- Department of Neurological Surgery, University of Washington, Seattle, WA, USA
Daniel L. Silbergeld
Department of Neurological Surgery, University of Washington, Seattle, WA, USA
DOI:10.4103/2152-7806.181987Copyright: © 2016 Surgical Neurology International This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Ene CI, Nerva JD, Morton RP, Barkley AS, Barber JK, Ko AL, Silbergeld DL. Safety and efficacy of carmustine (BCNU) wafers for metastatic brain tumors. Surg Neurol Int 06-May-2016;7:
How to cite this URL: Ene CI, Nerva JD, Morton RP, Barkley AS, Barber JK, Ko AL, Silbergeld DL. Safety and efficacy of carmustine (BCNU) wafers for metastatic brain tumors. Surg Neurol Int 06-May-2016;7:. Available from: http://surgicalneurologyint.com/surgicalint_articles/safety-and-efficacy-of-carmustine-bcnu-wafers-for-metastatic-brain-tumors/
Background:Carmustine (BCNU) wafers (Gliadel) prolongs local disease control and progression-free survival (PFS) in patients with malignant gliomas. However, in metastatic brain tumors, there is a paucity of evidence in support of its safety and efficacy. The goal of this study was to assess the safety and efficacy of Gliadel wafers in patients with metastatic brain tumors.
Methods:We retrospectively reviewed the University of Washington experience with Gliadel wafers for metastatic brain tumors between 2000 and 2015.
Results:Gliadel wafers were used in 14 patients with metastatic brain tumors during the period reviewed. There were no postoperative seizures, strokes, or hemorrhages. There was one postoperative wound infection necessitating return to the operating room. The mean time to tumor progression (n = 7) and death (n = 5) after Gliadel wafer implantation was 2.5 and 2.9 years, respectively. Age was the only variable affecting PFS in patients receiving Gliadel wafers. Patients n = 7) had a PFS of 0.52 years, whereas patients >53 years old (n = 7) had a PFS of 4.29 years (P = 0.02). There was no significant difference in PFS in relation to presenting Karnofsky Performance Status (P = 0.26), number of brain metastasis (P = 0.82), tumor volume (P = 0.54), prior surgery (P = 0.57), or prior radiation (P = 0.41). There were no significant differences in the mean survival in relationship to any variable including age.
Conclusions:BCNU wafers are a safe and a potentially efficacious adjunct to surgery and radiation for improving local disease control in metastatic brain tumors. Larger studies, however, are needed to examine overall efficacy and tumor specific efficacy.
Keywords: BCNU, carmustine, Gliadel, gliomas, metastatic brain tumor, progression free survival
Patients with brain metastases have a median survival of 4–10 months, as predicted by radiation therapy oncology group (RTOG) recursive partitioning analysis (RPA) class.[
Gliadel is a carmustine (BCNU)-infused wafer developed in the 1970s for direct delivery of chemotherapy to the tumor bed.[
We retrospectively reviewed 14 patients with metastatic brain tumors resection who underwent concomitant placement of Gliadel wafers. We report local toxicity (wound infections, postoperative seizures, and wound breakdown) as well as progression-free survival (PFS) and mean survival following Gliadel wafer implantation.
Following approval by the University of Washington Institutional Review Board, the medical records of patients undergoing metastatic brain tumor resection between 2000 and 2015 were reviewed. Fourteen cases with Gliadel wafer placement were identified and retrospectively reviewed. We documented demographic information, prior surgical intervention or radiation therapy, maximum tumor diameter, primary cancer type, postoperative complications, PFS (where progression is defined as the presence of nodular enhancement within/adjacent to the tumor bed based on follow-up imaging and/or clinical deterioration due to a neurological cause), and mean survival.
Tumor resection and BCNU wafer implantation
Surgery was performed by a single neurosurgeon (Daniel L. Silbergeld). Following resection of gross tumor, neuronavigation, and ultrasound were used to assess the tumor bed for any residual tumor. Eight Gliadel wafers were used to line the tumor bed. Postoperatively, a noncontrast head computed tomography was obtained to assess for immediate complications. A repeat magnetic resonance imaging was also performed within 48 h to determine the extent of resection. Length of stay and postoperative complications were documented.
Statistical analysis was performed by J. B. Peto-Peto and Tarone-Ware exact tests were used to determine statistical significance among the covariates of interest. PFS for all patients (n = 14) was calculated using Kaplan–Meier estimates. All analyses were carried out in StatXact (Cytel Incorporated, Cambridge, Massachusetts, U.S.A.).
Demographics, symptoms, and radiographic characteristics
Patient demographics are presented in
Criteria for Gliadel use included failure to achieve local control, good performance status, and stable systemic disease. All patients had received at least one form of therapy before recurrence and Gliadel wafer placement. Most patients (n = 10, 71%) had undergone a prior craniotomy for resection of a metastatic lesion before repeat craniotomy for recurrent tumor resection and Gliadel wafer placement. The average time between prior craniotomy and Gliadel wafers placement was 12.7 months (range 4.6–18.4). Twelve patients (86%) had also undergone prior radiation for the same metastatic lesion (85% gamma knife (GK) (Elekta, Stockholm, Sweden), 15% received both whole brain and GK). The average time between prior radiation treatment and Gliadel wafers placement was 13.3 months (range 3.5–25.3).
Postoperative complications and adjuvant therapy
There were no postoperative seizures, strokes, or hemorrhages. There was one wound infection [
Progression and death
Tumor recurrence occurred in seven patients (2/4 lung, 2/3 breast, 1/1 colorectal, 1/1 bladder, and 1 testicular;
Age was the only factor that affected PFS after BCNU wafer placement [
The management of brain metastasis continues to be an important topic as the incidence of brain metastases increases along with better control of systemic malignancies. Historically, a single metastasis treated with surgical resection and postoperative radiation as local recurrence rates is as high as 40% and distant recurrence in approximately 21%.[
In 1996, Ewend et al. published the first report of BCNU wafers with radiotherapy in various animal models of metastatic models.[
Here, we report results from a retrospective analysis conducted to assess the efficacy of BCNU wafers for metastatic brain lesions. Most patients underwent craniotomy and BCNU wafer placement for tumor recurrence following previous treatments. We found that patients in our cohort >53 years had a significantly longer PFS compared with patients <53 years following BCNU wafer implantation. This may be a statistical aberration due to the small number of patients, or may suggest that this treatment regimen may be more effective for achieving local disease control in a specific subset of patients. This age-related phenomenon has also been reported for recurrent GBM patients >55 years receiving bevacizumab (Avastin).[
As with any retrospective analysis, this study has significant limitations. The cohort is too small for any significant statistical analysis. Another limitation of our study is the small and heterogeneous sample size that precludes drawing conclusions about the differential sensitivity of various cancer types to BCNU wafers. Furthermore, without a control group, these results should be viewed as having potential selection bias. Future prospective double-blinded studies with a larger cohort will provide more insights into the impact of BCNU on patient PFS and overall survival compared with placebo. These large studies may also uncover other variables that could be relevant for survival in response to BCNU wafer implantation.
BCNU wafers (Gliadel) are a safe adjunct to surgery and radiation for prolonging local disease control in patients with metastatic brain tumors. In our series, patients >53-year-old with metastatic brain tumors showed a higher PFS compared with patients <53 years following Gliadel wafers administration. Gliadel wafers may provide an effective means of prolonging local disease control for patients with metastatic brain tumors. Larger studies, however, are needed to examine overall efficacy and tumor specific efficacy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Abel TJ, Ryken T, Lesniak MS, Gabikian P. Gliadel for brain metastasis. Surg Neurol Int. 2013. 4: S289-93
2. Attenello FJ, Mukherjee D, Datoo G, McGirt MJ, Bohan E, Weingart JD. Use of Gliadel (BCNU) wafer in the surgical treatment of malignant glioma: A 10-year institutional experience. Ann Surg Oncol. 2008. 15: 2887-93
3. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. 1995. 345: 1008-12
4. Chamberlain MC. Bevacizumab for the treatment of recurrent glioblastoma. Clin Med Insights Oncol. 2011. 5: 117-29
5. Deeken JF, Löscher W. The blood-brain barrier and cancer: Transporters, treatment, and Trojan horses. Clin Cancer Res. 2007. 13: 1663-74
6. Domb AJ, Rock M, Perkin C, Yipchuck G, Broxup B, Villemure JG. Excretion of a radiolabelled anticancer biodegradable polymeric implant from the rabbit brain. Biomaterials. 1995. 16: 1069-72
7. Ewend MG, Brem S, Gilbert M, Goodkin R, Penar PL, Varia M. Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control. Clin Cancer Res. 2007. 13: 3637-41
8. Ewend MG, Williams JA, Tabassi K, Tyler BM, Babel KM, Anderson RC. Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Res. 1996. 56: 5217-23
9. Fleming AB, Saltzman WM. Pharmacokinetics of the carmustine implant. Clin Pharmacokinet. 2002. 41: 403-19
10. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997. 37: 745-51
11. Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: Establishing a treatment paradigm. J Clin Oncol. 2007. 25: 2306-12
12. Grossman SA, Reinhard C, Colvin OM, Chasin M, Brundrett R, Tamargo RJ. The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers. J Neurosurg. 1992. 76: 640-7
13. Keskin O, Bahar I, Jernigan RL, Beutler JA, Shoemaker RH, Sausville EA. Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure. Anticancer Drug Des. 2000. 15: 79-98
14. Lukas RV, Gabikian P, Garza M, Chmura SJ. Treatment of brain metastases. Oncology. 2014. 87: 321-9
15. Nghiemphu PL, Liu W, Lee Y, Than T, Graham C, Lai A. Bevacizumab and chemotherapy for recurrent glioblastoma: A single-institution experience. Neurology. 2009. 72: 1217-22
16. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ.editors. Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA. 1998. 280: 1485-9
17. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990. 322: 494-500
18. Patel AJ, Suki D, Hatiboglu MA, Abouassi H, Shi W, Wildrick DM. Factors influencing the risk of local recurrence after resection of a single brain metastasis. J Neurosurg. 2010. 113: 181-9
19. Patel RR, Mehta MP. Targeted therapy for brain metastases: Improving the therapeutic ratio. Clin Cancer Res. 2007. 13: 1675-83
20. Tamargo RJ, Myseros JS, Epstein JI, Yang MB, Chasin M, Brem H. Interstitial chemotherapy of the 9L gliosarcoma: Controlled release polymers for drug delivery in the brain. Cancer Res. 1993. 53: 329-33
21. Valtonen S, Timonen U, Toivanen P, Kalimo H, Kivipelto L, Heiskanen O. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: A randomized double-blind study. Neurosurgery. 1997. 41: 44-8
22. Westphal M, Ram Z, Riddle V, Hilt D, Bortey E. Executive Committee of the Gliadel Study Group. Gliadel wafer in initial surgery for malignant glioma: Long-term follow-up of a multicenter controlled trial. Acta Neurochir (Wien). 2006. 148: 269-75
23. Zhang RD, Price JE, Fujimaki T, Bucana CD, Fidler IJ. Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol. 1992. 141: 1115-24