient no. Case 1
Pre HBV-DNA/ HBe Ag
In HBV-DNA/ HBeAg
Post HBV-DNA/ HBeAg (titer)
T-bil
ALT/AST
BUN/Cre
WBC
Hgb
Plt
Others
4.4
ND
\2.6
G0
G1
G0
G4
G1
G0
Alopecia G2
G0
G0
G0
G2
G1
G0
Alopecia G2
G2
G1
G0
G1
G1
G1
Esophagitis G1
0.1 Case 2 Case 3
ND
5.5
2.9
3.2
0.21
ND
ND
\2.6
\2.6
\2.6
0.22
0.23
0.30
Pre before starting entecavir, In a month after starting entecavir, Post more than 6 months after starting entecavir, ND no data, G grade by NCICTC version 3.0
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217
Table 4 Outcome of hepatitis B and overall survival after starting chemotherapy with entecavir Patient no.
Pre-severity of hepatitis
Post-severity of hepatitis
Incidence of hepatitis
Outcome about malignancy
Outcome about CH-B
OS time (month)
Case 1
G0
G1
–
Death for BC
Stable
Case 2
G0
G0
–
No rec
Stable
7
Case 3
G1
G0
–
6 M rec
Stable
10
8
Outcome about malignancy Dead by BC Alive without rec Alive with rec
CH-B chronic hepatitis B, BC breast cancer, M month, rec recurrence, OS time overall survival time from starting chemotherapy with entecavir
demonstrated that histological, virological, and biochemical improvements are significantly more obvious among patients administered entecavir than with lamivudine [9, 10]. Clinical studies have also demonstrated that resistance develops less frequently to entecavir than to lamivudine [18]. In our results, all patients completed several cytotoxic chemotherapies with steroids without developing severe hepatitis that could be attributable to HBV reactivation (Tables 2, 3, 4). Entecavir may prevent the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy for malignancies. Worsening hepatitis is a critical issue among patients with cancer, because induced liver failure might contribute to an increase in mortality. Colson et al. [19] reported a successful case of HBV reactivation undergoing cytotoxic chemotherapy by entecavir; however, it is more important to prevent worsening hepatitis to increase the compliance of chemotherapy and decrease the mortality. Entecavir should be considered both before cytotoxic chemotherapy and before lamivudine from these viewpoints. Conflict of interest statement
None declared.
References 1. Galbraith RM, Eddleston AL, Williams R, Zuckerman AJ. Fulminant hepatic failure in leukemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet. 1975;2:528–30. 2. Wands JR, Chura CM, Roll FJ, Maddrey WC. Serial studies of hepatitis associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology. 1975;68:105–12. 3. Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology. 2001;120:1009–22. 4. Yeo W, Ho WM, Hui P, Chan PKS, Lam KC, Lee JJ, et al. Use for lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients. Breast Cancer Res Treat. 2004;88:209–15. 5. Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519–28.
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