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Gliadel implants

Web Resources: Carmustine implants (Gliadel)
Recent Research Publications

Web Resources: Carmustine implants (Gliadel) (3 links)

Recent Research Publications

Murai S, Ichikawa T, Kurozumi K, et al.
Quantitative analysis of brain edema in patients with malignant glioma treated with BCNU wafers.
J Clin Neurosci. 2016; 33:148-153 [PubMed] Related Publications
BCNU wafers are a form of interstitial chemotherapy that is expected to improve the survival of patients with malignant glioma. However, their adverse events, especially brain edema, sometimes cause significant clinical symptoms. In this study, we performed a volumetric analysis of brain edema after the implantation of BCNU wafers and reported on the clinical course, and exacerbation factors of brain edema. Twelve patients who underwent surgical resection of supratentorial malignant glioma and BCNU wafer implantation, were enrolled. Radiographic quantitative analysis was conducted and compared with a historical control. The volume change in brain edema was divided into three groups and correlation with clinical symptoms was then evaluated. Compared with the control group, the brain edema in the BCNU wafer implantation group was significantly prolonged after surgery. Radiographic volumetric analysis revealed an increase of more than 25% at any time after surgery in four patients (33%) and a reduction of less than 25%, 1month after surgery in three patients (25%). Grade 3 clinical deterioration related to brain edema occurred in two patients and Grade 2 in one patient. Univariate analysis revealed that the radiographic deterioration of brain edema had no correlation with age, sex, diagnosis, tumor grade, preoperative volume of brain edema and tumor, residual tumor volume, or number of BCNU wafers. Radiographic quantitative analysis of brain edema indicated that BCNU wafer implantation may induce the prolongation and enlargement of brain edema with or without neurological deterioration. Brain edema may be controlled by intensive perioperative treatment with diuretics and corticosteroids.

Masuda Y, Ishikawa E, Yamamoto T, et al.
Early Postoperative Expansion of Parenchymal High-intensity Areas on T2-weighted Imaging Predicts Delayed Cerebral Edema Caused by Carmustine Wafer Implantation in Patients with High-grade Glioma.
Magn Reson Med Sci. 2016; 15(3):299-307 [PubMed] Related Publications
BACKGROUND: Carmustine (BCNU) wafer (Gliadel(®) Wafer) implantation after tumor resection is an approved treatment for high-grade glioma (HGG). These wafers change various characteristics on early postoperative magnetic resonance imaging (ep-MRI) including slight expansion of high-intensity areas on T2-weighted imaging (ep-T2-HIAs) into adjacent parenchyma without restricted diffusivity. We assessed the frequency of the ep-T2-HIAs after BCNU wafer implantation in HGG patients. Moreover, we focused on ep-T2-HIA expansion and its relation to delayed cerebral edema.
METHODS: Twenty-five consecutive HGG patients who underwent BCNU wafer implantation were assessed. First, patients were divided into ep-T2-HIA and non-ep-T2-HIA groups, and the incidence of delayed adverse effects was compared between the two groups. Subsequently, the patients were divided into delayed edema and non-delayed edema groups, and pre-, intra-, and postoperative data were compared between the two groups.
RESULTS: The ep-T2-HIA expansion and the delayed edema were evident in 9 cases (36%) and 12 cases (48%), respectively. In comparison of the ep-T2-HIA and non-ep-T2-HIA groups, delayed edema was the only delayed adverse effect associated with ep-T2-HIA expansion (P = 0.004). Univariate analysis showed a significantly higher ratio of delayed edema in the subgroups with maximal diameter of removed cavity ≤40 mm (P = 0.047) and the ep-T2-HIA expansion in comparison of the delayed edema and non-delayed edema groups. Multivariate analysis showed that the ep-T2-HIA expansion was the only independent factor associated with delayed edema (P = 0.021).
CONCLUSION: In BCNU wafer implantation cases, ep-T2-HIA expansion was a predictive factor for delayed cerebral edema.

Moriya J, Tanino MA, Takenami T, et al.
Rapid immunocytochemistry based on alternating current electric field using squash smear preparation of central nervous system tumors.
Brain Tumor Pathol. 2016; 33(1):13-8 [PubMed] Related Publications
The role of intraoperative pathological diagnosis for central nervous system (CNS) tumors is crucial for neurosurgery when determining the surgical procedure. Especially, treatment of carmustine (BCNU) wafers requires a conclusive diagnosis of high-grade glioma proven by intraoperative diagnosis. Recently, we demonstrated the usefulness of rapid immunohistochemistry (R-IHC) that facilitates antigen-antibody reaction under alternative current (AC) electric field in the intraoperative diagnosis of CNS tumors; however, a higher proportion of water and lipid in the brain parenchyma sometimes leads to freezing artifacts, resulting in poor quality of frozen sections. On the other hand, squash smear preparation of CNS tumors for cytology does not affect the frozen artifacts, and the importance of smear preparation is now being re-recognized as being better than that of the tissue sections. In this study, we established the rapid immunocytochemistry (R-ICC) protocol for squash smears of CNS tumors using AC electric field that takes only 22 min, and demonstrated its usefulness for semi-quantitative Ki-67/MIB-1 labeling index and CD 20 by R-ICC for intraoperative diagnosis. R-ICC by AC electric field may become a substantial tool for compensating R-IHC and will be applied for broad antibodies in the future.

Ohue S, Kohno S, Inoue A, et al.
Evaluation of serial changes on computed tomography and magnetic resonance imaging after implantation of carmustine wafers in patients with malignant gliomas for differential diagnosis of tumor recurrence.
J Neurooncol. 2016; 126(1):119-26 [PubMed] Related Publications
Carmustine wafers are approved for localized treatment of malignant glioma. In this study, overall changes in computed tomography (CT) and magnetic resonance (MR) images of malignant glioma patients treated with carmustine wafer implantation were evaluated. The subjects were 25 patients undergoing craniotomy for malignant glioma resection and carmustine wafer implantation. Changes in the appearance of wafers, the resection cavity, and the adjacent parenchyma on CT and MR imaging were evaluated retrospectively. On CT, the wafers changed from an initially high-dense to an iso-dense appearance. All MR studies showed a low-intense wafer within 2 days. The wafers changed to a high- or iso-intense appearance on fluid attenuated inversion recovery and T1-weighted imaging, whereas they changed to an iso- to low-intense appearance on T2-weighted imaging. Gas in the cavity increased gradually after surgery, achieved a peak at 1 week postoperatively, and then disappeared in 1-3 months. Increased volume of the resection cavity was observed in 48% of patients. Regarding changes in the adjacent parenchyma, obvious contrast enhancement at the wall of the resection cavity was seen in 91% of cases at 1 month, but this disappeared gradually. Edema around the resection cavity was increased in 7 patients (28%), of whom only two experienced symptoms due to edema. We conclude that these radiological changes after carmustine wafer implantation should be carefully followed up, because these changes can easily be mistaken for infectious disease or recurrent tumors.

Grossman R, Burger P, Soudry E, et al.
MGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel.
J Clin Neurosci. 2015; 22(12):1938-42 [PubMed] Related Publications
We examined the relationship between the O(6)-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0-14.5) and RFS was 9.4 months (95% CI 7.8-10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56-1.31; p=0.46). The patients aged over 70 years with MGMT methylation had a significantly longer median OS of 13.5 months, compared to 7.6 months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6 months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS.

Mehta AI, Linninger A, Lesniak MS, Engelhard HH
Current status of intratumoral therapy for glioblastoma.
J Neurooncol. 2015; 125(1):1-7 [PubMed] Related Publications
With emerging drug delivery technologies becoming accessible, more options are expected to become available to patients with glioblastoma (GBM) in the near future. It is important for clinicians to be familiar with the underlying mechanisms and limitations of intratumoral drug delivery, and direction of recent research efforts. Tumor-adjacent brain is an extremely complex living matrix that creates challenges with normal tissue intertwining with tumor cells. For convection-enhanced delivery (CED), the role of tissue anisotropy for better predicting the biodistribution of the infusate has recently been studied. Computational predictive methods are now available to better plan CED therapy. Catheter design and placement—in addition to the agent being used—are critical components of any protocol. This paper overviews intratumoral therapies for GBM, highlighting key anatomic and physiologic perspectives, selected agents (especially immunotoxins), and some new developments such as the description of the glymphatic system.

Xing WK, Shao C, Qi ZY, et al.
The role of Gliadel wafers in the treatment of newly diagnosed GBM: a meta-analysis.
Drug Des Devel Ther. 2015; 9:3341-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Standard treatment for high-grade glioma (HGG) includes surgery followed by radiotherapy and/or chemotherapy. Insertion of carmustine wafers into the resection cavity as a treatment for malignant glioma is currently a controversial topic among neurosurgeons. Our meta-analysis focused on whether carmustine wafer treatment could significantly benefit the survival of patients with newly diagnosed glioblastoma multiforme (GBM).
METHOD: We searched the PubMed and Web of Science databases without any restrictions on language using the keywords "Gliadel wafers", "carmustine wafers", "BCNU wafers", or "interstitial chemotherapy" in newly diagnosed GBM for the period from January 1990 to March 2015. Randomized controlled trials (RCTs) and cohort studies/clinical trials that compared treatments designed with and without carmustine wafers and which reported overall survival or hazard ratio (HR) or survival curves were included in this study. Moreover, the statistical analysis was conducted by the STATA 12.0 software.
RESULTS: Six studies including two RCTs and four cohort studies, enrolling a total of 513 patients (223 with and 290 without carmustine wafers), matched the selection criteria. Carmustine wafers showed a strong advantage when pooling all the included studies (HR = 0.63, 95% confidence interval (CI) = 0.49-0.81; P = 0.019). However, the two RCTs did not show a statistical increase in survival in the group with carmustine wafer compared to the group without it (HR = 0.51, 95% CI = 0.18-1.41; P = 0.426), while the cohort studies demonstrated a significant survival increase (HR = 0.59, 95% CI = 0.44-0.79; P < 0.0001).
CONCLUSION: Carmustine-impregnated wafers play a significant role in improving survival when used for patients with newly diagnosed GBM. More studies should be designed for newly diagnosed GBM in the future.

Burri SH, Prabhu RS, Sumrall AL, et al.
BCNU wafer placement with temozolomide (TMZ) in the immediate postoperative period after tumor resection followed by radiation therapy with TMZ in patients with newly diagnosed high grade glioma: final results of a prospective, multi-institutional, phase II trial.
J Neurooncol. 2015; 123(2):259-66 [PubMed] Related Publications
Temozolomide (TMZ) and BCNU have demonstrated anti-glioma synergism in preclinical models. We report final data from a prospective, multi-institutional study of BCNU wafers and early TMZ followed by radiation therapy with TMZ in patients with newly diagnosed malignant glioma. 65 patients were consented in 4 institutions, and 46 patients (43 GBM, 3 AA) were eligible for analysis. After resection and BCNU wafer placement, TMZ began on day four postoperatively. Radiation and TMZ (RT/TMZ) were then administered, followed by monthly TMZ at 200 mg/m2 for the first 26 patients, which was reduced to 150 mg/m2 for the remaining 20 patients. Non-hematologic toxicities were minimal. Nine of 27 patients (33 %) who received 200 mg/m2 TMZ, but only 1 of 20 (5 %) who received 150 mg/m2, experienced grade 3/4 thrombocytopenia. Median progression free survival (PFS) and overall survival (OS) period was 8.5 and 18 months, respectively. The 1-year OS rate was 76 %, which is a significant improvement compared with the historical control 1-year OS rate of 59 % (p = 0.023). However, there was no difference in 1-year OS compared with standard RT/TMZ (p = 0.12) or BCNU wafer followed by RT/TMZ (p = 0.87) in post hoc analyses. Early post-operative TMZ can be safely administered with BCNU wafers following resection of malignant glioma at the 150 mg/m2 dose level. Although there was an OS benefit compared to historical control, there was no indication of benefit for BCNU wafers and early TMZ in addition to standard RT/TMZ or early TMZ in addition to regimens of BCNU wafers followed by RT/TMZ.

Chaichana KL, Kone L, Bettegowda C, et al.
Risk of surgical site infection in 401 consecutive patients with glioblastoma with and without carmustine wafer implantation.
Neurol Res. 2015; 37(8):717-26 [PubMed] Related Publications
OBJECTIVES: Patients with glioblastoma (GBM) have an inherently shortened survival because of their disease. It has been recently shown that carmustine wafers in addition to other therapies (surgery, temozolomide, and radiation) can further extend survival. There is concern, however, that these therapies may increase infection risk. The goals of this study were to calculate the incidence of postoperative infection, evaluate if carmustine wafers changes the risk of infection and identify factors independently associated with an infection following GBM surgery.
METHODS: All patients who underwent non-biopsy, surgical resection of an intracranial GBM from 2007 to 2011 at a single institution were retrospectively reviewed. Stepwise multivariate proportional hazards regression analysis was used to identify factors associated with infection, including the use of carmustine wafers. Variables with P < 0.05 were considered statistically significant.
RESULTS: Four hundred and one patients underwent resection of an intracranial GBM during the reviewed period, and 21 (5%) patients developed an infection at a median time of 40 [28-286] days following surgery. The incidence of infection was not higher in patients who had carmustine wafers, and this remained true in multivariate analyses to account for differences in treatment cohorts. The factors that remained significantly associated with an increased risk of infection were prior surgery [RR (95% CI); 2.026 (1.473-4.428), P = 0.01], diabetes mellitus [RR (95% CI); 6.090 (1.380-9.354)], P = 0.02], and increasing duration of hospital stay [RR (95% CI); 1.048 (1.006-1.078); P = 0.02], where the greatest risk occurred with hospital stays > 5 days [RR (95% CI); 3.904 (1.003-11.620), P = 0.05].
DISCUSSION: These findings may help guide treatment regimens aimed at minimizing infection for patients with GBM.

Wait SD, Prabhu RS, Burri SH, et al.
Polymeric drug delivery for the treatment of glioblastoma.
Neuro Oncol. 2015; 17 Suppl 2:ii9-ii23 [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) remains an almost universally fatal diagnosis. The current therapeutic mainstay consists of maximal safe surgical resection followed by radiation therapy (RT) with concomitant temozolomide (TMZ), followed by monthly TMZ (the "Stupp regimen"). Several chemotherapeutic agents have been shown to have modest efficacy in the treatment of high-grade glioma (HGG), but blood-brain barrier impermeability remains a major delivery obstacle. Polymeric drug-delivery systems, developed to allow controlled local release of biologically active substances for a variety of conditions, can achieve high local concentrations of active agents while limiting systemic toxicities. Polymerically delivered carmustine (BCNU) wafers, placed on the surface of the tumor-resection cavity, can potentially provide immediate chemotherapy to residual tumor cells during the standard delay between surgery and chemoradiotherapy. BCNU wafer implantation as monochemotherapy (with RT) in newly diagnosed HGG has been investigated in 2 phase III studies that reported significant increases in median overall survival. A number of studies have investigated the tumoricidal synergies of combination chemotherapy with BCNU wafers in newly diagnosed or recurrent HGG, and a primary research focus has been the integration of BCNU wafers into multimodality therapy with the standard Stupp regimen. Overall, the results of these studies have been encouraging in terms of safety and efficacy. However, the data must be qualified by the nature of the studies conducted. Currently, there are no phase III studies of BCNU wafers with the standard Stupp regimen. We review the rationale, biochemistry, pharmacokinetics, and research history (including toxicity profile) of this modality.

Chowdhary SA, Ryken T, Newton HB
Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis.
J Neurooncol. 2015; 122(2):367-82 [PubMed] Free Access to Full Article Related Publications
Carmustine wafers (CW; Gliadel(®) wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction (P = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols.

Mu F, Lucas JT, Watts JM, et al.
Tumor resection with carmustine wafer placement as salvage therapy after local failure of radiosurgery for brain metastasis.
J Clin Neurosci. 2015; 22(3):561-5 [PubMed] Related Publications
Prolonged survival in brain metastasis patients increases recurrence rates and places added importance on salvage therapies. Research examining carmustine polymer wafers as an adjuvant therapy for brain metastasis is limited. We present a single institution retrospective series documenting the use of BCNU wafers placed in the cavity of resected recurrent brain metastases that had failed prior stereotactic radiosurgery (SRS). Between February 2002 and April 2013, a total of 31 patients with brain metastases failed SRS and underwent resection with intracavitary placement of carmustine wafers. Clinical outcomes including local control, survival, cause of death, and toxicity were determined from electronic medical records. Kaplan-Meier analysis was performed to assess local control and survival. Imaging features were reviewed and described for patients with serial post-operative follow-up imaging examinations over time. Overall survival at 6 months and 12 months was 63% and 36%, respectively. Fourteen of 31 patients (45%) died from neurologic causes. Local control within the resection cavity was 87% and 70% at 6 and 12 months, respectively. Five patients (16%) underwent further salvage therapy following carmustine wafer placement after local failure. Resection cavities of all six patients with follow-up imaging showed linear peripheral enhancement. Pericavity and wafer enhancement was present as early as the same day as surgery and persisted in all cases to 6 months or longer. Carmustine polymer wafers are an effective salvage treatment following resection of a brain metastasis that has failed prior SRS. For patients with successful local control after wafer implantation, linear enhancement at the cavity is common.

Zhang YD, Dai RY, Chen Z, et al.
Efficacy and safety of carmustine wafers in the treatment of glioblastoma multiforme: a systematic review.
Turk Neurosurg. 2014; 24(5):639-45 [PubMed] Related Publications
The aim of this study was to a conduct a systematic review of carmustine wafers (Gliadel wafers) for the treatment of glioblastoma multiforme (GBM) to assess the survival benefit and safety of this therapy. The inclusion criteria were 1) prospective or retrospective clinical trial; 2) patients who had undergone resection for primary GBM or first recurrence of GBM with or without carmustine wafer implantation; 3) patients with malignant gliomas that included GBM; 4) outcomes including survival analysis of the GBM population. Six trials met the inclusion criteria; four were randomized, controlled trials and two were retrospective. The trials varied with regard to the type of patients and interventions. In three of the trials, patients with GBM who received carmustine wafers had significantly longer median survival than patients who did not receive wafers. Implantation of carmustine wafers did not significantly improve progression-free survival. Carmustine wafers did not increase adverse effects. This systematic review suggests that carmustine wafers have demonstrated promise as an effective and tolerable treatment in comparison to other treatment strategies in patients with GBM.

Sai K, Zhong MG, Wang J, et al.
Safety evaluation of high-dose BCNU-loaded biodegradable implants in Chinese patients with recurrent malignant gliomas.
J Neurol Sci. 2014; 343(1-2):60-5 [PubMed] Related Publications
OBJECTIVES: Malignant gliomas are common primary brain tumors with dismal prognosis. The blood-brain barrier and unacceptable systemic toxicity limit the employment of chemotherapeutic agents. BCNU-impregnated biodegradable polymers (Gliadel®) have been demonstrated to prolong the survival of patients with malignant gliomas. Until now, no biodegradable drug delivery system has been commercially available in China. In the present study, we evaluated the safety of implants with high-dose BCNU in Chinese patients with recurrent malignant gliomas.
PATIENTS AND METHODS: Adults with supratentorial recurrent malignant glioma were eligible. High-dose BCNU-loaded PLGA implants (20mg of BCNU in each implant) were placed in the debulking cavity. The implants were investigated by a classical 3+3 design. Four levels of BCNU, up to 12 implants, were evaluated. Pharmacokinetic sampling was performed. The toxicity of the implants and the survival of patients were recorded.
RESULTS: Fifteen recurrent patients were enrolled with 12 glioblastomas and 3 anaplastic gliomas. Among 15 patients, 3 were treated with 3 implants (60 mg of BCNU), 3 with 6 implants (120 mg), 3 with 9 implants (180 mg) and 6 with 12 implants (240 mg). No dose-limiting toxicity was observed in the cohort of patients. Subgaleal effusion was the most common adverse event, presenting in 7 patients (46.7%). The median overall survival (OS) was 322 days (95% CI, 173-471 days). The 6-month, 1-year and 2-year survival rates were 66.7%, 40% and 13.3%, respectively.
CONCLUSIONS: The high-dose BCNU-loaded PLGA implants were safe for Chinese patients with recurrent malignant gliomas and further investigation for efficacy is warranted.

Cecchin D, Schiorlin I, Della Puppa A, et al.
Assessing response using 99mTc-MIBI early after interstitial chemotherapy with carmustine-loaded polymers in glioblastoma multiforme: preliminary results.
Biomed Res Int. 2014; 2014:684383 [PubMed] Free Access to Full Article Related Publications
Introduction. Early signs of response after applying wafers of carmustine-loaded polymers (gliadel) are difficult to assess with imaging because of time-related imaging changes. (99m)Tc-sestamibi (MIBI) brain single-photon emission tomography (SPET) has reportedly been used to reveal areas of cellularity distinguishing recurrent neoplasm from radionecrosis. Our aim was to explore the role of MIBI SPET in assessing response soon after gliadel application in glioblastoma multiforme (GBM). Methods. We retrospectively reviewed the charts on 28 consecutive patients with a radiological diagnosis of GBM who underwent MIBI SPET/CT before surgery (with intracavitary gliadel placement in 17 patients), soon after surgery, and at 4 months. The area of uptake was selected using a volume of interest that was then mirrored contralaterally to obtain a semiquantitative ratio. Results. After adjusting for ratio at the baseline, the effect of treatment (gliadel versus non-gliadel) was not statistically significant. Soon after surgery, however, 100% of patients treated with gliadel had a decreased ratio, as opposed to 62.5% of patients in the non-gliadel group (P = 0.0316). The difference between ratios of patients with radical versus partial resection reached statistical significance by a small margin (P = 0.0528). Conclusions. These data seem to suggest that the MIBI ratio could be a valuable tool for monitoring the effect of gliadel early after surgery.

Aoki T, Nishikawa R, Sugiyama K, et al.
A multicenter phase I/II study of the BCNU implant (Gliadel(®) Wafer) for Japanese patients with malignant gliomas.
Neurol Med Chir (Tokyo). 2014; 54(4):290-301 [PubMed] Free Access to Full Article Related Publications
Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.

Ishikawa E, Yamamoto T, Satomi K, et al.
Intraoperative pathological diagnosis in 205 glioma patients in the pre-BCNU wafer era: retrospective analysis with intraoperative implantation of BCNU wafers in mind.
Brain Tumor Pathol. 2014; 31(3):156-61 [PubMed] Related Publications
The present retrospective data analysis was performed to determine whether intraoperative pathological diagnosis (IOD) using frozen section (FS) could clearly distinguish high-grade glioma from WHO grade II gliomas. IOD was retrospectively compared to the pathological diagnosis using permanent paraffin sections (PS) of 205 glioma cases out of 356 brain tumor cases in the pre-Carmustine (BCNU) wafer era in Japan. The sensitivity and specificity of IOD regarding the whole glioma category were 96.1 and 98.0%, respectively. The positive predictive value and the underestimation ratio of glioma grading by IOD were 51.5 and 43.5% in all glioma cases. In addition, 54.5% of grade II glioma cases determined with IOD (grade II((FS))) were actually grade III or IV according to the PS pathology (grade III((PS)) or IV((PS)) cases). Recurrent cases and older age (≥50 years old) were predictive factors that resulted in underestimated grade II((FS)) group (grade II((FS))/III((PS)) + IV((PS))). The grade II((FS))/III((PS)) group tended to more frequently contain non-astrocytic tumors compared to the grade II((FS))/II((PS)) + IV((PS)) groups, although the difference was not statistically significant. In conclusion, the temporary WHO grade by IOD is underestimated in approximately half of glioma cases. We should pay attention to underestimation with IOD.

Shah RS, Homapour B, Casselden E, et al.
Delayed post-operative haemorrhage after carmustine wafer implantation: a case series from two UK centres.
Br J Neurosurg. 2014; 28(4):488-94 [PubMed] Related Publications
OBJECT: Significant haemorrhage following intracranial tumour resection may occur in 1-2% of cases and the majority occur within the first few hours post-operatively. Implantation of carmustine wafers has been associated with increased operative site complications in some series, but post-operative haematoma is not routinely reported. We analyzed the characteristics of post-operative haemorrhage after carmustine wafer insertion.
METHODS: We performed a retrospective audit of surgical site haematoma after tumour resection and insertion of carmustine wafers in two neurosurgical units in the UK (University Hospital of North Staffordshire, Stoke-on-Trent, March 2003 - July 2012; Wessex Neurological Centre, Southampton, October 2005 - January 2013).
RESULTS: During the specified time periods, carmustine wafers were inserted in 181 operations in 177 patients. We identified acute operative site haematomas after carmustine wafer insertion in 8 (4.4%) patients. All presented in a delayed fashion on or after Day 2 post-operatively. In contrast, acute operative site haematoma was present in 4/491 (0.81%) of patients who underwent resection without gliadel wafer insertion.
CONCLUSIONS: In contrast to the expected timing of bleeding following intracranial tumour resection, all carmustine wafer patients who experienced haemorrhage presented in a delayed fashion on or after Day 2 post-operatively. The causative factors for universally delayed post-operative haematoma after carmustine wafer insertion are unclear and further studies are required to characterize this phenomenon.

Samis Zella MA, Wallocha M, Slotty PJ, et al.
Evaluation of post-operative complications associated with repeat resection and BCNU wafer implantation in recurrent glioblastoma.
Acta Neurochir (Wien). 2014; 156(2):313-23 [PubMed] Related Publications
BACKGROUND: Patients with glioblastoma treated with BCNU wafer implantation for recurrence frequently receive frontline chemoradiotherapy with temozolomide as part of the Stupp protocol. A retrospective investigation was conducted of surgical complications in a cohort of these patients treated at a single institution.
METHODS: We searched our institutional database for patients treated between January 2006 and October 2012 who had recurrent glioblastoma previously treated with open surgery followed by the Stupp protocol and then underwent repeat resection with or without BCNU wafers for recurrent disease. Rates of select post-operative complications within 3 months of surgery were estimated.
RESULTS: We identified 95 patients with glioblastoma who underwent resection followed by the Stupp protocol as frontline treatment. At disease recurrence (first and second recurrence), 63 patients underwent repeat resection with BCNU wafer implantation and 32 without implantation. Generally, BCNU wafer use was associated with minor to moderate increases in rates of select complications versus non-implantation-wound healing abnormalities (14.2 vs. 6.2 %), cerebrospinal fluid leak (7.9 vs. 3.1 %), hydrocephalus requiring ventriculoperitoneal shunt (6.3 vs. 9.3 %), chemical meningitis (3.1 vs. 0 %), cerebral infections (3.1 vs. 0 %), cyst formation (3.1 vs. 3.1 %), cerebral edema (4.7 vs. 0 %), and empyema formations (1.5 vs. 0 %). Performance status was well maintained post-operatively in both groups. Median progression-free survival from the time of first recurrence was 6.0 and 5.0 months, respectively.
CONCLUSIONS: The use of the Stupp protocol as frontline therapy in patients with glioblastoma does not preclude the use of BCNU wafers at the time of progression.

Chamberlain MC
Treatment of newly diagnosed malignant glioma in the elderly people: new trials that impact therapy.
Int J Clin Pract. 2013; 67(12):1225-7 [PubMed] Related Publications
Glioblastoma (GB), World Health Organization Grade 4 glioma, is the most common malignant primary brain tumour with an annual incidence of 12,943 cases in the United States . It is a tumour of the elderly people with a median age of onset of 64 years, although children and young adults are also affected. GB is associated with a poor prognosis; despite best treatment, most community-based patients will not survive 1 year . Cures are rare and overall survival rates at 2 and 5 years are 26-48% and 12%, respectively, in highly selected, contemporary, clinical trial eligible patients . For protocol eligible US patients, the median survival is 16-17 months, which is partly a reflection of improved supportive care, recognition of pseudoprogression, exclusion of patients undergoing biopsy only and availability of bevacizumab at recurrence . Initial treatment for patients with high performance [Karnofsky Performance Status (KPS) > 60 and age < 71 years) consists of maximal safe surgical resection followed by adjuvant focal, external beam radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy and post-RT TMZ for 6 months . TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . The current standard treatment is based upon a European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) randomised, phase 3 trial of 573 patients with newly diagnosed GB (age 19-71 years and World Health Organization Performance Status ≤ 2) that compared RT alone [total dose 60 Gray (Gy)] to TMZ chemotherapy in combination with RT (total 60 Gy), followed by 6 months of post-RT TMZ (4,6,8).

Bregy A, Shah AH, Diaz MV, et al.
The role of Gliadel wafers in the treatment of high-grade gliomas.
Expert Rev Anticancer Ther. 2013; 13(12):1453-61 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Standard treatment includes surgery, radiation and chemotherapy. Prognosis is dismal with an average survival of approximately 1 year. Gliadel wafers are one treatment option, working as a source for local chemotherapy delivery. Their use is controversial with questionable survival benefit and potential side effects. We reviewed the literature in an effort to clarify their role in the treatment of high-grade gliomas. A systematic PubMed search was performed using the keywords 'Gliadel', 'carmustine' or 'BCNU wafers' in newly diagnosed high-grade glioma patients. Treatment regimen, and median survival were analyzed. Adverse event ratio was calculated by computing the number of adverse events in a study per patient receiving carmustine wafers. Nineteen studies with 795 patients were included in our review. Survival was 8.7-22.6 months with a mean overall survival (OS) of 16.2 months (control survival is approximately 14 months with surgery and adjuvant chemoradiotherapy). Adverse event ratio using Gliadel wafersin control group. Complication rate was 42.7%. Gliadel wafers may marginally increase survival and local control in newly diagnosed GBM patients but are associated with a high complication rate; therefore, we do not recommend using Gliadel wafers in patients with GBM. Further research may be warranted once a safer alternative to Gliadel wafers has been introduced.

Pereira DY, Yip AT, Lee BS, Kamei DT
Modeling mass transfer from carmustine-loaded polymeric implants for malignant gliomas.
J Lab Autom. 2014; 19(1):19-34 [PubMed] Related Publications
Significant advances in the encapsulation and release of drugs from degradable polymers have led to the Food and Drug Administration approval of Gliadel wafers for controlled local delivery of the chemotherapeutic drug carmustine to high-grade gliomas following surgical resection. Due to the localized nature of the delivery method, no pharmacokinetic measurements have been taken in humans. Rather, pharmacokinetic studies in animals and associated modeling have indicated the capability of carmustine to be delivered in high concentrations within millimeters from the implant site over approximately 5 days. Mathematical models have indicated that diffusion has a primary role in transport, which may be complemented by enhanced fluid convection from postsurgical edema in the initial 3 days following implantation. Carmustine's penetration distance is also presumably limited by its lipophilicity and permeability in the capillaries. This review discusses the mathematical models that have been used to predict the release and distribution of carmustine from a polymeric implant. These models provide a theoretical framework for greater understanding of systems for localized drug delivery while highlighting factors that should be considered in clinical applications. In effect, Gliadel wafers and similar drug delivery implants can be optimized with reduction in required time and resources with such a quantitative and integrative approach.

Chowdhary S, Chamberlain M
Bevacizumab for the treatment of glioblastoma.
Expert Rev Neurother. 2013; 13(8):937-49 [PubMed] Related Publications
Glioblastoma (GB) is the most common adult malignant primary brain tumor that arises from glial precursor cells. Survival in GB is variable ranging from 6 to 20 months notwithstanding current standard of care (SOC) treatment. Therapy has improved, but nonetheless GB is still invariably recurrent and incurable. Treatment options at recurrence include re-operation with or without carmustine (BCNU) wafer implantation (Gliadel), re-irradiation and standard/experimental chemo- or targeted therapy. Recurrent GB radiographic response rates to cytotoxic chemotherapy are less than 10% and median 6-month progression-free survival (PFS6) is 15%. With the recognition of the importance of tumor angiogenesis and the development of targeted therapy based on angiogenic inhibition, two pivotal trials of the VEGF-directed monoclonal antibody, bevacizumab (BEV, Avastin), were conducted in recurrent GB. Based upon the results of these two prospective US trials (median radiographic response rate: 25%; PFS6: 40%), BEV as a single agent was granted accelerated approval in the USA for recurrent GB. This review is a summary of current literature and clinical trials research in the role of BEV for the treatment of newly diagnosed and recurrent GB and potential future use of anti-angiogenic therapies in the management of GB.

Gutenberg A, Lumenta CB, Braunsdorf WE, et al.
The combination of carmustine wafers and temozolomide for the treatment of malignant gliomas. A comprehensive review of the rationale and clinical experience.
J Neurooncol. 2013; 113(2):163-74 [PubMed] Related Publications
Current treatment strategies in patients with newly-diagnosed glioblastoma include surgical resection with post-operative radiotherapy and concomitant/adjuvant temozolomide (the "Stupp protocol") or resection with implantation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafers in the surgical cavity followed by radiotherapy. In clinical practice, patients with malignant glioma treated with BCNU wafer often also receive adjuvant temozolomide. However, current treatment guidelines are unclear on whether and how these treatment practices can be combined, and no prospective phase 3 study has assessed the safety and efficacy of combining BCNU wafers with temozolomide and radiation in high-grade malignant glioma. The rationale for multimodal therapy comprising surgical resection with adjunct local BCNU wafers followed by radiotherapy and temozolomide is based on complementary and synergistic mechanisms of action between BCNU and temozolomide in preclinical studies; a shared primary resistance pathway, methylguanine-DNA methyltransferase (MGMT); and the opportunity to overcome resistance through MGMT depletion to boost cytotoxic activity. A comprehensive review of the literature identified 19 retrospective and prospective studies investigating the use of this multimodal strategy. Median overall survival in 14 studies of newly-diagnosed patients suggested a modest improvement versus resection followed by Stupp protocol or resection with BCNU wafers, with an acceptable and manageable safety profile.

Pizer B, Salehzadeh A, Brodbelt A, Mallucci C
Prolonged survival associated with the use of intraoperative carmustine (Gliadel) in a paediatric patient with recurrent grade III astrocytoma.
Br J Neurosurg. 2013; 27(4):516-8 [PubMed] Related Publications
A 15-year-old female presented with a middle cranial fossa anaplastic astrocytoma that was completely excised. She received local radiotherapy (54 Gy) and oral temozolomide. Five months after therapy, MRI showed local relapse. She underwent resection of the tumour with implantation of seven carmustine-impregnated wafers (Gliadel). She then received six cycles of procarbazine and lomustine therapy. Three years later, she is well and disease free. This case supports the further investigation of Gliadel in children and young people with relapsed high-grade glioma, particularly in the setting of a second complete resection.

Dörner L, Mustafa A, Rohr A, et al.
Growth pattern of tumor recurrence following bis-chloroethylnitrosourea (BCNU) wafer implantation in malignant glioma.
J Clin Neurosci. 2013; 20(3):429-34 [PubMed] Related Publications
Bis-chloroethylnitrosourea (BCNU; Gliadel, Eisai, Tokyo, Japan) is the only therapeutic agent for local chemotherapy of malignant gliomas approved by the US Food and Drug Administration and the European Medicines Agency. In a small patient cohort, it has previously been shown that glioblastomas recur locally despite treatment with BCNU. This raises concern about local treatment with BCNU as a stand-alone measure. The goal of this study was to analyze the growth pattern of tumor recurrence in a larger patient group: 41 patients were included in this study. Tumor recurrences were morphologically categorized as: local, diffuse, distant or multilocular. Thirty-three of the tumors (80%) that recurred were local or diffuse. These results show that BCNU implantation does not provide lasting local tumor control. Our data support the need to incorporate BCNU in to multimodal therapy schemes. The improved survival rates of patients who receive concomitant local and systemic adjuvant treatment support using local therapy to bridge the therapy-free interval of the initial postoperative phase.

Duntze J, Litré CF, Eap C, et al.
Implanted carmustine wafers followed by concomitant radiochemotherapy to treat newly diagnosed malignant gliomas: prospective, observational, multicenter study on 92 cases.
Ann Surg Oncol. 2013; 20(6):2065-72 [PubMed] Related Publications
OBJECTIVES: Study the feasibility and effectiveness of a treatment associated surgery, intraoperative chemotherapy (carmustine wafers), and concomitant radiochemotherapy (temozolomide) for the management of newly diagnosed, high-grade gliomas.
METHODS: Prospective multicenter study conducted in 17 French centers with a total of 92 patients with newly diagnosed malignant glioma treated by surgery, implanted Carmustine wafers (Gliadel(®)) followed by concomitant radiochemotherapy by temozolomide (Temodar(®)). Clinical, imaging, and survival data were collected to study toxicity-induced adverse events and efficacy.
RESULTS: A total of 20.6 % presented with adverse events during surgery, potentially attributable to carmustine, including 5 severe infections. Afterwards, 37.2 % of patients showed adverse events during radiochemotherapy and 40 % during adjuvant chemotherapy by temozolomide. We report a 10.5-month, median, progression-free survival and an 18.8-month median overall survival. No significant statistical difference was observed according to age, Karnofsky Performance Scale, or grade of the tumor. A prognostic difference at the limit of the significance threshold was observed according to the extent of the resection.
CONCLUSIONS: Multimodal treatment associating implanted carmustine chemotherapy and concomitant radiochemotherapy with temozolomide seems to yield better survival rates than those usually described when carmustine or temozolomide are used alone independently from one another. These interesting results were obtained without increased adverse events and would need to be validated during a phase 3 study.

Grimm SA, Chamberlain MC
State of the art and perspectives in the treatment of glioblastoma.
CNS Oncol. 2012; 1(1):49-70 [PubMed] Related Publications
Glioblastoma is the most common malignant primary brain tumor. Cures are rare and median survival varies from several to 22 months. Standard treatment for good performance patients consists of maximal safe surgical resection followed by radiotherapy with concurrent temozolomide (TMZ) chemotherapy and six cycles of postradiotherapy TMZ. At recurrence, treatment options include repeat surgery (with or without Gliadel wafer placement), reirradiation or systemic therapy. Most patients with good performance status are treated with cytotoxic chemotherapy or targeted biologic therapy following or in lieu of repeat surgery. Cytotoxic chemotherapy options include nitrosoureas, rechallenge with TMZ, platins, phophoramides and topoisomerase inhibitors, although efficacy is limited. Despite the intense effort of developing biologic agents that target angiogenesis and growth and proliferative pathways, bevacizumab is the only agent that has shown efficacy in clinical trials. It was awarded accelerated approval in the USA after demonstrating an impressive radiographic response in two open-label, prospective Phase II studies. Two randomized, Phase III trials of upfront bevacizumab have completed and may demonstrate survival benefit; however, results are pending at this time. Given the limited treatment options at tumor recurrence, consideration for enrollment on a clinical trial is encouraged.

De Bonis P, Anile C, Pompucci A, et al.
Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma.
Acta Neurochir (Wien). 2012; 154(8):1371-8 [PubMed] Related Publications
BACKGROUND: Combining Gliadel wafers and radiochemotherapy with TMZ may carry the risk of increased adverse events (AE). We analyzed the efficacy and safety in patients with glioblastoma who underwent multimodal treatment with implantation of Gliadel wafers.
METHODS: One hundred sixty-five consecutive patients with newly diagnosed (77 patients) or recurrent (88 patients) glioblastoma were studied. Forty-seven patients underwent surgery + Gliadel. The impact of age (≥65 vs. <65), resection extent (gross total vs. partial), use of Gliadel and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on overall survival (OS, for patients with newly diagnosed glioblastoma) and on recurrence-survival (for patients with recurrent glioblastoma) was analyzed with Cox regression. The impact of age, history (newly diagnosed vs. recurrent glioblastoma), number of Gliadel wafers implanted (0 vs. <8 vs. 8), resection extent (gross-total vs. partial) and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on the occurrence of AE and on the occurrence of implantation site-related AE (ISAE) was analyzed with the logistic regression model. Significance was set at p < 0.05.
RESULTS: Multivariate analysis showed the only factor associated with longer survival, both for newly diagnosed and for recurrent GBM, was resection extent. Both patients with a higher number of wafers implanted and patients with recurrent tumors were significantly at risk for AE and ISAE. Patients with eight Gliadel wafers implanted had a 3-fold increased risk of AE and a 5.6-fold increased risk of ISAE, and patients with recurrent tumor had a 2.8-fold increased risk of AE and a 9.3-fold increased risk of ISAE.
CONCLUSIONS: Adding Gliadel to standard treatment did not significantly improve the outcome. The toxicity after Gliadel use was significantly higher, both for patients with newly diagnosed and patients with recurrent glioblastoma.

Barr JG, Grundy PL
The effects of the NICE Technology Appraisal 121 (gliadel and temozolomide) on survival in high-grade glioma.
Br J Neurosurg. 2012; 26(6):818-22 [PubMed] Related Publications
OBJECTIVE: The prognosis of high-grade glioma (HGG) is poor with a median survival of about 1 year for glioblastoma. In 2007, NICE published a technology appraisal (TA121) recommending the use of carmustine wafers (Gliadel) and systemic therapy with temozolomide for selected patients with HGG. Outcomes for HGG surgery in the United Kingdom with these combined treatments have not been published.
DESIGN: Retrospective audit of consecutive patients in a single unit with carmustine wafer implantation.
SUBJECTS: Fifty-nine patients had carmustine wafers implanted at primary surgery, between October 2005 and October 2010 at Wessex Neurological Centre, Southampton, UK.
METHODS: Patients were given chemotherapeutic treatments strictly according to NICE TA121. Survival was calculated using Kaplan-Meier method.
RESULTS: Fifty-five patients had WHO grade IV tumours and four had grade III. Median age was 61 years. At follow-up, 39 patients had died. Median survival was 15.3 months. Eight patients (13.5%) experienced post-operative complications (including five infections) for which four had the carmustine wafers removed. Forty-seven (80%) patients were treated with radical radiotherapy (55-60 Gy) and six (10%) patients received palliative radiotherapy (30 Gy). Thirty-seven patients (63%) received concomitant temozolomide chemotherapy. In the subset of 37 patients receiving multimodal treatment with radical radiotherapy and concomitant temozolomide, median survival was 15.8 months compared with 7.4 months in those not receiving multimodal treatment.
DISCUSSION: Carmustine wafers for primary HGG surgery in accordance with the NICE TA121 were associated with a median survival of 15.3 months; this is improved compared with previously reported randomised trials. Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival. Increased incidence of infections was observed in cases receiving carmustine wafers.

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