Correspondence

Fatal Reactivation of Hepatitis B with Temozolomide

N Engl J Med 2007; 356:1591-1592April 12, 2007

Article

To the Editor:

Encouraging results have led to the use of temozolomide as a first-line therapy for glioblastoma.1 We report on a case of temozolomide-associated reactivation of hepatitis B, a complication that may warrant the use of prophylactic antiviral agents during treatment with this chemotherapy.2

A 65-year-old Chinese woman with a remote history of hepatitis B underwent total surgical resection of an enhancing mass in the left temporal lobe, which was diagnosed as glioblastoma. She received radiation therapy with concurrent daily temozolomide (at a dose of 75 mg per square meter of body-surface area), followed by three cycles of adjuvant temozolomide (200 mg per square meter on days 1 through 5 of a 28-day cycle). She was taking valproic acid for seizure prophylaxis, reported no use of alcohol or herbal remedies, and was otherwise healthy. Dexamethasone was tapered and eventually stopped during a 1-week period after surgery. She did not undergo hepatitis studies before starting treatment. Her liver enzyme levels were normal at baseline and before her first two cycles of adjuvant chemotherapy (Table 1Table 1Selected Laboratory Values during Temozolomide Treatment of the Patient.). Although there was a mild, asymptomatic elevation of the alanine aminotransferase level before the third cycle of temozolomide, the chemotherapy was administered as planned.

On day 27 of her third cycle of treatment, the patient was hospitalized because of rapidly progressing encephalopathy. The results of laboratory studies were consistent with acute liver failure, and valproic acid was discontinued. A hepatitis panel was negative for hepatitis C but positive for hepatitis B core antigen and hepatitis B surface antigen (HBsAg). The viral load was more than 500 million particles. Although the patient was treated with entecavir (1 mg daily), her liver function continued to deteriorate, and she died 2 weeks after admission. There was no evidence of tumor recurrence on magnetic resonance imaging after surgery. We attribute her death to hepatitis B reactivation resulting from the use of temozolomide, although hepatotoxic effects of valproic acid or of temozolomide itself cannot be completely ruled out.

It is estimated that more than 1.5 million HBsAg carriers reside in the United States.2 Treatment of hematologic cancers with chemotherapy and corticosteroids imparts a high risk of hepatitis B reactivation (>60%). Reactivation is also associated with pregnancy and liver transplantation and may occur spontaneously. In addition to morbidity from hepatitis, viral reactivation may disrupt cancer treatment, resulting in decreased overall survival. Because of the increasing use of temozolomide in the treatment of brain tumors and systemic cancers,3 prescribing clinicians should be aware of this potentially severe adverse event. Data support the use of antiviral agents for HBsAg carriers during chemotherapy.2 We recommend that hepatitis screening and viral prophylaxis be considered when they are clinically appropriate in patients receiving temozolomide.

Jai Grewal, M.D.
Caryl A. Dellinger, M.D.
W.K.A. Yung, M.D.
M.D. Anderson Cancer Center, Houston, TX 77030
jgrewal@mdanderson.org

Dr. Yung reports serving on an advisory board for and receiving grant and research support and honoraria from Schering-Plough.

3 References

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   Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996
   Full Text | Web of Science | Medline

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   Kohrt HE, Ouyang DL, Keeffe EB. Systematic review: lamivudine prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection. Aliment Pharmacol Ther 2006;24:1003-1016
   CrossRef | Web of Science | Medline

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   Mutter N, Stupp R. Temozolomide: a milestone in neuro-oncology and beyond? Expert Rev Anticancer Ther 2006;6:1187-1204
   CrossRef | Web of Science | Medline

Citing Articles (7)

Citing Articles

1. 1

   Krista A. Nifterik, Jaap den Berg, Ben J. Slotman, M. Vincent M. Lafleur, Peter Sminia, Lukas J. A. Stalpers. (2011) Valproic acid sensitizes human glioma cells for temozolomide and γ-radiation. Journal of Neuro-Oncology
   CrossRef

2. 2

   Yasunori Fujimoto, Naoya Hashimoto, Manabu Kinoshita, Yuko Miyazaki, Satoshi Tanaka, Takayuki Yakushijin, Tetsuo Takehara, Naoki Kagawa, Toshiki Yoshimine. (2011) Hepatitis B virus reactivation associated with temozolomide for malignant glioma: a case report and recommendation for prophylaxis. International Journal of Clinical Oncology
   CrossRef

3. 3

   Gil Redelman-Sidi, Christian Grommes, Genovefa Papanicolaou. (2011) Kitten-transmitted Bordetella bronchiseptica infection in a patient receiving temozolomide for glioblastoma. Journal of Neuro-Oncology 102:2, 335-339
   CrossRef

4. 4

   Marcus Niewald, Christian Berdel, Jochen Fleckenstein, Norbert Licht, Ralf Ketter, Christian Rübe. (2011) Toxicity after radiochemotherapy for glioblastoma using temozolomide - a retrospective evaluation. Radiation Oncology 6:1, 141
   CrossRef

5. 5

   Makoto OHNO, Yoshitaka NARITA, Yasuji MIYAKITA, Hideki UENO, Takamasa KAYAMA, Soichiro SHIBUI. (2011) Reactivation of Hepatitis B Virus After Glioblastoma Treatment With Temozolomide. Neurologia medico-chirurgica 51:10, 728-731
   CrossRef

6. 6

   William Norris, Angelo H Paredes, James H Lewis. (2008) Drug-induced liver injury in 2007. Current Opinion in Gastroenterology 24:3, 287-297
   CrossRef

7. 7

   (2007) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 16:11, i-xii
   CrossRef