Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience

ABSTRACT

Background: Carmustine (1,3-bis [2-chloroethyl]-1-nitrosourea, or BCNU) wafers are approved for recurrent glioblastoma and newly diagnosed malignant glioma (MG). Based on considerable clinical experience and use in multimodal regimens, the safety of BCNU wafers needs a re-evaluation.

Scope: A review of literature from 1996 to February 2008 was conducted on the safety of BCNU wafer in MG patients using search criteria in Medline, EMBASE, and BIOSIS. Abstracts from relevant US and European meetings were also evaluated. Three Phase III (two were pivotal) and 26 non-Phase III studies met inclusion criteria. Overall incidence was estimated for each adverse event (AE), and data from individual studies were summarised as median (range) rates. Comparisons were based on consistent similarities or differences across overall incidence, median rate and range.

Findings: BCNU wafer group AE rates from the two pivotal Phase III trials ranged from 4–23% for cerebral oedema, 4–9% for intracranial hypertension, 14–16% for healing abnormalities, 5% for CSF leaks, 4–5% for intracranial infection, 19–33% for seizures, 10% for deep vein thrombosis, and 8% for pulmonary embolus. There were no notable differences in AE rates between the two pivotal Phase III and 26 non-Phase III studies. For the non-pivotal studies, the overall incidence of AEs was low, ranging from 0.2% for intracranial hypertension to 9.6% for healing abnormalities. Healing abnormalities, intracranial infection, and seizures were the most consistently reported AEs, having been observed in 16, 12, and 11 studies, respectively. Rates of healing abnormalities appeared higher in recurrent than in newly diagnosed disease. There were no notable differences between BCNU wafer plus adjuvant treatment (e.g., temozolomide) and BCNU wafer alone, with the exception of haematologic toxicity.

Conclusion: This review of safety data for BCNU wafers provides reassurance that the AE rates reported in current treatment strategies including multimodal treatment approaches are comparable to those observed in the initial registration studies. The broad range of AE rates may reflect differences in the perioperative and postoperative management. Clinical experience suggests that strategies may exist to reduce the risk of complications.

Key words: :

• Adverse events
• BCNU wafer
• Carmustine wafer
• Implant
• Malignant glioma
• Safety profile
• Polymer

Acknowledgements

This review was developed with support and funding for editorial assistance from Archimedes Pharma. The authors, however, take full responsibility for the search methodology, the inclusion and interpretation of data and the opinions and conclusions expressed in this article, which are independent of and do not necessarily reflect those of the manufacturer of Gliadel (MGI Pharma, now part of Eisai Inc.) or its licensees (including Archimedes Pharma).

The authors disclose that they have no conflicts of interest and that no funding was received regarding this review. We would like to thank Michael Raffin and Joe Riley (both of Nexus Communications, Inc.) for their editorial support during preparation of this manuscript and Susan Wingeron (of Nexus Communications, Inc.) for project management; both of these activities were financially supported by Archimedes Pharma.

Notes

* Gliadel Wafer is a trade name of MGI Pharma, Bloomington, MN, USA, now a part of Eisai, Inc.; the product is distributed in the UK, France and Germany by Archimedes Pharma (Reading, UK)

† Temodar is a trade name of Schering-Plough, Kenilworth, NJ, USA

‡ BiCNU is a trade name of Bristol Myers Squibb Company, Princeton, NJ, USA

§ CeeNU is a trade name of Bristol Myers Squibb Company, Princeton, NJ, USA