Gliadel
Gliadel is a drug depot wafer that, when inserted into the resection cavity of the brain, will release carmustine (BCNU) as the depot degrades as a way to treat for glioblastoma. This therapy is composed of a biodegradable copolymer, 1,3-bis-(p-carboxyphenoxy)propane and sebacic acid, where each wafer holds 3.85% of BCNU by weight.[1][2]. Each wafer has a mass of 7.7 mg and it is recommended to coat the entire resection cavity with a maximum dose of 8 wafers [3]. As the first FDA approved form of interstitial therapy, it acts as a reference for future work that also aims to treat for glioblastoma [4].
Production and Characterization
Carmustine (BCNU) is an alkylating agent used to treat for a number of cancers [5]. The copolymer 1,3-bis-(p-carboxyphenoxy)propane (PCPP) and sebacic acid (SA), p(CPP:SA), is biodegradable and has tunable degradation rates depending on the ratio of the PCPP to SA [6][7]. Gliadel uses a ratio of 20:80 and this copolymer is made into microspheres that encapsulates BCNU by spray drying when dissolved in methylene chloride [8][9]. The microspheres are then compressed into wafers in the shape of discs with a diameter of 1.4 cm and 1 mm thick. PCPP:SA is also pH sensitive where it degrades much faster in basic conditions (higher pH) and the 20:80 ratio was chosen for Gliadel as it releases the drug at the same rate that it degrades and fully releases the drug within 2 weeks [6][7][10].
Animal Studies
PCPP:SA was tested for inflammatory responses to determine their biocompatibility in rabbits, rats, and mammalian cells and found no issues with the copolymer [7]. The polymer was implanted subcutaneously in rabbits and found no inflammatory response after 6 weeks. When tested in rats, the polymer did not invoke any inflammatory cells after 6 months. Mammalian cells were treated with the polymer and found that no inhibition of their growth was seen.
The polymer was also implanted in the frontal lobes of rabbit brains and showed no changes in behaviour or had any neurological issues [11]. There were also no findings of inflammation when tested in rabbit cornea. Further testing has shown that when the polymer encapsulates BCNU and tested in rabbit brains, local delivery of the drug is achieved in the brain and is sustained for up to 21 days [12].
This was also tested in rats where the polymer was implanted in their frontal lobe and it was found that there were no changes in their behaviour as well as no neurological issues arose with no local toxicities observed at the site of implantation [13]. Local delivery of BCNU using these wafers were tested in mice using a 9L gliosarcoma model where they were tested subcutaneously and intracranially [14]. It was found that subcutaneous tumor models had a significant delay in the growth of tumors and the intracranial models had an increase in survival. Rats who were treated with the wafer rather than by injection intracranially with BCNU had an increase in survival [15].
Monkeys were also tested for the efficacy of these wafers [16]. The wafers were implanted in the brains of monkeys and were then treated with radiation therapy. No neurological side effects were seen in any of the monkeys indicating that these wafers were safe for use intracranially. Local drug delivery is achieved in monkey brains using these wafers and its found that considerable amount of BCNU is found 5 cm away from the site of plant for up to 30 days [17]
Human trials and studies
A trial tested Gliadel against a placebo in 27 medical centers with 222 patients [9]. All patients had recurrent malignant brain tumors and required resection. Patients who received Gliadel had a median survival of 31 weeks whereas the placebo group had a median survival of 23 weeks. A meta-analysis by Chowdhary et al., found that in 60 studies those with newly-diagnosed high-grade glioma had a median survival of 16.4 months when treated with Gliadel as compared to those treated with non-Gliadels with a median survival of 13.1 months [18]. A literature review by Ashby et al., looked over Gliadel treating newly diagnosed high-grade glioma combined with radiation therapy and followed by temozolomide [19]. 11 trials encompassing 411 patients showed an increase in median survival by 3 to 4 months when treating patients with only just Gliadel or only just temozolomide. A meta-analysis by Xing et al., found that in 6 studies and 4 cohort studies, Gliadel treated patients with newly diagnosed glioblastoma had a significant benefit in treatment [1]. However, in 2 randomized controlled trials, there was no significant increase in survival between treatment groups.
Complications
With the insertion of a material into the brain, Gliadel can cause certain side effects post-operation [3]. In a study, 37% of patients experienced seizures with 20% of them worsening and 54% experiencing the seizure within 5 days after surgery. 23% of patients in a study experienced cerebral edema and intracranial hypertension. Intracerebral mass effect was also observed in a patient in the study and ultimately led to brain herniation due to being unresponsive to corticosteroids. 14-16% of patients in these studies also had impaired wound healing. 4% of patients had meningitis from the treatment, 2 were from bacterial sources and 1 was from chemical. Another warning when using Gliadel is that wafer migration may be seen if there are any empty spaces in the resection cavity that are larger than the wafer diameter. Caution should be taken when treated with Gliadel and are pregnant. BCNU has been found to be embryotoxic in rats.
References
- ↑ 1.0 1.1 Xing, Wei-kang; Shao, Chuan; Qi, Zhen-yu; Yang, Chao; Wang, Zhong (June 29, 2015). "The role of Gliadel wafers in the treatment of newly diagnosed GBM: a meta-analysis". Drug Design, Development and Therapy. 9: 3341–3348. doi:10.2147/DDDT.S85943. PMC 4492653. PMID 26170620.
- ↑ Ab, Fleming; Wm, Saltzman (May 2, 2002). "Pharmacokinetics of the carmustine implant". Clinical Pharmacokinetics. 41 (6): 403–419. doi:10.2165/00003088-200241060-00002. PMID 12074689 – via pubmed.ncbi.nlm.nih.gov. Unknown parameter
|s2cid=ignored (help) - ↑ 3.0 3.1 "GLIADEL® WAFER (carmustine implant), for intracranial use" (PDF).
- ↑ Pena, Erik S.; Graham-Gurysh, Elizabeth G.; Bachelder, Eric M.; Ainslie, Kristy M. (January 2, 2021). "Design of Biopolymer-Based Interstitial Therapies for the Treatment of Glioblastoma". International Journal of Molecular Sciences. 22 (23): 13160. doi:10.3390/ijms222313160. PMC 8658694 Check
|pmc=value (help). PMID 34884965 Check|pmid=value (help). - ↑ Weiss, Raymond B.; Issell, Brian F. (December 1, 1982). "The nitrosoureas: carmustine (BCNU) and lomustine (CCNU)". Cancer Treatment Reviews. 9 (4): 313–330. doi:10.1016/S0305-7372(82)80043-1. PMID 6762924 – via ScienceDirect.
- ↑ 6.0 6.1 Leong, K. W.; Brott, B. C.; Langer, R. (October 2, 1985). "Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation, and release characteristics". Journal of Biomedical Materials Research. 19 (8): 941–955. doi:10.1002/jbm.820190806. PMID 3880353 – via PubMed.
- ↑ 7.0 7.1 7.2 Leong, K. W.; D'Amore, P. D.; Marletta, M.; Langer, R. (January 2, 1986). "Bioerodible polyanhydrides as drug-carrier matrices. II. Biocompatibility and chemical reactivity". Journal of Biomedical Materials Research. 20 (1): 51–64. doi:10.1002/jbm.820200106. PMID 3949823 – via PubMed.
- ↑ Brem, H.; Mahaley, M. S.; Vick, N. A.; Black, K. L.; Schold, S. C.; Burger, P. C.; Friedman, A. H.; Ciric, I. S.; Eller, T. W.; Cozzens, J. W. (March 2, 1991). "Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas". Journal of Neurosurgery. 74 (3): 441–446. doi:10.3171/jns.1991.74.3.0441. PMID 1993909 – via PubMed.
- ↑ 9.0 9.1 Brem, H.; Piantadosi, S.; Burger, P. C.; Walker, M.; Selker, R.; Vick, N. A.; Black, K.; Sisti, M.; Brem, S.; Mohr, G. (April 22, 1995). "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. 345 (8956): 1008–1012. doi:10.1016/s0140-6736(95)90755-6. PMID 7723496 – via PubMed. Unknown parameter
|s2cid=ignored (help) - ↑ Dang, Wenbin; Daviau, Todd; Ying, Peter; Zhao, Yong; Nowotnik, David; Clow, Charles S; Tyler, Betty; Brem, Henry (October 1, 1996). "Effects of GLIADEL® wafer initial molecular weight on the erosion of wafer and release of BCNU". Journal of Controlled Release. 42 (1): 83–92. doi:10.1016/0168-3659(96)01371-5 – via ScienceDirect.
- ↑ Brem, H.; Kader, A.; Epstein, J. I.; Tamargo, R. J.; Domb, A.; Langer, R.; Leong, K. W. (May 2, 1989). "Biocompatibility of a biodegradable, controlled-release polymer in the rabbit brain". Selective Cancer Therapeutics. 5 (2): 55–65. doi:10.1089/sct.1989.5.55. PMID 2772427 – via PubMed.
- ↑ Grossman, S. A.; Reinhard, C.; Colvin, O. M.; Chasin, M.; Brundrett, R.; Tamargo, R. J.; Brem, H. (April 2, 1992). "The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers". Journal of Neurosurgery. 76 (4): 640–647. doi:10.3171/jns.1992.76.4.0640. PMID 1545259 – via PubMed.
- ↑ Tamargo, R. J.; Epstein, J. I.; Reinhard, C. S.; Chasin, M.; Brem, H. (February 2, 1989). "Brain biocompatibility of a biodegradable, controlled-release polymer in rats". Journal of Biomedical Materials Research. 23 (2): 253–266. doi:10.1002/jbm.820230209. PMID 2708412 – via PubMed.
- ↑ Tamargo, Rafael J.; Myseros, John S.; Epstein, Jonathan I.; Yang, Michael B.; Chasin, Mark; Brem, Henry (January 1, 1993). "Interstitial Chemotherapy of the 9L Gliosarcoma: Controlled Release Polymers for Drug Delivery in the Brain1". Cancer Research. 53 (2): 329–333. PMID 8417826 – via Silverchair.
- ↑ Buahin, K. G.; Brem, H. (November 2, 1995). "Interstitial chemotherapy of experimental brain tumors: comparison of intratumoral injection versus polymeric controlled release". Journal of Neuro-Oncology. 26 (2): 103–110. doi:10.1007/BF01060216. PMID 8787852 – via PubMed. Unknown parameter
|s2cid=ignored (help) - ↑ Brem, H.; Tamargo, R. J.; Olivi, A.; Pinn, M.; Weingart, J. D.; Wharam, M.; Epstein, J. I. (February 2, 1994). "Biodegradable polymers for controlled delivery of chemotherapy with and without radiation therapy in the monkey brain". Journal of Neurosurgery. 80 (2): 283–290. doi:10.3171/jns.1994.80.2.0283. PMID 8283268 – via PubMed.
- ↑ Fung, L. K.; Ewend, M. G.; Sills, A.; Sipos, E. P.; Thompson, R.; Watts, M.; Colvin, O. M.; Brem, H.; Saltzman, W. M. (February 15, 1998). "Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain". Cancer Research. 58 (4): 672–684. PMID 9485020 – via PubMed.
- ↑ Chowdhary, Sajeel A.; Ryken, Timothy; Newton, Herbert B. (April 2, 2015). "Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis". Journal of Neuro-Oncology. 122 (2): 367–382. doi:10.1007/s11060-015-1724-2. PMC 4368843. PMID 25630625.
- ↑ Ls, Ashby; Ka, Smith; B, Stea (August 24, 2016). "Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review". World Journal of Surgical Oncology. 14 (1): 225. doi:10.1186/s12957-016-0975-5. PMC 4997737. PMID 27557526.
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