Chemotherapy for Brain Tumors

Blood-Brain Barrier

Treatment of brain tumors with systemic chemotherapy poses unique challenges. Concentrations of chemotherapeutic agents within the central nervous system (CNS) depend on multiple factors, including ability of the agents to cross the blood-brain barrier (BBB), the volume of distribution of the drug in the brain parenchyma, and the extent to which the drug is actively transported out of the brain. Therefore, many promising compounds fail in CNS drug development due to limited access to the target sites in the brain. Foremost is the BBB, which impedes delivery of adequate concentrations of most chemotherapeutic agents to the tumor; the others include brain-tumor barrier (BTB), the blood–cerebrospinal fluid (CSF) barrier, and the brain-CSF barrier.

Paul Ehrlich first described BBB in 1985 when he noted that all body tissues except the brain were stained when certain vital dyes were injected intravenously into animals. The BBB critically controls the passage of drugs or other compounds from the blood to the CNS and protects the brain from the foreign and undesirable molecules. The major component of the BBB is a monolayer of brain capillary endothelial cells. The restriction of brain penetration arises from the presence of tight junctions between adjacent endothelial cells and interaction between astrocytes and endothelial cells. In contrast to other blood vessels in the body, the endothelial cells of brain capillaries lack intercellular fenestrations and have high electrical resistance and low ionic permeability, rendering them relatively impermeable to many water-soluble compounds. ^, The principal route to cross the BBB is by the process of lipid-mediated transport of small nonpolar molecules, either by passive diffusion or less frequently by catalyzed transport. For a drug to successfully reach the brain parenchyma requires its uptake across the luminal (blood-facing) membrane into the endothelial cells, its transport across their transcellular membrane, and finally efflux across the abluminal side (brain parenchyma–facing membrane into the interstitial fluid). The key to successful chemotherapy for brain tumors is adequate drug delivery to the tumor-infiltrated brain and the individual tumor cells. To cross the BBB, chemotherapeutic drugs administered systemically must be less than approximately 200 daltons in size, lipid soluble, not bound to plasma proteins, and minimally ionized. ^, As a result, there is a positive correlation between lipophilicity of the drug and its ability to cross BBB.

Role of Steroids

Steroids are important in the management of patients with brain tumors, particularly in patients with bulky disease and those who have hydrocephalus. Dexamethasone has the best CNS penetration of any of the steroids and is most commonly used in practice. Steroids decrease CSF production and cerebral blood flow and help to reduce vasogenic edema associated with tumor. However, the steroid can impair delivery of the chemotherapeutic agents to the tumor and blunt the effect of immunotherapy. The assessment of response to treatment can also be affected by steroid use. The steroids can potentially decrease the degree of gadolinium enhancement that is a surrogate for the leakiness of the blood vessels and decrease the measurable volume of the tumor. The guidelines for determining response criteria to chemotherapy currently require that the patient be on the same or a lower steroid dose as compared with baseline before determining an objective response. ^,

Efflux Transporters

Extrusion by active efflux pumps along the BBB is another reason for lower than predicted uptake of drugs. Drug transporters belong to two major superfamilies: adenosine triphosphate–binding cassette (ABC) and solute carrier transporters. ^, ABC transporters are integral membrane proteins, many of which are located in the plasma membrane and are primary active transporters; they couple ATP hydrolysis causing active efflux of their substrates against concentration gradients. The most extensively studied BBB transporter of the ABC family is P-glycoprotein (P-gp), initially discovered in 1976 ; additionally members of the multidrug resistance-associated protein (MRP) family and breast cancer resistance protein (BCRP) have also been identified in brain endothelial cells and choroid plexus epithelial cells. Anticancer agents were among the first drugs that were identified to be substrates of BBB efflux transporters (i.e., of P-gp as well as MRPs and BCRP).

DNA Repair Enzymes

Methylguanine methyltransferase (MGMT) is an enzyme that removes chloroethylation or methylation damage from the O(6) position of guanine following alkylating chemotherapy and hence is involved in DNA repair. Clinical response to alkylating agents such as temozolomide (TMZ) in glioblastoma (GBM) patients has been correlated to the activity of the MGMT repair enzyme. Clinical attempts at targeting the MGMT gene have been unsuccessful; for example, O(6)-benzylguanine an AGT substrate that inhibits AGT by suicide inactivation, caused systemic toxicity when combined with TMZ. ^,

Poly (ADP-ribose) polymerase-1 (PARP-1) is an enzyme that catalyzes the transfer of β-nicotinamide adenine dinucleotide to poly(ADP-ribose). PARP-1 enzyme catalyzes the synthesis of polymers for DNA repair after injury, and PARP-1 influences both direct repair and base excision repair of DNA after injury from alkylating agents or ionizing radiation and is a key enzyme in the DNA repair pathways complementary to and downstream of MGMT. Hence the PARP-1 enzyme inhibition is an attractive target for glioma therapy; PARP-1 inhibitors have also been shown to overcome resistance to TMZ in both mismatch repair–proficient and mismatch repair–deficient gliomas cells in culture, and numerous PARP-1 inhibitors are in clinical trials in patients with high-grade gliomas. ^,

Intra-Arterial Chemotherapy

The goal of this approach is to deliver chemotherapy intra-arterially so that the tissue perfused by that artery is exposed to higher plasma concentrations of the drug during the first passage through the circulation. The principal advantage to this approach is to maximize the amount of drug crossing through the BBB and minimize systemic side effects. Theoretical modeling suggests that intra-arterial infusion can produce a 10-fold increase in peak drug concentrations as compared with intravenous (IV) infusion. However, two phase III trials failed to show a survival benefit for IAC chemotherapy. ^, A large trial of more than 300 patients with newly diagnosed malignant glioma conducted by Brain Tumor Study Group to assess the efficacy of IAC chemotherapy in which patients were randomly assigned to IAC or IV BCNU with or without IV 5-fluorouracil and radiation therapy (RT). This study was closed early when an interim analysis showed shorter survival times in patients receiving IAC. The side effects of the IAC in these two studies included catheter-related complications such bleeding, infection, thrombosis, treatment-related neurotoxicity, leukoencephalopathy, cortical necrosis, and ipsilateral blindness. ^,

Intra-Cerebrospinal Fluid Chemotherapy

Intra-CSF chemotherapy involves administration of drugs either into the lateral ventricle, usually through a surgically implanted subcutaneous device, such as an Ommaya reservoir, or instilling the drug into the lumbar subarachnoid space (i.e., intrathecal therapy). A benefit of this approach is that small doses of chemotherapeutic agents given intrathecally can produce high concentrations within the CSF with minimal systemic toxicity. However, abnormal CSF flow and obstruction either due to tumor or scarring from prior surgical interventions impair its utility in the treatment for primary brain tumors. Intrathecal administration of drug has limited penetration into the brain parenchyma and is generally used in treatment or prophylaxis of leptomeningeal disease. Side effects include increased risks of neurotoxicity (especially with radiation) and chemical meningitis.

Manipulating the Permeability of the Blood-Brain Barrier or Methods to Cause Blood-Brain Barrier Disruption

Various agents have been used to modify BBB and/or BTB in an attempt to increase the drug concentration in the tumor. Drug delivery to brain tumors can potentially be improved by increasing the permeability of the BBB with hyperosmolar solutions such as mannitol and vasoactive compounds such as bradykinin analogues that induce an osmotic opening of the BBB and BTB. ^, Hyperosmolar solutions increase capillary permeability by temporarily opening the intercellular tight junctions of the brain endothelium that results in increased movement of water-soluble substances. Complications with this approach include increased risk of stroke and seizures, and no clinical benefit has been demonstrated with this approach so far.

High-dose chemotherapy (HDCT) is theoretically promising as it theoretically should increase the peak concentration of an unbound drug in the circulation and result in greater transfer of a drug across the BBB. The associated myelosuppression seen with this approach requires use of autologous hematopoietic cell rescue, and treatment-related morbidity is substantial. The survival using this approach is similar to that achieved by conventional chemotherapy or targeted therapy, and its use has largely been abandoned. ^,

Wafers/Implantable Polymers

Surgical implantation of solid-phase reagents permits constant drug delivery into the tumor without significant systemic or local side effects. The most commonly used “wafer” is a copolymer matrix with carmustine that is implanted directly into the tumor resection cavity at the time of surgical intervention. This therapy has been approved for patients with newly diagnosed and recurrent high-grade gliomas. ^,

Convection-Enhanced Delivery

CED involves direct intratumoral infusion with various chemotherapeutic drugs. It was designed to use pharmacologic agents that would not normally cross the BBB, and this approach is particularly useful for the delivery of large molecules. Drugs are delivered through one to several catheters placed stereotactically directly within the tumor mass or around the tumor or the resection cavity, and it allows distribution of substances throughout the interstitium via positive-pressure infusion. Several classes of drugs are amenable to this technology, including chemotherapeutics, immunotherapies, or targeted drugs. Two multicenter randomized controlled trials in patients with recurrent GBM (PRECISE and TransMID) demonstrated that CED of agents was safe and well tolerated; however, there was no difference in efficacy compared with standard method of delivery.

Low-Grade Gliomas

Low-grade gliomas (LGGs) comprise approximately 20% CNS glial tumors, with approximately 1800 new cases of LGG diagnosed each year in the United States. With the 2016 edition of the World Health Organization (WHO) classification, the classification of glioma has changed to include not only the histopathologic appearance but molecular patterns. In fact, in certain cases the molecular and chromosomal patterns take higher precedence than histologic appearance. The codeletion of 1p and 19q chromosome is a defining feature of oligodendrogliomas, which represent 3.7% of all primary brain and CNS tumors. Oligodendrogliomas could be classified into either WHO grade II or grade III tumors based on the cellular atypia, presence of mitosis, vascular proliferation, and necrosis. Astrocytic tumors have intact 1p and 19q chromosomes, and they are divided by the presence or absence of IDH1/2 mutations. The patients with IDH wild-type low-grade astrocytoma have poor outcomes almost comparable to IDH wild-type GBM.

Patients with LGG typically present between the second and fourth decades of life. The optimal role of surgical resection in the long-term outcome of patients with LGG remains controversial, and the debate about the effect on outcome of its timing and extent persists. Nevertheless, surgery continues to be indispensable to provide tissue for histopathologic diagnosis and importantly molecular characterization that is prognostic and helps to determine therapy approach. Retrospective studies have shown that more extensive resection rather than simple debulking is more beneficial and greater than 99% resection yields improved overall survival (OS) and progression-free survival (PFS).