Intrathecal administration of drugs like Ara-C and mafosfamide has been used in medulloblastoma, pineoblastoma, and recurrent brain tumors to bypass the BBB. The persistent therapeutic challenge due to nonhomogeneous dispersion is associated with ineffective volume of drug dispersion due to varying molecular weights and diffusivities. In addition, one must consider that follow-up neuropsychological evaluations suggest that these therapeutic regimens are not without consequences to the developing nervous system (Partap et al. 2011; Blaney et al. 2005).

Convection enhanced delivery (CED) is another regional administration method of biologic agents using intracranial catheters connected to target sites with a continuous positive pressure gradient. This provides improved delivery of molecules to the tumor and overcomes limitations of intrathecal chemotherapy. Using this technique, delivery of transferrin-CRM107, a conjugate of human transferrin (Tf) and a genetic mutant of diphtheria toxin (CRM107) to tumoral areas, showed peritumoral toxicity, tumor response, and safety in adults. Studies are in development to translate this application to deliver immunotoxins to tumoral cavities after surgical resection of pediatric brain tumors (Laske et al. 1997). Recently, CED delivery of topotecan has shown responses in glioblastoma and currently is in clinical trial for patients with DIPG (Bruce et al. 2011); however, challenges continue in optimal defining of convective distribution based on volume of agents infused, and concerns of retrograde reflux of drugs which can cause CNS toxicity.

BBB disruption is a method used to enhance drug delivery to tumor sites by using vasoactive substances. This allows therapeutics to enter the brain through this barrier. Bradykinin, a potent vasodilator, and its analogue lobradimil (RMP-7) have been used in clinical trials to enhance and facilitate the entry of carboplatin in treating PNET, HGG, and ependymoma. Though initial response was seen in phase I trials, the use of lobradimil and carboplatin in phase II trials was found to be inactive in childhood HGG and other tumors (Felix et al. 2013; Warren et al. 2006; Ford et al. 1998).

Intra-arterial (IA) delivery of chemotherapeutic agents through cannulated carotid or vertebral artery has been used for over three decades in different malignancies with evidence of higher concentration of infused agents at tumor sites (Hori et al. 1987). This approach has been performed alone or with the use of agents like mannitol, which induce BBB disruption, and enhances delivery of drugs. Phase III studies in adults with glioblastoma using this modality showed increased toxicities and no survival benefit over conventional delivery techniques (Imbesi et al. 2006; Hiesiger et al. 1995). Few studies using IA chemotherapy in children with brain tumors have been performed. Methotrexate or carboplatin delivered through this route in CNS tumors showed objective responses in some patients (Dahlborg et al. 1998). IA use of cisplatin or carboplatin in adults and children with brain stem glioma along with etoposide and intravenous interferon has been studied and indicates good responses in patients with reasonable tolerability (Fujiwara et al. 1994). Another study using IA chemotherapy with disruption of BBB was performed in 27 patients as a salvage therapy for recurrent CNS tumors, which showed some promising survival results and acceptable toxicity data (Jahnke et al. 2008). The use of IA melphalan in DIPG patients is in clinical trial. Though this route of administration sounds promising, to date, no data has shown benefit over intravenous route. Further studies need to be profiled to conclusively define safety and efficacy of this route of administration of biologic agents in children with brain tumors.

Intratumoral use of chemotherapeutic agents into CNS tumors directly using chemotherapy impregnated wafers, gels, spheres, or injection of agents into the site has been evaluated. In addition to overcoming the BBB, it also helps in reducing dispersion of the drug beyond the desired site. Adult studies using wafers containing BCNU within a biodegradable polymer (Gliadel^®) were inserted at the surgical sites in recurrent or newly diagnosed malignant gliomas. This approach showed some efficacy; however, toxicities included cerebrospinal fluid leak, edema, and treatment-related necrosis (Nagpal 2012; Valtonen et al. 1997). To enhance clinical efficacy, use of carmustine wafers followed by chemoradiotherapy with temozolomide in adults with newly diagnosed malignant gliomas showed a modest overall survival of 18 months (Kleinberg et al. 2004). A limitation of the use of these wafers is the restricted diffusion of chemotherapeutic agents across tissues beyond implanted surgical cavity site, undermining its access and clinical efficacy in infiltrative brain tumors. Although the role of these agents has been demonstrated in adults, no study has shown convincing safety and efficacy of its use in childhood brain tumors.