Major Research Findings

Carmustine implant, also known as Gliadel wafer, is a controlled-release delivery system of the chemotherapy drug carmustine, designed to treat recurrent glioblastoma multiforme. 5 This treatment has been approved as an adjunct to surgical resection because clinical trials demonstrated its effectiveness and good tolerability. 5 The drug's localized action in brain tissue means direct pharmacokinetic measurements after implantation have not been conducted in humans. 5 Nevertheless, extensive research has been done on drug distribution and clearance in rodent and non-human primate brains at various times after implantation. 5 In vitro and in vivo studies also investigated the degradation of the polymer matrix, the release kinetics of carmustine, and the metabolic fate of the drug and polymer degradation products. 5 GLIADEL wafers have been shown to release carmustine over a period of approximately 5 days in vivo; when in continuous contact with interstitial fluid, they should degrade completely over a period of 6 to 8 weeks. 5 Metabolic elimination studies have shown that sebacic acid monomers are excreted in the form of expired CO(2), while 1,3-bis-(p-carboxyphenoxy)propane monomers are primarily excreted through urine. Carmustine degradation products are also mainly eliminated through urine. 5 Animal pharmacokinetic studies and related modeling indicate that this treatment modality can achieve high-dose delivery (millimolar concentrations) within millimeters of the polymer implant. However, the penetration distance of carmustine from the delivery site is limited. 5 This limited spread is likely due to the high transcapillary permeability of this lipophilic molecule. 5 Nevertheless, significant convective flows resulting from postsurgical edema may enhance the diffusive transport of the drug in the hours following wafer implantation, leading to a larger short-term spread of the drug. 5 Additionally, in non-human primates, significant doses have been observed in distant brain regions (centimeters away from the implant) for up to a week. 5 This drug distribution is likely due to transport from the implant site by cerebral blood flow or cerebrospinal fluid flow, suggesting that while the drug can penetrate the blood-brain barrier at the delivery site, it may re-enter within the brain tissue. 5

Clinical trial data on Carmustine implant (Gliadel Wafer) in Japanese patients with malignant glioma is limited, prompting a postmarketing surveillance study to evaluate Gliadel's safety in real-world clinical practice in Japan. 1 This study enrolled all patients who underwent malignant glioma surgeries and received Gliadel placement from its market launch (January 9, 2013) to July 10, 2013, using a central registration system from 229 institutions. 1 Up to eight Gliadel wafers (containing 61.6 mg of carmustine) were used intraoperatively to cover the tumor resection cavity, depending on its size and shape. 1 The observation period lasted for 3 months after Gliadel placement, and patients were followed up for 1 year postoperatively. 1 Safety was assessed by the incidence of adverse events (AEs) and adverse drug reactions (ADRs). 1

The study included 558 patients, with most (66.7%) receiving eight Gliadel wafers. 1 The percentage of patients experiencing ADRs was 35.7% (365 ADR episodes in 199 patients). 1 Of the AEs of particular interest, the most common were cerebral edema (22.2%, 124/558 patients), convulsion (9.9%, 55/558 patients), impaired healing (4.8%, 27/558 patients), and infection (3.4%, 19/558 patients). 1

This first comprehensive postmarketing surveillance report on Gliadel's safety in real-world clinical practice in Japan suggests that the risk of toxicity associated with Gliadel placement is relatively tolerable. 1 Clinicians should carefully evaluate and consider the survival benefits of Gliadel placement, taking into account the possibility of toxicities. 1

This phase I trial aimed to (1) determine the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion to suppress O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite. 4

Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) possesses characteristics that make it an attractive option for combination therapies, such as broad-spectrum antitumor activity, the ability to cross the blood-brain barrier, a good safety profile with nonoverlapping toxicities, an oral formulation, and the ability to overcome resistance to nitrosoureas. 6 Preclinical and phase I trials have demonstrated the additive or synergistic activity of temozolomide combined with carmustine against solid tumors, including malignant glioma, and the sequence-dependent effects of the combination. 6 When carmustine is administered before temozolomide, toxicity is lower and the maximum tolerated dose is higher. 6 Studies have also examined the combination of temozolomide with the topoisomerase I inhibitor irinotecan (CPT-11), an alkaloid derivative of camptothecin that has shown activity against malignant glioma. Temozolomide followed by CPT-11 proved more effective than either agent alone. 6 A significant challenge for investigators is determining the optimal schedule for temozolomide and CPT-11 among various options. 6 Completed and ongoing studies on temozolomide in combination with carmustine, including polifeprosan carmustine implant (Gliadel wafers; Aventis Pharmaceuticals, Parsippany, NJ), and CPT-11 are described. 6

This report describes a case of Candida meningitis following Gliadel wafer (polifeprosan 20 with carmustine implant) placement, successfully treated with a combination of intrathecal and intravenous amphotericin B. 3

Anaplastic astrocytoma has a poor prognosis with conventional treatment. 2 Multidisciplinary treatment is necessary to control the disease; however, treatment side effects can negatively impact a patient's quality of life (QOL). 2 Carmustine-impregnated wafers (Gliadel®, Eisai Co. Ltd. Tokyo, Japan), a treatment modality for anaplastic astrocytoma, has been reported to cause drug-induced fever as a side effect. 2

Benefits and Risks

Benefits Summary

Carmustine implant has proven to be an effective and well-tolerated adjunct to surgical resection in the treatment of recurrent glioblastoma multiforme. 5 This implant can locally deliver high concentrations of carmustine to brain tissue, potentially inhibiting tumor growth. 5

Risks Summary

Carmustine implant may cause side effects such as cerebral edema, convulsions, impaired healing, and infections. 1

Comparison between Studies

Commonalities in Studies

All of these studies indicate that carmustine implant is an effective treatment option for recurrent glioblastoma multiforme. 5 However, these studies delve into different aspects related to the safety and efficacy of carmustine implant. 5

Differences in Studies

Study 5 focuses on the pharmacokinetics of carmustine and the degradation of the polymer matrix. 5 Study 1 assesses the safety of carmustine implant in real-world clinical practice in Japan. 1 Study 4 evaluates the safety and pharmacokinetics of a combination therapy involving carmustine implant and continuous infusion of O6-BG. 4 Study 6 examines the effectiveness of combining temozolomide with carmustine. 6 Study 3 is a case report of Candida meningitis that occurred after Gliadel wafer placement. 3 Study 2 is a case report of fever induced by carmustine implant. 2

Consistency and Contradictions in Findings

While these studies suggest carmustine implant is an effective treatment for recurrent glioblastoma multiforme, they do not completely align on the risk of side effects. 5

Points to Consider for Application in Daily Life

Carmustine implant is an effective treatment for recurrent glioblastoma multiforme, but it carries side effects. 1 The decision to use carmustine implant should be made in consultation with a physician after carefully evaluating the patient's risks and benefits. 1

Limitations of Current Research

Research on the long-term safety and efficacy of carmustine implant is still inadequate. 1

Future Research Directions

Further research is needed to evaluate the long-term safety and efficacy of carmustine implant. 1

Conclusion

Carmustine implant is an effective treatment option for recurrent glioblastoma multiforme, but it comes with potential side effects. 5 The decision to use carmustine implant should be made in collaboration with a physician after thoroughly evaluating the individual patient's risks and benefits. 1